Forearm vasoconstriction to endothelin-1 is impaired, but constriction to sarafotoxin 6c and vasodilatation to BQ-123 unaltered, in patients with essential hypertension.
The importance of endothelin-1 (ET-1) in the pathophysiology of essential hypertension is unclear. We therefore compared the effects of endothelin ET(A) receptor blockade and the stimulation of ET(A) and ET(B) receptors, and their interaction with the sympathetic nervous system, in the forearm resistance vessels of patients with essential hypertension and healthy control subjects. A total of 27 untreated patients with essential hypertension (blood pressure >160/100 mmHg) and 25 normotensive (blood pressure <140/90 mmHg) age- and sex-matched control subjects participated in these studies. A total of 10 patients and 10 controls took part in each phase. Locally active doses of study drugs were infused into the non-dominant brachial artery, while forearm blood flow was measured by venous occlusion plethysmography. A 60 min infusion of BQ-123 (an ET(A) receptor antagonist; 100 nmol/min) significantly increased forearm blood flow by 40+/-8% in hypertensive patients and by 35+/-5% in controls, with no difference between groups (P=0.49). Forearm vasoconstriction to ET-1 (an ET(A) and ET(B) receptor agonist; 5 pmol/min) for 90 min was significantly blunted in hypertensive patients (21+/-4%) compared with control subjects (37+/-3%; P=0.0001). Forearm vasoconstriction to sarafotoxin S6c (an ET(B) receptor agonist; 10 pmol/min) for 90 min was similar in hypertensive patients (44+/-5%) and control subjects (48+/-4%; P=0.95). Sympathetically mediated vasoconstriction produced by lower-body negative pressure was not different in hypertensive patients compared with controls, and was not affected by infusion of ET-1 or sarafotoxin S6c. There were no differences in the observed increase in forearm blood flow with a control vasodilator (sodium nitroprusside) or the observed decrease in forearm blood flow with a control vasoconstrictor (noradrenaline) between hypertensive patients and control subjects. BQ-123 produced a significant increase in forearm blood flow in hypertensive patients, consistent with the anti-hypertensive actions of this agent. In conclusion, forearm vasoconstriction to ET-1, but not to sarafotoxin S6c, was reduced in patients with essential hypertension, consistent with possible down-regulation of the ET(A) receptor in this condition.
Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Edinburgh, Scotland, U.K.
Charles J
CJ
Ferro
William G
WG
Haynes
Malcolm F
MF
Hand
David J
DJ
Webb
D000109:Acetylcholine; D001916:Brachial Artery / Q000187:drug effects / Q000503:physiopathology; D016022:Case-Control Studies; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009599:Nitroprusside; D009638:Norepinephrine; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D014757:Viper Venoms
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D009599:Nitroprusside; D000109:Acetylcholine; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D009638:Norepinephrine