Impaired endothelium-dependent vasodilation in patients with essential hypertension. Evidence that nitric oxide abnormality is not localized to a single signal transduction pathway.
BACKGROUND
Patients with essential hypertension have abnormal endothelium-dependent vascular relaxation, largely related to reduced bioactivity of nitric oxide (NO). The purpose of the present investigation was to determine whether this defect is due to a deficit at the specific intracellular signal-transduction pathway level or is a consequence of a more generalized endothelial abnormality.


RESULTS
The responses of the forearm vasculature to acetylcholine and bradykinin (endothelium-dependent agents that act through different signal transduction pathways) and to sodium nitroprusside (a direct dilator of vascular smooth muscle) were studied in 10 hypertensive patients (5 men, 5 women; aged 48 +/- 9 years old [mean +/- SD]) and 12 control subjects (6 men, 6 women; aged 48 +/- 7 years old). To determine the contribution of NO to bradykinin-induced vasodilation, the vascular responses to bradykinin were also measured after administration of NG-monomethyl-L-arginine, an arginine analogue that inhibits the synthesis of NO. Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. The response to acetylcholine was significantly blunted in hypertensive patients (maximal blood flow, 7.5 +/- 2 versus 16.6 +/- 8 mL.min-1.100 mL-1 in control subjects [mean +/- SD]; P < .005). Similarly, the vasodilator effect of bradykinin was significantly reduced in hypertensive patients compared with control subjects (maximal blood flow, 8.7 +/- 2 versus 15.8 +/- 6 mL.min-1.100 mL-1 in control subjects; P < .005). A significant correlation was found between the maximal blood flow with acetylcholine and that with bradykinin (r = .89). No significant differences were found between the two groups for vascular response to sodium nitroprusside. NG-monomethyl-L-arginine significantly blunted the response to bradykinin in control subjects (maximal blood flow decreased from 15.8 +/- 6 to 10.1 +/- 2 mL.min-1.100 mL-1, P < .003). In contrast, inhibition of NO synthesis did not modify the response to bradykinin in hypertensive patients (maximal blood flow, 8.7 +/- 2 and 8.5 +/- 3 before and during infusion of NG-monomethyl-L-arginine, respectively; P = NS). As a consequence, the response to bradykinin after inhibition of NO synthesis was not significantly different between the two groups.


CONCLUSIONS
Patients with essential hypertension have impaired endothelium-dependent vasodilator responses to both acetylcholine and bradykinin. These findings indicate that the endothelial dysfunction in this condition is not related to a specific defect of a single intracellular signal-transduction pathway and suggest a more generalized abnormality of endothelial vasodilator function.
Panza
J A
JA
Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. 20892.
García
C E
CE
Kilcoyne
C M
CM
Quyyumi
A A
AA
Cannon
R O
RO
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001132:Arm / Q000098:blood supply; D001920:Bradykinin / Q000494:pharmacology; D005260:Female; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D015398:Signal Transduction; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D019323:omega-N-Methylarginine
D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D000109:Acetylcholine; D001920:Bradykinin