Valsartan improves endothelial dysfunction in hypertension: a randomized, double-blind study.
Endothelial dysfunction can predict cardiac outcomes in hypertension and reversing this abnormality has become an attractive therapeutic objective. We tested the hypothesis that blocking the angiotensin type 1 (AT(1)) receptor with valsartan in comparison with amlodipine would lead to an improvement in forearm resistance artery endothelial dysfunction. In total, 25 hypertensive subjects (mean age 60 years, SD 8) with a mean daytime ambulatory blood pressure (BP) of 154 (10)/97 (6) mmHg were randomized following a 3-week placebo run-in period to a double-blind, crossover trial of 16-week treatment periods with either valsartan or amlodipine, separated by a 3-week washout period. Intra-arterial infusions of acetylcholine (ACh) and N(G)-monomethyl-L-arginine (L-NMMA) were used to assess stimulated and basal endothelium-dependent nitric oxide (NO) release, respectively. Coinfusion of ACh and L-NMMA was employed to investigate the existence of an NO-independent vasodilatory pathway. Valsartan and amlodipine each lowered the clinical BP to the same extent (139 [7]/87 [6] and 139 [11]/89 [4] mmHg, respectively). The vasodilatory response to ACh was significantly increased with valsartan (maximal percentage change in forearm blood flow (max. DeltaFBF%) 301 [47] vs. 185 [34], mean [SEM]; P < 0.05) as compared with placebo, but remained unchanged with amlodipine. Both valsartan and amlodipine similarly increased the vasoconstrictive response to L-NMMA (max. DeltaFBF%-43 [5], -42 [5], respectively, vs. -26 [3] baseline; P < 0.001). The vasodilatory response after coinfusion of ACh and L-NMMA was significantly (P < 0.05) enhanced only with valsartan. Valsartan reserved peripheral endothelial dysfunction through both NO-dependent and -independent pathways, while for the same degree of BP control, amlodipine had only a partial effect on NO bioactivity.
Tzemos
Nikolaos
N
Hypertension Research Centre, Division of Medicine and Therapeutics, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. nikotzemos@yahoo.co.uk
Lim
Pitt O
PO
MacDonald
Thomas M
TM
D000109:Acetylcholine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001774:Blood Chemical Analysis; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D013777:Tetrazoles; D014665:Vasodilator Agents; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D000068756:Valsartan; D052250:Nitric Oxide Synthase Type III; D014633:Valine; D000109:Acetylcholine