Cerebral blood flow during inhibition of brain nitric oxide synthase activity in normal, hypertensive, and stroke-prone rats

Makoto Izuta, Nathalie Clavier, Jeffrey Kirsch, Richard J. Traystman

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Because tonic production of nitric oxide (NO) is important in regulating cerebrovascular tone and NO may be important in the mechanism of brain injury from focal ischemia, we speculated that stroke predisposition in spontaneously hypertensive stroke-prone rats (SHR-SP) may be related to impaired tonic production of NO. This study was designed to test the hypothesis that the cerebral blood flow (CBF) response to inhibition of NO synthase in SHR-SP would be different than that observed in normal Wistar-Kyoto (WKY) rats and non-stroke-prone spontaneously hypertensive rats (SHR). Methods Pentobarbital-anesthetized, mechanically ventilated rats were tested for CBF response to saline, 5 or 20 mg/kg IV of NG-monomethyl-L-arginine (L-NMMA), or 20 mg/kg IV of Nomega-nitro-L-arginine (L-NA). In addition, specificity for an NO-dependent mechanism was assessed by determining the ability to reverse any alteration in CBF with L-arginine. Hemorrhage was used to minimize any increase in mean arterial blood pressure (MABP) from NO synthase inhibition. In a separate cohort of rats, differential sensitivity of NO synthase for inhibition by nitro-arginine analogues was determined. Results Baseline MABP was greater in SHR-SP (185 plus minus 3, n equals 38) and SHR (169 plus minus 3, n equals 38) compared with WKY rats (101 plus minus 2 mm Hg, n equals 38, P less than.05). Baseline CBF was similar between strains; however, cerebrovascular resistance was higher in SHR-SP (2.16 plus minus 0.09, n equals 27) and SHR (1.94 plus minus 0.07, n equals 27) compared with WKY rats (1.23 plus minus 0.06 mm Hg/mL per minute per 100 g, n equals 27, P less than.05). CBF was unchanged with 5 mg/kg L-NMMA or with L-arginine in the absence of L-NMMA in each strain. CBF decreased similarly in SHR and SHR-SP (n equals 9 each) in response to 20 mg/kg L-NMMA (SHR, 85 plus minus 6 to 67 plus minus 6; SHR-SP, 87 plus minus 7 to 69 plus minus 5 mL/min per 100 g) and was completely reversed by L-arginine. CBF did not decrease with 20 mg/kg L-NMMA in WKY rats. Administration of L-NA (n equals 5 each) produced similar reduction of CBF (WKY rats, 67 plus minus 6%; SHR, 49 plus minus 9%; SHR-SP, 61 plus minus 6% of baseline) and inhibition of NO synthase in each strain (approximate equal 80% inhibition). Conclusions There was no difference in the cerebrovascular response to NO synthase inhibition in SHR-SP and non-stroke-prone SHR. Therefore, it is unlikely that an altered sensitivity of NO synthase to inhibition can explain predisposition to stroke in SHR-SP.

Original languageEnglish (US)
Pages (from-to)1079-1085
Number of pages7
JournalStroke
Volume26
Issue number6
StatePublished - 1995
Externally publishedYes

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Cerebrovascular Circulation
Nitric Oxide Synthase
Stroke
omega-N-Methylarginine
Inbred SHR Rats
Brain
Inbred WKY Rats
Arginine
Arterial Pressure
Nitric Oxide
Pentobarbital
Brain Injuries

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing
  • Neuroscience(all)

Cite this

Cerebral blood flow during inhibition of brain nitric oxide synthase activity in normal, hypertensive, and stroke-prone rats. / Izuta, Makoto; Clavier, Nathalie; Kirsch, Jeffrey; Traystman, Richard J.

In: Stroke, Vol. 26, No. 6, 1995, p. 1079-1085.

