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In the single dose study, the aortic blood pressure in conscious normotensive rats, 2-kidney, 1-clip renal hypertensive rats (2K-RHR), 1-kidney, 1-clip renal hypertensive rats (1K-RHR) or DOCA hypertensive rats was measured for 24 hr after the oral administration of angiotensin converting enzyme (ACE) inhibitors such as MK-421 or captopril. MK-421 at 3 mg/kg and captopril at 10 mg/kg markedly lowered the blood pressure of 2K-RHR. MK-421 at 10 mg/kg and captopril at 30 mg/kg only modestly lowered the blood pressure of 1K-RHR. In contrast, both ACE inhibitors failed to reduce blood pressure in DOCA and normotensive rats. In the repeated dose study, the systolic blood pressures in normotensive rats, 2K-RHR or spontaneously hypertensive rats (SHR) were measured twice a week for 3 weeks treatment of either MK-421 at 3 mg/kg or captopril at 10 mg/kg. Both ACE inhibitors produced significant antihypertensive effects in these model rats, and the effects were sustained throughout the treatment period. The antihypertensive effects in 2K-RHR were greater than those in SHR and normotensive rats. These results indicate that MK-421 and captopril cause the most significant antihypertensive effect in 2K-RHR in which the renin-angiotensin system played a dominant role in blood pressure regulation. The antihypertensive effect of MK-421 was approximately 3 times as potent as that of captopril in these hypertensive models.

The present study was undertaken to compare the antihypertensive effects of beta-blocking agents and to clarify the relations between antihypertensive effects and beta-blocking actions. In this study, blood pressure was measured by a direct cannulation of the abdominal aorta. Subcutaneous administration of carteolol and pindolol caused a significant fall in mean blood pressure in both normotensive and spontaneously hypertensive rats, whereas propranolol produced a rise in blood pressure. Maximum fall in blood pressure was observed 3 approximately 7 hr after the administration of carteolol and pindolol. In order to determine the beta-blocking action, changes in heart rate and blood pressure in response to isoproterenol (3 microgram/kg i.v.) were observed during the experiment. beta-Blocking action was found as early as 1 hr after subcutaneous administration. Carteolol showed the most effective blocking action throughout the experiment. Although beta-blocking agents lowered the blood pressure in this experiment, there was no apparent parallel between antihypertensive effects and beta-blocking action on the cardiac function.

Pharmacological properties of ifenprodil, a vasodilating agent similar in chemical structure to isoxsuprine were investigated. In anesthetized dogs and cats, ifenprodil (0.3 approximately 1 mg/kg, i.v.) caused a temporary prominent depressor response with an increment in heart rate and an occasional enlargement of pulse pressure followed by a mildly durable hypotension. These two phases of hypotension of ifenprodil could not be demonstrated in spinal rats and cats. Ifenprodil also decreased the pressor response of norepinephrine and reversed the pressor effect of epinephrine to a depressor one. The lowering effect of ifenprodil on the constant-rate perfused pressure of vertebral artery in dogs was half as potent as isoxsuprine. Ifenprodil significantly reduced the contraction to norepinephrine in the isolated guinea-pig vas deferens. This was greater than the constrictor response produced by preganglionic sympathetic nerve stimulation. The inhibitory effect of ifenprodil was less potent than that of phentolamine on the responses to norepinephrine in isolated rabbit ascending aorta strips. In the isolated guinea-pig right atrium, ifenprodil (10(-5) g/ml) showed slightly negative inotropic and chronotropic effects, and reduced the responses to isoproterenol. It is suggested that the two phases of lowering effects of ifenprodil on the constant-rate perfusion pressure of either vertebral or femoral artery in dogs are due to a possible neurogenic and an alpha-adrenolytic action, but the precise mechanism is not clear. Ifenprodil like isoxsuprine has a weak beta-sympathetic effect.