Adiponectin, an adipocyte-derived protein, has been suggested to play an important role in insulin sensitivity. We examined the association between insulin sensitivity (M value) evaluated by the euglycemic-hyperinsulinemic glucose clamp and adiponectin concentrations in 30 essential hypertensives (EHT) and 20 normotensives (NT) and investigated the effect of blockade of the renin-<em>angiotensin</em> system (RAS) on adiponectin concentrations. EHT were divided into <em>1</em>2 insulin-resistant EHT (EHT-R) and <em>1</em>8 non-insulin-resistant EHT (EHT-N) using mean-<em>1</em> SD of the M value in NT. There were no intergroup differences in age, gender, and body mass index (BMI). EHT-R had significantly higher levels of insulin and triglyceride and lower levels of adiponectin than did NT and EHT-N. EHT-R had higher levels of free fatty acid and lower levels of high-density lipoprotein (HDL) cholesterol than did EHT-N. Adiponectin concentrations were positively correlated with M value and HDL cholesterol and negatively correlated with BMI, insulin, free fatty acid, and triglyceride but not with blood pressure. M value, BMI, and HDL cholesterol were independent determinants of adiponectin concentrations in multiple and stepwise regression analyses. Sixteen EHT were treated with an <em>angiotensin</em>-converting enzyme inhibitor (temocapril, 4 mg/d; n=9) or an <em>angiotensin</em> II receptor blocker (candesartan, 8 mg/d; n=<em>7</em>) for 2 weeks. Treatment with temocapril or candesartan significantly decreased blood pressure and increased M value and adiponectin concentrations but did not affect BMI and HDL cholesterol. These results suggest that hypoadiponectinemia is related to insulin resistance in essential hypertension and that RAS blockade increases adiponectin concentrations with improvement in insulin sensitivity.

We have demonstrated that the <em>angiotensin</em>-converting enzyme (ACE) genotype is associated with Alzheimer's disease (AD) in the Japanese population (). To determine why ACE affects susceptibility to AD, we examined the effect of purified ACE on aggregation of the amyloid beta-peptide (A beta) in vitro. Surprisingly, ACE was found to significantly inhibit A beta aggregation in a dose response manner. The inhibition of aggregation was specifically blocked by preincubation of ACE with an ACE inhibitor, lisinopril. ACE was confirmed to retard A beta fibril formation with electron microscopy. ACE inhibited A beta deposits on a synthaloid plate, which was used to monitor A beta deposition on autopsied brain tissue. ACE also significantly inhibited A beta cytotoxicity on PC<em>1</em>2 h. The most striking fact was that ACE degraded A beta by cleaving A beta-(<em>1</em>-40) at the site Asp(<em>7</em>)-Ser(8). This was proven with reverse-phase HPLC, amino acid sequence analysis, and MALDI-TOF/MS. Compared with A beta-(<em>1</em>-40), aggregation and cytotoxic effects of the degradation products A beta-(<em>1</em>-<em>7</em>) and A beta-(8-40) peptides were reduced or virtually absent. These findings led to the hypothesis that ACE may affect susceptibility to AD by degrading A beta and preventing the accumulation of amyloid plaques in vivo.

<em>1</em> The selectivity and specificity of RX <em>7</em>8<em>1</em>094 [2-(2-(<em>1</em>,4 benzodioxanyl))2-imidazoline HCl] for alpha-adrenoceptors have been examined in peripheral tissues. 2 In isolated tissue experiments RX <em>7</em>8<em>1</em>094 was a competitive antagonist at prejunctional alpha 2-adrenoceptors situated on the sympathetic nerve terminals of the rat (pA2 = 8.56) and mouse (pA2 = <em>7</em>.93) vas deferens and on the parasympathetic nerve terminals of the guinea-pig ileum (pA2 = 8.55). 3 Although RX <em>7</em>8<em>1</em>094 was also a competitive antagonist at the postjunctional alpha <em>1</em>-adrenoceptors of the rat anococcygeus muscle (pA2 = 6.<em>1</em>0) its affinity for these receptors was markedly less than that displayed for prejunctional sites. From pA2 values obtained in the rat vas deferens and anococcygeus muscle the calculated alpha 2/alpha <em>1</em>-adrenoceptor selectivity ratio for RX <em>7</em>8<em>1</em>094 was 288. 4 The rank order of alpha 2/alpha <em>1</em>-adrenoceptor selectivities for the antagonists studied was RX <em>7</em>8<em>1</em>094 greater than RS 2<em>1</em>36<em>1</em> greater than yohimbine greater than piperoxan greater than phentolamine greater than WB 4<em>1</em>0<em>1</em> greater than prazosin. 5 RX <em>7</em>8<em>1</em>094 had extremely low affinity for beta-adrenoceptors, histamine receptors, cholinoceptors, 5-hydroxytryptamine and opiate receptors in vitro. 6 In pithed rats, intravenous administration of RX <em>7</em>8<em>1</em>094 antagonized the prejunctional alpha 2-adrenoceptor agonist effects of clonidine and guanabenz on electrically-induced contractions of the vas deferens and anococcygeus muscle respectively. <em>7</em> In the vas deferens the rank order of alpha 2-adrenoceptor antagonist potencies was RX <em>7</em>8<em>1</em>094 greater than phentolamine greater than piperoxan greater than yohimbine greater than RS 2<em>1</em>36<em>1</em> greater than WB 4<em>1</em>0<em>1</em>. Only RX <em>7</em>8<em>1</em>094, yohimbine and RS 2<em>1</em>36<em>1</em> were active against guanabenz in the anococcygeus muscle. 8 In the pithed rat, RX <em>7</em>8<em>1</em>094 preferentially antagonized the pressor responses evoked by postjunctional alpha 2-adrenoceptor activation by UK <em>1</em>4,304 although higher doses also inhibited the effects of phenylephrine and cirazoline at postjunctional alpha <em>1</em>-adrenoceptors. 9 RX <em>7</em>8<em>1</em>094 had little effect on the cardiovascular responses to 5-hydroxytryptramine, <em>angiotensin</em> II, histamine, acetylcholine and isoprenaline in pithed rats and rats anaesthetized with pentobarbitone. <em>1</em>0 These results demonstrate that RX <em>7</em>8<em>1</em>094 is a potent and selective alpha 2-adrenoceptor antagonist with a high degree of specificity for these receptors.

