Vascular selectivity of felodipine

Abstract

Felodipine, a new antihypertensive 'calcium antagonist', was tested in animal experiments which specifically demonstrated its vascular selectivity. In vitro inorganic and organic calcium antagonists were added cumulatively to the spontaneously active rat portal vein, and the paced papillary muscle of the rat, residing in the same organ bath. Felodipine was the first compound tested to display a 100-fold vascular selectivity in this test system. In the portal vein the spontaneous activity and noradrenaline (norepinephrine)-induced responses are reduced by the drug in therapeutic concentrations in an insurmountable way, indicating that felodipine prevents activation of the vascular effector cells or interferes with the contractile process, possibly due to an intracellular action on Ca2+-binding proteins. The negative myocardial effect of felodipine, attainable only in vitro, is characterised by surmountable antagonism of the inotropic response to added adrenergic agonists or Ca2+ and is compatible with calcium influx inhibition. In vivo, felodipine was given to conscious dogs with indwelling arterial and venous catheters. The animals were studied in the horizontal position and at 45 degrees tilt. Felodipine (1 mumol/kg) and minoxidil (4 mumol/kg) lowered mean arterial blood pressure by 20 to 25%, due to reduced peripheral resistance with a reflex rise in cardiac output. Following head-up tilt (2 min) there was no orthostatic hypotension, and stroke volume was well maintained. This strongly indicates that arterial resistance vessels, but not venous capacitance vessels or myocardium, were directly affected by felodipine.