title: Additive effects of cilnidipine, an L-/N-type calcium channel blocker, and an angiotensin II receptor blocker on reducing cardiorenal damage in Otsuka Long-Evans Tokushima Fatty rats with type 2 diabetes mellitus.
abstract: Cilnidipine (Cil), which is an L-/N-type calcium channel blocker (CCB), has been known to provide renal protection by decreasing the activity of the sympathetic nervous system (SNS) and the renin-angiotensin system. In this study, we compared the effects of the combination of Cil and amlodipine (Aml), which is an L-type CCB, with an angiotensin (Ang) II receptor blocker on diabetic cardiorenal damage in spontaneously type 2 diabetic rats. Seventeen-week-old Otsuka Long-Evans Tokushima Fatty rats were randomly assigned to receive Cil, Aml, valsartan (Val), Cil + Val, Aml + Val, or a vehicle (eight rats per group) for 22 weeks. Antihypertensive potencies were nearly equal among the CCB monotherapy groups and the combination therapy groups. The lowering of blood pressure by either treatment did not significantly affect the glycemic variables. However, exacerbations of renal and heart failure were significantly suppressed in rats administered Cil or Val, and additional suppression was observed in those administered Cil + Val. Although Val increased the renin-Ang system, Aml + Val treatment resulted in additional increases in these parameters, while Cil + Val did not show such effects. Furthermore, Cil increased the ratio of Ang-(1-7) to Ang-I, despite the fact that Val and Aml + Val decreased the Ang-(1-7) levels. These actions of Cil + Val might be due to their synergistic inhibitory effect on the activity of the SNS, and on aldosterone secretion through N-type calcium channel antagonism and Ang II receptor type 1 antagonism. Thus, Cil may inhibit the progression of cardiorenal disease in type 2 diabetes patients by acting as an N-type CCB and inhibiting the aldosterone secretion and SNS activation when these drugs were administered in combination with an Ang II receptor blocker.
authors: Division of Diabetes and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Japan ; Department of Clinical Research, National Hospital Organization, Utsunomiya National Hospital, Utsunomiya, Japan.
authors: Yutaka
authors: Y
authors: Mori
authors: Research Center, Ajinomoto Pharmaceuticals Co, Ltd, Kanagawa, Japan.
authors: Shizuka
authors: S
authors: Aritomi
authors: Research Center, Ajinomoto Pharmaceuticals Co, Ltd, Kanagawa, Japan.
authors: Kazumi
authors: K
authors: Niinuma
authors: Research Center, Ajinomoto Pharmaceuticals Co, Ltd, Kanagawa, Japan.
authors: Tarou
authors: T
authors: Nakamura
authors: Division of Diabetes and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Japan.
authors: Kenichi
authors: K
authors: Matsuura
authors: Division of Diabetes and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Japan.
authors: Junichi
authors: J
authors: Yokoyama
authors: Division of Diabetes and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, Japan.
authors: Kazunori
authors: K
authors: Utsunomiya
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism; D059347:Cardio-Renal Syndrome / Q000188:drug therapy*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004095:Dihydropyridines; D008297:Male; D051381:Rats; D020334:Rats, Inbred OLETF
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D004095:Dihydropyridines; C065927:cilnidipine
keywords: angiotensin; calcium channel blocker; combination therapy; type 2 diabetes mellitus