Chronic infusion of <em>angiotensin</em> (Ang) II leads to the development of hypertension and enhances intrarenal Ang II content to levels greater than can be explained from the circulating concentrations of the peptide. We previously reported that renal <em>angiotensin</em>ogen (Ao) mRNA is enhanced in Ang II-dependent hypertension and may contribute to augmented intrarenal Ang II levels, but the Ao protein levels were not significantly increased. Because a high-salt diet (H/S) has been shown to suppress renal expression of Ao mRNA, we examined the effects of chronic Ang II infusion on kidney and liver Ao mRNA and protein levels in male Sprague-Dawley rats (n=<em>1</em>2) maintained on an 8% salt diet. Ang II was administered via osmotic minipumps (40 ng/min) to <em>1</em> group (n=6) while the remaining rats were sham-operated. A H/S diet alone did not alter systolic blood pressure in sham animals (<em>1</em>09+/-6 mm Hg at day <em>1</em>2); however, Ang II infusions to the H/S rats significantly increased systolic blood pressure (<em>1</em>6<em>7</em>+/-<em>7</em> at day <em>1</em>2) and intrarenal Ang II content (459+/-<em>1</em>0<em>7</em> fmol/g versus 2<em>7</em>0+/-42) despite a marked suppression of plasma renin activity (0.9+/-0.2 ng Ang I. mL(-<em>1</em>). h(-<em>1</em>) versus 2.8+/-<em>1</em>.3). Ang II infusions significantly increased kidney Ao mRNA compared with the H/S diet alone by <em>1</em>.9+/-0.<em>1</em>-fold. Western blot analysis of kidney protein extracts showed that the Ang II-infused rats had increased kidney Ao protein levels compared with the H/S diet alone (<em>1</em>.9+/-0.<em>1</em>-fold). Liver Ao mRNA and protein and plasma Ao protein were also significantly increased by Ang II infusions. These data demonstrate the effects of Ang II infusion to stimulate Ao mRNA and protein. Thus, the augmented intrarenal Ang II in Ang II-dependent hypertension may result, in part, by a positive amplification mechanism to activate renal expression of AO:

BACKGROUND

Use of generic drugs, which are bioequivalent to brand-name drugs, can help contain prescription drug spending. However, there is concern among patients and physicians that brand-name drugs may be clinically superior to generic drugs.

OBJECTIVE

To summarize clinical evidence comparing generic and brand-name drugs used in cardiovascular disease and to assess the perspectives of editorialists on this issue.

METHODS

Systematic searches of peer-reviewed publications in MEDLINE, EMBASE, and International Pharmaceutical Abstracts from January <em>1</em>984 to August 2008.

METHODS

Studies compared generic and brand-name cardiovascular drugs using clinical efficacy and safety end points. We separately identified editorials addressing generic substitution.

METHODS

We extracted variables related to the study design, setting, participants, clinical end points, and funding. Methodological quality of the trials was assessed by Jadad and Newcastle-Ottawa scores, and a meta-analysis was performed to determine an aggregate effect size. For editorials, we categorized authors' positions on generic substitution as negative, positive, or neutral.

RESULTS

We identified 4<em>7</em> articles covering 9 subclasses of cardiovascular medications, of which 38 (8<em>1</em>%) were randomized controlled trials (RCTs). Clinical equivalence was noted in <em>7</em> of <em>7</em> RCTs (<em>1</em>00%) of beta-blockers, <em>1</em>0 of <em>1</em><em>1</em> RCTs (9<em>1</em>%) of diuretics, 5 of <em>7</em> RCTs (<em>7</em><em>1</em>%) of calcium channel blockers, 3 of 3 RCTs (<em>1</em>00%) of antiplatelet agents, 2 of 2 RCTs (<em>1</em>00%) of statins, <em>1</em> of <em>1</em> RCT (<em>1</em>00%) of <em>angiotensin</em>-converting enzyme inhibitors, and <em>1</em> of <em>1</em> RCT (<em>1</em>00%) of alpha-blockers. Among narrow therapeutic index drugs, clinical equivalence was reported in <em>1</em> of <em>1</em> RCT (<em>1</em>00%) of class <em>1</em> antiarrhythmic agents and 5 of 5 RCTs (<em>1</em>00%) of warfarin. Aggregate effect size (n = 83<em>7</em>) was -0.03 (95% confidence interval, -0.<em>1</em>5 to 0.08), indicating no evidence of superiority of brand-name to generic drugs. Among 43 editorials, 23 (53%) expressed a negative view of generic drug substitution.

CONCLUSIONS

Whereas evidence does not support the notion that brand-name drugs used in cardiovascular disease are superior to generic drugs, a substantial number of editorials counsel against the interchangeability of generic drugs.

BACKGROUND

An echocardiographic substudy of the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial was designed to test the ability of losartan to reduce left ventricular (LV) mass more than atenolol.

RESULTS

A total of 960 patients with essential hypertension and LV hypertrophy (LVH) on screening ECG were enrolled at centers in <em>7</em> countries and studied by echocardiography at baseline and after <em>1</em>, 2, 3, 4, and 5 years' randomized therapy. Clinical examination and blinded readings of echocardiograms in 45<em>7</em> losartan-treated and 459 atenolol-treated participants with>> or =<em>1</em> follow-up measurement of LV mass index (LVMI) were used in an intention-to-treat analysis. Losartan-based therapy induced greater reduction in LVMI from baseline to the last available study than atenolol with adjustment for baseline LVMI and blood pressure and in-treatment pressure (-2<em>1</em>.<em>7</em>+/-2<em>1</em>.8 versus -<em>1</em><em>7</em>.<em>7</em>+/-<em>1</em>9.6 g/m2; P=0.02<em>1</em>). Greater LVMI reduction with losartan was observed in women and men, participants >65 or <65 years of age, and with mild or more severe baseline hypertrophy. The difference between treatment arms in LVH regression was due mainly to reduced concentricity of LV geometry in both groups and lesser increase in LV internal diameter in losartan-treated patients.

CONCLUSIONS

Antihypertensive treatment with losartan, plus hydrochlorothiazide and other medications when needed for pressure control, resulted in greater LVH regression in patients with ECG LVH than conventional atenolol-based treatment. Thus, angiotensin receptor antagonism by losartan has superior efficacy for reversing LVH, a cardinal manifestation of hypertensive target organ damage.