Research output: Contribution to journalArticle

Izuta, Makoto ; Clavier, Nathalie ; Kirsch, Jeffrey ; Traystman, Richard J. / Cerebral blood flow during inhibition of brain nitric oxide synthase activity in normal, hypertensive, and stroke-prone rats. In: Stroke. 1995 ; Vol. 26, No. 6. pp. 1079-1085.
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title = "Cerebral blood flow during inhibition of brain nitric oxide synthase activity in normal, hypertensive, and stroke-prone rats",
abstract = "Because tonic production of nitric oxide (NO) is important in regulating cerebrovascular tone and NO may be important in the mechanism of brain injury from focal ischemia, we speculated that stroke predisposition in spontaneously hypertensive stroke-prone rats (SHR-SP) may be related to impaired tonic production of NO. This study was designed to test the hypothesis that the cerebral blood flow (CBF) response to inhibition of NO synthase in SHR-SP would be different than that observed in normal Wistar-Kyoto (WKY) rats and non-stroke-prone spontaneously hypertensive rats (SHR). Methods Pentobarbital-anesthetized, mechanically ventilated rats were tested for CBF response to saline, 5 or 20 mg/kg IV of NG-monomethyl-L-arginine (L-NMMA), or 20 mg/kg IV of Nomega-nitro-L-arginine (L-NA). In addition, specificity for an NO-dependent mechanism was assessed by determining the ability to reverse any alteration in CBF with L-arginine. Hemorrhage was used to minimize any increase in mean arterial blood pressure (MABP) from NO synthase inhibition. In a separate cohort of rats, differential sensitivity of NO synthase for inhibition by nitro-arginine analogues was determined. Results Baseline MABP was greater in SHR-SP (185 plus minus 3, n equals 38) and SHR (169 plus minus 3, n equals 38) compared with WKY rats (101 plus minus 2 mm Hg, n equals 38, P less than.05). Baseline CBF was similar between strains; however, cerebrovascular resistance was higher in SHR-SP (2.16 plus minus 0.09, n equals 27) and SHR (1.94 plus minus 0.07, n equals 27) compared with WKY rats (1.23 plus minus 0.06 mm Hg/mL per minute per 100 g, n equals 27, P less than.05). CBF was unchanged with 5 mg/kg L-NMMA or with L-arginine in the absence of L-NMMA in each strain. CBF decreased similarly in SHR and SHR-SP (n equals 9 each) in response to 20 mg/kg L-NMMA (SHR, 85 plus minus 6 to 67 plus minus 6; SHR-SP, 87 plus minus 7 to 69 plus minus 5 mL/min per 100 g) and was completely reversed by L-arginine. CBF did not decrease with 20 mg/kg L-NMMA in WKY rats. Administration of L-NA (n equals 5 each) produced similar reduction of CBF (WKY rats, 67 plus minus 6{\%}; SHR, 49 plus minus 9{\%}; SHR-SP, 61 plus minus 6{\%} of baseline) and inhibition of NO synthase in each strain (approximate equal 80{\%} inhibition). Conclusions There was no difference in the cerebrovascular response to NO synthase inhibition in SHR-SP and non-stroke-prone SHR. Therefore, it is unlikely that an altered sensitivity of NO synthase to inhibition can explain predisposition to stroke in SHR-SP.",
author = "Makoto Izuta and Nathalie Clavier and Jeffrey Kirsch and Traystman, {Richard J.}",
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T1 - Cerebral blood flow during inhibition of brain nitric oxide synthase activity in normal, hypertensive, and stroke-prone rats

AU - Izuta, Makoto

AU - Clavier, Nathalie

AU - Kirsch, Jeffrey

AU - Traystman, Richard J.

