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Infarct scar, a requisite to the rebuilding of necrotic myocardium following myocardial infarction (MI), has long been considered inert. Earlier morphologic studies suggested healing at the infarct site was complete within 6-8 weeks following MI and resultant scar tissue, albeit necessary, was acellular and simply fibrillar collagen. Utilizing molecular and cellular biologic technologies, recent studies indicate otherwise. Infarct scar is composed of phenotypically transformed fibroblast-like cells, termed myofibroblasts (myoFb) because they express alpha-smooth muscle actin (alpha-SMA) and these microfilaments confer contractile behavior in response to various peptides and amines. These cells are nourished by a neovasculature and are persistent at the MI site, where they are metabolically active expressing components requisite to angiotensin (Ang) peptide generation, including converting enzyme, receptors for AngII and transforming growth factor (TGF)-beta1. They continue to elaborate fibrillar type I collagen. Their generation of these peptides contribute to ongoing scar tissue collagen turnover and to fibrous tissue formation of noninfarcted myocardium. Infarct scar contraction accounts for its thinning and its tonus may contribute to abnormal ventricular chamber stiffness with diastolic dysfunction. Infarct scar is a dynamic tissue: cellular, vascularized, metabolically active and contractile. Pharmacologic interventions with angiotensin converting enzyme inhibitor or AT1 receptor antagonist has proven effective in attenuating scar tissue metabolic activity and minimizing adverse accumulation of fibrous tissue in noninfarcted myocardium.
Cardiovasc Res 2000 May
PMID:Infarct scar: a dynamic tissue. 1077 28

Vascular injury stimulates AT1-receptor expression and nitric oxide (NO) production in smooth muscle cells (SMCs). We examined the ability of AT1 agonists and antagonists to regulate vascular tone ex vivo in injured arteries and the possible modulation by SMC-derived NO. Rings of rat carotid arteries were isolated at day 7 after endothelial denudation and stimulated with angiotensin (Ang) II in the absence or presence of the AT1 antagonists losartan, L-158,809, or EXP-3174. Freshly denuded contralateral arteries were used as controls. AngII-induced contractions were similar in control and injured arteries. Losartan caused an insurmountable inhibition of AngII-induced contractions in injured but not control arteries. Enhanced inhibition of AngII in injured arteries also was observed in the presence of L-158,809 and EXP-3174. In the presence of the NO synthesis inhibitor nitromonomethyl-L-arginine (L-NMMA), maximal contractions to AngII were greater in injured than in control vessels, and AT1-receptor blockade with losartan was surmountable in all vessels. Mechanical removal of superficial neointimal SMCs attenuated NO production and normalized the efficacy of losartan in injured arteries. These results suggest a role for NO in reducing the biologic effects of AT1-receptor agonists and potentiating the efficacy of AT1 antagonists in vessels undergoing remodeling after injury.
J Cardiovasc Pharmacol 2000 May
PMID:Evidence that nitric oxide regulates AT1-receptor agonist and antagonist efficacy in rat injured carotid artery. 1081 69

Angiotensin II AT1-receptor blockers (AT1-s) prolong survival in experimental postischemic (coronary artery ligation) heart failure (CHF) in rats. The goal of this study was to investigate whether potential beneficial effects of short- and/or long-term treatment with AT1-s on coronary dynamics, function, and structure develop along with the drug-induced survival prolongation in this model. Coronary blood flow was measured (fluorescent microspheres) in conscious sham, untreated, and irbesartan-treated (50 mg/kg daily for 6 weeks or 6 months, starting 8 days after surgery) CHF rats at baseline and at maximal vasodilatation induced by dipyridamole, and coronary dilatation reserve (CDR) was calculated as the ratio of maximal to baseline coronary flow. Coronary endothelial function was assessed in vitro by measuring the coronary relaxant responses to acetylcholine in the three groups of animals. Finally, cardiac hypertrophy and pericoronary fibrosis also were investigated. In CHF rats, left (LV) and right (RV) ventricular CDR were markedly depressed at both 7 weeks and 6 months after ligation, whereas coronary endothelial function was significantly impaired only after 6 months. Short-term AT1-receptor blockade with irbesartan did not prevent CDR deterioration at 7 weeks, nor did it significantly oppose cardiac hypertrophy and pericoronary fibrosis development. Prolonged AT1-receptor blockade prevented both RV CDR deterioration and coronary endothelial function impairment. It also limited significantly the increase in LV end diastolic pressure and the development of cardiac hypertrophy and pericoronary fibrosis. In conclusion, in postischemic CHF in rats, alterations of CDR precede those of coronary endothelial function. Long-, but not short-term AT1-receptor blockade prevents endothelial function degradation, opposes RV CDR impairment, prevents pericoronary fibrosis development, and improves systemic hemodynamics. These effects of AT1-s on coronary dynamics, function, and structure (i.e., on myocardial perfusion) may contribute to the drug-induced survival prolongation in this model.
J Cardiovasc Pharmacol 2000 Sep
PMID:Effects of angiotensin II AT1-receptor blockade on coronary dynamics, function, and structure in postischemic heart failure in rats. 1097 90