BACKGROUND

An activated vasoconstrictive, proliferative, and fibrotic axis of the renin <em>angiotensin</em> system (<em>angiotensin</em>-converting enzyme [ACE]/<em>angiotensin</em> [Ang]II/AngII type <em>1</em> receptor) has been implicated in the pathophysiology of pulmonary fibrosis (PF) and pulmonary hypertension (PH). The recent discovery of a counterregulatory axis of the renin <em>angiotensin</em> system composed of ACE2/Ang-(<em>1</em>-<em>7</em>)/Mas has led us to examine the role of this vasoprotective axis on such disorders.

OBJECTIVE

We hypothesized that Ang-(<em>1</em>-<em>7</em>) treatment would exert protective effects against PF and PH.

METHODS

Lentiviral packaged Ang-(<em>1</em>-<em>7</em>) fusion gene or ACE2 cDNA was intratracheally administered into the lungs of male Sprague Dawley rats. Two weeks after gene transfer, animals received bleomycin (2.5 mg/kg). In a subsequent study, animals were administered monocrotaline (MCT, 50 mg/kg).

RESULTS

In the PF study, bleomycin administration resulted in a significant increase in right ventricular systolic pressure, which was associated with the development of right ventricular hypertrophy. The lungs of these animals also exhibited excessive collagen deposition, decreased expression of ACE and ACE2, increased mRNA levels for transforming growth factor β and other proinflammatory cytokines, and increased protein levels of the AT₁R. Overexpression of Ang-(<em>1</em>-<em>7</em>) significantly prevented all the above-mentioned pathophysiological conditions. Similar protective effects were also obtained with ACE2 overexpression. In the PH study, rats injected with MCT developed elevated right ventricular systolic pressure, right ventricular hypertrophy, right ventricular fibrosis, and pulmonary vascular remodeling, all of which were attenuated by Ang-(<em>1</em>-<em>7</em>) overexpression. Blockade of the Mas receptor abolished the beneficial effects of Ang-(<em>1</em>-<em>7</em>) against MCT-induced PH.

CONCLUSIONS

Our observations demonstrate a cardiopulmonary protective role for the ACE2/Ang-(<em>1</em>-<em>7</em>)/Mas axis in the treatment of lung disorders.

BACKGROUND

The formation of <em>angiotensin</em>-(<em>1</em>-<em>7</em>) from either <em>angiotensin</em> (Ang) I or Ang II in failing human hearts is not well understood.

RESULTS

Angiotensinase activity in left and right ventricular membranes from <em>1</em>4 idiopathic dilated cardiomyopathy (IDC), 8 primary pulmonary hypertension (PPH), and <em>1</em>3 nonfailing human hearts was measured with either <em>1</em>25I-Ang I or <em>1</em>25I-Ang II as substrate. Ang-(<em>1</em>-<em>7</em>)-forming activity from <em>1</em>25I-Ang I was inhibited by thiorphan. With <em>1</em>25I-Ang II as substrate, Ang-(<em>1</em>-<em>7</em>) formation was inhibited by the ACE2-specific inhibitor C<em>1</em>6. Western blotting with an anti-ACE2 antibody confirmed the presence of ACE2. Angiotensinase activity with <em>1</em>25I-Ang I as substrate was increased in failing IDC left ventricles (LVs) compared with nonfailing LVs (P<0.00<em>1</em>). Ang-(<em>1</em>-<em>7</em>)-forming activity with <em>1</em>25I-Ang II as substrate was increased in both failing LVs and right ventricles (RVs) of IDC hearts and only in failing RVs of PPH hearts (PPH LV, 5<em>1</em>.<em>1</em>2+/-5.25; PPH RV, 89.9<em>7</em>+/-<em>1</em><em>1</em>.2<em>1</em>; IDC LV, <em>1</em>39.<em>7</em>+/-2<em>1</em>.96; and IDC RV, <em>1</em>92.<em>7</em>+/-5.43; NF LV, 32.89+/-5.38; NF RV 40.49+/-<em>1</em>0.66 fmol/min per milligram (P<0.05 PPH RV versus PPH LV; P<0.05 PPH RV versus NF RV; P<0.00<em>1</em> IDC LV versus NF LV; P<0.00<em>1</em> IDC RV versus NF RV).

CONCLUSIONS

Ang-(<em>1</em>-<em>7</em>)-forming activity from both Ang I and Ang II was increased in failing human heart ventricles but was mediated by at least two different <em>angiotensin</em>ases. The first, which demonstrated substrate preference for Ang I, was neutral endopeptidase (NEP)-like. The second was ACE2, as demonstrated by Western blotting and inhibition of activity with C<em>1</em>6.

Agonistic autoantibodies to the <em>angiotensin</em> II type I receptor (AT<em>1</em>-AA) and endothelin -<em>1</em> (ET-<em>1</em>) are suggested to be important links between placental ischemia and hypertension during preeclampsia. Activation of the <em>angiotensin</em> II type <em>1</em> receptor (AT<em>1</em>R) increases endothelial cell production of ET-<em>1</em>; however, the importance of ET-<em>1</em> in response to AT<em>1</em>-AA-mediated AT<em>1</em> R activation during preeclampsia is unknown. Furthermore, the role of AT<em>1</em>-AA-mediated increases in blood pressure during pregnancy remains unclear. The objective of this study was to test the hypothesis that AT<em>1</em>-AA, increased to levels observed in preeclamptic women and placental ischemic rats, increases mean arterial pressure (MAP) by activation of the ET-<em>1</em> system. Chronic infusion of purified rat AT<em>1</em>-AA into normal pregnant (NP) rats for <em>7</em> days increased AT<em>1</em>-AA from 0.68+/-0.5 to <em>1</em>0.88+/-<em>1</em>.<em>1</em> chronotropic units (P<0.00<em>1</em>). The increased AT<em>1</em>-AA increased MAP from 99+/-<em>1</em> to <em>1</em><em>1</em>9+/-2 mm Hg (P<0.00<em>1</em>). The hypertension was associated with significant increases in renal cortices (<em>1</em><em>1</em>-fold) and placental (4-fold) ET-<em>1</em>. To determine whether ET-<em>1</em> mediates AT<em>1</em>-AA-induced hypertension, pregnant rats infused with AT<em>1</em>-AA and NP rats were treated with an ET(A) receptor antagonist. MAP was <em>1</em>00+/-<em>1</em> mm Hg in AT<em>1</em>-AA+ET(A) antagonist-treated rats versus 98+/-2 mm Hg in ET(A) antagonist-treated rats. Collectively, these data support the hypothesis that one potential pathway whereby AT<em>1</em>-AAs increase blood pressure during pregnancy is by an ET-<em>1</em>-dependent mechanism.

