Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid dysfunction produces marked cardiovascular responses; the renin-angiotensin system (RAS) is important in control of the cardiovascular system. We have measured changes in the plasma RAS and in angiotensin II (AT) receptors in experimentally hyperthyroid, euthyroid, or hypothyroid rats. Hyperthyroidism activated the plasma RAS, increasing plasma angiotensinogen by 85% after 7-day triiodothyronine (T3) treatment, plasma renin activity (PRA) by 47% and concentration by 52%, and plasma AT by 1.250%. Hypothyroidism reduced plasma angiotensinogen by 71%, PRA by 73%, and plasma AT by 81% without altering plasma renin concentration (PRC). Plasma aldosterone was reduced by 39% in hyperthyroid rats and by 95% in hypothyroid rats. AT receptors were characterized in heart, liver, adrenal gland, and kidney. Cardiac, liver, and kidney AT receptor densities increased in hyperthyroidism by 73, 113, and 75%, respectively; adrenal gland receptor density decreased by 39%. Similar results were observed in hypothyroidism except that adrenal gland receptor density was markedly increased by 205%. AT receptor subtypes were characterized in ventricular homogenates by the selective antagonist losartan. Hyperthyroidism markedly increased AT2-subtype density by 204% in left ventricle, and by 304% in right ventricle and decreased AT1-subtype density by 38% and 31% in left and right ventricles, respectively. AT2-subtype density increased by 168% in hypothyroid rats; AT1-subtype density was unchanged. Thyroid dysfunction causes significant changes in the RAS and in AT receptor density, especially of the AT2 subtype. Although a physiological function has not yet been reported for AT2 receptors, our results suggest that selective AT2-receptor antagonists may prove therapeutically useful in treatment of cardiovascular disease in thyroid dysfunction.
J Cardiovasc Pharmacol 1993 Sep
PMID:Renin-angiotensin system in thyroid dysfunction in rats. 750 37

The object of this study was to differentiate losartan, an AT1-selective angiotensin II (ANG II) receptor antagonist, from enalapril, an angiotensin-converting enzyme (ACE) inhibitor, by measuring forearm vascular responses to AI, AII, and bradykinin. Eight healthy men were studied in a randomised, 4-period crossover study in which placebo, enalapril (10 mg), losartan (20 mg) and losartan (100 mg) were given double-blind on separate occasions. Forearm blood flow was measured by venous occlusion plethysmography during sequential infusions of ANG I, ANG II, and bradykinin into the brachial artery 4-6 h after dosing. Analysis of variance for repeated measures indicated that losartan inhibited constriction to ANG I and ANG II (both p < 0.02) in a dose-dependent manner without significantly influencing vasodilator responses to bradykinin. Enalapril (10 mg) inhibited AI similarly to losartan 100 mg without significantly influencing responses to angiotensin II, and augmented vasodilator responses to bradykinin (p < 0.0001). In human forearm vasculature, oral losartan (20-100 mg) inhibits vasoconstriction to ANG I and ANG II without significantly influencing bradykinin-induced vasodilation, whereas enalapril selectively inhibits ANG I-induced vasoconstriction while potentiating the vasodilator effect of bradykinin.
J Cardiovasc Pharmacol 1993 Oct
PMID:Comparison of angiotensin-converting enzyme inhibition with angiotensin II receptor antagonism in the human forearm. 750 60

We describe the pharmacologic properties of SC-52458, 5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(1H-tetrazol - 5-ylphenyl)]pyridine, a novel nonpeptide angiotensin II (AII) receptor antagonist. SC-52458 was a potent inhibitor of [125I]AII binding to AT1 receptors in rat adrenal cortex and uterine smooth muscle membranes (IC50 values of 2.8 and 6.9 nM, respectively). Contraction of rabbit aortic rings by AII was antagonized by SC-52458 in a competitive and reversible manner (pA2 of 8.18). SC-52458 had no effect on the activity of angiotensin converting enzyme (ACE) or renin in vitro. In normotensive rats, administration of SC-52458, either intravenously (i.v.) or by gavage, inhibited the pressor response to AII. Daily treatment with SC-52458 at 20, 30, and 50 mg/kg by gavage for 4 days decreased blood pressure (BP) in conscious, spontaneously hypertensive rats (SHR). Further studies in renal-artery ligated rats and sodium-deficient dogs demonstrated that oral administration of SC-52458 decreased BP and that this activity was correlated with significant plasma levels of the compound. SC-52458 is an orally active, competitive AT1-receptor antagonist with antihypertensive properties.
J Cardiovasc Pharmacol 1993 Oct
PMID:Pharmacology of SC-52458, an orally active, nonpeptide angiotensin AT1 receptor antagonist. 750 65