We tested the hypothesis that a combination of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II type 1 receptor antagonist (AT1-ant) may have an additive cardioprotective effect in mice with heart failure (HF), because these two agents could have other mechanisms of action besides interrupting the renin-angiotensin system. ACEi prevent degradation of bradykinin. During treatment with AT1-ant, increased angiotensin II could activate AT2 receptors, with an antitrophic effect. To test this hypothesis, we used a mouse model of HF induced by myocardial infarction. Seven days after surgery, mice were divided into six groups and treated for 23 weeks: (a) sham ligation; (b) HF-vehicle; (c) HF-ACEi; (d) HF-AT1-ant; (e) HF-ACEi + AT1-ant (half dose of each); and (f) HF-ACEi + AT1-ant (full dose of each). Cardiac function was evaluated in conscious mice during the treatment period. The HF-vehicle group showed significantly decreased left ventricular (LV) ejection fraction (EF), shortening fraction (SF), and cardiac output (CO) and increased LV dimensions, interstitial collagen, and myocyte cross-sectional area (MCSA) compared with controls. Treatment with ACEi or AT1-ant significantly increased EF, SF, and CO and decreased LV dimensions and MCSA in mice with HF. However, a combination of these drugs did not improve cardiac function more than ACEi or AT1-ant alone. We concluded that ACEi and AT1-ant have similar cardioprotective effects and may reach maximal effect when given individually; thus no further improvement can be achieved with combined therapy in mice with HF.
J Cardiovasc Pharmacol 2000 Oct
PMID:Effects of ACE inhibitor, AT1 antagonist, and combined treatment in mice with heart failure. 1102 48

The single oral administration of a mixed endothelin-A-and -B- (ETA/ETB) receptor antagonist, J-104132 (L-753,037) decreased the blood pressure in conscious spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP) and Dahl salt-sensitive hypertensive rats fed high-salt diet (DS-H) at doses of 3 and 10 mg/kg, with a duration of approximately 24 h. The magnitude of the antihypertensive effects was greater in DS-H than in SHR and SHRSP Preproendothelin-1 mRNA expression in the kidney and aorta was greater (about twofold) in DS-H than that in nonnotensive Dahl salt-resistant rats fed high-salt diet (DR-H), while there was no difference in preproendothelin-1 mRNA expression between SHR and Wistar Kyoto rats (WKY). An AT1-receptor antagonist, MK-954 (Losartan), also attenuated hypertension in SHR and SHRSP at oral doses of 3 and 10 mg/kg, but bad no effect in DS-H. The concomitant treatment with MK-954 and J-104132 showed additive antihypertensive effects in SHR and SHRSP. In DS-H, MK-954 potentiated the antihypertensive effects of J-104132. From these results, we suggest that: (1) the contribution of endothelin (ET) to the maintenance of hypertension is greater in salt-sensitive hypertensive models than in SHR and SHRSP; (2) the antihypertensive efficacy of ETA/ETB blockade is augmented by AT1-receptor blockade; (3) ET blockers alone or in combination with AT1 antagonists could be useful in the treatment of hypertension for patients who do not respond adequately to renin-angiotensin system inhibitors alone.
J Cardiovasc Pharmacol 2000 Nov
PMID:Antihypertensive effects of a mixed endothelin-A- and -B-receptor antagonist, J-104132, were augmented in the presence of an AT1 -receptor antagonist, MK-954. 1107 14