OBJECTIVE

To report criteria for the diagnosis of intraocular sarcoidosis, taking into account suggestive clinical signs and appropriate laboratory investigations and biopsy results.

METHODS

Concensus workshop of an international committee on nomenclature.

METHODS

An international group of uveitis specialists from Asia, Africa, Europe, and America met in a concensus conference in Shinagawa, Tokyo on October 28-29, 2006. Based on questionnaires that had been sent out prior to the conference, the participants discussed potential intraocular clinical signs eligible for a diagnosis of ocular sarcoidosis. A refined definition of clinical signs, which received two-thirds majority of votes, was included in the list of signs consistent with ocular sarcoidosis. Laboratory investigations were similarly discussed and those tests reaching a two-thirds majority were retained for the diagnosis of ocular sarcoidosis. Finally diagnostic criteria were proposed based on ocular signs, laboratory investigations, and biopsy results.

RESULTS

The concensus conference identified seven signs in the diagnosis of intraocular sarcoidosis: (<em>1</em>) mutton-fat keratic precipitates (KPs)/small granulomatous KPs and/or iris nodules (Koeppe/Busacca), (2) trabecular meshwork (TM) nodules and/or tent-shaped peripheral anterior synechiae (PAS), (3) vitreous opacities displaying snowballs/strings of pearls, (4) multiple chorioretinal peripheral lesions (active and/or atrophic), (5) nodular and/or segmental peri-phlebitis (+/- candlewax drippings) and/or retinal macroaneurism in an inflamed eye, 6) optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule, and (<em>7</em>) bilaterality. The laboratory investigations or investigational procedures that were judged to provide value in the diagnosis of ocular sarcoidosis in patients having the above intraocular signs included (<em>1</em>) negative tuberculin skin test in a BCG-vaccinated patient or in a patient having had a positive tuberculin skin test previously, (2) elevated serum <em>angiotensin</em> converting enzyme (ACE) levels and/or elevated serum lysozyme, (3) chest x-ray revealing bilateral hilar lymphadenopathy (BHL), (4) abnormal liver enzyme tests, and (5) chest CT scan in patients with a negative chest x-ray result. Four levels of certainty for the diagnosis of ocular sarcoidosis (diagnostic criteria) were recommended in patients in whom other possible causes of uveitis had been excluded: (<em>1</em>) biopsy-supported diagnosis with a compatible uveitis was labeled as definite ocular sarcoidosis; (2) if biopsy was not done but chest x-ray was positive showing BHL associated with a compatible uveitis, the condition was labeled as presumed ocular sarcoidosis; (3) if biopsy was not done and the chest x-ray did not show BHL but there were 3 of the above intraocular signs and 2 positive laboratory tests, the condition was labeled as probable ocular sarcoidosis; and (4) if lung biopsy was done and the result was negative but at least 4 of the above signs and 2 positive laboratory investigations were present, the condition was labeled as possible ocular sarcoidosis.

CONCLUSIONS

Various clinical signs, laboratory investigations, and biopsy results provided four diagnostic categories of sarcoid uveitis. The categorization allows prospective multinational clinical trials to be conducted using a standardized nomenclature, which serves as a platform for comparison of visual outcomes with various therapeutic modalities.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) significantly reduce cardiovascular mortality associated with hypercholesterolemia. There is evidence that statins exert beneficial effects in part through direct effects on vascular cells independent of lowering plasma cholesterol. We characterized the effect of a 30-day treatment with atorvastatin in normocholesterolemic, spontaneously hypertensive rats (SHR). Systolic blood pressure was significantly decreased in atorvastatin-treated rats (<em>1</em>84+/-5 versus 204+/-6 mm Hg for control). Statin therapy improved endothelial dysfunction, as assessed by carbachol-induced vasorelaxation in aortic segments, and profoundly reduced <em>angiotensin</em> II-induced vasoconstriction. <em>Angiotensin</em> type <em>1</em> (AT(<em>1</em>)) receptor, endothelial cell NO synthase (ecNOS), and p22phox mRNA expression were determined with quantitative reverse transcription-polymerase chain reaction. Atorvastatin treatment downregulated aortic AT(<em>1</em>) receptor mRNA expression to 44+/-<em>1</em>2% of control and reduced mRNA expression of the essential NAD(P)H oxidase subunit p22phox to 63+/-<em>7</em>% of control. Aortic AT(<em>1</em>) receptor protein expression was consistently decreased. Vascular production of reactive oxygen species was reduced to 62+/-<em>1</em>2% of control in statin-treated SHR, as measured with lucigenin chemiluminescence assays. Accordingly, treatment of SHR with the AT(<em>1</em>) receptor antagonist fonsartan improved endothelial dysfunction and reduced vascular free-radical release. Moreover, atorvastatin caused an upregulation of ecNOS mRNA expression (<em>1</em>38+/-<em>7</em>% of control) and an enhanced ecNOS activity in the vessel wall (209+/-46% of control). Treatment of SHR with atorvastatin causes a significant reduction of systolic blood pressure and a profound improvement of endothelial dysfunction mediated by a reduction of free radical release in the vasculature. The underlying mechanism could in part be based on the statin-induced downregulation of AT(<em>1</em>) receptor expression and decreased expression of the NAD(P)H oxidase subunit p22phox, because AT(<em>1</em>) receptor activation plays a pivotal role for the induction of this redox system in the vessel wall.

BACKGROUND

Accumulating evidence suggests that C-reactive protein (CRP), in addition to predicting vascular disease, may actively facilitate lesion formation by inciting endothelial cell activation. Given the central importance of <em>angiotensin</em> type <em>1</em> receptor (AT<em>1</em>-R) in the pathogenesis of atherosclerosis, we examined the effects of CRP on AT<em>1</em>-R expression and kinetics in vascular smooth muscle (VSM) cells. In addition, the effects of CRP on VSM migration, proliferation, and reactive oxygen species (ROS) production were evaluated in the presence and absence of the <em>angiotensin</em> receptor blocker, losartan. Lastly, the effects of CRP (and losartan) on neointimal formation were examined in vivo in a rat carotid angioplasty model.

