Blockade of endogenous nitric oxide production results in moderate hypertension, reducing sympathetic activity and shortening bleeding time in healthy volunteers.
BACKGROUND
Short-term infusion of NG-monomethyl-L-arginine (L-NMMA) reversibly inhibits endogenous nitric oxide (NO) production in humans. We studied responses to more long-lasting (60 min) infusions, at doses high enough to cause effective inhibition of endogenous NO.


METHODS
Eight healthy volunteers had catheters (pulmonary, arterial and venous) placed. Measurements included hemodynamics, endogenous NO levels in nasal air, bleeding time, and cyclic guanosine monophosphate (cGMP) and catecholamines in plasma. L-NMMA was infused at 0.3 mg.kg-1.min-1 during 30 min, followed by 0.15 (n = 6) or 0.3 (n = 2) mg.kg-1.min-1 during 30 min.


RESULTS
L-NMMA significantly elevated mean arterial pressure by 12 +/- 3%, due to an increase in systemic vascular resistance. Cardiac output decreased by 23 +/- 3%, due to a decrease in stroke volume. Pulmonary vascular resistance (P < 0.05) increased, but mean pulmonary arterial pressure was stable. Forearm vascular resistance (P < 0.05) decreased. Bleeding time was shortened by 31 +/- 4% (P < 0.01). L-NMMA infusion reduced NO concentrations in nasal air by 64 +/- 2% (P < 0.01). Arterial pressure remained elevated and nasal NO remained depressed 90 min after the infusion, whereas most other responses were reversed at that time. Plasma cGMP showed only minor changes. Plasma norepinephrine decreased, suggesting reflexogenic inhibition of sympathetic activity, whereas epinephrine levels were low and stable throughout the experiment.


CONCLUSIONS
Dosage of (13.5 mg.kg-1 in 60 min) L-NMMA infusion in humans was well tolerated. Pronounced and long-lasting inhibition of endogenous NO production, as evidenced by measurements in nasal air, resulted in unevenly distributed vasoconstriction, a transient decrease in cardiac output, and reflexogenic sympathetic withdrawal. Furthermore, bleeding time was shortened, suggesting platelet activation.
Albert
J
J
Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
Schedin
U
U
Lindqvist
M
M
Melcher
A
A
Hjemdahl
P
P
Frostell
C
C
D000293:Adolescent; D000328:Adult; D001760:Bleeding Time; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002395:Catecholamines / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000209:etiology*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D012039:Regional Blood Flow / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects*; D013997:Time Factors; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D002395:Catecholamines; D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D006152:Cyclic GMP