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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertension, low-density lipoprotein (LDL), and fibrinogen are risk factors for atherosclerosis. We investigated the effect of reducing blood pressure, by blocking the renin-angiotensin system (RAS), on the accumulation of these atherogenic proteins in arterial walls and other tissues in conscious, unrestrained, normotensive and hypertensive rats. The accumulation of LDL and fibrinogen, labeled respectively with 125I and 131I via the adduct tyramine cellobiose ([125I]-TC-LDL and [131I]-TC-fibrinogen) was compared in aortic walls, heart, lung, skeletal muscle, liver, kidney, and adrenal gland during the final 24 h of treatment with either the angiotensin-converting enzyme (ACE) inhibitor captopril or the angiotensin II-receptor I (AT1) antagonist losartan. In normotensive rats, the blood pressure was decreased only by losartan. In spontaneously hypertensive rats (SHRs), the blood pressure was decreased by both losartan and captopril. Captopril had no significant effect on the accumulation of LDL or fibrinogen by the aortic wall. Losartan significantly increased the accumulation of LDL by the aortic wall of SHRs. Neither agent produced any change in LDL or fibrinogen accumulation in any of the other tissues. These results indicate that although blocking the RAS at either the enzymic or receptor level produces significant decrease of blood pressure in hypertensive animals, only losartan has any affect on LDL accumulation by the aortic wall.
J Cardiovasc Pharmacol 1997 Jan
PMID:Effect of captopril and losartan on blood pressure and accumulation of LDL and fibrinogen by aortic wall and other tissues in normotensive and hypertensive rats. 900 81

Cardiac beta-adrenergic receptors are the primary driving force for the enhancement of contractility in response to sympathetic stimulation. Angiotensin II influences cardiac function by modulating sympathetic activity and by activating cardiac angiotensin II receptors. The aim of this study was to determine whether activation of cardiac angiotensin II receptors modulates the responsiveness of the heart to beta-adrenergic receptor activation. Male Sprague-Dawley rats were anesthetized and the hearts isolated and perfused with oxygenated Krebs-Henseleit buffer (KHB). Coronary artery perfusion pressure, left ventricular pressure (LVP), left ventricular dP/dtmax, and heart rate (HR) were measured. Bolus administration of the beta-adrenergic receptor agonists, isoproterenol, dobutamine, and salbutamol, produced dose-related increases in LVP, LV dP/dt(max), and HR. Addition of angiotensin-II (10-100 nM) to the KHB slightly increased coronary perfusion pressure but did not alter baseline LVP, LV dP/dt(max), or HR. Angiotensin II reduced the increase in LVP, LV dP/dt(max), and HR elicited by isoproterenol and dobutamine but did not affect responses to salbutamol. The inhibitory effect of angiotensin II was blocked by the AT1-receptor antagonist, losartan, and the protein kinase C inhibitor, calphostin C (50 nM). Activation of protein kinase C with phorbol-12, 13-dibutyrate (PDBu; 10 nM) reduced cardiac responses to all three agonists, although the effects were less on responses elicited by salbutamol. These data suggest that activation of protein kinase C by angiotensin II decreases the responsiveness of the rat heart to beta 1-adrenergic stimulation and that angiotensin II-mediated protein kinase C activation may differ from that activated by phorbol esters.
J Cardiovasc Pharmacol 1997 Feb
PMID:Activation of protein kinase C by angiotensin II decreases beta 1-adrenergic receptor responsiveness in the rat heart. 905 76