RESULTS

The effects of human recombinant CRP (0 to <em>1</em>00 microg/mL) on AT<em>1</em>-R transcript, mRNA stability, and protein expression were studied in cultured human VSM cells. AT<em>1</em>-R binding was assessed with <em>1</em>25I-labeled <em>angiotensin</em> II (Ang II). VSM migration was assessed with wound cell migration assays, whereas VSM proliferation was determined with [3H]-incorporation and cell number. The effects of CRP (and losartan) on Ang II-induced ROS production were evaluated by 2',7'-dichlorofluorescein fluorescence. Lastly, the effects of CRP (and losartan) on neointimal formation, VSM cell migration, proliferation, and matrix formation were studied in vivo in a rat carotid artery balloon injury model. CRP markedly upregulated AT<em>1</em>-R mRNA and protein expression and increased AT<em>1</em>-R number on VSM cells. CRP promoted VSM migration and proliferation in vitro and increased ROS production. Furthermore, CRP potentiated the effects of Ang II on these processes. In the rat carotid artery angioplasty model, exposure to CRP resulted in an increase in cell migration and proliferation, collagen and elastin content, and AT<em>1</em>-R expression, as well as an increase in neointimal formation; these effects were attenuated by losartan.

CONCLUSIONS

CRP, at concentrations known to predict cardiovascular events, upregulates AT<em>1</em>-R-mediated atherosclerotic events in vascular smooth muscle in vitro and in vivo. These data lend credence to the notion that CRP functions as a proatherosclerotic factor as well as a powerful risk marker.

The last decade has seen the discovery of several new components of the renin-<em>angiotensin</em> system (RAS). Among them, <em>angiotensin</em> converting enzyme-2 (ACE2) and the Mas receptor have forced a reevaluation of the original cascade and led to the emergence of a new arm of the RAS: the ACE2/ANG-(<em>1</em>-<em>7</em>)/Mas axis. Accordingly, the new system is now seen as a balance between a provasoconstrictor, profibrotic, progrowth axis (ACE/ANG-II/AT(<em>1</em>) receptor) and a provasodilatory, antifibrotic, antigrowth arm (ACE2/ANG-(<em>1</em>-<em>7</em>)/Mas receptor). Already, this simplistic vision is evolving and new components are branching out upstream [ANG-(<em>1</em>-<em>1</em>2) and (pro)renin receptor] and downstream (<em>angiotensin</em>-IV and other <em>angiotensin</em> peptides) of the classical cascade. In this review, we will summarize the role of the ACE2/ANG-(<em>1</em>-<em>7</em>)/Mas receptor, focusing on the central nervous system with respect to cardiovascular diseases such as hypertension, chronic heart failure, and stroke, as well as neurological diseases. In addition, we will discuss the new pharmacological (antagonists, agonists, activators) and genomic (knockout and transgenic animals) tools that are currently available. Finally, we will review the latest data regarding the various signaling pathways downstream of the Mas receptor.

<em>Angiotensin</em>-converting enzyme 2 (ACE2) is a monocarboxypeptidase capable of metabolizing <em>angiotensin</em> (Ang) II into Ang <em>1</em> to <em>7</em>. We hypothesized that ACE2 is a negative regulator of Ang II signaling and its adverse effects on the kidneys. Ang II infusion (<em>1</em>.5 mg/kg⁻¹/d⁻¹) for 4 days resulted in higher renal Ang II levels and increased nicotinamide adenine dinucleotide phosphate oxidase activity in ACE2 knockout (Ace2(-/y)) mice compared to wild-type mice. Expression of proinflammatory cytokines, interleukin-<em>1</em>β and chemokine (C-C motif) ligand 5, were increased in association with greater activation of extracellular-regulated kinase <em>1</em>/2 and increase of protein kinase C-α levels. These changes were associated with increased expression of fibrosis-associated genes (α-smooth muscle actin, transforming growth factor-β, procollagen type Iα<em>1</em>) and increased protein levels of collagen I with histological evidence of increased tubulointerstitial fibrosis. Ang II-infused wild-type mice were then treated with recombinant human ACE2 (2 mg/kg⁻¹/d⁻¹, intraperitoneal). Daily treatment with recombinant human ACE2 reduced Ang II-induced pressor response and normalized renal Ang II levels and oxidative stress. These changes were associated with a suppression of Ang II-mediated activation of extracellular-regulated kinase <em>1</em>/2 and protein kinase C pathway and Ang II-mediated renal fibrosis and T-lymphocyte-mediated inflammation. We conclude that loss of ACE2 enhances renal Ang II levels and Ang II-induced renal oxidative stress, resulting in greater renal injury, whereas recombinant human ACE2 prevents Ang II-induced hypertension, renal oxidative stress, and tubulointerstitial fibrosis. ACE2 is an important negative regulator of Ang II-induced renal disease and enhancing ACE2 action may have therapeutic potential for patients with kidney disease.

BACKGROUND

Increasing evidence suggests that genetic background plays an important role in the development of progressive glomerulosclerosis. The remnant kidney model (RKM) of progressive renal disease has been used extensively in rats. However, C5<em>7</em>BL/6 mice are resistant to glomerulosclerosis with RKM induced by either pole amputation or renal artery ligation. A pole resection protocol, applied in 129/Sv mice, induced only mild glomerulosclerosis. We present here a highly reproducible, modified RKM approach to successfully establish a glomerulosclerosis model in mice.

METHODS

Male C5<em>7</em>BL/6 (N = 1<em>7</em>), 129/Sv (N = 20) and Swiss-Webster (N = 3) mice underwent RKM as follows: the lower branch of the left renal artery was ligated to produce about one third infarct; the upper pole of the left kidney (about one third kidney size) was removed by cautery and the right kidney was nephrectomized to induce a total 5/6 nephrectomy (Nx). In some C5<em>7</em>BL/6 mice, <em>7</em>/8 nephrectomy was induced by removing additional renal mass from the upper pole of the left kidney by cautery. Systolic blood pressure (BP) was measured in conscious mice using a tail-cuff blood pressure monitor and animals were sacrificed at 9, 12, 18, and 24 weeks after nephrectomy. Kidneys were harvested for morphologic analysis.

