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 investigated the selectivity of losartan as an angiotensin II (ANG II) antagonist in contractile experiments using segments of small mesenteric arteries and rings of aorta from rat. The concentration-effect curve of ANG II was not different in mesenteric arteries with an without endothelium. In both resistance and conductance vessels, it was shifted toward larger concentrations by losartan (3 nM) with similar apparent inhibition constant (KB) values: 4.1 +/- 1.8 nM (n = 6) in small mesenteric arteries and 1.9 nM (n = 6) in aorta. These values agree with the known affinity of losartan for AT1 receptors. At 1 microM, the AT2-selective ligand CGP 42112A had no effect on contractile responses induced by norepinephrine (NE), serotonin, or neuropeptide Y (NPY). However, it inhibited vasoconstriction elicited by prostaglandin F2 alpha (PGF2 alpha). This latter effect was also noted in the aorta. Similarly, losartan also competitively antagonized aortic contractile responses elicited by U 46619, a thromboxane A2 analogue (TXA2), with a pA2 value of 5.7. Two losartan analogues, DuP 532 and EXP 3174 (a metabolite of losartan), < or = 30 microM, did not antagonize U 46619, showing structural requirements for this antagonistic action of losartan. We conclude that in both rat resistance and conductance vessels, ANG II induces vasoconstriction through activation of AT1 receptors which are selectively blocked by losartan at nanomolar concentrations and that at micromolar concentrations, losartan may also block the vascular TXA2/PGF2 alpha (TP) receptor.
J Cardiovasc Pharmacol 1995 Nov
PMID:Effects of losartan on contractile responses of conductance and resistance arteries from rats. 863 81

Seven hundred ten high speed rotational atherectomy (HSRA) procedures were performed in a single consecutive series of 656 patients. Stand alone HSRA was performed in 253 patients (35%). HSRA with adjunctive low pressure (< or = 2 ATM) balloon angioplasty (LP BA) was performed in 221 patients (31%), and HSRA with adjunctive high pressure (> or = 4 ATM) balloon angioplasty (HP BA) was performed in 236 patients (34%). Prognostically unfavorable Type B2 and C lesions dominated the study group (74.7%). Procedural success rate was 96%. Emergency coronary artery bypass surgery was performed in 1.4% of cases, Q wave myocardial infarction occurred in 3.4% and death, related to procedure, was consequent in 0.5% of cases. Incidence of flow limiting dissections was 3.1%, distal spasm was 5.3%, and "no reflow" phenomenon was 1.8%. The recent technique modifications included continuous advancer/guiding catheter infusion of the nitroglycerin-verapamil mixture, limitation of duration of lesion engagement by the burr, stepwise increase in the burr size, decrease of rotational speed, and strict control of rpm drop during lesion ablation. Evolution of the interventional technique involved trends towards decrease of the use of HP BA in conjunction with steady increase in the percentage of SA and LP BA procedures over time. These technique changes resulted in complete absence of "no reflow" in 1994, as well as a generalized decrease in overall coronary vascular reactivity from all burr passes.
Cathet Cardiovasc Diagn 1995 Dec
PMID:Effects of technique modification on immediate results of high speed rotational atherectomy in 710 procedures on 656 patients. 871 79

To assess the role of angiotensin II (AII) in the development of myocardial dysfunction during ischemia and reperfusion, the effects of either oral pretreatment with 1 mg/kg losartan or treatment with 4.5 mu M losartan in vitro were compared with effects measured in the respective placebo or in vitro control groups in an isolated rat working-heart model. Both groups treated with losartan showed significant improvement (p < 0.005) in functional recovery following 20 min of ischemia compared with the respective control groups. Coronary flow (CF) and cardiac output (CO) were also significantly increased during reperfusion in the drug treatment groups compared with controls (p < 0.05 to p < 0.001). The recovery of mechanical function, CO, and CF was significantly more rapid in hearts from rats treated orally with losartan than in hearts treated with losartan in vitro. As measured by 31P-nuclear magnetic resonance, the changes observed in ATP levels and in intracellular pH during ischemia and reperfusion were essentially the same under either treatment regimen. This article describes the initial observation of a significant reduction in myocardial dysfunction during reperfusion following 20 min of global ischemia in the isolated perfused heart as a result of acute AII AT1 receptor antagonism by losartan administered either directly in vitro or by oral pretreatment.
J Cardiovasc Pharmacol 1996 Feb
PMID:Use of losartan to examine the role of the cardiac renin-angiotensin system in myocardial dysfunction during ischemia and reperfusion. 872 Apr 14