The pharmacologic profile of a novel angiotensin I (AT1) receptor antagonist 606A was studied in various in vitro and in vivo preparations. The 606A showed a high affinity at AT1 receptors [inhibition constant (Ki), 12.8 +/- 0.4 nM] in rabbit adrenal cortical membrane and a low affinity to AT2 receptors (Ki, > 1 mM) in bovine cerebellar membrane, indicating potent and selective AT1 properties. In the guinea pig aorta, 606A reduced the maximal angiotensin II-induced contraction (pD'2, 9.06 +/- 0.04), whereas EXP3174 showed suppression of the maximum response and a shift to the right of the concentration-response curve at lower and higher concentrations, respectively (conventionally calculated pd'2, 8.61 +/- 0.23). The 606A had no effects on KC1-, norepinephrine-, serotonin-, and endothelin-1-induced contractions or any agonist activities. In anesthetized dogs, 606A inhibited the angiotensin II-induced pressor response 35 times more potently than losartan. In renal hypertensive rats and spontaneously hypertensive rats (SHRs), 606A decreased systolic blood pressure 10 and 3 times more potently than losartan, respectively, without any chronotropic effects. By repeated administration of 606A to SHRs for 2 weeks, an augmentation of the hypotensive effect was observed No rebound phenomena occurred after discontinuation. These results indicate the 606A is a potent AT1-selective insurmountable angiotensin II receptor antagonist having more potent angiotensin II receptor antagonistic and hypotensive effects than losartan in in vivo models. 606A is suggested to be a useful agent for the treatment of patients with hypertension.
J Cardiovasc Pharmacol 1997 Feb
PMID:The pharmacologic profile of 606A, a novel angiotensin II receptor antagonist. 905 80

This study was designed to assess in normal volunteers the potency, efficacy, and tolerability of the new nonpeptidic, orally active, angiotensin (Ang) II subtype 1 (AT1)-receptor antagonist SC-52458. After a randomized, single-blind, placebo-controlled protocol, two groups of eight healthy men ingested placebo or increasing single oral doses (10, 25, and 50 mg or 100, 150, and 200 mg) of SC-52458. Finger blood pressure (BP) was continuously monitored (Finapres), and BP response to repeated intravenous challenges with Ang II was compared with baseline BP response to the same dose of Ang II. Up to 24 h after drug intake, effects on plasma renin activity (PRA), Ang II, and aldosterone and pharmacokinetics were estimated. One, 4, and 10 h after the 200-mg dose, diastolic BP response to Ang II challenges was decreased from 30.3 to 2.6 mm Hg (mean +/- SEM; n = 8; i.e., to 8.3 +/- 1.1% of baseline response), 10.1 mm Hg (35.4 +/- 1.8%), and 17.5 mm Hg (58.7 +/- 1.8%), respectively. SC-52458 produced dose-related increases in PRA and Ang II concentrations < or = 10 h after drug intake. Plasma aldosterone concentrations tended to be decreased for < or = 24 h after SC-52458 doses of > or = 100 mg. No drug-related side effects were observed. The pharmacokinetics were linear over the dose range of 10-150 mg (t1/2 = 1.14-2.39 h). Efficacy was dose dependent, with a peak effect after 1 h. In conclusion, the novel AT1-receptor antagonist SC-52458 is well tolerated and orally active. It produces a rapid-onset inhibition of the renin-angiotensin system and reduces BP response to Ang II for > or = 10 h. These characteristics promise strong antihypertensive properties for SC-52458.
J Cardiovasc Pharmacol 1997 Apr
PMID:SC-52458, an orally active angiotensin II-receptor antagonist: inhibition of blood pressure response to angiotensin II challenges and pharmacokinetics in normal volunteers. 915 52

Elevated levels of angiotensin (Ang II) and its degradation products angiotensin III (Ang III) and angiotensin IV (Ang IV) may contribute to the regulation of vascular tone under various clinical circumstances. We investigated the contractile effects of Ang III and Ang IV in endothelium-denuded human saphenous vein (SV) preparations and compared them with those of Ang II. The veins were suspended in organ chambers, and changes in isometric force were recorded. Ang II (0.1-100 nM), Ang III (1 nM-3 microM), and Ang IV (0.3 microM-0.1 mM) caused concentration-dependent contractions with comparable maximal responses (Emax). Ang III was 16 times less active than Ang II, whereas Ang IV was approximately 2,700-fold less potent than Ang II. In the presence of the aminopeptidase-A and -M inhibitor amastatin (10 microM), the potencies of Ang III and Ang IV were increased by approximately 16 and 12 times, respectively, although no changes of Ang II potency were observed. The AT1-selective Ang II receptor antagonist losartan (10 and 100 nM) but not the AT2-selective antagonist PD123177 (1 microM), shifted the concentration-response curves (CRC) for the angiotensin peptides to the right in a parallel manner. Preincubation with indomethacin (10 microM), a cyclooxygenase inhibitor, did not influence the CRCs for any of the angiotensin peptides studied. Tachyphylaxis was investigated by constructing a second series of CRCs for the angiotensin peptides after an interval of 60 min. Ang II showed strong tachyphylaxis (the Emax value of the second Ang II CRC was approximately 50% of the first), whereas Ang III and Ang IV did not. Our results indicate that in endothelium-denuded human SV, both Ang III and Ang IV are less potent but similarly efficacious vasoconstrictor agents compared with Ang II. Endogenous aminopeptidase activity may counteract the effects of the angiotensin peptides. The contractile responses to all three peptides are mediated via AT1-receptors but not AT2-receptors.
J Cardiovasc Pharmacol 1997 Apr
PMID:Comparative vasoconstrictor effects of angiotensin II, III, and IV in human isolated saphenous vein. 915 53