RESULTS

BP in C5<em>7</em>BL/6 mice increased slightly after 5/6 nephrectomy over time without significant difference compared to baseline blood pressure except at 8 weeks (blood pressure at week 0, 98 +/- 1 mm Hg; week 4, 105 +/- 2 mm Hg; week 8, 113 +/- 4 mm Hg; and week 12, 110 +/- 3 mm Hg). Blood presssure remained normal in C5<em>7</em>BL/6 mice at 18 weeks after <em>7</em>/8 nephrectomy (103 +/- 2 mm Hg). Blood pressure in 129/Sv mice increased significantly after 5/6 nephrectomy from 4 to 12 weeks (week 0, 112 +/- 3 mm Hg; week 4, 161 +/- 9 mm Hg; week 8, 166 +/- 5 mm Hg; and week 12, 1<em>7</em>6 +/- 5 mm Hg; P < 0.01 weeks 4, 8, and 12 vs. week 0 blood pressure). Urine protein excretion in C5<em>7</em>BL/6 mice increased only at 4 weeks after 5/6 nephrectomy, and was back to normal at 8 and 12 weeks (week 0, 13.2 +/- 1.4 mg/24 hours; week 4, 20.5 +/- 1.8 mg/24 hours; week 8, 18.8 +/- 1.6 mg/24 hours; and week 12, 1<em>7</em>.2 +/- 1.2 mg/24 hours, P < 0.05 week 4 vs. week 0). 129/Sv mice developed significant proteinuria 12 weeks after 5/6 nephrectomy compared to their baseline and to levels achieved in C5<em>7</em>BL/6 mice (week 0, 1<em>7</em>.2 +/- 1 mg/24 hours; week 4, 14.9 +/- 1.8 mg/24 hours; week 8, 23.8 +/- 6.<em>7</em> mg/24 hours; and week 12, 36.3 +/- 6.6 mg/24 hours, P < 0.01 week 12 vs. week 0; P < 0.01 129/Sv vs. C5<em>7</em>BL/6 at week 12). Mortality varied in response to nephrectomy injury in the different strains. Ten percent of C5<em>7</em>BL/6 and 43% of 129/Sv died within 12 weeks after 5/6 nephrectomy. Although 50% of C5<em>7</em>BL/6 mice died by 12 weeks after <em>7</em>/8 nephrectomy, there was only mild glomerulosclerosis (<5%) in C5<em>7</em>BL/6 mice even at 24 weeks after 5/6 nephrectomy or 18 weeks after <em>7</em>/8 nephrectomy. In contrast, glomerulosclerosis was marked in both 129/Sv mice and Swiss-Webster mice as early as 9 weeks after 5/6 nephrectomy: 42% of glomeruli showed sclerosis in 129/Sv mice [average sclerosis index (SI), 0 to 4+ scale, 1.08] vs. 24% in Swiss-Webster mice (average SI, 0.5<em>7</em>). Tubulointerstitial fibrosis developed in parallel with glomerulosclerosis in both 129/Sv and Swiss-Webster mice.

CONCLUSIONS

We conclude that genetic background is one of the important factors determining the susceptibility to the development of glomerulosclerosis in mice. We speculate that the superior effects of renal artery ligation plus cautery to produce glomerulosclerosis may result from higher blood pressure responses due to local ischemia activating the renin-angiotensin system.

BACKGROUND

This study is the first to examine the effect of direct angiotensin II type 2 (AT(2)) receptor stimulation on postinfarct cardiac function with the use of the novel nonpeptide AT(2) receptor agonist compound 21 (C21).

RESULTS

Myocardial infarction (MI) was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with C21 (0.01, 0.03, 0.3 mg/kg per day IP) was started 24 hours after MI and was continued until euthanasia (7 days after MI). Infarct size was assessed by magnetic resonance imaging, and hemodynamic measurements were performed via transthoracic Doppler echocardiography and intracardiac Millar catheter. Cardiac tissues were analyzed for inflammation and apoptosis markers with immunoblotting and real-time reverse transcription polymerase chain reaction. C21 significantly improved systolic and diastolic ventricular function. Scar size was smallest in the C21-treated rats. In regard to underlying mechanisms, C21 diminished MI-induced Fas-ligand and caspase-3 expression in the peri-infarct zone, indicating an antiapoptotic effect. Phosphorylation of the p44/42 and p38 mitogen-activated protein kinases, both involved in the regulation of cell survival, was strongly reduced after MI but almost completely rescued by C21 treatment. Furthermore, C21 decreased MI-induced serum monocyte chemoattractant protein-1 and myeloperoxidase as well as cardiac interleukin-6, interleukin-1beta, and interleukin-2 expression, suggesting an antiinflammatory effect.

CONCLUSIONS

Direct AT(2) receptor stimulation may be a novel therapeutic approach to improve post-MI systolic and diastolic function by antiapoptotic and antiinflammatory mechanisms.

BACKGROUND

<em>Angiotensin</em>-converting enzyme (ACE)2, a homologue of ACE, which is insensitive to ACE inhibitors and forms <em>angiotensin</em>-(<em>1</em>-<em>7</em>) [Ang-(<em>1</em>-<em>7</em>)] from <em>angiotensin</em> II (Ang II) with high efficiency was investigated in response to chronic blockade with lisinopril, losartan, and both drugs combined.

METHODS

Thirty-six adult Lewis rats were assigned to receive these medications in their drinking water for 2 weeks while their arterial pressure, water intake, and urine volume were recorded throughout the study. Measures of renal excretory variables included assessing excretion rates of <em>angiotensin</em> I (Ang I), Ang II and Ang-(<em>1</em>-<em>7</em>) while blood collected at the completion of the study was used for measures of plasma <em>angiotensin</em> concentrations. Samples from renal cortex were assayed for renin, <em>angiotensin</em>ogen (Aogen), neprilysin, <em>angiotensin</em> types <em>1</em> and 2 (AT(<em>1</em>) and AT(2)) and mas receptor mRNAs by semiquantitative reverse transcriptase (RT) real-time polymerase chain reaction (PCR). ACE2 activity was determined as the rate of Ang II conversion into Ang-(<em>1</em>-<em>7</em>).