The effects of CV-11974, a potent nonpeptide antagonist of the angiotensin II (AII) type-1 receptor (AT1), on cytosolic free calcium concentration ([Ca2+]i), hyperplasia, and hypertrophy of cultured vascular smooth muscle cells (VSMC) from rat aorta were studied. [Ca2+]i was measured by fura 2, and hyperplasia and hypertrophy were determined by incorporation of [3H]thymidine and [3H]leucine, respectively. CV-11974 had no effect on [Ca2+]i itself, but suppressed 10(-7) M AII-induced increase in [Ca2+]i dose dependently at concentrations from 10(-10) M and completely at 10(-7) M. CV-11974 suppressed both Ca2+ release from intracellular Ca2+ stores and Ca2+ influx from the extracellular space. However, CV-11974 had no effect on the increases in [Ca2+]i induced by prostaglandin F2 alpha (PGF2 alpha), a potent vasoconstrictor, or ionomycin, a Ca2+ ionophore. These results indicate that the suppressive effects of CV-11974 act on the binding of AII and its specific receptors. AII 10(-7) M increased the synthesis of DNA and protein to 1.5 and 1.7 times the control values, respectively. CV-11974 had no effect on synthesis of DNA or protein, but suppressed the AII-stimulated synthesis of DNA and protein dose dependently at concentrations > or = 10(-8) and 10(-10) M, respectively and completely at 10(-6) M. These results indicate that AII increases [Ca2+]i and synthesis of DNA and protein in VSMC through activation of AT1. CV-11974 showed no partial agonistic effects on AII. Thus, CV-11974 may act not only as an antihypertensive agent, but also as an inhibitor of vascular injury stimulated by AII.
J Cardiovasc Pharmacol 1994 Feb
PMID:Effects of an angiotensin II receptor antagonist, CV-11974, on angiotensin II-induced increases in cytosolic free calcium concentration, hyperplasia, and hypertrophy of cultured vascular smooth muscle cells. 751 44

The renin-angiotensin system (RAS) has been proposed to play a major role in causing the heart to hypertrophy during pressure overload. We examined whether blockade of this system by the angiotensin-converting enzyme (ACE) inhibitors enalapril (0.5 to 20 mg/kg p.o.) or ramipril (1.0 mg/kg p.o.) or the angiotensin receptor (AT1) antagonist losartan (3.0 mg/kg p.o.) could prevent pressure overload-induced hypertrophy. Pressure overload was produced by abdominal aortic constriction in rats. Cardiac hypertrophy was assessed by an increase in the ratio of left ventricular (LV) weight to body weight and total protein content of the left ventricle. Treatment with enalapril or ramipril, initiated 3 weeks after aortic banding and continued for 3 more weeks, failed to prevent the progression or cause regression of cardiac hypertrophy. Treatment for 6 weeks with ramipril initiated immediately after aortic banding also failed to prevent cardiac hypertrophy. Losartan treatment initiated 3 weeks after aortic banding and continued for 3 more weeks resulted in a slight but significant reduction in the extent of cardiac hypertrophy (45.6% hypertrophy in controls and 35.6% hypertrophy in losartan-treated animals, p < 0.05, n = 11 and 10, respectively). Surgical removal of bands 3 weeks after placement reduced cardiac hypertrophy to a greater extent than that observed in losartan-treated animals. These results suggest that angiotensin may not play a major role in causing pressure overload-induced hypertrophy or in maintaining such hypertrophy.
J Cardiovasc Pharmacol 1994 Feb
PMID:Role of angiotensin in pressure overload-induced hypertrophy in rats: effects of angiotensin-converting enzyme inhibitors, an AT1 receptor antagonist, and surgical reversal. 751 60

