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

We studied pharmacologic profiles of KRH-594, dipotassium (Z)-2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4 -thiadiazolin-2-ylidene]aminocarbonyl]-1-cyclopentenecarb oxylate, a novel angiotensin II (AII)-receptor antagonist. KRH-594 potently displaced specific binding of [125I]-AII from AT1 receptor with a Ki of 0.39 nM in rat liver membranes, but not from AT2 receptor in bovine cerebellar membranes (Ki > 10 microM). KRH-594 exhibited no affinity for 21 other receptors and two enzymes [50% inhibitory concentration (IC50) > 10 microM], demonstrating its high specificity toward AT1 receptors. In isolated rabbit aorta, KRH-594 caused nonparallel shifts to the right of the dose-response curve to AII and decreased the maximal response with a pK(B) of 10.4. We evaluated the in vivo efficacy and the duration of action in freely moving rats under nonfasting conditions. In normotensive rats, orally administered KRH-594 inhibited AII-induced pressor responses with a 50% inhibitory dose (ID50) of 0.39 mg/kg. In spontaneously hypertensive rats (SHRs), both KRH-594 (1 mg/kg p.o.) and losartan (10 mg/kg p.o.) exerted similar blood pressure-reducing effects, and their effects were still significant at 24 h after drug administration. We concluded that KRH-594 is a specific and efficacious AT1 antagonist that may find its use in the treatment of human hypertension.
J Cardiovasc Pharmacol 1997 Nov
PMID:Pharmacologic profiles of KRH-594, a novel nonpeptide angiotensin II-receptor antagonist. 938 43

Inhibition of the angiotensin-converting enzyme (ACE) in developing left ventricular (LV) hypertrophy has been demonstrated to have inhibitory effects on myocardial growth. An important mechanism of action of ACE inhibition is modulation of myocardial AT1 Ang II-receptor activity. However, whether and to what extent AT1 Ang II-receptor blockade may influence LV and myocyte function during the hypertrophic process remains unclear. Accordingly, our project examined the relation between changes in LV and myocyte function during the LV hypertrophic process that occurs after recovery from long-term rapid pacing. Dogs were randomly assigned to the following treatment groups: (a) Pace and Recovery, long-term rapid pacing (4 weeks; 216 +/- 2 beats/min) followed by a 4-week recovery period (n = 6); (b) Recovery/AT1 Block, concomitant AT1 Ang II-receptor blockade [irbesartan (SR 47436; BMS-186295) 30 mg/kg b.i.d.] administered during the 4-week recovery period (n = 5); and (c) Control, sham controls (n = 6). There was no difference in mean arterial pressure in any of the three groups. With pacing and recovery, LV end-diastolic volume and mass were increased by >50% from control values. The significant LV remodeling that occurred with recovery from long-term rapid pacing was associated with a decline in LV ejection fraction (59 +/- 3% vs. 68 +/- 4%) and myocyte velocity of shortening (43 +/- 3 microm/s vs. 63 +/- 3 microm/s) when compared with controls (p < 0.05). With recovery from long-term rapid pacing, LV myocyte length (176 +/- 6 microm vs. 150 +/- 1 microm) and cross-sectional area were increased (292 +/- 7 microm2 vs. 227 +/- 6 microm2) compared with controls (p < 0.05). With AT1 Ang II block during recovery from rapid pacing, LV end-diastolic volume was similar to untreated recovery values, but LV mass was normalized. LV ejection fraction was not different from control values with AT1 Ang II-receptor block. Steady-state myocyte velocity of shortening with AT1 Ang II block was similar to control values (55 +/- 5 microm/s), but percentage shortening remained reduced from control (3.55 +/- 0.37% vs. 4.71 +/- 0.12%, respectively, p < 0.05) and was similar to untreated recovery (3.59 +/- 0.23%). With AT1 Ang II block, myocyte length was similar to untreated recovery values, but cross-sectional area was reduced (260 +/- 5 microm2, p < 0.05). Thus AT1 Ang II-receptor blockade instituted in this model of developing LV hypertrophy, significantly reduced LV mass but did not reduce the degree of LV dilation. The cellular basis for these effects of AT1 Ang II-receptor blockade included persistent abnormalities in LV myocyte geometry. AT1 Ang II-receptor blockade improved certain indices of myocyte contractile function from untreated hypertrophy values. These findings suggest that in this pacing-recovery model, the development of LV hypertrophy and myocyte contractile dysfunction may be caused, at least in part, by AT1 Ang II-receptor activation.
J Cardiovasc Pharmacol 1997 Nov
PMID:Angiotensin II subtype-1 receptor blockade during the development of left ventricular hypertrophy in dogs: effects on ventricular and myocyte function. 938 45