The aim of this study was to examine, using autoradiography, the distribution of endothelin (ET) and angiotensin receptors in the two phenotypic states of normal (NCA) and atherosclerotic human coronary arteries [coronary artery disease (CAD)]. ET and angiotensin receptors in epicardial coronary arteries were visualized with 0.1 nM [125I]ET-1 and 0.4nM [125I]Sar1, Ile8 angiotensin-II, respectively. Developed images were quantified using computer-assisted densitometry. In both NCA and CAD vessels the density of ET(A)-receptors was much greater in the medial compared to the intimal smooth muscle layer. ET(B)-receptors were predominantly localized to perivascular nerves in NCA and CAD. Overall binding of angiotensin II to the media of NCA was significantly greater than to the intimal layer. The angiotensin type I receptor (AT1) predominated in both the media and intima of NCA and this subtype was downregulated with CAD. Fewer angiotensin type 2 receptors (AT2) were found in the media of NCA with a significant upregulation of AT2 in both the media and the thickened intima of CAD.
J Cardiovasc Pharmacol 2000 Nov
PMID:Changes in ET(A)-, AT1- and AT2-receptors in the phenotypically transformed intimal smooth muscle layer of human atherosclerotic coronary arteries. 1107 31

The cardioprotective effect of angiotensin converting enzyme (ACE) inhibitors and angiotensin type I (AT1) receptor blockers may relate to their antithrombotic effect. We determined the differential effects of the ACE inhibitor quinapril and the AT1 receptor blocker losartan on arterial thrombus formation in the rat. Sprague-Dawley rats were fed regular chow or chow mixed with low-dose quinapril (0. 6 mg/kg/day), high-dose quinapril (1.2 mg/kg/day), or losartan (10 mg/kg/day) for 15 days. Abdominal aorta was exposed and wrapped with Whatman paper impregnated with 29% FeCl(3) (ferric chloride). Time to occlusive thrombus formation and weight of the thrombus were recorded. Aortic superoxide anion generation, platelet aggregation, plasma angiotensin II levels, and morphology of the thrombus were also examined. Both losartan and quinapril caused similar reductions in arterial pressure. Losartan did not affect the time to thrombus formation, whereas quinapril (both low and high doses) delayed the time to thrombus formation (P<.01 vs control). Weight of the thrombus was similar in all groups of rats. Platelet aggregation was inhibited by approximately 50 in both quinapril- and losartan-treated rats. The high-dose quinapril-treated rats showed markedly reduced vascular superoxide anion generation compared with the control rats (P<.05). Plasma angiotensin II levels were unaffected by quinapril treatment but were elevated 7-fold in losartan-treated rats (P <.001 vs. control rats). The thrombi in the control rats consisted of platelet aggregates, fibrin, and red blood cells. The intravascular platelet aggregates were much smaller in the quinapril-treated rats (P<.05 vs. control), but were similar in control and losartan-treated rats. In conclusion, quinapril but not losartan prolongs time to arterial thrombus formation and results in smaller platelet aggregates in the thrombus. Both quinapril and losartan decrease platelet aggregation, but only quinapril decreases superoxide anion generation. This effect on superoxide anion generation as well as mechanisms other than AT1 receptor blockade may underlie the salutary effect of quinapril on arterial thrombogenesis.
J Cardiovasc Pharmacol Ther 2000 Apr
PMID:Inhibition of arterial thrombogenesis by quinapril but not losartan. 1115 Mar 91

