Role of the L-arginine-nitric oxide pathway in the changes in cerebrovascular reactivity following hemorrhagic hypotension and retransfusion

Csaba Szabo, C. Csaki, Z. Benyo, M. Reivich, A. G B Kovach

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

We studied the involvement of the L-arginine-nitric oxide pathway in the changes in cerebrovascular reactivity following hemorrhagic hypotension and retransfusion. Feline middle cerebral arteries were prepared from control animals killed under anesthesia and from anesthetised animals subjected to hemorrhagic hypotension (stepwise bleeding to 90, 70, and 50 mmHg, maintained for 20 min at each level) followed by retransfusion (20 min). Two-mm-long vessel segments were suspended in organ chambers containing Krebs-Henseleit solution (37°C, gassed with 95% O2-5% CO2) for isometric force measurements. Contractions to noradrenaline (norepinephrine), relaxations to acetylcholine, ATP, adenosine, and SIN-1, a nitric oxide donor compound, were compared in the vessels of the control and hemorrhage-subjected animals. Contractile responses to noradrenaline were significantly enhanced after hemorrhage, whereas relaxations to acetylcholine, ATP, and adenosine were significantly reduced. Relaxations to SIN-1, however, remained unchanged. L- Arginine did not cause relaxations in control vessels but relaxed the arteries after hemorrhage and retransfusion. To clarify the involvement of the L-arginine-nitric oxide pathway in these alterations, we studied the effect of exogenous application of L-arginine, the precursor of endothelium- derived relaxing factor (EDRF) and N(G)-nitro-L-arginine (NOLA), a competitive antagonist of the EDRF-producing enzyme on the vascular responses in vitro. Similar to the effect of hypotension and retransfusion, NOLA enhanced the noradrenaline-induced contractions and inhibited the acetylcholine-induced and purinoceptor-mediated relaxations in the control arteries. In the control vessels in vitro, L-arginine treatment did not modify any contractile or relaxant response. At the same time, in vitro L- arginine treatment inhibited the hemorrhagic hypotension-induced enhancement of the contractions to noradrenaline and restored the diminished relaxations to acetylcholine (but not to ATP or adenosine). In the vessels after hemorrhage, NOLA neither further enhanced the already markedly enhanced noradrenaline-induced contractions nor further inhibited the relaxations caused by ATP and adenosine. In the case of acetylcholine, however, NOLA caused a further inhibition of the relaxations. The effect of in vivo L-Arg infusion (30 mg/kg initial bolus and 10 mg/kg/min infusion) during hemorrhagic hypotension and retransfusion on the in vitro vascular reactivity was similar to that of the in vitro L-arginine treatment. The present study demonstrates that even short-lasting hemorrhagic hypotension combined with retransfusion markedly inhibits nitric oxide-mediated, agonist-induced endothelium-dependent cerebrovascular responses. In vivo or in vitro L- arginine treatment is able to restore normal responses to some agents. Our data raise the possibility of an exhaustion of the endogeneous vascular L- arginine pools in this pathophysiological condition.

Original languageEnglish (US)
Pages (from-to)307-316
Number of pages10
JournalCirculatory Shock
Volume37
Issue number4
StatePublished - 1992
Externally publishedYes

Fingerprint

Hypotension
Arginine
Nitric Oxide
Norepinephrine
Acetylcholine
Adenosine
Hemorrhage
Adenosine Triphosphate
Blood Vessels
Endothelium-Dependent Relaxing Factors
Arteries
Controlled Hypotension
Purinergic Receptors
Nitric Oxide Donors
Felidae
Middle Cerebral Artery
Endothelium
In Vitro Techniques
Anesthesia

Keywords

  • contraction
  • endothelium-dependent relaxation
  • hemorrhagic hypotension
  • L- arginine
  • middle cerebral artery
  • NG-nitro-L-arginine
  • nitric oxide
  • shock
  • vascular smooth muscle

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Role of the L-arginine-nitric oxide pathway in the changes in cerebrovascular reactivity following hemorrhagic hypotension and retransfusion. / Szabo, Csaba; Csaki, C.; Benyo, Z.; Reivich, M.; Kovach, A. G B.

In: Circulatory Shock, Vol. 37, No. 4, 1992, p. 307-316.

Research output: Contribution to journalArticle

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AU - Csaki, C.

AU - Benyo, Z.

AU - Reivich, M.

