Intracarotid infusion of the nitric oxide synthase inhibitor, L-NMMA, modestly decreases cerebral blood flow in human subjects.
BACKGROUND
The authors hypothesized that if nitric oxide (NO) was a determinant of background cerebrovascular tone, intracarotid infusion of NG-monomethyl-L-arginine (L-NMMA), a NO synthase (NOS) inhibitor, would decrease cerebral blood flow (CBF) and intracarotid L-arginine would reverse its effect.


METHODS
In angiographically normal cerebral hemispheres, after the initial dose-escalation studies (protocol 1), the authors determined the effect of intracarotid L-NMMA (50 mg/min for 5 min) on CBF and mean arterial pressure (MAP) over time (protocol 2). Changes in CBF and MAP were then determined at baseline, during L-NMMA infusion, and after L-NMMA during L-arginine infusion (protocol 3). To investigate effects of higher arterial blood concentrations of L-NMMA, changes in CBF and MAP were assessed at baseline and after a bolus dose of L-NMMA (250 mg/1 min), and vascular reactivity was tested by intracarotid verapamil (1 mg/min, protocol 4). CBF changes were also assessed during induced hypertension with intravenous phenylephrine (protocol 5).


RESULTS
Infusion of L-NMMA (50 mg/min for 5 min, n = 7, protocol 2) increased MAP by 17% (86 +/- 8 to 100 +/- 11 mmHg; P < 0.0001) and decreased CBF by 20% (45 +/- 8 to 36 +/- 6 ml. 100 g-1. min-1; P < 0.005) for 10 min. Intracarotid l-arginine infusion after L-NMMA (protocol 3) reversed the effect of L-NMMA. Bolus L-NMMA (protocol 4) increased MAP by 20% (80 +/- 11 to 96+/-13 mmHg; P< 0.005), but there was no significant decrease in CBF. Intracarotid verapamil increased CBF by 41% (44+/- 8 to 62 +/- 9 ml. 100 g-1. min-1; P< 0.005). Phenylephrine-induced hypertension increased MAP by 20% (79 +/- 9 to 95 +/- 6 mmHg; P = 0.001) but did not affect CBF.


CONCLUSIONS
The results suggest that intracarotid L-NMMA modestly decreases CBF, and the background tone of cerebral resistance vessels may be relatively insensitive to NOS inhibition by the intraarterial route.
Joshi
S
S
Departments of Anesthesiology, Neurological Surgery, and Radiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Young
W L
WL
Duong
D H
DH
Ostapkovich
N D
ND
Aagaard
B D
BD
Hashimoto
T
T
Pile-Spellman
J
J
D000328:Adult; D000368:Aged; D001120:Arginine / Q000494:pharmacology; D002339:Carotid Arteries; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019323:omega-N-Methylarginine / Q000008:administration & dosage / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase