Acute hemodynamic effects of pinacidil and hydralazine in essential hypertension

Abstract

In a double-blind, randomized, crossover study, the effects of intravenous pinacidil, 0.2 mg/kg, were compared with those of hydralazine, 0.3 mg/kg, before and after beta-adrenoceptor blockade in six subjects with hypertension. Both drugs equally reduced total peripheral resistance by about 40%. Pinacidil reduced mean blood pressure by an average of 30 mm Hg, while the reduction after hydralazine was 10 mm Hg. The difference in antihypertensive effect resulted from greater increases in heart rate, cardiac contractility (systolic time intervals), and cardiac index (thermodilution) after hydralazine. These effects after hydralazine could not be fully abolished by beta-blockade, as could the effects after pinacidil. Pinacidil decreased pulmonary blood pressure, whereas there was a slight rise in pulmonary blood pressure after hydralazine. Forearm blood flow (venous occlusion strain gauge plethysmography) increased equally after both drugs; thus pinacidil decreased forearm vascular resistance more than hydralazine did. Serum concentrations of both drugs were within the therapeutic range and correlated with the fall in mean blood pressure. Five subjects complained of side effects after hydralazine, but none were reported after pinacidil. Hydralazine increased myocardial oxygen consumption (as estimated from the rate-pressure product) by 35%; there was no change after pinacidil. It is suggested that hydralazine has direct cardiostimulatory effects that limit its antihypertensive effectiveness. These effects increase myocardial oxygen consumption and may be responsible for the common and sometimes severe cardiovascular side effects of hydralazine.

The initial hemodynamic response to newer antihypertensive agents at rest and during exercise: Review of visacor, doxazosin, nisoldipine, tiapamil, perindoprilat, pinacidil, dilevalol, and carvedilol

“…These hemodynamic effects remained constant for 1 hour. Similar immediate hemodynamic effects have previously been reported from a group of six hypertensive patients studied by Carlsen et al [28] and from a similar group by Goldberg [29].…”

“…An increase SI also contributes to the rise in CI. Since this may be abolished by beta blockade, the rise in SI is most likely to be secondary to sympathetic stimulation [28].…”

Pharmacokinetic and Pharmacodynamic Evaluation of Two Different Oral Formulations of Pinacidil, a Potassium Channel Opener

“…These observations were made in single dose and short term studies (Carlsen et al , 1983(Carlsen et al , 1985Kardel et Drug Invest. 3 (5) 1991.…”

“…Recently, it has been suggested that the mechanism of action is dependent upon the opening of potassium channels in vascular smooth muscle cells (Southerton et al 1988;Videbaek et al 1988). Previous investigations have shown a close correlation between the serum concentration of pinacidil and the effect on blood pressure (Carlsen et al , 1983(Carlsen et al , 1985Kardel et al 1981). The biological halflife (t.;,) in serum is short, approximately 2 to 3 hours (Carlsen et al 1983).…”

Pharmacokinetic‐pharmacodynamic modeling between pinacidil or pinacidil‐N‐oxide plasma levels and systemic and regional hemodynamic effects in healthy volunteers

“…However, as with any potent vasodilator, its clinical use is sometimes associated with some characteristic and undesirable side effects which can lead to treatment withdrawal (Ward, 1984;Zachariah et al, 1986;McBurney et al, 1988b;Goldberg et al, 1988Goldberg et al, , 1989a. In order to limit these side effects, the relationships between P plasma concentrations and P antihypertensive effects were investigated at an early stage (Carlsen et al, 1981(Carlsen et al, , 1983(Carlsen et al, , 1985Kardel et al, 1981;Ward et al, 1984), and a range of effective and safe P plasma concentrations was determined. Simultaneously, controlled release formulations were developed in an attempt to avoid too high peak concentrations (Carlsen et al, 1983;Laher and Hickey, 1985;McBurney et al, 1985McBurney et al, , 1987McBurney et al, , 1988a.…”