Introduction
Pharmacological nitric oxide (NO) synthase inhibition with nitro-L-arginine methyl ester (L-NAME) causes acute hypertension in otherwise normotensive humans (Sander et al. 1999). Thus, NO constitutes an important endogenous antihypertensive mechanism, primarily related to its pivotal role in tonic endothelium-dependent vasodilatation. The aim of the present study was to test the extent to which NO synthase inhibition causes vasoconstriction in different vascular beds.
Methods
In healthy echogenic young adults during supine rest, we measured mean arterial pressure (MAP), heart rate, cardiac output, and blood flow in the common carotid, brachial, femoral, superior mesenteric and renal arteries by noninvasive ultrasound Doppler techniques as well as forearm and calf blood flow by venous occlusion plethysmography. These variables were obtained before, during and for 2 hours after L-NAME (4 mg/kg intravenously over 1 hour). All protocols were approved by the ethics committee for Copenhagen and Frederiksberg Counties, and all subjects gave written informed consent.
Results
L-NAME caused robust increases in MAP (+21±2 mmHg), which were sustained for more than 2 hours after end of L-NAME-infusion. The maximum increase in MAP occurred late in all subjects (1-2 hours after end of L-NAME-infusion) confirming previously published results (Sander et al.1999). The new findings are threefold: 1) L-NAME caused a 23±13% decrease in cardiac output, chiefly related to bradycardia (heart rate decreased by 18±3%), and a 56±14% increase in total peripheral resistance; 2) surprisingly L-NAME, despite decreasing cardiac output, caused no significant changes in brachial, femoral and carotid artery blood flows as well as only minor changes in calf blood flow (10%) and forearm blood flow (20%); and 3) in contrast, L-NAME severely restrained renal and superior mesenteric artery blood flow by 30±10 and 39±11% respectively. When calculated as MAP/blood flow, regional vascular resistances were all significantly increased, but to very variable degrees depending on the L-NAME-induced effects on blood pressure. Subsequent administration of the NO synthase substrate, L-arginine (200 mg/kg intravenously over 15 minutes), caused substantial reversal of the L-NAME-effects in all vascular beds, providing evidence for the specificity of L-NAME to induce acute hypertension due to NO synthase inhibition.
Conclusions
Systemic L-NAME in humans causes an acute form of hypertension characterized by a widespread increase in vascular resistance. However, the renal and mesenteric vasoconstrictor responses dominate over skeletal muscle and carotid vascular responses. These data provide preliminary evidence for large differences in the tonic NO-dependent vasodilatation between different vascular beds in resting humans.
References
Sander M, Chavoshan B & Victor RG. 1999 Hypertension 33:937-42.