The effect of angiotensin II (Ang II) on inositol phosphate (IP) production and atrial natriuretic peptide (ANP) release was studied in sliced rat atrial tissue. The ability of Ang II (10(-7) M) to stimulate IP accumulation was detected after 1 min of incubation, and the maximal increase was observed at 5 min. In (2-3H) inositol-labeled atrial tissue, Ang II induced the formation of (2-3H) inositol monophosphate (IP1) in a dose-dependent manner. The effect of Ang II (10(-7) M) on IP1 was prevented by losartan (10(-7) M) but was not affected by PD123319 (10(-7) M). Similar effects were observed on Ang II-induced ANP release in the presence of these antagonists. The mechanism of ANP liberation induced by this peptide was independent of cyclic adenosine monophosphate (cAMP) and regulated by nitric oxide (NO). The role of Ca2+ in the effect of Ang II was tested by 1,2-bis (o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetra (acetoxymethyl) ester (BAPTA-AM; 10(-5) M), a chelator of intracellular Ca2+ that prevented the release of ANP by Ang II stimulation. We concluded that Ang II induced IP production and ANP release through AT1 receptors. Stimulation of ANP release by Ang II was dependent on intracellular Ca2+.
J Cardiovasc Pharmacol 1997 May
PMID:Angiotensin II-induced phosphoinositide production and atrial natriuretic peptide release in rat atrial tissue. 921 2

The structure and function of small arteries of different vascular beds in spontaneously hypertensive rats (SHRs) are altered relative to Wistar-Kyoto (WKY) control rats, and these differences may be blunted under treatment with angiotensin-converting enzyme inhibitors. To determine whether this effect of angiotensin-converting enzyme inhibitors was caused by the interruption of the renin-angiotensin system, our experiments were conducted with an AT1 angiotensin-receptor antagonist to evaluate its ability to induce regression of hypertrophy of resistance arteries in SHRs. The result of treatment of SHRs with losartan, an orally active selective angiotensin AT1 receptor antagonist was examined at a low (20 mg/kg/day) and a high (60 mg/kg/day) oral dose in SHRs once blood pressure had been elevated for some time. SHRs were treated for 12 weeks with losartan. Blood pressure was significantly reduced by losartan treatment from 210 +/- 2 mm Hg in untreated SHRs to 181 +/- 1 mm Hg (low dose) and 156 +/- 4 mm Hg (high dose) (p < 0.01). Cardiac and aortic hypertrophy were dose-dependently reduced in treated SHRs. Coronary, renal, mesenteric, and femoral small arteries (luminal diameter, 200-250 microm) studied on an isometric wire myograph and pressurized mesenteric small arteries examined under isobaric conditions exhibited significant hypertrophy and inward remodeling in SHRs in comparison to WKY rats. Losartan treatment resulted in a dose-dependent reduction in the media thickness and mediato-lumen ratio in small arteries from the four vascular beds studied on the wire myograph and in pressurized mesenteric small arteries. Endothelium-dependent relaxation studied in pressurized arteries was enhanced, and acetylcholine-induced endothelium-dependent contractions studied on the wire myograph were abolished in losartan-treated SHRs relative to untreated SHRs. In WKY rats, treatment had no effect. These results demonstrate that treatment with the selective angiotensin II receptor antagonist losartan, even at doses that reduce blood pressure only moderately, induces regression of cardiovascular hypertrophy and of endothelial dysfunction in genetic hypertension in the rat.
J Cardiovasc Pharmacol 1997 Jul
PMID:Effect of AT1 angiotensin-receptor blockade on structure and function of small arteries in SHR. 926 24