We characterised the blood pressure (BP) and hormonal responses to the oral angiotensin II (Ang II) receptor antagonist irbesartan (SR47436/BMS-186295) or placebo in normal men with an activated renin-angiotensin system (RAS) during salt depletion. We also evaluated safety and tolerability. Twelve healthy, normotensive male volunteers followed a standardised salt-depletion regimen for 3 days before each study day. Six different single oral doses of irbesartan (1, 5, 10, 25, 50, and 100 mg) were administered double-blind in a three-panel, dose escalation with placebo randomised in each panel. Supine and erect BP and heart rate (HR), serum and urinary electrolytes: plasma renin activity (PRA), and Ang II were measured at intervals. Urinary electrolytes were measured for the 24-h period before dosing (to confirm salt depletion) and for 24 h afterward. No drug-related side effects were noted. There was a dose-related decrease in supine and erect systolic and diastolic BP (SBP, DBP) with irbesartan from 10 mg and beyond, with no change in HR. Supine mean arterial pressure (MAP) decreased by 18.8 mm Hg. There was a dose-related reactive increase in PRA (to 35 ng/ml/h) and Ang II (to 450 pg/ml) with irbesartan. Irbesartan is an orally active AT1 receptor antagonist. In salt-deplete normal men, it has a dose-related haemodynamic, hormonal, and electrolyte profile characteristic of AT1 antagonists. The dose range studied did not show a plateau or maximum effect.
J Cardiovasc Pharmacol 1996 Jul
PMID:Dose-ranging study of the angiotensin II receptor antagonist irbesartan (SR 47436/BMS-186295) on blood pressure and neurohormonal effects in salt-deplete men. 879 43

We compared the consequences of chronic angiotensin-converting enzyme (ACE) inhibition with quinapril and of specific AT1 blockade with losartan in a renin-dependent model of hypertension, the (mRen2)27 transgenic rats (TG). Animals were orally treated with 10 mg/kg/24 h of either quinapril (TGQ, n = 13) or losartan (TGL, n = 12) from age 4 to age 9 weeks. Indirect systolic blood pressure (SBP), and sodium and water balances were measured for 3 consecutive weeks. Nine-week-old rats were instrumented to record aortic BP in the conscious state. In addition, they received an infusion of glucose and saline to increase their diuresis and thus allow accurate assessment of their renal excretion during short time periods. These rats were studied for three one-h periods: (a) baseline, (b) after the administration of a bradykinin (BK) antagonist, and (c) after a cross-treatment; i.e., TGQ rats receiving losartan (10 mg/kg intravenously, i.v.) and TGL rats receiving quinapril (10 mg/kg i.v.). TGL rats differed from TGQ rats by an unconsistently lower indirect SBP associated with significantly lower urinary volume and sodium excretion, whereas the sodium balance did not differ between the two groups. In conditions of fixed sodium intake the aortic BP of TGQ rats was still nonsignificantly different from that of TGL rats, and TGQ rats also exhibited two-fold higher natriuresis. The BK antagonist had no effect in either group, whereas losartan decreased the BP of TGQ rats. We conclude that in TG rats ACE inhibition is associated with an increased natriuresis as compared with specific AT1 blockade, an effect that is independent of the sodium intake. Because a BK antagonist had no effect, such a difference might be due to an antinatriuretic effect of AT2 receptors in chronic conditions.
J Cardiovasc Pharmacol 1996 Apr
PMID:Comparison between chronic converting enzyme inhibition and AT1 blockade in mRen2 transgenic rats. 884 62