To determine contribution of the autonomic nervous system to cardiovascular reactivity to noise, acoustic startle stimulus (110 dB, 1-20 kHz, 0.150 s) was administered to 35 subjects (19 women, 16 men) with mild essential hypertension. Among these patients, 10 were unmedicated and 25 were receiving long-term monotherapy (10 were taking 100 mg atenolol, 5 were taking 10 mg prazosin, and 10 were taking 50 mg losartan daily). Polygraphic recordings were obtained in supine position. Blood pressure (BP) and heart rate (HR) levels were stable until the noise was administered. In the unmedicated group BP and HR were elevated during the first 10 s. BP returned to resting levels after this period. The calculated hemodynamic indexes showed a biphasic change in total peripheral resistance (TPR), with an overall vasoconstriction associated with the BP rise phase, preceding a delayed vasodilation. The lowest HR changes were observed in the beta-blocker group with increases of 6 beats/min and 3 beats/min after the first and second noise stimulations, compared with 10 beats/min and 5 beats/min in the unmedicated group. Prazosin significantly reduced the BP rises to 7 mm Hg and 6 mm Hg for systolic BP and diastolic BP after the first stimulation compared with 22 mm Hg and 17 mm Hg in the untreated group (p < 0.01). The second stimulation after prazosin determined -5 mm Hg and 1 mm Hg changes for systolic BP and diastolic BP respectively, compared to rises of 13 mmHg for systolic BP and 10 mmHg for diastolic BP in the untreated group (p < 0.01). The hemodynamic percentage changes resulting from the first stimulation indicated prazosin markedly reduced the noise-induced rise in TPR (p < 0.05). No effect of beta-blocker was detectable using percentage changes. The rises in BP were amplified in the losartan-treated subjects compared with the other groups. Because of a low resting TPR in this group, the percentage changes in TPR resulting from noise were amplified in the subjects treated with the AT1 receptor antagonist. In conclusion the acoustic startle stimulus appeared as a simple and reliable procedure for inducing transient increases due to a rise in TPR. Cardiovascular responses differed according to the antihypertensive monotherapy, with a limited effect of noise in the prazosin-treated group.
J Cardiovasc Pharmacol 2001 Jan
PMID:Antihypertensive monotherapy and cardiovascular responses to an acoustic startle stimulus. 1115 67

This review deals with similarities and differences between the effects of ACE inhibitors and AT1-receptor blockers in the kidney. Specific receptor blockade has demonstrated that the beneficial effects of AT1 blockers arise from two mechanisms: the reduction of the AT1 receptor mediated response and the increase in plasma levels of Ang II through the AT1-receptor blockade, which leads to increased stimulation of the AT2 receptor (the so-called yin-yang effect). Both ACE inhibition and AT1-receptor blockade provide significant renal protection in the majority of experimental animal models of kidney diseases. AT1 receptor blockade may offer additional clinical benefits over ACE inhibitor treatment, particularly in the kidney, where AT1-receptor blockade does not cause the fall in glomerular filtration rate seen with ACE inhibitor treatment. A number of long-term clinical studies currently running should show the real value of this new class of compounds in the management of hypertension and associated cardiorenal diseases.
Cardiovasc Drug Rev 2001
PMID:Angiotensin receptor blockers and the kidney: possible advantages over ACE inhibition? 1131 2

The present study aimed to determine the action of angiotensin II and to pharmacologically analyze mechanisms of their action in isolated uterine arteries. Canine and human uterine artery strips were suspended in Ringer-Locke solutions for isometric tension recording. Canine and human uterine arteries responded to angiotensin II with transient contraction followed by relaxation, which were abolished by losartan, an AT1 receptor subtype antagonist. Cyclooxygenase inhibitors augmented the contraction and abolished the relaxation. The relaxation was also abolished or suppressed by tranylcypromine, a prostaglandin I2 synthesis inhibitor. The relaxant response of dog uterine arteries to angiotensin II was partially suppressed by endothelium denudation but was not influenced by nitric oxide synthase inhibitor. Conversely, the response of human uterine arteries to the peptide was unaffected by endothelium denudation. The antagonists used and endothelium denudation did not inhibit the relaxation caused by a prostaglandin I2 analogue. It appears that the angiotensin II-induced relaxation is mediated by vasodilator prostaglandins, possibly prostaglandin I2, released from both endothelium and subendothelial tissues in dog uterine arteries. In human uterine arteries, the vasodilator prostaglandin is released from subendothelial tissues due to AT1 receptor stimulation by the peptide.
J Cardiovasc Pharmacol 2001 May
PMID:Mechanisms of relaxation induced by angiotensin II in isolated canine and human uterine arteries. 1133 9


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