AU - Kovach, A. G B

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N2 - We studied the involvement of the L-arginine-nitric oxide pathway in the changes in cerebrovascular reactivity following hemorrhagic hypotension and retransfusion. Feline middle cerebral arteries were prepared from control animals killed under anesthesia and from anesthetised animals subjected to hemorrhagic hypotension (stepwise bleeding to 90, 70, and 50 mmHg, maintained for 20 min at each level) followed by retransfusion (20 min). Two-mm-long vessel segments were suspended in organ chambers containing Krebs-Henseleit solution (37°C, gassed with 95% O2-5% CO2) for isometric force measurements. Contractions to noradrenaline (norepinephrine), relaxations to acetylcholine, ATP, adenosine, and SIN-1, a nitric oxide donor compound, were compared in the vessels of the control and hemorrhage-subjected animals. Contractile responses to noradrenaline were significantly enhanced after hemorrhage, whereas relaxations to acetylcholine, ATP, and adenosine were significantly reduced. Relaxations to SIN-1, however, remained unchanged. L- Arginine did not cause relaxations in control vessels but relaxed the arteries after hemorrhage and retransfusion. To clarify the involvement of the L-arginine-nitric oxide pathway in these alterations, we studied the effect of exogenous application of L-arginine, the precursor of endothelium- derived relaxing factor (EDRF) and N(G)-nitro-L-arginine (NOLA), a competitive antagonist of the EDRF-producing enzyme on the vascular responses in vitro. Similar to the effect of hypotension and retransfusion, NOLA enhanced the noradrenaline-induced contractions and inhibited the acetylcholine-induced and purinoceptor-mediated relaxations in the control arteries. In the control vessels in vitro, L-arginine treatment did not modify any contractile or relaxant response. At the same time, in vitro L- arginine treatment inhibited the hemorrhagic hypotension-induced enhancement of the contractions to noradrenaline and restored the diminished relaxations to acetylcholine (but not to ATP or adenosine). In the vessels after hemorrhage, NOLA neither further enhanced the already markedly enhanced noradrenaline-induced contractions nor further inhibited the relaxations caused by ATP and adenosine. In the case of acetylcholine, however, NOLA caused a further inhibition of the relaxations. The effect of in vivo L-Arg infusion (30 mg/kg initial bolus and 10 mg/kg/min infusion) during hemorrhagic hypotension and retransfusion on the in vitro vascular reactivity was similar to that of the in vitro L-arginine treatment. The present study demonstrates that even short-lasting hemorrhagic hypotension combined with retransfusion markedly inhibits nitric oxide-mediated, agonist-induced endothelium-dependent cerebrovascular responses. In vivo or in vitro L- arginine treatment is able to restore normal responses to some agents. Our data raise the possibility of an exhaustion of the endogeneous vascular L- arginine pools in this pathophysiological condition.

AB - We studied the involvement of the L-arginine-nitric oxide pathway in the changes in cerebrovascular reactivity following hemorrhagic hypotension and retransfusion. Feline middle cerebral arteries were prepared from control animals killed under anesthesia and from anesthetised animals subjected to hemorrhagic hypotension (stepwise bleeding to 90, 70, and 50 mmHg, maintained for 20 min at each level) followed by retransfusion (20 min). Two-mm-long vessel segments were suspended in organ chambers containing Krebs-Henseleit solution (37°C, gassed with 95% O2-5% CO2) for isometric force measurements. Contractions to noradrenaline (norepinephrine), relaxations to acetylcholine, ATP, adenosine, and SIN-1, a nitric oxide donor compound, were compared in the vessels of the control and hemorrhage-subjected animals. Contractile responses to noradrenaline were significantly enhanced after hemorrhage, whereas relaxations to acetylcholine, ATP, and adenosine were significantly reduced. Relaxations to SIN-1, however, remained unchanged. L- Arginine did not cause relaxations in control vessels but relaxed the arteries after hemorrhage and retransfusion. To clarify the involvement of the L-arginine-nitric oxide pathway in these alterations, we studied the effect of exogenous application of L-arginine, the precursor of endothelium- derived relaxing factor (EDRF) and N(G)-nitro-L-arginine (NOLA), a competitive antagonist of the EDRF-producing enzyme on the vascular responses in vitro. Similar to the effect of hypotension and retransfusion, NOLA enhanced the noradrenaline-induced contractions and inhibited the acetylcholine-induced and purinoceptor-mediated relaxations in the control arteries. In the control vessels in vitro, L-arginine treatment did not modify any contractile or relaxant response. At the same time, in vitro L- arginine treatment inhibited the hemorrhagic hypotension-induced enhancement of the contractions to noradrenaline and restored the diminished relaxations to acetylcholine (but not to ATP or adenosine). In the vessels after hemorrhage, NOLA neither further enhanced the already markedly enhanced noradrenaline-induced contractions nor further inhibited the relaxations caused by ATP and adenosine. In the case of acetylcholine, however, NOLA caused a further inhibition of the relaxations. The effect of in vivo L-Arg infusion (30 mg/kg initial bolus and 10 mg/kg/min infusion) during hemorrhagic hypotension and retransfusion on the in vitro vascular reactivity was similar to that of the in vitro L-arginine treatment. The present study demonstrates that even short-lasting hemorrhagic hypotension combined with retransfusion markedly inhibits nitric oxide-mediated, agonist-induced endothelium-dependent cerebrovascular responses. In vivo or in vitro L- arginine treatment is able to restore normal responses to some agents. Our data raise the possibility of an exhaustion of the endogeneous vascular L- arginine pools in this pathophysiological condition.

KW - contraction

KW - endothelium-dependent relaxation

KW - hemorrhagic hypotension

KW - L- arginine

KW - middle cerebral artery

KW - NG-nitro-L-arginine

KW - nitric oxide

KW - shock

KW - vascular smooth muscle

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