T-TYPE AND L-TYPE CALCIUM-CHANNEL BLOCKERS EXERT OPPOSITE EFFECTS ON RENIN SECRETION AND RENIN GENE-EXPRESSION IN CONSCIOUS RATS

1 This study aimed to investigate and to compare the effects of pharma cological T-type calcium channel and of L-type calcium channel blockad e on the renin system. To this end, male healthy Sprague-Dawley rats w ere treated with the T-channel blocker mibefradil or with the L-channe l blocker amlodipine at doses of 5 mg kg(-1), 15 mg kg(-1) and 45 mg k g(-1) per day for four days and their effects on plasma renin activity (PRA) and kidney renin mRNA levels were determined. 2 Whilst amlodipi ne lowered basal systolic blood pressure at 5 mg kg(-1), mibefradil ha d no effect on basal blood pressure in the whole dose range examined. Amlodipine dose-dependently induced up to 7 fold elevation of PRA and renin mRNA levels. Mibefradil significantly lowered PRA and renin mRNA levels at 5 mg kg(-1) and moderately increased both parameters at a d ose of 45 mg kg(-1), when PRA and renin mRNA levels were increased by 100% and 30%, respectively. In primary cultures of renal juxtaglomerul ar cells neither amlodipine nor mibefradil (0.1-10 mu M) changed renin secretion. 3 In rats unilateral renal artery clips (2K-1C) mibefradil and amlodipine at doses of 15 mg kg(-1) day(-1) were equally effectiv e in lowering blood pressure. In contrast mibefradil (5 mg kg(-1) and 15 mg kg(-1) day(-1)) significantly attenuated the rise of PRA and ren in mRNA levels, whilst amlodipine (15 mg kg(-1)) additionally elevated the rise of PRA and renin mRNA levels in response to renal artery dip ping. 4 These findings suggest that T-type calcium channel blockers ca n inhibit renin secretion and renin gene expression in vivo, whilst L- type calcium channel blockers act as stimulators of the renin system. Since the inhibitory effect of T-type antagonists is apparent in vivo but not in vitro, one may infer that the effect on the renin system is indirect rather than directly mediated at the level of renal juxtaglo merular cells.