Major Role of Nitric Oxide in the Mediation of Regional CO₂ Responsiveness of the Cerebral and Spinal Cord Vessels of the Cat

Abstract

Summary: The role of nitric oxide (NO) in the mediation of cerebrovascular CO2 responsiveness was studied in 10 distinct brain and spinal cord regions of the anesthetized, ventilated, temperature-controlled, normoxic cat. Re gional CBF was measured with 15-f.Lm radiolabeled mi crospheres in hypocapnic, normocapnic, and hypercap nic conditions. CO2 responsiveness of each region was determined from the equation of the best-fit regression lines to the obtained flow values. The effect of altered endothelial and/or neuronal NO synthesis on CO2 respon siveness was studied following either selective blockade of the NO synthase enzyme by N"'-nitro-L-arginine methyl ester (L-NAME; 3 or 30 mg/kg i.v.) or simulta neous administration of L-NAME (3 mg/kg i.v.) and a large dose of the NO precursor L-arginine (30 mg/kg i.v.). it functions as a small, lipophilic, chemically unsta ble molecule, sparingly soluble in aqueous medium, which rapidly diffuses through all types of biologi cal membrane barriers (Ignarro, 1989(Ignarro, , 1990 Abbreviations used: L-NAME, NW-nitro-L-arginine methyl es ter; rCBF, regional CBF; rSBF, regional spinal cord blood flow. 49in a significant reduction of the steady-state regional blood flow values and in an almost complete abolition of the CO2 sensitivity in each region studied. Changes of the basal flow values as well as the reduction of the regional CO2 sensitivity were dose dependent. Hypothalamic, sensorimotor cortical, and cerebellar regions were the ar eas most sensitive to the NO blockade. Impaired CO2 responsiveness following NO synthase inhibition, how ever, was reversed in these regions by simultaneous ad ministration of a large dose of intravenously injected L-ar ginine. These findings suggest a major role of nitric oxide in the mediation of regional cerebrovascular CO2 respon siveness in cats. Key Words: L-Arginine-Cerebral blood flow-C02 responsiveness-Endothelium-derived relax ing factor-Nitric oxide-Nitric oxide synthase-Spinal cord blood flow. 1990) and astrocytes (Murphy et aI., 1990).Although NO is a very small and highly diffusible molecule, the extent of its transcellular communi cation is limited by the fact that it has an ultra-short half-life (estimated to be <5 s in biological tissues), and its diffusion distance during this time is in the range of 50-100 /.Lm. The responses to NO, there fore, are likely to be regional, localized responses (Ignarro, 1990). In the present study, it was hypoth esized that nitric oxide might mediate one of the most characteristic reactions of the cerebrovascular

The Pharmacology of Nitric Oxide in the Peripheral Nervous System of Blood Vessels

“…Involvement of NO in this phenomenon has been discussed by and . In anesthetized rats (Iadecola, 1992;Wang et al, 1992a) and cats (Sandor et al, 1994), the hypercapnia-induced increase in cerebral blood flow was suppressed by intravenous or topical applications of NOS inhibitors, and L-arginine reversed the effect. However, no or only slight inhibition by NOS inhibitors has been reported in the goat , cat (Goadsby, 1994), pig (Parfenova et al, 1994), and monkey (McPherson et al, 1995).…”

Adaptation of the hypothalamic blood flow to chronic nitric oxide deficiency is independent of vasodilator prostanoids

“…This observation is consistent with our previous report in cats (Kovách et al, 1992) and indicates that L-arginine availability is not a rate-limiting factor of the resting NO production. L-Arginine, however, was shown to reverse L-NAME-induced cerebrovascular NOS-inhibition in a previous study (Sándor et al, 1994), and therefore we analyzed its effect also in chronically L-NAME pretreated animals (n=12). L-Arginine infusion normalized the MABP ( Fig.…”

“…After the last measurements, the anesthetized animals were rapidly exsanguinated and hypothalamic tissue samples were excised and frozen rapidly. Total hypothalamic NOS activity was measured on the basis of the formation of labeled citrulline from labeled L-arginine (Nagy et al, 2000, Sándor et al, 1994. Tissue samples were homogenized in brain homogenizing solution containing 50 mM Tris-HCl (pH 7.4), 0.3 M sucrose, 0.1 mM EDTA, 1 mM dithioerythritol and 1 mM phenyl-methyl-sulfonylfluorid (PMSF, protease inhibitor).…”

Endocannabinoids in cerebrovascular regulation

“…It was shown in intraparenchymal cerebral arterioles that, at normal pH, CO 2 fails to produce any significant vasodilation, indicating that it is the change in extracellular proton levels and not the CO 2 concentration that is responsible for the alteration of the vascular tone (157). The fast changes in pH that occur during hypercapnia were shown to modulate NO production, and it has been proposed that the extracellular pH may be the main trigger of hypercapnia-induced, NOdependent relaxation of the cerebral arteries (204,205).…”

“…Hypoxic and hypercapnic stimuli can act on cerebral blood vessels by releasing various local mediators. Both endothelial and neural mechanisms are involved in the CBF regulation related to changes in arterial blood-gas tensions (204). H/H may be accompanied by extra-and/or intracellular acidosis, leading to relaxation of the cerebrovascular smooth muscle (205).…”