In this study the pharmacokinetics, and the hemodynamic and diuretic/natriuretic effects of three different doses of felodipine ER-10, 20, and 40 mg--were evaluated in healthy subjects. There was a linear correlation between the dose of felodipine, Cmax, and AUC24, showing that the absorption was linearly related to the dose. The diastolic blood pressure was reduced by 15-20% after the two highest doses. The maximal blood-pressure lowering effect was seen 4 hours after drug intake, and a small reduction in diastolic blood pressure was still present after 24 hours. This was, however, not statistically significant but was related to a sustained effective plasma concentration of the drug (6 nmol/l). Systolic blood pressure was not affected. The two highest doses of felodipine ER produced a significant increase in heart rate 2 and 6 hours after the dose, compared with placebo. There was also a significant decrease in forearm vascular resistance after the 20- and 40-mg doses. Both diuresis and natriuresis were significantly increased by about 100% each during the first 4 hours after the 20-mg dose. Following the 40-mg dose, diuresis and natriuresis were lower than after 20 mg and were not significantly different from placebo.
The hemodynamic effects of the calcium entry blocker felodipine were studied during and after different infusion rates. Eight healthy normotensive volunteers had their individual pharmacokinetics of felodipine determined, and they subsequently entered a double-blind, randomized, crossover study. Individualized infusions of felodipine were given by a computerized infusion pump to reach plasma concentrations of 6 ng/ml (15.6 nmol/L) after 20 minutes, to be sustained for 8 hours (fast infusion) or the same plasma concentration after 8 hours (slow infusion). Control infusions with saline and vehicle were given. Blood pressure, heart rate, ECG conduction times, and baroreceptor sensitivity by the Valsalva test were measured, as well as the plasma concentrations of felodipine. The infusion system used produced the expected plasma concentration-time profiles with higher plasma concentrations after the fast infusion until 8 hours. Both slow and fast infusion increased heart rate (p less than 0.05) and produced a similar decrease in diastolic blood pressure (p less than 0.05). Slow infusion therefore reduced blood pressure more effectively. The tachycardia after the fast infusion was more pronounced during the first hour of the infusion but was indistinguishable from the slow infusion later, when plasma concentrations were still significantly different. Baroreceptor responsiveness was diminished by both felodipine treatments. There was no obvious difference in side effects caused by the two infusion regimes. The initial tachycardia after felodipine can be diminished by a slow rate of administration of the drug with a similar effect on blood pressure.
Blood pressure and heart rate were recorded in the sea gull, Larus argentatus, under light pentibarbitone anaesthesia. Clonidine 10(-7) and 10(-8) mol . kg-1 (27 and 2.7 microgram . kg-1) i.v. produced a biphasic effect on blood pressure, a brief initial increase being followed by a prolonged hypotensive response. There was an immediate reduction in heart rate rate which persisted throughout the hypotensive phase. After spinal transection at the level of C4, clonidine administration elicited hypertension and bradycardia. Bilateral vagotomy abolished the effect of clonidine on heart rate but did not alter the blood pressure response. Vagotomy in combination with spinal transection abolished the effect of clonidine on heart rate but the hypertensive response was accentuated. Yohimbine 10(-7) or 10(-6) mol . kg-1 (0.039 or 0.39 mg . kg-1) given 5 min after clonidine 10(-7) mol.kg-1 (27 microgram . kg-1) effectively antagonized the cardiovascular effects of clonidine, while prazosin 10(-7) or 10(-6) mol . kg (0.042 or 0.42 mg . kg-1) had no such effect. We conclude that clonidine acts in the central nervous system of the sea gull to produce a lowering of blood pressure and heart rate. These effects are mediated by central inhibition of sympathetic activity and, in the case of the heart rate, mostly by central activation of vagal activity to the heart. This central action of clonidine involves activation of alpha-adrenoceptors which are blocked by yohimbine but not by prazosin and therefore may belong to the alpha 2 subtype.
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