The renin-angiotensin system is a major contributor to the pathophysiology of cardiovascular diseases such as congestive heart failure and hypertension. Antagonizing angiotensin (Ang) II at the receptor site may produce fewer side effects than inhibition of the promiscuous converting enzyme. The present study was designed to assess in healthy human subjects the effect of LRB081, a new orally active AT1-receptor antagonist, on the pressor action of exogenous Ang II. At the same time, plasma hormones and drug levels were monitored. At 1-week intervals and in a double-blind randomized fashion, 8 male volunteers received three doses of LRB081 (10, 40, and 80 mg) and placebo. Blood pressure (BP) was measured at a finger by photoplethysmograph. The peak BP response to intravenous injection of a standard dose of Ang II was determined before and for < or = 24 h after administration of an oral dose of LRB081 or placebo. After drug administration, the blood BP response to Ang II was expressed in percent of the response before drug administration. At the same time, plasma renin activity (PRA), Ang II, aldosterone, catecholamine (radioassays), and drug levels (by high-performance liquid chromatography) were monitored. After LRB081 administration, a dose dependent inhibition of the BP response to Ang II was observed. Maximal inhibition of the systolic BP response was 54 +/- 3 (mean +/- SEM), 63 +/- 2, and 93 +/- 1% with 10, 40, and 80 mg LRB081, respectively. The time to peak was 3 h for 6 subjects and 4 and 6 h for 2 others. Preliminary plasma half-life (t1/2) was calculated at 2 h. With the highest dose, the inhibition remained significant for 24 h (31 +/- 5%, p < 0.05). Maximal BP-blocking effect and maximal plasma drug level coincided, suggesting that the unmetabolized LRB081 is responsible for the antagonistic effect. PRA and Ang II increased dose dependently after LRB081 intake. Aldosterone, epinephrine, and norepinephrine concentrations remained unchanged. No clinically significant adverse reaction was observed during the study. LRB081 is a well-tolerated, orally active, potent, and long-acting Ang II receptor antagonist. Unlike in the case of losartan, no active metabolite of LRB081 has been shown to be responsible for the main effects.
J Cardiovasc Pharmacol 1996 Aug
PMID:Clinical and hormonal effects of the new angiotensin II receptor antagonist LRB081. 885 81

We examined the renal hemodynamic modifications induced by a selective angiotensin II (AII) AT1 receptor antagonist, losartan, in 10 patients with essential hypertension. In this single-blind study, renal hemodynamic parameters were determined twice (patients were their own controls) first after a 15-day single-blind placebo run-in period and again after a 1-month losartan period. The dosage of losartan was 50 mg/day. Glomerular filtration rate (GFR, inulin clearance), renal plasma flow [RPF; para-aminohippurate (PAH) clearance], microalbuminuria, sodium excretion, proximal sodium tubular reabsorption (lithium clearance), and acid uric metabolism were measured. After 1-month losartan treatment, systolic and diastolic BP (SBP, DBP) decreased significantly throughout the 210-min recording whereas heart rate (HR) was unchanged. GFR (100 +/- 19 vs. 96 +/- 17 ml/min/1.73 m2) and RPF (471 +/- 118 vs. 468 +/- 108 ml/ min/1.73 m2) were not altered by losartan. Rather than occurrence of any modification in filtration fraction (FF), a significant decrease in microalbuminuria was evident (57 +/- 77 vs. 40 +/- 59 mg/24 h, p < 0.05). Urinary sodium excretion was not modified, but an almost significant (p = 0.07) decrease in proximal sodium reabsorption was observed (72.9 +/- 7.7 vs. 68.1 +/- 6.4% of filtered sodium). The increase in renal uric clearance accounted for the significant decrease in serum uric acid (195 +/- 49 vs. 183 +/- 43 microM; p < 0.05). After 1-month losartan treatment, renal function was well preserved; the decrease in uric acid may be of clinical interest when adjuvent diuretic therapy is required.
J Cardiovasc Pharmacol 1996 Aug
PMID:Effects of losartan on renal function in patients with essential hypertension. 885 82

Imidazoline/guanidinium receptive sites (IGRS) are shown to be present in the subfornical organ and hypothalamic arcuate nucleus by a derivative of cirazoline, 2-(3-amino-4-[125I]iodophenoxy)methylimidazoline ([125I]AMIPI). Because many of the nonpeptide angiotensin II (Ang II) receptor antagonists contain imidazole ring structures, they may interact with IGRS. Therefore, we studied competitive activity of Ang II and several nonpeptide Ang II receptor antagonists [DuP 753 (losartan), EXP 3174, CV11974, and PD123319] at IGRS in rat forebrain. The results showed specific binding of 944 +/- 169 fmol/mg protein in the subfornical organ (n = 11) and of 367 +/- 27 fmol/mg protein in the arcuate nucleus (n = 6) at 0.4 nM [125I]AMIPI, as defined by competition with 10 microM cirazoline. Specific [125I]AMIPI binding was competed for completely by 10 microM idazoxan or clonidine as further characterization of IGRS. Ang II and the nonpeptide AT1 and AT2 antagonists did not significantly compete for specific [125I]AMIPI binding in either brain region at concentrations of 10 microM (< 20% competition with each compound), which is 10- to 100-fold higher than the concentration necessary to compete completely for their respective Ang II receptor subtypes. Only at the highest concentration (100 microM) did losartan compete significantly for binding (56 +/- 8%). Therefore, Ang II receptor antagonists interact with IGRS in rat forebrain cardiovascular areas only at high concentrations.
J Cardiovasc Pharmacol 1996 Sep
PMID:Interactions of nonpeptide angiotensin II receptor antagonists at imidazoline/guanidinium receptor sites in rat forebrain. 887 90