PY - 1995

Y1 - 1995

N2 - Because tonic production of nitric oxide (NO) is important in regulating cerebrovascular tone and NO may be important in the mechanism of brain injury from focal ischemia, we speculated that stroke predisposition in spontaneously hypertensive stroke-prone rats (SHR-SP) may be related to impaired tonic production of NO. This study was designed to test the hypothesis that the cerebral blood flow (CBF) response to inhibition of NO synthase in SHR-SP would be different than that observed in normal Wistar-Kyoto (WKY) rats and non-stroke-prone spontaneously hypertensive rats (SHR). Methods Pentobarbital-anesthetized, mechanically ventilated rats were tested for CBF response to saline, 5 or 20 mg/kg IV of NG-monomethyl-L-arginine (L-NMMA), or 20 mg/kg IV of Nomega-nitro-L-arginine (L-NA). In addition, specificity for an NO-dependent mechanism was assessed by determining the ability to reverse any alteration in CBF with L-arginine. Hemorrhage was used to minimize any increase in mean arterial blood pressure (MABP) from NO synthase inhibition. In a separate cohort of rats, differential sensitivity of NO synthase for inhibition by nitro-arginine analogues was determined. Results Baseline MABP was greater in SHR-SP (185 plus minus 3, n equals 38) and SHR (169 plus minus 3, n equals 38) compared with WKY rats (101 plus minus 2 mm Hg, n equals 38, P less than.05). Baseline CBF was similar between strains; however, cerebrovascular resistance was higher in SHR-SP (2.16 plus minus 0.09, n equals 27) and SHR (1.94 plus minus 0.07, n equals 27) compared with WKY rats (1.23 plus minus 0.06 mm Hg/mL per minute per 100 g, n equals 27, P less than.05). CBF was unchanged with 5 mg/kg L-NMMA or with L-arginine in the absence of L-NMMA in each strain. CBF decreased similarly in SHR and SHR-SP (n equals 9 each) in response to 20 mg/kg L-NMMA (SHR, 85 plus minus 6 to 67 plus minus 6; SHR-SP, 87 plus minus 7 to 69 plus minus 5 mL/min per 100 g) and was completely reversed by L-arginine. CBF did not decrease with 20 mg/kg L-NMMA in WKY rats. Administration of L-NA (n equals 5 each) produced similar reduction of CBF (WKY rats, 67 plus minus 6%; SHR, 49 plus minus 9%; SHR-SP, 61 plus minus 6% of baseline) and inhibition of NO synthase in each strain (approximate equal 80% inhibition). Conclusions There was no difference in the cerebrovascular response to NO synthase inhibition in SHR-SP and non-stroke-prone SHR. Therefore, it is unlikely that an altered sensitivity of NO synthase to inhibition can explain predisposition to stroke in SHR-SP.

AB - Because tonic production of nitric oxide (NO) is important in regulating cerebrovascular tone and NO may be important in the mechanism of brain injury from focal ischemia, we speculated that stroke predisposition in spontaneously hypertensive stroke-prone rats (SHR-SP) may be related to impaired tonic production of NO. This study was designed to test the hypothesis that the cerebral blood flow (CBF) response to inhibition of NO synthase in SHR-SP would be different than that observed in normal Wistar-Kyoto (WKY) rats and non-stroke-prone spontaneously hypertensive rats (SHR). Methods Pentobarbital-anesthetized, mechanically ventilated rats were tested for CBF response to saline, 5 or 20 mg/kg IV of NG-monomethyl-L-arginine (L-NMMA), or 20 mg/kg IV of Nomega-nitro-L-arginine (L-NA). In addition, specificity for an NO-dependent mechanism was assessed by determining the ability to reverse any alteration in CBF with L-arginine. Hemorrhage was used to minimize any increase in mean arterial blood pressure (MABP) from NO synthase inhibition. In a separate cohort of rats, differential sensitivity of NO synthase for inhibition by nitro-arginine analogues was determined. Results Baseline MABP was greater in SHR-SP (185 plus minus 3, n equals 38) and SHR (169 plus minus 3, n equals 38) compared with WKY rats (101 plus minus 2 mm Hg, n equals 38, P less than.05). Baseline CBF was similar between strains; however, cerebrovascular resistance was higher in SHR-SP (2.16 plus minus 0.09, n equals 27) and SHR (1.94 plus minus 0.07, n equals 27) compared with WKY rats (1.23 plus minus 0.06 mm Hg/mL per minute per 100 g, n equals 27, P less than.05). CBF was unchanged with 5 mg/kg L-NMMA or with L-arginine in the absence of L-NMMA in each strain. CBF decreased similarly in SHR and SHR-SP (n equals 9 each) in response to 20 mg/kg L-NMMA (SHR, 85 plus minus 6 to 67 plus minus 6; SHR-SP, 87 plus minus 7 to 69 plus minus 5 mL/min per 100 g) and was completely reversed by L-arginine. CBF did not decrease with 20 mg/kg L-NMMA in WKY rats. Administration of L-NA (n equals 5 each) produced similar reduction of CBF (WKY rats, 67 plus minus 6%; SHR, 49 plus minus 9%; SHR-SP, 61 plus minus 6% of baseline) and inhibition of NO synthase in each strain (approximate equal 80% inhibition). Conclusions There was no difference in the cerebrovascular response to NO synthase inhibition in SHR-SP and non-stroke-prone SHR. Therefore, it is unlikely that an altered sensitivity of NO synthase to inhibition can explain predisposition to stroke in SHR-SP.

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