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

Abstract

The aim of our study was to investigate the adaptation of the hypothalamic circulation to chronic nitric oxide (NO) deficiency in rats. Hypothalamic blood flow (HBF) remained unaltered during chronic oral administration of the NO synthase (NOS) inhibitor N G -nitro-L-arginine methyl ester (L-NAME, 1 mg/ml drinking water) although acute NOS blockade by intravenous L-NAME injection (50 mg/kg) induced a dramatic HBF decrease. In chronically NOS blocked animals, however, acute L-NAME administration failed to influence the HBF. Reversal of chronic NOS blockade by intravenous L-arginine infusion evoked significant hypothalamic hyperemia suggesting the appearance of a compensatory vasodilator mechanism in the absence of NO. In order to clarify the potential involvement of vasodilator prostanoids in this adaptation, cyclooxygenase (COX) mRNA and protein levels were determined in the hypothalamus, but none of the known isoenzymes (COX-1, COX-2, COX-3) showed upregulation after chronic NOS blockade. Furthermore, levels of vasodilator prostanoid (PGI 2 , PGE 2 and PGD 2 ) metabolites were also not elevated. Interestingly, however, hypothalamic levels of vasoconstrictor prostanoids (TXA 2 and PGF 2α ) decreased after chronic NOS blockade. COX inhibition by indomethacin but not by diclofenac decreased the HBF in control animals. However, neither indomethacin nor diclofenac induced an altered HBF-response after chronic L-NAME treatment. Although urinary excretion of PGI 2 and PGE 2 metabolites markedly increased during chronic NOS blockade, indicating COX activation in the systemic circulation, we conclude that the adaptation of the hypothalamic circulation to the reduction of NO synthesis is independent of vasodilator prostanoids. Reduced release of vasoconstrictor prostanoids, however, may contribute to the normalization of HBF after chronic loss of NO.

Molecular imaging with engineered physiology

“…2e) evoked by wtCGRP, before and after systemic intravenous injection of the nNOS inhibitor N -nitro-L-arginine methyl ester (L-NAME; 50 mg kg −1 ) (ref. 15) were statistically indistinguishable ( t -test P >0.05). Although L-NAME injection itself appeared to induce a small average increase in the baseline brain signal before CGRP infusion (3.5±2.3%), this change was not statistically significant ( t -test P =0.11, n =4).…”

Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging

“…The microvascular endothelium is involved in many aspects of the regulation of CBF. Endothelial NO contributes to setting resting CBF demonstrated by studies showing that acute blockade of NO synthases attenuates basal CBF and leads to hypoperfusion (117). Also, systemic administration of the NO precursor L-arginine increased CBF velocity in humans (88).…”

Regulation of cerebral blood flow in mammals during chronic hypoxia: a matter of balance

“…2). In the brain, vascular smooth muscle tone is closely controlled by endogenous substances, such as nitric oxide (NO; Bailey et al 2009 b ) and prostanoids (Hortobágyi et al 2007), as well as C‐natriuretic peptide (Kobayashi et al 1994) and endothelin‐1 (Henze et al 2007) produced by the neighbouring endothelial and neuronal cells (Fig. 2).…”