Peptide metabolites of angiotensin I and II are active components of the renin-angiotensin system. One such peptide is angiotensin-(1-7), which has been shown to be present in various tissues and has properties distinct from those of angiotensin II. We examined the effects of angiotensin-(1-7) on endothelium-intact and denuded rat aorta. Second, we evaluated whether an interaction occurred between angiotensin-(1-7) and angiotensin peptides, as well as noradrenaline. Finally, we addressed whether the responses to angiotensin-(1-7) were mediated by an AT1 receptor. Angiotensin-(1-7) produced concentration-dependent relaxations of the rat aorta that were significantly greater in endothelium-intact preparations (81.1 +/- 18.9% and 29.6 +/- 2.9% for intact and denuded, respectively). Angiotensin-(1-7) inhibited responses generated to angiotensin I, II, III, and noradrenaline. In endothelium-denuded preparations, angiotensin-(1-7) produced a rightward shift of the concentration-effect curves to angiotensin II and noradrenaline. In addition, the inhibition against angiotensin I and II was significantly greater in endothelium-intact preparations [mean median inhibitory concentration (IC50) values for endothelium-intact preparations, 1.25 x 10(-9) M and 1.57 x 10(-9) M for angiotensin I and II, respectively; and for endothelium-denuded preparations, 1.77 x 10(-8) M and 1.17 x 10(-8) M for angiotensin I and II, respectively). Losartan did not affect relaxations in endothelium-intact preparations but caused a significant potentiation of the relaxation by angiotensin-(1-7) in denuded preparations. We conclude that angiotensin-(1-7) is a component of the renin-angiotensin system that acts to modulate the pressor effects of angiotensin II and noradrenaline.
J Cardiovasc Pharmacol 1997 Nov
PMID:Angiotensin-(1-7) and the rat aorta: modulation by the endothelium. 938 51

The effects of long-term angiotensin-converting enzyme (ACE) inhibition, angiotensin II (AT1)-receptor blockade, calcium-entry blockade, or cyclosporin A treatment on rat aortic wall structure were investigated to determine the role of the renin-angiotensin system in the physiologic regulation of vascular structure in vivo. Groups of 15 Wistar rats were treated for 6 weeks either with the ACE inhibitors lisinopril or fosinopril or with the AT1-antagonists D 8731 or losartan (each 10 mg/kg/day) or with the calcium antagonist isradipine, 60 mg/kg/day, or cyclosporin A, 15 mg/kg/day, or a combination of cyclosporin with one of the vasodilators. Media thickness, vascular smooth-muscle cell density, and intima thickening were measured in histologic sections of the abdominal aorta. In addition, aortic contractility and heart weight were determined. Long-term ACE inhibition, AT1-receptor blockade, and calcium-entry blockade reduced aortic media thickness and increased media smooth-muscle cell density. Only ACE inhibition significantly reduced the extent of intima lesions. Media thickness correlated well with the maximal aortic contraction to phenylephrine and serotonin but not to angiotensin II. ACE inhibition and AT1-receptor blockade decreased heart weight, whereas calcium antagonism increased it. Cyclosporin treatment was without effect on any of these parameters. The data demonstrate a significant long-term influence of the renin-angiotensin system on aortic wall structure and function in Wistar rats.
J Cardiovasc Pharmacol 1998 Jan
PMID:Regulation of aortic wall structure by the renin-angiotensin system in Wistar rats. 945 74

Arterial constriction by angiotensin II (Ang II) in the human forearm is inhibited by the infusion of the AT1-receptor antagonist losartan. We investigated venous constriction by Ang II in the forearm of 19 healthy subjects (23 +/- 1 years) and the inhibitory effects of losartan. Furthermore, we investigated, in both the arterial and venous systems, whether the constrictor effects of Ang II are calcium influx dependent by determining the influence of nicardipine. Arterial forearm blood flow (FBF) and maximal venous outflow (MVO) were measured by venous-occlusion plethysmography. Sodium nitroprusside (5-12.5 ng/kg/min) was infused to predilate the forearm vasculature. Ang II (0.1, 1, and 10 ng/kg/min) was infused before and during losartan (0.3 and 3 microg/kg/min) or nicardipine (0.05 and 0.15 microg/kg/min), respectively. Ang II decreased FBF (Emax-FBF) by 79 +/- 4% and MVO (Emax-MVO) by 28 +/- 3% (p < 0.05). Nicardipine at 0.05 and 0.15 microg/kg/min reduced Emax-FBF from -79 +/- 4% to -48 +/- 4% and -6 +/- 2%, respectively (p < 0.05). Losartan in both doses completely inhibited Emax-MVO (p < 0.05), whereas nicardipine did not influence the venoconstriction by Ang II (p > 0.05). In conclusion, Ang II causes a constriction of both arteries and veins in the human forearm, which may be inhibited by losartan. The arterial constriction appears to be caused by an AT1-receptor-mediated calcium influx via L-type calcium channels. In contrast, the venoconstrictor effect of Ang II proved insensitive to the calcium antagonist nicardipine.
J Cardiovasc Pharmacol 1998 Jan
PMID:Venoconstriction by angiotensin II in the human forearm is inhibited by losartan but not by nicardipine. 945 77

