Modification of vasopressin- and angiotensin II- induced changes by calcium antagonists in the peripheral circulation of anaesthetized rabbits.

Investigations into the site of vasodilator and antivasoconstrictor activity of calcium antagonists previously performed in cats were extended to a second species, barbiturate-anaesthetized rabbits, and a second vasoconstrictor agent, vasopressin. The dihydropyridine derivative darodipine (code name PY 108-068; 10, 30 and 100 micrograms kg-1 i.v.) showed systemic haemodynamic effects comparable to those seen in cats at half these doses. Darodipine effected regional vasodilatation (measured with tracer microspheres) in the heart, brain and skeletal muscles as in cats. Only the vessels of the adrenals (dilated in rabbits but not in cats), and the kidneys and skin (constricted in rabbits but not in cats) responded differently to darodipine. Angiotensin II (A II; 0.15 and 1.5 micrograms kg-1 min-1) constricted the same vascular beds in rabbits as in cats, namely the heart, kidneys, small intestine, pancreas, spleen, skin and arterio-venous shunts (inferred from microspheres reaching the lungs), the only exceptions being the vessels of the stomach and liver (constriction only in cats) and the adrenals (constriction only in rabbits). Darodipine (30 and 100 micrograms kg-1) attenuated the A II-induced vasoconstriction in the same vascular beds in rabbits as in cats including the kidneys, which were constricted after administration of the antagonist alone. These results indicate surprisingly small species differences for the vasodilator effects of darodipine as well as the attenuation of the vasoconstrictor effects of A II. Lysine-vasopressin (2 and 50 mu kg-1 min-1) did not increase blood pressure in anaesthetized rabbits but dose-dependently lowered heart rate, cardiac output, total peripheral conductance and myocardial contractile force (measured with a strain gauge). Vasopressin constricted all peripheral vascular beds dose-dependently, except for those of the kidney and liver. The effects of vasopressin persisted in the animals infused with placebo solution. Darodipine (30 and 100 micrograms kg-1), but not verapamil (300 and 1000 micrograms kg-1) reversed the vasopressin-induced cardiac depression and decrease in cardiac output. This probably also explains most of the apparent differences between the effects of the two calcium antagonists on the peripheral circulation. Both calcium antagonists diminished the vasopressin constriction in most vascular beds except those of the spleen, skin and arterio-venous shunts. Most of the effects were dose-related but not strictly competitive, as far as this can be judged based on two doses of agonist and antagonist. 9 As with A II the effects of vasopressin were diminished in vascular beds not normally dilated by calcium antagonists. 10 Calcium antagonists display two typical patterns of activity. The vasodilator pattern consists of dilatation of the vesels of the heart, brain and, to a degree varying with the agents, skeletal muscle. The antivasoconstrictor effects occur in some but not all of the vessels constricted by the constrictor agent, vasoconstriction of the spleen, skin and arterio-venous shunts being resistant to the action of calcium antagonists. The pattern of antivasoconstrictor activity appears to depend on the constrictor compound used, inasmuch as such agents constrict different vascular beds.