Inhibition of the acute effects of angiotensin II by the receptor antagonist irbesartan in normotensive men.

Irbesartan (SR 47436, BMS 186295) is an imidazole derivative that specifically binds to the angiotensin type 1 receptor. The purpose of this study was to assess the inhibitory effect of irbesartan on the pressor action of exogenous angiotensin II in healthy subjects, to evaluate the dose dependency and duration of this inhibition, and to determine the effect of irbesartan on plasma components of the renin-angiotensin system. Forty-two healthy male volunteers maintained on ad libitum sodium intake were enrolled in a randomized, double-blind, placebo-controlled, parallel-design, dose-ranging study. On 2 study days 1 week apart, volunteers were given either a placebo or the active drug at one of the chosen doses (5, 25, 50, 75, 100, 150, or 300 mg). The pressor effects of an individually titrated test dose of exogenous angiotensin II as well as plasma levels of angiotensin II, active renin, aldosterone, and treatment drug were determined before and throughout the 24 h after drug administration. The inhibitory effect of irbesartan on the pressor response to angiotensin II was observed within 1 h after dosing, peaked between 2 and 4 h, and lasted more than 24 h for doses of 25 mg and more. The effect was clearly dose related. Two and 24 h after administration of irbesartan, 300 mg, the response of arterial blood pressure (systolic and diastolic) to a given dose of angiotensin II was reduced by approximately 100% and 60%, respectively. Plasma concentrations of angiotensin II and active renin increased markedly after irbesartan administration, whereas plasma concentrations of aldosterone decreased. No evidence was found that the high levels of circulating angiotensin II observed after irbesartan administration could override the inhibitory effect of irbesartan on any of the measured parameters up to 24 h after dose. In conclusion, irbesartan appears to be a well-tolerated, orally active, potent antagonist of the renin-angiotensin system in men.

Blockade of angiotensin II type 1 receptors: effect on carotid and radial artery structure and function in hypertensive humans.

Converting-enzyme inhibition reduces cardiovascular hypertrophy in hypertensive subjects. Whether the blockade of angiotensin II type 1 (AT(1)) receptors reduces arterial hypertrophy has never been investigated. In a double-blind study versus placebo in subjects with essential hypertension, the effect of the AT(1) blocker irbesartan (150 mg/day for 8 weeks) on blood pressure, wall thickness, diameter and stiffness of the common carotid and radial arteries was studied, using echotracking techniques of high resolution. With irbesartan, mean blood pressure decreased significantly and proportionally to the baseline levels of active renin, and angiotensin I and II. There was a significant decrease in radial artery wall thickness. The percent change from baseline (+/- SEM) was -10.51 +/- 3.42 versus 6.18 +/- 4.77. There was no significant change in diameter or distensibility. This effect was correlated neither to blood pressure changes nor to hormonal baseline levels of the renin-angiotensin system. Carotid wall thickness and diameter were unchanged. Thus a 2-month treatment with an AT(1) antagonist significantly reduced radial but not carotid artery wall thickness. Blood pressure reduction could be explained on the basis of circulating renin-angiotensin activity. On the contrary, radial artery wall thickness reduction was independent of the baseline circulating renin-angiotensin activity and was not correlated with the effects of AT(1) blockade on blood pressure, thus implying the involvement of local hemodynamic and/or cellular mechanisms.

Clopidogrel antiplatelet activity is independent of age and presence of atherosclerosis.

The pharmacodynamic and pharmacokinetic effects of clopidogrel 75 mg taken once daily in the morning before breakfast for 10 days were compared among three groups: 12 healthy young subjects, 10 healthy elderly subjects (>65 years) and 10 otherwise healthy elderly subjects with atherosclerosis, manifested by intermittent claudication. Platelet aggregation induced by 5 microM of ADP was measured in plasma samples taken at screening, 2 hours after dosing on day 1 to day 9; 2, 5, and 24 hours after dosing on day 10; and on alternate days until day 24. The inhibition of platelet aggregation was expressed as the percent reduction in maximum platelet aggregation with respect to baseline. The bleeding time was measured at screening, 5 hours after dosing on day 10, and on day 18. Plasma concentrations of SR26334, the main circulating metabolite of clopidogrel, were determined before dosing on day 1 to day 10 and at regular intervals over 72 hours after dosing on day 10. Inhibition of platelet aggregation appeared 2 hours after the first dose, became significant after the second dose, and progressed to a steady-state value of 55 to 57% by day 7 in the three groups, with no statistically significant difference between groups. A moderate, statistically significant prolongation of bleeding time of similar extent (prolongation factor of 1.5 to 1.6) was found on day 10 in the three groups. The pharmacodynamic parameters generally returned to baseline within 8 days after treatment. Based on AUC(0-24th) values, drug exposures were very similar for the two groups of elderly subjects but approximately twice that for the young group. The pharmacodynamic effects of clopidogrel were comparable in all three groups.

