Endogenous endothelin-1 limits exercise-induced vasodilation in hypertensive humans.
Essential hypertension is a common disorder, associated with increased endothelin-1-mediated vasoconstrictor tone at rest. We hypothesized that increased vasoconstrictor activity of endothelin-1 might explain why the normal decrease in peripheral vascular resistance in response to exercise is attenuated in hypertensive patients. Therefore, we investigated the effect of endothelin A (ET(A)) receptor blockade on the vasodilator response to handgrip exercise. Forearm blood flow responses to handgrip exercise (15%, 30%, and 45% of maximum voluntary contraction) were assessed in hypertensive patients and matched normotensive subjects, before and after intra-arterial infusions of the ET(A) receptor antagonist BQ-123; a control dilator, hydralazine; and placebo (saline). Preinfusion (baseline) vasodilation in response to exercise was significantly attenuated at each workload in hypertensive patients compared with normotensive subjects. Intra-arterial infusions of hydralazine and saline did not increase the vasodilator response to exercise in either hypertensives or normotensives at any workload. The vasodilator response to exercise was markedly enhanced after BQ-123 at the 2 higher workloads in hypertensives (157+/-48%, P<0.01; 203+/-58%, P<0.01) but not in normotensives. This suggests that the impaired vasodilator response to exercise in hypertensive patients is, at least in part, a functional limitation caused by endogenous ET(A) receptor-mediated vasoconstriction. Treatment with endothelin receptor antagonists may, therefore, increase exercise capacity in essential hypertension.
McEniery
Carmel M
CM
Clinical Pharmacology Unit and Research Centre, University of Endinburgh, Western General Hospital, United Kingdom. cmm41@cam.ac.uk
Wilkinson
Ian B
IB
Jenkins
David G
DG
Webb
David J
DJ
D000328:Adult; D000959:Antihypertensive Agents / Q000494:pharmacology; D018592:Cross-Over Studies; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D005542:Forearm / Q000098:blood supply; D018737:Hand Strength / Q000502:physiology*; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology*; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D016037:Single-Blind Method; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D006830:Hydralazine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)