Distinct action of aranidipine and its active metabolite on renal arterioles, with special reference to renal protection.
Aranidipine, a newly developed calcium antagonist, possesses unique pharmacologic characteristics in that its metabolite (M-1) still has antihypertensive action. We examined the effects of both agents on renal microcirculation using the isolated perfused hydronephrotic rat kidney. During norepinephrine-induced constriction, the addition of aranidipine dilated both afferent and efferent arterioles in a dose-dependent manner; at 10(-6) M, 83 +/- 6% and 90 +/- 6% reversal, respectively. In contrast, its active metabolite exerted dilator action predominantly on the afferent arteriole (79 +/- 4% vs. 44 +/- 17% at 10(-6) M for afferent and efferent arterioles, respectively). We further examined the long-term (8 weeks) effect of these agents on the development of renal injury in salt-loaded subtotally nephrectomized spontaneously hypertensive rats. Both aranidipine and M-1 reduced blood pressure by a similar magnitude. The decreases in proteinuria were observed in the aranidipine-treated group at weeks 6, 8, and 10, whereas in the M-1 group, significant reduction was attained only at week 6. Histopathologic examination revealed that both treatments improved glomerular and arteriolar sclerosis. Glomerular sclerosis, however, was less pronounced in the aranidipine-treated group than in the M-1 group. In conclusion, aranidipine has dilator action on both arterioles, whereas M-1 caused predominant dilation of afferent arterioles. Such metabolic changes may constitute a determinant of efferent arteriolar action of the calcium antagonist.
Nakamura
A
A
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Hayashi
K
K
Fujiwara
K
K
Ozawa
Y
Y
Honda
M
M
Saruta
T
T
D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009392:Nephrectomy; D009638:Norepinephrine / Q000494:pharmacology; D011507:Proteinuria / Q000652:urine; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012079:Renal Circulation / Q000187:drug effects*; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013599:Systole
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D017673:Sodium Chloride, Dietary; C059427:aranidipine; D003404:Creatinine; D009638:Norepinephrine