Hemodynamic effects of Corwin (ICI 118,587), a new cardioselective beta-adenoceptor partial agonist

Abstract

To describe the mechanisms of action of Corwin (ICI 118,587), a new cardioselective beta-adrenoceptor partial agonist, ten cardiac patients with mild to moderate functional cardiac impairment were studied. Hemodynamic measurements were made at rest and during three consecutive levels of submaximal exercise, before and 10 min after intravenous administration of 0.2 mg/kg of the drug. At rest, Corwin increased heart rate (HR) from 75 to 88 bpm and mean systemic blood pressure (BP) and decreased mean pulmonary capillary wedge pressure (PCWP); the resting cardiac output (CO) tended to increase in patients with a slow control HR. During exercise of low intensity (control HR: 103 bpm), the drug had no significant effect, except for a slight decrease in BP. During exercise of moderate and heavy intensity (control HR: 121 and 149 bpm), Corwin decreased HR (-10 and -24 bpm), BP and PCWP; at the heaviest exercise level, CO also decreased after Corwin. Thus, at rest, when the sympathetic tone is low, Corwin acts mainly as a beta-adrenoceptor agonist. As the sympathetic tone progressively increases with the intensity of the exercise, the beta-adrenoceptor antagonist action of Corwin becomes apparent and is most evident at the highest exercise level. In contrast to a full antagonist, these effects of Corwin appear to be less marked and they are accompanied by an unchanged or decreased PCWP. Corwin has thus interesting hemodynamic properties which deserve further investigation.

The pharmacology of xamoterol: a basis for modulation of the autonomic control of the heart.

“…No change was observed in resting pulmonary artery wedge pressure in this study; this may be a result of the relatively large doses of oral diuretics received by this group of patients. The acute effects of xamoterol on exercise haemodynamics are less well documented (Detry et al, 1983(Detry et al, , 1984Watanabe et al, 1986;Sato et al, 1987). However, in four other studies, exercise heart rate was uniformly lowered by 10 to 15%, as in this study.…”

“…mean) falling midway in this transition zone, and there was a small fall in resting heart rate. A number of other studies have reported the effects of intravenous xamoterol on resting and exercise haemodynamics (Detry et al, 1983(Detry et al, , 1984Rousseau et al, 1983;Ikaheimo & Takkunen, 1984;Simonsen, 1984;Molajo & Bennett, 1985;Amende et al, 1986;Bhatia et al, 1986;Watanabe et al, 1986;Kayanakis & Snow, 1987;Sato et al, 1987 and in other studies, left ventricular dP/dtmax improved by 17 to 46% (Rousseau et al, 1983;Ikaheimo & Takkunen, 1984;Simonsen, 1984;Amende et al, 1986). Pulmonary artery wedge pressure was reduced by up to one-third.…”

“…However, in four other studies, exercise heart rate was uniformly lowered by 10 to 15%, as in this study. Only one investigation (Detry et al, 1983) has demonstrated a small although significant reduction in exercise cardiac output and systolic blood pressure. Overall, despite the reduction in heart rate, exercise cardiac output and blood pressure levels are unimpaired.…”

The pharmacokinetics of xamoterol in liver disease.

“…In normal man, resting heart rate is increased (Hashimoto et al, 1986) but heart rate at high levels of exercise is reduced (Harry et al, 1981), indicating Padrenoceptor agonist activity when levels of sympathetic tone are low, and 3-adrenoceptor antagonist activity when levels are high (Detry et al, 1983;Sato et al, 1987). Systolic time intervals are reduced, indicating positive inotropic activity (Marlow et al, 1982;Hashimoto et al, 1986).…”

Long‐term studies with xamoterol in heart failure.

“…Xamoterol is a newly developed P3-adrenoceptor partial agonist which has potentially useful haemodynamic effects in patients with mild or moderate heart failure (Detry et al, 1983;Rousseau et al, 1983). Evidence for the long-term efficacy and safety of xamoterol is considered in this review.…”