Effects of Nitric Oxide Synthase Inhibition on Regional Cerebral Blood Flow and Vascular Resistance in Conscious and Isoflurane-Anesthetized Rats

The aim of this study was to estimate the effect of Nitric Oxide synthase (NOS)-inhibition (L-NMMA) on the diameter of the middle cerebral artery (MCA) and on regional cerebral blood flow (rCBF). Furthermore, to assess the effect of L-NMMA on acetazolamide induced increases in MCA blood velocity (Vmean) and rCBF. In an open crossover design 12 healthy subjects attended the laboratory twice. The first day 6 mg/kg L-LNMMA i.v. over 15 min preceded 1 g acetazolamide iv over 5 min. Eight days later only acetazolamide was given. Vmean in MCA was determined with transcranial Doppler (TCD) and rCBF with Xe-133 inhalation SPECT at baseline, after L-NMMA and 25 and 55 min after acetazolamide infusion. After L-NMMA the decrease in rCBFMCA was 6.8% (± 7.4) ( P < 0.019, n = 12), whereas Vmean was not affected ( P = 0.83, n = 8). The change in MCA diameter was estimated to -1.3% ( P = 0.44, n = 8). L-NMMA did not affect acetazolamide increases in Vmean ( P = 0.67, n = 8) nor rCBF ( P = 0.29, n = 12). The percentage increase of Vmean was 1.5 times that of rCBF ( n = 8). Our data suggest that the basal tone of human cerebral arterioles but not of conduit arteries is NO-dependent. The action of acetazolamide in man is not NO-dependent.

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Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids

Journal of Clinical Investigation ◽

10.1172/jci15481e1 ◽

2003 ◽

Vol 111 (5) ◽

pp. 759-759

Author(s):

Florian P. Limbourg ◽

Zhihong Huang ◽

Jean-Christophe Plumier ◽

Tommaso Simoncini ◽

Masayuki Fujioka ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

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Cerebral Blood Flow During Inhibition of Brain Nitric Oxide Synthase Activity in Normal, Hypertensive, and Stroke-Prone Rats

Stroke ◽

10.1161/01.str.26.6.1079 ◽

1995 ◽

Vol 26 (6) ◽

pp. 1079-1085 ◽

Cited By ~ 19

Author(s):

Makoto Izuta ◽

Nathalie Clavier ◽

Jeffrey R. Kirsch ◽

Richard J. Traystman

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Nitric Oxide Synthase ◽

Oxide Synthase ◽

Brain Nitric Oxide ◽

Nitric Oxide Synthase Activity

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Endothelium-derived nitric oxide mediates hypoxic vasodilation of resistance vessels in humans

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.271.3.h1182 ◽

1996 ◽

Vol 271 (3) ◽

pp. H1182-H1185 ◽

Cited By ~ 33

Author(s):

M. L. Blitzer ◽

S. D. Lee ◽

M. A. Creager

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Nitric Oxide Synthase ◽

Vascular Resistance ◽

Forearm Blood Flow ◽

Vasodilator Response ◽

Healthy Humans ◽

Resistance Vessels ◽

Oxide Synthase ◽

Forearm Vascular Resistance

Endothelium-derived nitric oxide (EDNO) contributes to basal systemic vascular resistance under normoxic conditions. The purpose of this investigation was to determine whether EDNO contributes to the regulation of limb vascular resistance during hypoxia in healthy humans. Forearm blood flow was assessed by venous occlusion plethysmography. Hypoxia was induced by delivering a mixture of N2 and O2 via a gas blender adjusted to reduce the PO2 to 50 mmHg. During hypoxia, forearm blood flow increased from 2.4 +/- 0.2 to 3.0 +/- 0.3 ml.100 ml-1.min-1 (P < 0.001), and forearm vascular resistance decreased from 38 +/- 3 to 29 +/- 3 units (P < 0.001). The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 2,000 micrograms/min intra-arterially) was administered to eight subjects. The percent increase in forearm vascular resistance after administration of L-NMMA was greater during hypoxia than normoxia (67 +/- 14 vs. 39 +/- 15%, P < 0.05). L-NMMA reduced the forearm vasodilator response to hypoxia from 27 +/- 3 to 11 +/- 5% (P = 0.01). To exclude the possibility that this attenuated response to hypoxia was a consequence of vasoconstriction and not specific for nitric oxide synthase inhibition, six subjects received intra-arterial phenylephrine. Phenylephrine did not affect the vasodilator response to hypoxia (17 +/- 3 vs. 21 +/- 6%, P = NS). It is concluded that EDNO contributes to hypoxia-induced vasodilation in the forearm resistance vessels in healthy humans.

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Rapamycin Induces an eNOS (Endothelial Nitric Oxide Synthase) Dependent Increase in Brain Collateral Perfusion in Wistar and Spontaneously Hypertensive Rats

Stroke ◽

10.1161/strokeaha.120.029781 ◽

2020 ◽

Vol 51 (9) ◽

pp. 2834-2843

Author(s):

Daniel J. Beard ◽

Zhaojin Li ◽

Anna M. Schneider ◽

Yvonne Couch ◽

Marilyn J. Cipolla ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Nitric Oxide Synthase ◽

Spontaneously Hypertensive Rats ◽

Infarct Volume ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Background and Purpose: Rapamycin is a clinically approved mammalian target of rapamycin inhibitor that has been shown to be neuroprotective in animal models of stroke. However, the mechanism of rapamycin-induced neuroprotection is still being explored. Our aims were to determine if rapamycin improved leptomeningeal collateral perfusion, to determine if this is through eNOS (endothelial nitric oxide synthase)-mediated vessel dilation and to determine if rapamycin increases immediate postreperfusion blood flow. Methods: Wistar and spontaneously hypertensive rats (≈14 weeks old, n=22 and n=15, respectively) were subjected to ischemia by middle cerebral artery occlusion (90 and 120 minutes, respectively) with or without treatment with rapamycin at 30-minute poststroke. Changes in middle cerebral artery and collateral perfusion territories were measured by dual-site laser Doppler. Reactivity to rapamycin was studied using isolated and pressurized leptomeningeal anastomoses. Brain injury was measured histologically or with triphenyltetrazolium chloride staining. Results: In Wistar rats, rapamycin increased collateral perfusion (43±17%), increased reperfusion cerebral blood flow (16±8%) and significantly reduced infarct volume (35±6 versus 63±8 mm 3 , P <0.05). Rapamycin dilated leptomeningeal anastomoses by 80±9%, which was abolished by nitric oxide synthase inhibition. In spontaneously hypertensive rats, rapamycin increased collateral perfusion by 32±25%, reperfusion cerebral blood flow by 44±16%, without reducing acute infarct volume 2 hours postreperfusion. Reperfusion cerebral blood flow was a stronger predictor of brain damage than collateral perfusion in both Wistar and spontaneously hypertensive rats. Conclusions: Rapamycin increased collateral perfusion and reperfusion cerebral blood flow in both Wistar and comorbid spontaneously hypertensive rats that appeared to be mediated by enhancing eNOS activation. These findings suggest that rapamycin may be an effective acute therapy for increasing collateral flow and as an adjunct therapy to thrombolysis or thrombectomy to improve reperfusion blood flow.

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