The effect of valsartan on the angiotensin II pressor response in healthy normotensive male subjects.

OBJECTIVE: Valsartan is an oral antagonist of angiotensin II that competes with angiotensin II for the AT1-receptor and is being developed as an antihypertensive agent. This study assessed the ability of 80 mg valsartan to inhibit the pressor effect of exogenous angiotensin II in healthy normotensive men, first after a single dose and then after multiple doses once daily for 7 days. METHODS: This was a single-center, double-blind, placebo-controlled, randomized crossover study. Six healthy men underwent angiotensin II challenges to determine a suitable dose required to increase their systolic blood pressure by approximately 30 mm Hg. Each subject then received an 80 mg dose of valsartan or matching placebo. The inhibition of the angiotensin II pressor effect was determined by the systolic blood pressure response to repeated angiotensin II challenges at multiple time points. RESULTS: Systolic blood pressure responses to angiotensin II challenges after single and multiple doses of valsartan were significantly lower than placebo, indicating that valsartan blocked the blood pressure response to angiotensin II. The maximum blocking effect was observed within 2 to 3 hours. Mean data suggested that differences in effect between valsartan and placebo were similar after both single and multiple doses and persisted up to 24 hours after administration. The angiotensin II blocking effect was maintained up to this time, despite low plasma valsartan levels and minimal accumulation after multiple doses. CONCLUSION: Valsartan, 80 mg, is a potent angiotensin II antagonist with a rapid onset of action and persistent angiotensin II inhibition up to 24 hours. There is no attenuation of this effect after multiple doses.

Influence of nutritional status on the pharmacokinetics and pharmacodynamics of pentobarbital.

The influence of dietary protein deficiency on the pharmacokinetics and pharmacodynamics of pentobarbital was investigated in male Sprague-Dawley rats fed for 4 weeks on a 23% (control) or 5% (low) protein diet ad libitum. Following a single iv dose of 40 mg/kg sodium pentobarbital, the average mean residence time (MRT) was prolonged by 144% (2.3 +/- 0.2 to 5.6 +/- 1.5 hr, mean +/- SD) in the protein-deficient rats, whereas the mean total body clearance (CL) per kilogram of body weight decreased from 0.56 +/- 0.09 to 0.22 +/- 0.06 liter/hr/kg. As a result, the terminal disposition rate constant was decreased by approximately 60% (0.398 +/- 0.037 to 0.178 +/- 0.050 hr-1 when compared to rats on a normal protein diet. No significant differences were found in the two groups of rats with respect to the apparent steady state volume of distribution (Vss). In order to investigate the effect of nutritional status on the concentration-pharmacologic activity relationship, pentobarbital was infused iv at a constant rate of 0.55 mg/min until the animals lost their righting reflex (16 +/- 3 min and 8 +/- 1 min in control and protein-deficient animals, respectively). The total dose and concentration of pentobarbital in plasma were not significantly different between the two groups of animals. However, the concentrations of pentobarbital in plasma water (unbound) and brain were appreciably higher in the rats on a low protein diet. Thus, a diet low in protein appears to be associated with a decreased sensitivity of the central nervous system to the depressant effect of pentobarbital.