Elevated prorenin levels associate with microvascular complications in patients with diabetes mellitus, possibly because prorenin affects vascular function in diabetes mellitus, for example by generating angiotensins following its binding to the (pro)renin receptor [(P)RR]. Here we evaluated whether the renin inhibitor aliskiren, with or without the putative (P)RR antagonist handle region peptide (HRP) improved the disturbed vascular function in diabetic TGR(mREN2)27 rats, a high-prorenin, high-(P)RR hypertensive model.
Telemetry transmitters were implanted to monitor blood pressure. After 3 weeks of treatment, rats were sacrificed, and iliac and mesenteric arteries were removed to evaluate vascular reactivity.
Diabetes mellitus enhanced the contractile response to nitric oxide synthase (NOS) blockade, potentiated the response to phenylephrine, diminished the effectiveness of endothelin type A (ETA) receptor blockade and allowed acetylcholine to display constrictor, cyclo-oxygenase-2 mediated, endothelium-dependent responses in the presence of NOS inhibition and blockers of endothelium-derived hyperpolarizing factors. Aliskiren normalized blood pressure, suppressed renin activity, and reversed the above vascular effects, with the exception of the altered effectiveness of ETA receptor blockade. Remarkably, when adding HRP on top of aliskiren, its beneficial vascular effects either disappeared or were greatly diminished, although HRP did not alter the effect of aliskiren on blood pressure and renin activity.
Renin inhibition improves vascular dysfunction in diabetic hypertensive rats, and HRP counteracts this effect independently of blood pressure and angiotensin. (P)RR blockade therefore is unlikely to be a new tool to further suppress the renin–angiotensin system (RAS) on top of existing RAS blockers.
Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
*Wendy W. Batenburg and Mieke van den Heuvel contributed equally to the writing of this article.
Correspondence to Professor Dr. A.H.J. Danser, PhD, Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Room EE1418b, Dr Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands. Tel: +31 10 7043540; fax: +31 10 7044733; e-mail: firstname.lastname@example.org
Abbreviations: (P)RR, (pro)renin receptor; ACh, acetylcholine; Ang, angiotensin; COX, cyclo-oxygenase; CRC, concentration–response curve; EDCF, endothelium-derived contractile factor; EDHF, endothelium-derived hyperpolarizing factor; EKA, enzyme-kinetic assay; ETA/ETB receptor, endothelin receptor type A or B; HPRT1, hypoxanthine phosphoribosyl transferase-1; HRP, handle region peptide; MAP, mean arterial pressure; MAPK, mitogen-activated protein kinases; NOS, NO synthase; PRA, plasma renin activity; RAS, renin–angiotensin system; Ren2, TGR(mREN2)27; SKCa/IKCa channels, small/intermediate conductance Ca2+-activated K+-channel; SNAP, S-nitroso-N-penicillamine; STZ, streptozotocin; U46619, 9,11-dideoxy-11α,9α-epoxy-methano-prostaglandin F2α
Received 8 June, 2012
Revised 27 August, 2012
Accepted 30 October, 2012