In an observer-blind four-way crossover study, 7 healthy volunteers received in random sequence, one month apart, atenolol 100 mg od, propranolol (slow release) 160 mg od, pindolol 5 mg tid, and nebivolol 5 mg od for a period of seven days, followed by a single-blind placebo washout period of seven days. The decrease of peak exercise heart rate and systolic blood pressure was significant (p = 0.02) and comparable for the four drugs studied and varied between 15% and 23% for heart rate and between 15% and 20% for systolic blood pressure. Although no statistically significant difference was observed among the four drug regimens, the decrease of peak exercise heart rate was less pronounced with nebivolol than with the three reference beta-blocking agents. The ratio of the preejection period (PEPc) to the left ventricular ejection time (LVETc), an indirect measure of left ventricular performance, tended to increase with atenolol and propranolol and remained unchanged with pindolol. PEPc/LVETc progressively and significantly improved with nebivolol from a control value of 0.37 +/- 0.012 to 0.31 +/- 0.009 (p = 0.03) after seven days of treatment, owing to a decrease in PEPc and an increase in LVETc, suggestive of a combined effect both on preload and afterload. Postexercise LVETc, an index of the intrinsic positive inotropy of exercise, was significantly suppressed by atenolol, propranolol, and pindolol, but not during treating with nebivolol. These data suggest that nebivolol is a beta 1-selective adrenergic antagonist with an unusual hemodynamic profile, probably improving left ventricular compliance.
De Cree, J., H. Geukens, J. Leempoels, and H. Verhaegen: Haemodynamic effects in man during exercise of a single oral dose of narbivolol (R 67555), a new beta-l-adrenoceptor blocking agent: A comparative study with atenolol, pindolol, and propranolol. Drug Dev. Res. 8:109-117, 1986.In eight normal volunteers R 67555 at 5 mg and 10 mg significantly lowered the exerciseinduced increase of systolic blood pressure by 20 and 25%, and the exercise-induced increase of heart rate by 20 and 21% respectively. The blood pressure lowering effect of R 67555 6 hr after intake was comparable to that observed after atenolol, pindolol, and propranolol. In contrast, the lowering of exercise-induced increase of heart rate was significantly less with R 67555 than with the other beta-blockers tested. The ratio of PEP,/ LVET,, a measure of left ventricular performance, significantly increased 3 hr after intake of atenolol, propranolol, and 10 mg of R 67555 but not after pindolol and 5 mg of R 67555. Six hr after administration of pindolol and of 5 mg of R 67555, the ratio PEPdLVET, was significantly lowered as compared with control values. The post-exercise left ventricular ejection time (LVET,) significantly shortened 3 hr and 6 hr after intake of 5 mg and 10 mg of R 67555, whereas a trend to prolongation was observed after administration of atenolol, pindolol, and propranolol.
1. In a double-blind placebo-controlled crossover study a 4 week treatment with ketanserin was shown to reduce systolic and diastolic blood pressure markedly and significantly in 10 patients with essential hypertension. Heart rate remained virtually unchanged during the whole observation period. Systolic time intervals, reflecting cardiac output, did not change during the ketanserin phase, whereas these values deteriorated during the placebo period.2. Ketanserin, a novel 5-hydroxytryptamine (5HTJ-receptor antagonist with a high selectivity for blood vessels and thrombocytes, most probably acts by decreasing the venous capacitance bed constriction, and by counteraction of the amplifying effects of serotonin on noradrenaline and other vasoactive amines.
In a first experiment, an acute intravenous administration of 10 mg R 41 468, a pure serotonin-receptor blocking agent with high selectivity for blood vessels and thrombocytes and devoid of central effects, dramatically reduced systolic and diastolic blood pressure in 23 elderly hypertensive patients. Heart rate and cardiac output remained virtually unchanged. In a second double-blind placebo-controlled cross-over study a highly significant decrease of systolic and diastolic blood pressure was obtained in 14 elderly hypertensive patients during an 8-day oral treatment with 40 mg t.i.d. of R 41 468. No serious side-effects were observed. An oral maintenance therapy with R 41 468 for 3 weeks showed a further reduction of blood pressure, resulting in a normalization of blood pressure, taking into account the advanced age of the patients. R 41 468 most probably acts by decreasing the venous capacitance bed constriction. Essential hypertension might be causally related to an impairment of venous function, in which serotonin might be an important pressor factor.
In a subacute experiment 7 apparently healthy volunteers received a daily oral dose of 5 mg nebivolol for seven days, followed by a seven-day washout period with placebo. From the first day during treatment with nebivolol, peak exercise heart rate and systolic blood pressure, as measured during a standardized submaximal treadmill exercise, significantly decreased by 15% and 19% respectively. A prolonged treatment for one week did not further increase the response of exercise heart rate and systolic blood pressure to nebivolol. However, the ratio of preejection period (PEPc) to left ventricular ejection time (LVETc), an indirect and valuable measure of left ventricular performance, progressively and significantly decreased during the seven-day treatment period with nebivolol from a mean value of 0.37 +/- 0.012 to 0.31 +/- 0.009. The improvement of systolic time intervals resulted from a shortening of the PEPc and a lengthening of the LVETc. At rest, heart rate did not change significantly with nebivolol, whereas both systolic and diastolic blood pressure gradually and significantly lowered. The postexercise LVETc significantly shortened during treatment with nebivolol, and this shortening was more pronounced after seven days of treatment. After discontinuation of treatment with nebivolol, all these effects persisted for more than thirty hours after the last intake and gradually returned to pretreatment values thereafter. From these data it appears that nebivolol effectively reduces blood pressure at rest and during exercise in healthy volunteers, beneficially influencing preload and afterload, as measured by systolic time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)
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