The purpose of our study was test the hypothesis that endogenous angiotensin II contributes to the basal coronary artery tone by acting at vascular ATP-sensitive K+ (K+ATP) channels. Coronary blood flow (CBF) and other hemodynamic parameters were measured in anesthetized dogs. Intracoronary infusion of the selective antagonists of angiotensin II AT1 receptors (L-158,809 and E4177) increased CHF without affecting other hemodynamic parameters, indicating that endogenous angiotensin II caused coronary vaso-constriction through the AT1 subtype receptors. Coronary vasodilation in response to AT1 receptor antagonists was blunted by pretreatment with glibenclamide (a specific inhibitor of K+ATP channels; p < 0.01) but not by either an adenosine-receptor antagonist or an inhibitor of nitric oxide synthesis. Coronary vasodilation in response to AT1-receptor antagonists was partly reduced (p < 0.01) by PD-123319 (the AT2-receptor antagonist). Glibenclamide had no effect on coronary vasodilation induced by sodium nitroprusside. These results indicate that in dogs in vivo, coronary vasodilation in response to AT 1-receptor antagonists inhibited markedly by glibenclamide and partly by PD-123319, suggesting that endogenous angiotensin II contributes to the maintenance of basal coronary vascular tone by acting at K+ATP channels through its receptors.
J Cardiovasc Pharmacol 1997 Sep
PMID:Glibenclamide, a specific inhibitor of ATP-sensitive K+ channels, inhibits coronary vasodilation induced by angiotensin II-receptor antagonists. 930 Mar 14

Combined therapy with an angiotensin-II type I receptor (AT1) antagonist and an angiotensin-converting enzyme (ACE) inhibitor results in more complete suppression of the renin-angiotensin system. Accordingly, the blood-pressure response and safety of combining AT1-receptor blockade with losartan for ACE inhibition were evaluated in patients with congestive heart failure who were already treated with maximally recommended or tolerated doses of an ACE inhibitor. Forty-three patients with symptomatic congestive heart failure were evaluated biweekly for 1 month before addition of losartan and weekly during administration of losartan at a daily dose of 25 mg for the first week and 50 mg for the second week. Systolic blood pressure, which remained unchanged before addition of losartan, decreased from 122 +/- 18 mm Hg to 112 +/- 17 and 107 +/- 17 mm Hg (p < 0.001) after 1 week of 25 mg and 1 week of 50 mg losartan, respectively. Diastolic blood pressure also significantly decreased. The decreases in blood pressure were well tolerated by all patients, even by those in whom symptomatic hypotension developed during uptitration of ACE inhibition. Serum potassium and sodium and parameters of renal function remained unchanged. Combining AT1-receptor blockade with losartan to maximally recommended or tolerated ACE inhibition appears safe and leads to further vasodilatation in symptomatic patients with congestive heart failure.
J Cardiovasc Pharmacol 1997 Oct
PMID:Angiotensin II-receptor blockade further reduces afterload safely in patients maximally treated with angiotensin-converting enzyme inhibitors for heart failure. 933 16

This study delineates the role of angiotensin II type I (AT1) receptor in the remodeling of Syrian cardiomyopathic hamsters. Twelve cardiomyopathic (T0-2) hamsters received L-158,809 treatment and libitum in their drinking water (27 micrograms/ml) and 9 cardiomyopathic and 9 normal FL-B hamsters received tap water from 1 to 4 months of age. Although pharmacologically effective with regard to complete suppression of the blood pressure response to angiotensin II infusion, L-158,809 did not diminish the progression or severity of cardiomyopathy. Heart weight/100 g body weight and left ventricular wall thickness adjusted for body weight of both L-158,809 and cardiomyopathic control hamsters did not differ and exceeded those of F1-B controls (p < 0.05). Myocardial material properties (e.g., stiffness and density) of cardiomyopathic hamsters treated with L-158,809 were not affected. Thus, the progression of fibrosis, calcification, and necrosis in T0-2 cardiomyopathic hamsters was not sensitive to AT1 receptor blockade.
Cardiovasc Drugs Ther 1997 Sep
PMID:Angiotensin II receptor blockade in Syrian hamster (T0-2) cardiomyopathy does not affect microscopic cardiac material properties: implications for mechanisms of tissue remodeling. 935 56


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