Pathophysiologic levels of angiotensin II (AII) produce myocyte necrosis. We investigated whether the cardiotoxic effects of AII are mediated through the AII type I receptor (AT1). Seven groups (4-6 rats/group) were given AII (150 ng/min) alone or in combination with the AT1 antagonist losartan (7.5 mg/day). Groups were as follows: A1, A4, and L1 received AII for 2 days; A2 and L2 received AII for 9 days; and A3 and L3 received AII for 2 days and again for 2 days 5 days later. Groups L1, L2, and L3 also received losartan 2 days before and throughout the AII infusion period. All rats except those in group A4 were killed at the end of their respective infusion periods (group A4 rats were killed 7 days after infusion). Group A1 had multifocal areas of recent myocyte injury. Groups A2 and A4 had multifocal scars and only a few new areas of myocyte damage. Group A3, in addition to scar formation, had de novo areas of necrosis. There was no evidence of myocyte necrosis in groups L1, L2, and L3. Thus, AII-related myocyte necrosis is receptor mediated. Moreover, a chronic increase in AII appears to cause cardioprotective downregulation of the AT1 receptor.
J Cardiovasc Pharmacol 1994 Apr
PMID:Angiotensin II (AII)-induced myocyte necrosis: role of the AII receptor. 751 3

To determine whether cardiac unloading by inhibition of angiotensin I (AI) to AII conversion by captopril or blockade of the AII receptor (AT1) by losartan was more effective in prevention of the detrimental hemodynamic consequences of myocardial infarction (MI), inhibition of metabolic production of AII by captopril was compared with blockade of AT1 with losartan in Sprague-Dawley rats with large MI. Infarcts were created by surgical occlusion of the left main coronary artery and oral drug therapy initiated immediately and continued until hemodynamic evaluation seven days later. Heart weight was unchanged in untreated infarcted animals, whereas captopril reduced heart weight in control animals and losartan increased heart weight in infarcted animals. Left ventricular (LV) peak systolic blood pressure (SBP) was lower in treated and untreated infarcted animals. Although captopril reduced end-diastolic pressure (EDP) to a greater degree than losartan, all infarcted group showed an increase in this parameter with respect to similarly treated controls. LV peak rates of pressure increase and decay in infarcted hearts were decreased significantly more by captopril than by losartan administration. Captopril also impaired right side cardiac function more than losartan when peak rate of pressure increase was evaluated. Thus, inhibition of the effects of AII during cardiac failure improved but did not normalize cardiac pump performance.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1994 Apr
PMID:Efficacy of angiotensin-converting enzyme inhibition and AT1 receptor blockade on cardiac pump performance after myocardial infarction in rats. 751 8

The effects of four nonpeptide angiotensin receptor antagonists, i.e., losartan (AT1) PD123177 (AT2), and 4'-[(2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazole-1-yl)- methyl]biphenyl-carboxylic acid (BIBS 39; AT1 and AT2), and 2-n-butyl-1-[4-(6-carboxy-2,5-di-chlorbenzoylamino)-benzyl]-6-N- (methylaminocarbonyl)-n-pentylamino-benzimidazole (BIBS 222; AT1 and AT2) on cardiovascular responses to angiotensin II (AII) were investigated in propranolol-pretreated pithed rats. AII (0.01-10 nmol/kg intravenously, i.v.) induced a dose-dependent increase in diastolic blood pressure (DBP), the rate of increase in left ventricular pressure (LVdP/dtmax), cardiac output (CO), and total peripheral resistance (TPR) without changing LV end-diastolic pressure (LVEDP) or heart rate (HR). Losartan 3 and 10 mg/kg i.v. caused dose-dependent parallel rightward shifts of the dose-response curves (DBP and LVdP/dtmax) without altering the maximal responses to AII. PD123177 (100 mg/kg i.v.) did not influence the dose-response curves for AII significantly. BIBS 39 (1, 3, and 10 mg/kg i.v.) and BIBS 222 (1, 3, and 10 mg/kg, i.v.) shifted the dose-response curves (DBP and LVdP/dtmax) for AII to the right. Although these two compounds (BIBS 39 1, 3, and 10 mg/kg and BIBS 222 1 and 3 mg/kg) did not alter the maximal increase in DBP to angiotensin AII, they decreased the maximal increase in LVdP/dtmax by approximately 35%. BIBS 39 (3 and 10 mg/kg) significantly reduced the increase in CO caused by AII and therefore mean arterial pressure (MAP), whereas the AII-induced increase in TPR remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1994 Jul
PMID:Effect of various angiotensin receptor antagonists on cardiovascular responses to angiotensin II in pithed rats. 752 74

