Luciano Dorigotti

Pharmacological studies on cadralazine: a new antihypertensive vasodilator drug.

Summary Cadralazine is a new, orally effective antihypertensive vasodilator. Acute experiments indicate that the compound reduces blood pressure and increases heart rate. The doses which reduce systolic blood pressure by 25% (ED25) are very similar after oral and intravenous administration (spontaneously hypertensive rats, 1.8 mg/kg, p.o.; 2.3 mg/kg, i.v.; renal hypertensive dogs, 0.26 mg/kg, p.o.; 0.24 mg/kg, i.v.; awake normotensive dogs, 0.98 mg/kg, p.o.; 1.01 mg/kg, i.v.). By both routes the peak effect is reached after 3–5 hr, and the activity lasts more than 24 hr. Repeated oral administration in spontaneously hypertensive rats reduces blood pressure with no evidence of tolerance. Cadralazine reverses hypertensive responses to epinephrine in awake normotensive dogs and anesthetized cats. The inhibition of the increase in blood pressure induced by sympathetic outflow activation in pithed rats parallels the antihypertensive activity in onset, intensity, and duration. The effects of cadralazine are not due to a blockade of α-adrenoceptors, sympathetic neurons, or ganglionic transmission. Cadralazine has no antihistaminic, anticholinergic, or spasmolytic activity and no specific effect on behavioral tests. In comparison with hydralazine, cadralazine has less acute toxicity and a greater activity by the oral route.

Renal function studies with propildazine alone and in combination with propranolol in dogs

The vasodilator antihypertensive propildazine acutely administered in awake dogs (0.1 mg/kg i.v.) produced an arterial blood pressure drop accompanied by tachycardia, decreased urine volume and urinary sodium excretion, and increased urinary potassium excretion. A transient, quickly reversible decrease in glomerular filtration rate was observed; on the contrary, the reduction in urine volume and urinary sodium excretion was longer lasting. There was indirect evidence that sodium retention was mainly caused by increased tubular reabsorption. Decreases in renal resistance, renal extraction of p-aminohippurate, and filtration fraction were observed together with an increase in renal plasma flow. Propildazine at the above dose in combination with propranolol (1 mg/kg i.v.) had a hypotensive effect with a smaller increase in heart rate and without significant variations in urine volume or urinary sodium excretion. These effects could be attributed to antagonism of the reflex-activated sympathoadrenal system by propranolol. In these conditions, the glomerular filtration rate was not significantly modified, while the effects on other renal parameters were similar to those observed with propildazine.