RESULTS

Comparable blood pressure reductions were obtained in rats medicated with either lisinopril or losartan, whereas both drugs produced a greater decrease in arterial pressure. Polyuria was recorded in all three forms of treatment associated with reduced osmolality but no changes in creatinine excretion. Lisinopril augmented plasma levels and urinary excretion rates of Ang I and Ang-(<em>1</em>-<em>7</em>), while plasma Ang II was reduced with no effect on urinary Ang II. Losartan produced similar changes in plasma and urinary Ang-(<em>1</em>-<em>7</em>) but increased plasma Ang II without changing urinary Ang II excretion. Combination therapy mimicked the effects obtained with lisinopril on plasma and urinary Ang I and Ang-(<em>1</em>-<em>7</em>) levels. Renal cortex Aogen mRNA increased in rats medicated with either lisinopril or the combination, whereas all three treatments produced a robust increase in renal renin mRNA. In contrast, ACE, ACE2, neprilysin, AT(<em>1</em>), and mas receptor mRNAs remained unchanged with all three treatments. Renal cortex ACE2 activity was significantly augmented in rats medicated with lisinopril or losartan but not changed in those given the combination.

CONCLUSIONS

Our data revealed a role for ACE2 in Ang-(<em>1</em>-<em>7</em>) formation from Ang II in the kidney of normotensive rats as primarily reflected by the increased ACE2 activity measured in renal membranes from the kidney of rats given either lisinopril or losartan. The data further indicate that increased levels of Ang-(<em>1</em>-<em>7</em>) in the urine of animals after ACE inhibition or AT(<em>1</em>) receptor blockade reflect an intrarenal formation of the heptapeptide.

BACKGROUND

The migration of monocytes into the vessel wall is a critical event leading to the development of atherosclerosis. Monocyte chemoattractant protein-<em>1</em> (MCP-<em>1</em>) is the main chemotactic factor involved in this phenomenon, and nuclear factor-kappa B (NF-kappa B) is one of the nuclear factors controlling its expression. ACE inhibitors have been useful in some experimental models of atherosclerosis. In this work, we addressed the hypothesis that <em>angiotensin</em> II (Ang II) may be implicated in the recruitment of monocytes into the vessel wall through the activation of NF-kappa B and the induction of MCP-<em>1</em> expression.

RESULTS

Accelerated atherosclerosis was induced in the femoral arteries of rabbits by endothelial desiccation and atherogenic diet for 7 days. Atherosclerotic vessels exhibited an increase in NF-kappa B-like activity, and p50 and p65 NF-kappa B subunits were identified as components of this activity. MCP-<em>1</em> (mRNA and protein) was also expressed in the injured vessels coincidently with the neointimal macrophage infiltration. ACE inhibition with quinapril reduced these three parameters. In cultured monocytic and vascular smooth muscle cells. Ang II elicited an increase in NF-kappa B activation and MCP-<em>1</em> expression that was prevented by preincubation of cells with pyrrolidinedithiocarbamate, an inhibitor of NF-kappa B activation.

CONCLUSIONS

The present data support a role for Ang II in neointimal monocyte infiltration through NF-kappa B activation and MCP-<em>1</em> expression in a model of accelerated atherosclerosis in rabbits. Our results suggest that ACE inhibitors may have a beneficial effect in early atherosclerosis.

BACKGROUND

Angiotensin converting enzyme type 2 (ACE2) is a new member of the brain renin-angiotensin system, that might be activated by an overactive renin-angiotensin system.

OBJECTIVE

To clarify the role of central ACE2 using a new transgenic mouse model with human (h)ACE2 under the control of a synapsin promoter, allowing neuron-targeted expression in the central nervous system.

RESULTS

Syn-hACE2 (SA) transgenic mice exhibit high hACE2 protein expression and activity throughout the brain. Baseline hemodynamic parameters (telemetry), autonomic function, and spontaneous baroreflex sensitivity (SBRS) were not significantly different between SA mice and nontransgenic littermates. Brain-targeted ACE2 overexpression attenuated the development of neurogenic hypertension (Ang II infusion: 600 ng/kg per minute for 14 days) and the associated reduction of both SBRS and parasympathetic tone. This prevention of hypertension by ACE2 overexpression was reversed by blockade of the Ang-(1-7) receptor (d-Ala7-Ang-[1-7]; 600 ng/kg per minute). Brain angiotensin II type 2 (AT(2))/AT(1) and Mas/AT(1) receptor ratios were significantly increased in SA mice. They remained higher following Ang II infusion but were dramatically reduced after Ang-(1-7) receptor blockade. ACE2 overexpression resulted in increased NOS and NO levels in the brain, and prevented the Ang II-mediated decrease in NOS expression in regions modulating blood pressure regulation.

CONCLUSIONS

ACE2 overexpression attenuates the development of neurogenic hypertension partially by preventing the decrease in both SBRS and parasympathetic tone. These protective effects might be mediated by enhanced NO release in the brain resulting from Mas and AT(2) receptor upregulation. Taken together, our data highlight the compensatory role of central ACE2 and its potential benefits as a therapeutic target for neurogenic hypertension.

Although loop diuretics are widely used in heart failure (HF), their effect on outcomes has not been evaluated in large clinical trials. This study sought to determine the dose-dependent relation between loop diuretic use and HF prognosis. A cohort of <em>1</em>,354 patients with advanced systolic HF referred to a single center was studied. Patients were divided into quartiles of equivalent total daily loop diuretic dose: 0 to 40, 4<em>1</em> to 80, 8<em>1</em> to <em>1</em>60, and>><em>1</em>60 mg. The cohort was <em>7</em>6% male, with a mean age of 53+/-<em>1</em>3 years and a mean ejection fraction of 24+/-<em>7</em>%. The mean diuretic dose equivalence was <em>1</em>0<em>7</em>+/-8<em>7</em> mg. The diuretic quartile groups were similar in terms of gender, body mass index, ischemic cause of HF, history of hypertension, and spironolactone use, but the highest quartile was associated with a smaller ejection fraction and lower serum sodium and hemoglobin levels but higher serum blood urea nitrogen and creatinine levels. There was a decrease in survival with increasing diuretic dose (83%, 8<em>1</em>%, 68%, and 53% for quartiles <em>1</em>, 2, 3, and 4, respectively). Even after extensive co-variate adjustment (age, gender, ischemic cause of HF, the ejection fraction, body mass index, pulmonary capillary wedge pressure, peak oxygen consumption, beta-blocker use, <em>angiotensin</em>-converting enzyme inhibitor or <em>angiotensin</em> receptor blocker use, digoxin use, statin use, serum sodium, blood urea nitrogen, creatinine, hemoglobin, cholesterol, systolic blood pressure, and smoking history), diuretic quartile remained an independent predictor of mortality (quartile 4 vs quartile <em>1</em> hazard ratio 4.0, 95% confidence interval <em>1</em>.9 to 8.4). In conclusion, in this cohort of patients with advanced HF, there was an independent, dose-dependent association between loop diuretic use and impaired survival. Higher loop diuretic dosages identify patients with HF at particularly high risk for mortality.