The unilateral microinjection of the cholinergic agonist carbachol (CCh) directly into the posterior hypothalamic nucleus (PHN) of conscious rats evokes a dose-dependent increase in mean arterial pressure (MAP). Blockade of peripheral alpha-adrenoceptors and V1-vasopressin receptors completely inhibits this response, suggesting that the increase in MAP is mediated by increases in sympathoadrenal excitation and circulating vasopressin. Combining beta-adrenoceptor blockade with alpha-adrenoceptor and V1-vasopressin receptor blockade results in the return of a pressor response. To determine if neuropeptide Y (NPY) might be responsible for this increase, the putative NPY and irreversible alpha 1-adrenoceptor antagonist benextramine was added to alpha 2- and beta-adrenoceptor and V1-vasopressin receptor blockade provided by yohimbine, propranolol, and [D(CH2)5-Tyr(Me)]AVP (AVPX), respectively. Benextramine noncompetitively inhibited the pressor response to intravenous injection of NPY and the increase in MAP evoked by CCh microinjection into adrenergic and V1-vasopressin receptor-blocked rats, whereas benextramine competitively inhibited the pressor response to angiotensin II (AII). Furthermore, the combination of losartan, the selective AT1-AII receptor antagonist that completely blocked the increase in MAP evoked by intravenous AII, and adrenergic and V1-vasopressin receptor antagonists did not attenuate the pressor response evoked by CCh microinjection into the PHN or the increase in MAP evoked by intravenous injection of NPY. These results indicate that AII was not responsible for the CCh-evoked increase in MAP in the presence of adrenergic and V1-vasopressin receptor blockade. The similarity in the antagonism of the increase in MAP evoked by intravenous NPY injection and by CCh microinjection into the PHN of adrenergic- and V1-vasopressin receptor-blocked rats suggests that NPY might be released from sympathetic neurons after activation of the sympathetic nervous system by central administration of CCh into the PHN.
J Cardiovasc Pharmacol 1996 Sep
PMID:Evidence of systemic neuropeptide Y release after carbachol administration into the posterior hypothalamic nucleus. 887 93

KT3-671, a nonpeptide AT1 receptor antagonist, was administered to 20-week-old stroke-prone spontaneously hypertensive rats (SHRSP) daily for 3 weeks. Its effects on systolic, mean, and diastolic arterial blood pressure (SAP, MAP, DAP), heart rate and locomotor activity were investigated with radiotelemetry. A clear diurnal variation in blood pressure, heart rate, and locomotor activity was observed in synchrony with the light cycle. KT3-671 at a daily dose of 10 mg/kg orally (p.o), produced a significant and consistent reduction in blood pressure, preventing the development of hypertension. KT3-671 reduced SAP more than DAP, suggesting that it may affect both vascular tone and cardiac output. Although KT3-671 did not affect diurnal rhythms in heart rate and locomotor activity, it did cause a slight but significant reduction in heart rate. The MAP determined 23 h after the administration of KT3-671 showed a significant reduction from the day 2 of therapy to the day 3 after discontinuation of therapy, suggesting a long duration of antihypertensive action. There was no rebound increase in blood pressure after discontinuation of KT3-671 therapy. These results suggest that KT3-671 may be potentially useful in the therapy of hypertension.
J Cardiovasc Pharmacol 1996 Mar
PMID:Effect of repeated administration of KT3-671, a nonpeptide AT1 receptor antagonist, on diurnal variation in blood pressure, heart rate, and locomotor activity in stroke-prone spontaneously hypertensive rats as determined by radiotelemetry. 890 3


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