We examined the effects of U-97018, an AT1 receptor antagonist, on the pressor response to intracerebroventricularly (i.c.v.) administered angiotensin II (AII) in conscious normotensive rats in comparison to losartan, EXP 3174, EXP 655, and saralasin. In an i.c.v. study, U-97018, losartan, and EXP 3174 reduced the pressor response. EXP 655, an AT2 selective antagonist, also inhibited the pressor response to i.c.v. AII. U-97018 combined with EXP 655 did not fully eliminate the pressor response to i.c.v. AII. Moreover, saralasin, a nonselective peptide AII antagonist, also failed to abolish the pressor response to i.c.v. AII. Therefore, both AT1- and AT2-receptors probably are functional in inhibiting the pressor response to i.c.v. AII and that a part of the i.c.v. AII-induced pressor response occurs through non-AT1- and non-AT2-receptors. In an intravenous (i.v.) study, U-97018, losartan, and EXP 3174 reduced the pressor response to i.c.v. AII. At 10 mg/kg orally (p.o.), which is an antihypertensive dose in spontaneously hypertensive rats (SHR), neither U-97018 nor losartan reduced the pressor response to i.c.v. AII even at 180 min after administration. This result indicates that neither U-97018 nor losartan, at the oral antihypertensive dose, reaches the brain in sufficient amount to affect the pressor response to i.c.v. AII.
J Cardiovasc Pharmacol 1995 Jun
PMID:Effects of U-97018 on pressor responses to intracerebroventricularly administered angiotensin II in conscious normotensive rats. 756 32

We investigated the effect of a genetically engineered recombinant human hemoglobin (rHb1.1), specially designed to be used as a blood substitute, on the ability of various well-known vasodilators to relax the rabbit isolated aortic rings precontracted with the alpha-adrenoceptor agonist phenylephrine (PE) or with KCl (for nifedipine only). The vasorelaxant effects of nitroglycerin (NTG) and of sodium nitroprusside (SNP), two nitrovasodilators whose effects are mediated by nitric oxide (NO), were inhibited in a concentration-dependent manner by rHb1.1 (1.5 and 15 microM). Those elicited by isoproterenol, papaverine, histamine, adenosine, atriopeptin II, hydralazine, nifedipine, and cromakalim were comparatively little affected or not affected by rHb1.1 (15 microM). The ability of captopril to inhibit the vasoconstrictor action of angiotensin I (AT1) in the rabbit aortic rings was not reduced by rHb1.1 (15 microM). Our results suggest that rHb1.1 shares with purified human Hb the ability to inhibit selectively the vasorelaxant effect of NO-releasing substances such as NTG and SNP. Because the targeted plasma concentration of rHb1.1, when used as a blood substitute, is greater (approximately 50 times) than the highest concentration of rHb1.1 used in this study, significant drug interactions can be predicted between NO donors and rHb1.1.
J Cardiovasc Pharmacol 1995 Apr
PMID:Recombinant human hemoglobin (rHb1.1) selectively inhibits vasorelaxation elicited by nitric oxide donors in rabbit isolated aortic rings. 759 27


1 2 3 4 5 6 7 8 9 10 Next >>