Contrasting effects of selective T- and L-type calcium channel blockade on glomerular damage in DOCA hypertensive rats.
Mibefradil and amlodipine are calcium antagonists with different channel selectivities. Mibefradil blocks both L- and T-type calcium channels; although in the usual pharmacological doses, it predominantly blocks the T-type channels. In contrast, amlodipine selectively blocks L-type channels. The goal of the present study was to assess whether this differential selectivity would result in different effects on end-organ damage in experimental hypertension. For this purpose, deoxycorticosterone acetate (DOCA)-salt hypertensive rats were treated either with equipotent doses of mibefradil or amlodipine (30 mg. kg(-1). d(-1) as food admix). Despite the fact that both drugs decreased systolic arterial pressure to the same extent (140+/-5 mm Hg in the mibefradil group and 144+/-3 mm Hg in the amlodipine group versus 225+/-5 mm Hg in the untreated-DOCA group), only mibefradil decreased proteinuria (35. 5+/-6.5 versus 103.3+/-14.1 mg/24 h in untreated DOCA-salt animals) and prevented glomerular lesions. Both drugs, however, prevented the occurrence of vascular renal lesions. To elucidate the mechanism responsible for this difference, we evaluated in an additional series of experiments the effects of mibefradil and amlodipine on plasma and renal renin concentrations, as well as the effects of the addition of enalapril, an ACE inhibitor, given on top of both drugs on proteinuria. Amlodipine, in contrast to mibefradil, markedly stimulated the plasma (17.8+/-2.6 ng Ang I. mL(-1). h(-1) in the amlodipine group versus 3.9+/-0.4 ng Ang I. mL(-1). h(-1) in the mibefradil group and 3.2+/-0.3 ng Ang I. mL(-1). h(-1) in the untreated-DOCA group) and renal (2.42+/-0.37 ng Ang I. mL(-1). h(-1) in the amlodipine group versus 0.36+/-0.04 ng Ang I. mL(-1). h(-1) in the mibefradil group and 0.26+/-0.08 ng Ang I. mL(-1). h(-1) in the untreated-DOCA group) renin concentrations. Stimulation of the renin-angiotensin system could explain the absence of a renal protective effect of amlodipine. This was also suggested by the fact that enalapril given in addition to amlodipine could decrease proteinuria. In conclusion, T-type channel blockade by mibefradil decreases blood pressure without stimulation of the renin-angiotensin system and therefore prevents most of the glomerular damage in DOCA hypertensive rats.
Karam
H
H
INSERM U367, Paris, France.
Clozel
J P
JP
Bruneval
P
P
Gonzalez
M F
MF
Ménard
J
J
D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D015220:Calcium Channels / Q000187:drug effects*; D003326:Coronary Circulation; D003900:Desoxycorticosterone; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020748:Mibefradil / Q000494:pharmacology / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000097:blood / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D017311:Amlodipine; D020748:Mibefradil; D003900:Desoxycorticosterone; D012083:Renin