OBJECTIVE

The PAREPET (Prediction of ARrhythmic Events with Positron Emission Tomography) study sought to test the hypothesis that quantifying inhomogeneity in myocardial sympathetic innervation could identify patients at highest risk for sudden cardiac arrest (SCA).

BACKGROUND

Left ventricular ejection fraction (LVEF) is the only parameter identifying patients at risk of SCA who benefit from an implantable cardiac defibrillator (ICD).

METHODS

We prospectively enrolled 204 subjects with ischemic cardiomyopathy (LVEF ≤35%) eligible for primary prevention ICDs. Positron emission tomography (PET) was used to quantify myocardial sympathetic denervation ((<em>1</em><em>1</em>)C-meta-hydroxyephedrine [(<em>1</em><em>1</em>)C-HED]), perfusion ((<em>1</em>3)N-ammonia) and viability (insulin-stimulated (<em>1</em>8)F-2-deoxyglucose). The primary endpoint was SCA defined as arrhythmic death or ICD discharge for ventricular fibrillation or ventricular tachycardia >240 beats/min.

RESULTS

After 4.<em>1</em> years follow-up, cause-specific SCA was <em>1</em>6.2%. Infarct volume (22 ± <em>7</em>% vs. <em>1</em>9 ± 9% of left ventricle [LV]) and LVEF (24 ± 8% vs. 28 ± 9%) were not predictors of SCA. In contrast, patients developing SCA had greater amounts of sympathetic denervation (33 ± <em>1</em>0% vs. 26 ± <em>1</em><em>1</em>% of LV; p = 0.00<em>1</em>) reflecting viable, denervated myocardium. The lower tertiles of sympathetic denervation had SCA rates of <em>1</em>.2%/year and 2.2%/year, whereas the highest tertile had a rate of 6.<em>7</em>%/year. Multivariate predictors of SCA were PET sympathetic denervation, left ventricular end-diastolic volume index, creatinine, and no <em>angiotensin</em> inhibition. With optimized cut-points, the absence of all 4 risk factors identified low risk (44% of cohort; SCA (<em>1</em>%/year); whereas ≥2 factors identified high risk (20% of cohort; SCA ∼<em>1</em>2%/year).

CONCLUSIONS

In ischemic cardiomyopathy, sympathetic denervation assessed using (<em>1</em><em>1</em>)C-HED PET predicts cause-specific mortality from SCA independently of LVEF and infarct volume. This may provide an improved approach for the identification of patients most likely to benefit from an ICD. (Prediction of ARrhythmic Events With Positron Emission Tomography [PAREPET]; NCT0<em>1</em>400334).

The purpose of the present study was to evaluate the effect of <em>angiotensin</em> II type <em>1</em> receptor (AT<em>1</em>R) antagonist on chronic structural remodeling in atrial fibrillation (AF).

BACKGROUND

We previously reported that an AT<em>1</em>R antagonist, candesartan, prevents acute electrical remodeling in a rapid pacing model. However, the effect of candesartan on chronic structural remodeling in AF is unclear.

METHODS

Sustained AF was induced in 20 dogs (<em>1</em>0 in a control group and <em>1</em>0 in a candesartan group) by rapid pacing of the right atrium (RA) at 400 beats/min for five weeks. Candesartan was administered orally (<em>1</em>0 mg/kg/day) for one week before rapid pacing and was continued for five weeks. The AF duration, atrial effective refractory period (AERP) at four sites in the RA, and intra-atrial conduction time (CT) from the RA appendage to the other three sites were measured every week.

RESULTS

The mean AF duration in the control group after five weeks was significantly longer than that with candesartan (<em>1</em>,333 +/- 725 vs. 4<em>1</em><em>1</em> +/- 30<em>1</em> s, p < 0.0<em>1</em>). The degree of AERP shortening after five weeks was not significantly different between the two groups. The CT from the RA appendage to the low RA after five weeks with candesartan was significantly shorter than that in the control (43 +/- <em>1</em>4 vs. 68 +/- <em>1</em>0 ms, p < 0.05). The candesartan group had a significantly lower percentage of interstitial fibrosis than the control group (7 +/- 2% vs. <em>1</em>6 +/- <em>1</em>% at the RA appendage, p < 0.00<em>1</em>).

CONCLUSIONS

Candesartan can prevent the promotion of AF by suppressing the development of structural remodeling.

BACKGROUND

It has been proposed that an activated renin <em>angiotensin</em> system (RAS) causes an imbalance between the vasoconstrictive and vasodilator mechanisms involving the pulmonary circulation leading to the development of pulmonary hypertension (PH). Recent studies have indicated that <em>angiotensin</em>-converting enzyme 2 (ACE2), a member of the vasoprotective axis of the RAS, plays a regulatory role in lung pathophysiology, including pulmonary fibrosis and acute lung disease. Based on these observations, we propose the hypothesis that activation of endogenous ACE2 can shift the balance from the vasoconstrictive, proliferative axis (ACE-Ang II-AT<em>1</em>R) to the vasoprotective axis [ACE2-Ang-(<em>1</em>-<em>7</em>)-Mas] of the RAS, resulting in the prevention of PH.

OBJECTIVE

We have taken advantage of a recently discovered synthetic activator of ACE2, XNT (<em>1</em>-[(2-dimethylamino) ethylamino]-4-(hydroxymethyl)-<em>7</em>-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one), to study its effects on monocrotaline-induced PH in rats to support this hypothesis.

METHODS

The cardiopulmonary effects of XNT were evaluated in monocrotaline-induced PH rat model.

RESULTS

A single subcutaneous treatment of monocrotaline in rats resulted in elevated right ventricular systolic pressure, right ventricular hypertrophy, increased pulmonary vessel wall thickness, and interstitial fibrosis. These changes were associated with increases in the mRNA levels of renin, ACE, <em>angiotensin</em>ogen, AT<em>1</em> receptors, and proinflammatory cytokines. All these features of PH were prevented in these monocrotaline-treated rats by chronic treatment with XNT. In addition, XNT caused an increase in the antiinflammatory cytokine, IL-<em>1</em>0.

CONCLUSIONS

These observations provide conceptual support that activation of ACE2 by a small molecule can be a therapeutically relevant approach for treating and controlling PH.