Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs

Abstract

1 The systemic and regional haemodynamic effects of the potassium channel activator EMD 52692 or its solvent were investigated after intravenous and after intracoronary administration in anaesthetized pigs.2 Consecutive intravenous 10min infusions of EMD 52692 (0.15, 0.30, 0.60, 1.20pgkg Imin-'; n = 7) dose-dependently decreased mean arterial blood pressure by up to 50%. This was entirely due to peripheral vasodilatation, since cardiac output did not change. Heart rate increased by up to 50%, while left ventricular end diastolic pressure decreased dose-dependently from 6 + mmHg to 3 + mmHg (P <0.05), and stroke volume decreased from 30 + 2 ml to 21 + 2 ml (P < 0.05). Left ventricular dP/dt.. was not affected. 3 Although cardiac output did not change, EMD 52692 caused a redistribution of blood flow from the arteriovenous anastomoses to the capillary channels. Blood flow to the adrenals, small intestine, stomach, bladder, spleen and brain increased, while renal blood flow decreased and blood flow to several muscle groups and skin were not altered. Vascular conductance was increased dose-dependently in all organs, except for the kidneys, where after the initial increase, vascular conductance returned to baseline with the highest dose. Particularly striking were the effects on the vasculature of the brain. With the highest dose of EMD 52692 blood flow more than doubled, while vascular conductance increased four fold. 4 Transmural myocardial blood flow increased slightly, which was entirely due to an increase in subepicardial blood flow. Myocardial O2-consumption and segment length shortening were not significantly affected. 5 After consecutive 10min intracoronary infusions (0.0095, 0.019, 0.0375 and 0.075Sugkg-'min-1; n = 7) into the left anterior descending coronary artery (LADCA), mean arterial blood pressure was maintained with the lowest two doses, but decreased by up to 15% with the higher doses, whereas heart rate increased by up to 24%. Blood flow to the LADCA-perfused myocardium doubled with the highest dose, the subepicardium benefitting the most. Coronary venous O2-saturation increased dose-dependently from 23 + 2% to 60 + 4%, while myocardial 02-consumption of the LADCA-perfused myocardium was not affected by the drug. 6 It is concluded that EMD 52692 is a potent vasodilator, with particularly pronounced effects on vasculature of the brain. Its selectivity for vascular smooth muscle cells exceeds that for the myocytes, since with doses that are much higher than those of potential clinical interest no negative inotropic effects were observed. The compound primarily dilates arteries but some venodilatation may also occur.

Cardiovascular effects of the novel potassium channel opener bimakalim in conscious pigs after myocardial infarction: A comparative study with nicorandil

“…The study also indicates that the potency of bimakalim as an arterial vasodilator is considerably larger than that of nicorandil, as approximately 250 times higher doses of the latter drug were needed to produce comparable reductions in systemic vascular resistance (Figures 1 and 2), which confirms earlier observations with the two compounds in anesthetized pigs [8,10]. The vasodilator response of bima- Table 1).…”

“…In anesthetized pigs, cardiac output and LVdP/dtma x did not change, while left ventricular end-diastolic pressure and stroke volume decreased during infusion of bimakalim in the same dose range as in the present study [8]. The major reason for the increase in cardiac output in the present study is the unchanged stroke volume, as the increases in heart rate were similar in both studies.…”

“…In anesthetized pigs bimakalim decreased arterial blood pressure due to systemic vasodilatation, increased heart rate, and had no effect on left ventricular filling pressure and the inotropic state of the myocardium [8]. It has well been established, however, that anesthetic agents may interfere with the cardiovascular actions of pharmacological agents.…”

“…The benzopyran derivative bimakalim (EMD 52 692, SR 44866) is a novel potassium channel activator [4][5][6][7] that has been shown to have a 100-to 300-fold higher affinity for vascular smooth muscle than for cardiac muscle [5,6]. By comparison to bimakalim, five times higher doses of cromakalim (BRL 34915) were needed to cause similar reductions in the arterial blood pressure of spontaneous hypertensive rats [7].In anesthetized pigs bimakalim decreased arterial blood pressure due to systemic vasodilatation, increased heart rate, and had no effect on left ventricular filling pressure and the inotropic state of the myocardium [8]. It has well been established, however, that anesthetic agents may interfere with the cardiovascular actions of pharmacological agents.…”

Bimakalim: A Promising KATP Channel Activating Agent

“…Bimakalim, at doses ranging from 300 ng to 1.2 mg/kg/min, in either anesthetized (51) or consious pigs (11), showed characteristics of a potent vasodilator, with a particularly pronounced effect on the vasculature of the brain. The hemodynamic profile of bimakalim or its vehicle were first investigated after intravenous and intracoronary administration in Although cardiac output did not change, bimakalim caused a redistribution of blood flow from the arteriovenous anastomoses to the capillary channels.…”