Renal response to the angiotensin II receptor subtype 1 antagonist irbesartan versus enalapril in hypertensive patients.

OBJECTIVE: To compare the acute and sustained renal hemodynamic effects on hypertensive patients of 100 mg irbesartan and 20 mg enalapril each once daily. PATIENTS: Twenty patients (aged 35-70 years) with uncomplicated, mild-to-moderate essential hypertension and normal serum creatinine levels completed this study. STUDY DESIGN: After random allocation to treatment (n=10 per group), administration schedule (morning or evening) was determined by further random allocation, with crossover of schedules after 6 weeks' therapy. Treatment and administration assignments were double-blind. Twenty-four-hour ambulatory blood pressure was monitored before and after 6 and 12 weeks of therapy. Renal hemodynamics were determined on the first day of drug administration and 12 and 24 h after the last dose during chronic treatment. RESULTS: Administration of each antihypertensive agent induced a renal vasodilatation with no significant change in glomerular filtration rate. However, the time course appeared to differ: irbesartan had no significant acute effect 4 h after the first dose, but during chronic administration a renal vasodilatory response was found 12 and 24 h after the dose; enalapril was effective acutely and 12 h after administration, but no residual effect was found 24 h after the dose. Both antihypertensive agents lowered mean ambulatory blood pressure effectively, with no significant difference between treatments or between administration schedules (morning versus evening). CONCLUSIONS: Irbesartan and enalapril have comparable effects on blood pressure and renal hemodynamics in hypertensive patients with normal renal functioning. However, the time profiles of the renal effects appear to differ, which might be important for long-term renoprotective effects.

Acute renal effects of AT1-receptor blockade after exogenous angiotensin II infusion in healthy subjects.

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.

Hemodynamic and biochemical effects of the AT1 receptor antagonist irbesartan in hypertension.

We studied the hemodynamic, neurohumoral, and biochemical effects of the novel angiotensin type 1 (AT1) receptor antagonist irbesartan in 86 untreated patients with essential hypertension on a normal sodium diet. According to a double-blind parallel group trial, patients were randomized to a once-daily oral dose of the AT1 receptor antagonist (1, 25, or 100 mg) or placebo after a placebo run-in period of 3 weeks. Randomization medication was given for 1 week. Compared with placebo, 24-hour ambulatory blood pressure did not change with the 1-mg dose, and it fell (mean and 95% confidence interval) by 7.0 (4.2-9.8)/6.1 (3.9-8.1) mm Hg with the 25-mg dose and by 12.1 (8.1-16.2)/7.2 (4.9-9.4) mm Hg with the 100-mg dose. Heart rate did not change during either dose. With the 25-mg dose, the antihypertensive effect was attenuated during the second half of the recording, and with the 100-mg dose, it was maintained for 24 hours. Baseline values of renin and the antihypertensive response to the 25- and 100-mg doses were well correlated (r = .68, P < .01). Renin did not change with the 1-mg dose, but it rose threefold to fourfold with the 25-mg dose and fourfold to fivefold with the 100-mg dose 4 to 6 hours after administration. With the 100-mg dose, renin was still elevated twofold 24 hours after dosing. The changes in renin induced by the AT1 receptor antagonist were associated with parallel increments in angiotensin I and angiotensin II. Aldosterone, despite AT1 receptor blockade, did not fall.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of a new calcium antagonist, SR 33557, in patients with coronary artery disease and normal left ventricular function.