In 10 healthy normotensive volunteers on a normal sodium diet, we evaluated the renal effects of a single oral dose of 50 mg of irbesartan (SR 47436, BMS 186295), an angiotensin II AT1-receptor antagonist, in baseline conditions and during an exogenous angiotensin II infusion (2.5 ng/kg/min). We used a double-blind, placebo-controlled, crossover design. Hormones, blood pressure, renal hemodynamics, and urinary electrolytes were measured during each phase. To examine further the determinants of glomerular filtration at the microcirculation level, fractional clearance of neutral dextran was performed, and sieving curves were applied on a hydrodynamic model of ultrafiltration. Irbesartan administration was followed by an increase in active renin and plasma angiotensin II concentrations and renal plasma flow without change of systemic blood pressure, glomerular filtration rate, or plasma aldosterone concentration. Irbesartan did not affect either sieving curves or glomerular ultrafiltration determinants. Angiotensin II infusion at 2.5 ng/kg/min elicited a slight pressor response accompanied by a decrease in glomerular filtration rate and renal plasma flow and an enhancement of fractional dextran clearance over the radius range explored (3.4-5.4 nm). The transcapillary glomerular pressure gradient deltaP and the ultrafiltration coefficient kf were computed to increase by 9% and to decrease by 23%, respectively, without change in intrinsic membrane properties. Pretreatment with irbesartan prevented all these effects of angiotensin II.
J Cardiovasc Pharmacol 1998 Feb
PMID:Acute renal effects of AT1-receptor blockade after exogenous angiotensin II infusion in healthy subjects. 947 75

There is no agreement on the effect of angiotensin II receptor blockade in the setting of ischemic reperfusion. Our aim was to assess the acute effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II AT1-subtype receptor blockade in pig heart. Five groups of open-chest pigs received 1 hour of left anterior descending (LAD) coronary artery occlusion and 2 hours of reperfusion. Left ventricular pressure was monitored by an intraventricular catheter, and regional segment shortening (%SS) in the LAD-supplied territory was measured by ultrasonic crystals implanted in the subendocardium. Group 1 (n = 6) served as the control; groups 2 (n = 6) and 3 (n = 6) received the angiotensin II receptor blocker, EXP 3174 (C22H21Cl1N6O2), and the ACE inhibitor, enalaprilat, respectively, prior to LAD occlusion; group 4 (n = 6) was preconditioned with two cycles of 10 minutes of coronary occlusion and 30 minutes of reperfusion; and group 5 (n = 6) underwent preconditioning with additional administration of EXP 3174 prior to the 60-minute occlusion period. Infarct sizes were measured by p-nitrobluetetrazolium staining and were expressed in percent of the ischemic area of risk. The angiotensin II receptor blocker EXP 3174 and enalaprilat reduced infarct sizes significantly (35.3 +/- 17.1% and 40.1 +/- 15.1%, respectively) compared with controls (71.2 +/- 12.8%, P < 0.05), and EXP 3174 augmented the infarct size-limiting effects of preconditioning by ischemia (10.5 +/- 6% vs. 28.6 +/- 5.3%, P < 0.05). Regional contractile dysfunction during reperfusion demonstrated no changes after angiotensin II receptor blockade. Angiotensin II receptor blockade reduced infarct size comparable with that obtained with angiotensin converting-enzyme inhibition. The infarct size-limiting effects of ischemic preconditioning were augmented by administration of the angiotensin II receptor antagonist EXP 3174. These data support the concept that blockade or inhibition of angiotensin II before coronary occlusion is protective in a swine model of acute ischemia and reperfusion.
Cardiovasc Drugs Ther 1997 Nov
PMID:Angiotensin II receptor antagonist EXP 3174 reduces infarct size comparable with enalaprilat and augments preconditioning in the pig heart. 949 8

