Exaggerated hypotensive responses to calcium antagonists in spontaneously hypertensive rats

The hypotensive effects of intravenous injection and infusion of diltiazem, l- and d-verapamil were investigated in conscious and anaesthetized rats with spontaneous hypertension (SHR) and normal blood pressure (NT-WKY). The inhibitory actions of these calcium-influx blockers on the pressor responses to angiotensin II (AII) and noradrenaline (NA) were also examined in anaesthetized SHR and NT-WKY. The intravenous injections of these three drugs (0.03, 0.1, 0.3, 1.0 mg/kg) lowered mean arterial pressure (MAP) in a dose related manner in conscious NT-WKY and SHR. The small dose of the blockers administered by intravenous infusion (0.02 mg/kg per min) also decreased MAP in both groups. The potency of the antihypertensive action was in the order l-verapamil greater than d-verapamil = diltiazem. The fall in blood pressure expressed as percentage of the initial MAP produced by the compounds was significantly enhanced in SHR compared to NT-WKY. The pressor responses to AII (0.03, 0.1, 0.3, 1.0 micrograms/kg i.v.) were suppressed by the intravenous infusion of 20 micrograms/kg per min with l-verapamil but not with d-verapamil, diltiazem and vehicle in NT-WKY, while no calcium blocker significantly diminished the vasopressor action of AII in SHR. The pressor effects of NA (0.3, 1.0, 3.0, 10.0 micrograms/kg i.v.) were inhibited by the same doses of l-verapamil and diltiazem but not with d-verapamil and vehicle in NT-WKY. Diltiazem reduced the response to NA in SHR but the other compounds (l- and d-verapamil) did not alter the pressor response to NA in SHR. The pressor responses to arginine vasopressin (3, 10, 30 and 100 mU/kg i.v.) were not altered by diltiazem infusion in either SHR or NT-WKY. It is concluded that these compounds are different in the potency of their hypotensive action and also the inhibition of the pressor responses to AII and NA. Calcium entry blockers are more effective antihypertensive agents in SHR than in NT-WKY. It appears that their inhibitory effects on the responses to AII and NA do not explain the exaggerated hypotensive responses in SHR.