Nitric oxide mediation of chemoregulation but not autoregulation of cerebral blood flow in primates

Abstract

The authors sought to develop a model for assessing in vivo regulation of cerebral vasoregulation by nitric oxide (NO), originally described as endothelial-derived relaxing factor, and to use this model to establish the role of NO in the regulation of cerebral blood flow (CBF) in primates. By using regional intraarterial perfusion, the function of NO in cerebral vasoregulation was examined without producing confounding systemic physiological effects. Issues examined were: whether resting vasomotor tone requires NO; whether NO mediates vasodilation during chemoregulation and autoregulation of CBF; and whether there is a relationship between the degree of hypercapnia and hypotension and NO production. Twelve anesthetized (0.5% isoflurane) cynomolgus monkeys were monitored continuously for cortical CBF, PaCO2, and mean arterial pressure (MAP), which were systematically altered to provide control and experimental curves of chemoregulation (CBF vs. PaCO2) and autoregulation (CBF vs. MAP) during continuous intracarotid infusion of 1) saline and 2) an NO synthase inhibitor (NOSI), either L-n-monomethyl arginine or nitro L-arginine. During basal conditions (PaCO2 of 38-42 mm Hg) NOSI infusion of internal carotid artery (ICA) reduced cortical CBF from 62 (saline) to 53 ml/100 g/per minute (p<0.01), although there was no effect on MAP. Increased CBF in response to hypercapnia was completely blocked by ICA NOSI. The difference in regional (r)CBF between ICA saline and NOSI infusion increased linearly with PaCO2 when PaCO2 was greater than 40 mm Hg, indicating a graded relationship of NO production, increasing PaCO2, and increasing CBF. Diminution of CBF with NOSI infusion was reversed by simultaneous ICA infusion of L-arginine, indicating a direct role of NO synthesis in the chemoregulation of CBF. Hypotension and hypertension were induced with trimethaphan camsylate (Arfonad) and phenylephrine at constant PaCO2 (40 +/- 1 mm Hg). Autoregulation in response to changes in MAP from 50 to 140 mm Hg was unaffected by ICA infusion of NOSI. In primates, cerebral vascular tone is modulated in vivo by NO; continuous release of NO is necessary to maintain homeostatic cerebral vasodilation; vasodilation during chemoregulation of CBF is mediated directly by NO production; autoregulatory vasodilation with hypertension is not mediated by NO; and increasing PaCO2 induces increased NO production.

Role of Nitric Oxide in the Regulation of Cerebral Blood Flow in Humans

“…24 However, from animal studies, it appears that NO is involved in the chemoregulation (vide infra) without significantly affecting the pressor-dependent regulation. 6,25 Also, in humans, under anesthetic effect, the direct infusion of SNP into the carotid artery did not affect the CBF indexes during phenylephrine administration. 11 This study and others encourage the view that NO is not involved in the mechanoregulation of CBF.…”

“…Furthermore, the effect of L-NMMA on regional CBF is linearly correlated with PaCO 2 and is reversed by L-arginine, suggesting a graded relation of NO production and PaCO 2 . 6 In one investigation in humans, hypercapnia-induced vasodilation was significantly blunted by administration of L-NMMA. 9 Our study shows that NO is involved not only in the CBF response to hypercapnia but also in the CBF response to normocapnia and hypocapnia.…”

“…Even though it has emerged from animal studies that nitric oxide (NO) is necessary to maintain CO 2 -mediated CBF, it does not appear to be involved in cerebral mechanoregulation. [5][6][7] Numerous human investigations were conducted during the past decade to explore the role of NO in CBF regulation.…”

Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH

“…Since the discovery that nitric oxide (NO), an endothelium-derived relaxing factor 22 , has 1000 times higher affinity for hemoglobin than oxygen 52 , neurosurgeons and neuroscientists have been interested in its role in cerebral vasospasm after SAH 2,8,16,44,45,55,[64][65][66]70,87,90,92,94,95,103 . NO influence on blood flow 11,15,99,106,113 , disappearance of neuronal nitric oxide synthase (nNOS) immunoreactivity from the arteries in spasm 75 , endothelial nitric oxide synthase (eNOS) dysfunction in cerebral vessels after SAH 37 , decreased levels of nitrite in the cerebrospinal fluid (CSF) during vasospasm development 40,70,76 , as well NO affinity for the heme moiety 52 together, strongly suggest that decreased availability of NO in the cerebral arterial wall after SAH is responsible for delayed cerebral vasospasm 70 . Recent research has significantly advanced our understanding of the NO-related pathophysiologic changes in the cerebral arteries leading to vasospasm and introduced new possibilities for NO-based therapy for vasospasm 23,76,98 .…”

Source and cause of endothelin-1 release to cerebrospinal fluid after subarachnoid hemorrhage

“…On the other hand, if oxyhemoglobin, an agent purportedly responsible for vasospasm, [31,46] eliminates the action of vasodilatory agent(s), [18,22,43,52] then vasospasm could result from the unopposed action of a constricting agent like ET-1. Recently, it was reported that nitric oxide (NO), [20,22,50] a potent vasodilator, [20,22,42] is directly involved in the regulation of CBF. Moreover, a reversal of vasospasm by direct intracarotid infusion of NO solution [1] indicates that there may be decreased availability of NO at the time of vasospasm.…”