Low-voltage-activated T-type Ca2+ channels are present in most excitable tissues including the heart (mainly pacemaker cells), smooth muscle, central and peripheral nervous systems, and endocrine tissues, but also in non-excitable cells, such as osteoblasts, fibroblasts, glial cells, etc. Although they comprise a slightly heterogeneous population, these channels share many defining characteristics: small conductance (< 10 pS), similar Ca2+ and Ba2+ permeabilities, slow deactivation, and a voltage-dependent inactivation rate. In addition, activation at low voltages, rapid inactivation, and blockade by Ni2+ are classical properties of T-type Ca2+ channels, which are less specific. T-type Ca2+ channels are weakly blocked by standard Ca2+ antagonists. Pharmacological blockers are scarce and often lack specificity and/or potency. The physiological modulation of T-type Ca2+ currents is complex: they are enhanced by endothelin-1, angiotensin II (AT1-receptor), ATP, and isoproterenol (cAMP-independent), but are reduced by angiotensin II (AT2-receptor), somatostatin and atrial natriuretic peptide. Norepinephrine enhances these currents in some cells but decreases them in others. T-type Ca2+ currents have many known or suggested physiological and pathophysiological roles in growth (protein synthesis, cell differentiation, and proliferation), neuronal firing regulation, some aspects of genetic hypertension, cardiac hypertrophy, cardiac fibrosis, cardiac rhythm (normal and abnormal), and atherosclerosis. Mibefradil is a new Ca2+ antagonist that is effective in hypertension and angina pectoris. Its favorable pharmacological profile and limited side effects appear to be related to selective block of T-type Ca2+ channels: mibefradil reduces vascular resistance and heart rate without negative inotropy or neurohormonal stimulation, and it also has significant antiproliferative actions.
Cardiovasc Drugs Ther 1997 Dec
PMID:T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. 951 67

This study assessed the role of angiotensin (Ang) AT1 and AT2 receptors as modulators of the plasma clearance of Ang II. Groups of male spontaneously hypertensive rats (SHRs; n = 25) were given an intravenous injection of either saline, losartan, PD123319, losartan in combination with PD123319, or Sar1-Thr8-Ang II. One hour later, Ang II (0.5 microg/kg) was infused for 15 min into a vein. Immediately thereafter, arterial blood samples were collected at regular intervals for the assay of plasma Ang II levels by radioimmunoassay. The infusion of Ang II significantly increased baseline mean arterial pressure (MAP) in rats pretreated with either saline or PD123319 but not in those receiving losartan, losartan combined with PD123319, or Sar1-Thr8-Ang II. The plasma clearance of Ang II was significantly greater in rats injected with either PD123319, losartan combined with PD123319, or Sar1-Thr8-Ang II compared to those injected either saline or losartan. Furthermore, the half-life of Ang II in rats pretreated with saline or losartan was significantly greater than that measured in the other three groups. These results suggest that plasma clearance of Ang II in the SHRs is independent of an AT1 receptor, but plasma levels of the peptide are unexpectedly protected by an AT2 receptor-dependent mechanism.
J Cardiovasc Pharmacol 1998 Mar
PMID:Role of AT1 and AT2 receptors in the plasma clearance of angiotensin II. 951 93

It has been postulated that exaggerated renal sensitivity to angiotensin II may be involved in the development and maintenance of hypertension in the spontaneously hypertensive rat (SHR). The purpose of this study was to compare the renal vascular responses to short-term angiotensin II infusions (50 ng/kg/min, i.v.) in conscious SHRs and Wistar-Kyoto (WKY) rats. Renal cortical blood flow was measured in conscious rats by using quantitative renal perfusion imaging by magnetic resonance, and blood pressure was measured by an indwelling carotid catheter attached to a digital blood pressure analyzer. Renal vascular responses to angiotensin II were similar in control SHRs and WKY rats. Pretreatment with captopril to block endogenous production of angiotensin II significantly augmented the renal vascular response to exogenous angiotensin II in the SHRs but not in the WKY rats. The renal vascular responses to angiotensin II were significantly greater in captopril-pretreated SHRs than in WKY rats (cortical blood flow decreased by 1.66 +/- 0.13 ml/min/g cortex in WKY rats compared with 2.15 +/- 0.14 ml/min/g cortex in SHR; cortical vascular resistance increased by 10.5 +/- 1.4 mm Hg/ml/min/g cortex in WKY rats compared with 15.6 +/- 1.7 mm Hg/ml/min/g cortex in SHRs). Responses to angiotensin II were completely blocked in both strains by pretreatment with the angiotensin II AT1-receptor antagonist losartan. Results from this study in conscious rats confirm previous findings in anesthetized rats that (a) the short-term pressor and renal vascular responses to angiotensin II are mediated by the AT1 receptor in both SHRs and WKY rats, and (b) the renal vascular responses to angiotensin II are enhanced in SHRs compared with WKY rats when endogenous production of angiotensin II is inhibited by captopril pretreatment.
J Cardiovasc Pharmacol 1998 Jun
PMID:Renal vascular responses to angiotensin II in conscious spontaneously hypertensive and normotensive rats. 964 69


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