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 pharmacological T-type calcium channel and of L-type calcium channel blockade on the renin system. To this end, male healthy Sprague-Dawley rats were treated with the T-channel blocker mibefradil or with the L-channel blocker amlodipine at doses of 5 mg kg(-1), 15 mg kg(-1) and 45 mg kg(-1) per day for four days and their effects on plasma renin activity (PRA) and kidney renin mRNA levels were determined. 2. Whilst amlodipine lowered basal systolic blood pressure at 5 mg kg(-1), mibefradil had 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 dose of 45 mg kg(-1), when PRA and renin mRNA levels were increased by 100% and 30%, respectively. In primary cultures of renal juxtaglomerular cells neither amlodipine nor mibefradil (0.1-10 microM) 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 effective 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 renin mRNA levels, whilst amlodipine (15 mg kg(-1)) additionally elevated the rise of PRA and renin mRNA levels in response to renal artery clipping. 4. These findings suggest that T-type calcium channel blockers can 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 juxtaglomerular cells.
Wagner
C
C
Physiologisches Institut, Universität Regensburg, Germany.
Krämer
B K
BK
Hinder
M
M
Kieninger
M
M
Kurtz
A
A
D017311:Amlodipine / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D004792:Enzyme Precursors / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D007606:Juxtaglomerular Apparatus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020748:Mibefradil; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000502:physiology; D012083:Renin / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D004792:Enzyme Precursors; D012333:RNA, Messenger; D013764:Tetrahydronaphthalenes; D017311:Amlodipine; D020748:Mibefradil; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D012260:Ribonucleases; D012083:Renin