SR 33557 is a new calcium antagonist which in vitro demonstrated selectivity for smooth muscle over cardiac muscle. To assess the hemodynamic effects of SR 33557 in humans, SR 33557 was administered intravenously (i.v.) in 9 patients with normal systolic left ventricular function [LV ejection fraction (EF) = 63.7 +/- 8%] undergoing right and left catheterization. Baseline measurements were recorded before and during right atrial pacing (100 beats/min), after which 5 mg SR 33557 was infused in 10 min and hemodynamic parameters were continuously recorded until 30 min after discontinuation of the infusion. Effects of SR 33557 were evident from discontinuation of the infusion, maximal between the tenth and twentieth min after discontinuation of the infusion. Without atrial pacing, the main effect of SR 33557 infusion was to decrease heart rate (HR) from 77.7 +/- 10.7 to 61.9 +/- 9.3 beats/min (p < 0.001). Cardiac index (CI) did not change; stroke volume index (SVI) increased from 44.2 +/- 13 to 50.4 +/- 15 ml.m-2, (p < 0.05). Mean arterial pressure (MAP) decreased from 104.7 +/- 29.6 to 94.3 +/- 22.9 mm Hg (p < 0.05) with no change in filling pressures or systemic vascular resistance (SVR). Consequently, rate-pressure product (RPP) decreased from 8,211 +/- 3,092 to 5,906 +/- 2,025 mm Hg.beat-1 (p < 0.01). Peak positive LVdP/dt decreased from 1,711 +/- 257 to 1,533 +/- 194 (p < 0.01). During the pacing phase, none of the hemodynamic parameters differed from baseline; especially peak positive LVdP/dt remained unchanged. SR 33557 has negative chronotropic action but shows no direct negative inotropic effect in patients with normal systolic LV function.

Acute effects of a pseudo-tetrapeptide as renin inhibitor on blood pressure and renin-angiotensin system of sodium-repleted and sodium-depleted hypertensive patients.

The blood pressure and renin-angiotensin system effects of the new renin inhibitor, SR 43845 ([N-(pyridyl-3-propionyl)-phenylalanyl- histidyl-(3S,4S) ACHPA-isoleucylamino]-2-methyl-2-dihydroxy-1,3-propane), were studied in 12 hypertensive patients on a normal sodium intake who received a 30-min infusion of intravenous SR 43845 at one of 3 doses: 30, 100 or 300 micrograms/kg (4 patients per group). Eight further patients were infused with the 300 micrograms/kg dose 24 h after 80 mg furosemide orally. In sodium-repleted patients, the 30, 100 and 300 micrograms/kg doses induced a rapid fall in diastolic blood pressure (DBP) which culminated at 4.5, 7.5 and 3.9 mmHg, respectively. Salt depletion increased the renin inhibitor-induced fall in DBP to 10.8 mmHg. DBP was back to baseline at 60 min after starting the lowest dose and 180 min after starting the highest dose. Heart rate did not change. In four of the sodium-depleted patients, 50 mg captopril was given orally at T = 180 min, when blood pressure had returned to baseline. The decrease in BP (8.8 mmHg) was similar to that initially obtained with the renin inhibitor (10.1 mmHg). Plasma angiotensin (Ang) I was dose-dependently reduced by 62, 93 and 92% of baseline values 10 min after the start of the infusion in sodium-repleted patients, and by 90% in sodium-depleted patients; it returned to baseline in both situations between 180 and 360 min. Plasma Ang II levels changed in parallel with those of plasma Ang I.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of calcium antagonists on adrenaline-induced hypokalaemia.

Long term treatment with nifedipine and nitrendipine, but not verapamil and diltiazem, may reduce plasma potassium levels in hypertensive patients. To test the hypothesis that this effect is related to adrenaline-mediated influx of potassium from the extracellular space, the effect of adrenaline infusions (12.5, 25 and 50 ng/kg/min) on plasma potassium levels was assessed in normotensive subjects after administration of placebo for 4 days, and after administration of nitrendipine, verapamil or diltiazem for 4 days. The adrenaline-induced decrease in plasma potassium levels was enhanced in subjects receiving nitrendipine, but was unaffected in those subjects receiving verapamil or diltiazem. The effects of adrenaline on blood glucose levels, heart rate and blood pressure were uninfluenced in subjects receiving nitrendipine or verapamil, and were blunted in subjects receiving diltiazem. These results suggest that enhancement of the adrenaline-induced intracellular transfer of potassium from the extracellular space is relatively specific to dihydropyridine calcium antagonists.