Cerebral microvascular dilation during hypotension and decreased oxygen tension: a role for nNOS

Abstract

Bauser-Heaton HD, Bohlen HG. Cerebral microvascular dilation during hypotension and decreased oxygen tension: a role for nNOS. Am J Physiol Heart Circ Physiol 293: H2193-H2201, 2007. First published July 13, 2007; doi:10.1152/ajpheart.00190.2007 and neuronal nitric oxide synthase (nNOS) are implicated as important contributors to cerebral vascular regulation through nitric oxide (NO). However, direct in vivo measurements of NO in the brain have not been used to dissect their relative roles, particularly as related to oxygenation of brain tissue. We found that, in vivo, rat cerebral arterioles had increased NO concentration ([NO]) and diameter at reduced periarteriolar oxygen tension (PO 2) when either bath oxygen tension or arterial pressure was decreased. Using these protocols with highly selective blockade of nNOS, we tested the hypothesis that brain tissue nNOS could donate NO to the arterioles at rest and during periods of reduced perivascular oxygen tension, such as during hypotension or reduced local availability of oxygen. The decline in periarteriolar PO 2 by bath manipulation increased [NO] and vessel diameter comparable with responses at similarly decreased PO 2 during hypotension. To determine whether the nNOS provided much of the vascular wall NO, nNOS was locally suppressed with the highly selective inhibitor N-(4S)- (4-amino-5-[aminoethyl]aminopentyl)-NЈ-nitroguanidine. After blockade, resting [NO], PO 2, and diameters decreased, and the increase in [NO] during reduced PO 2 or hypotension was completely absent. However, flow-mediated dilation during occlusion of a collateral arteriole did remain intact after nNOS blockade and the vessel wall [NO] increased to ϳ80% of normal. Therefore, nNOS predominantly increased NO during decreased periarteriolar oxygen tension, such as that during hypotension, but eNOS was the dominant source of NO for flow shear mechanisms. nitric oxide; brain; arterioles; in vivo; microelectrode; neuronal nitric oxide synthase SUPPRESSION OF NITRIC OXIDE (NO) formation by an intravascular arginine analog decreases cerebral blood flow by 10 -40% (17,18,40,42). This indicates that a source of NO actively influences cerebral resistance vessels at rest. Furthermore, Jones et al. (25) and Kajita et al. (26) found that, during hypotension, the lower limit of brain blood flow autoregulation was increased to ϳ90 mmHg in the presence of nitroarginine compared with ϳ65 mmHg in the natural state. The observations of reduced resting blood flow and impaired flow autoregulation indicate that NO regulation has important roles in both maintaining brain resting blood flow and dilatory responses to hypotension. These various observations would predict that, when the various NO synthase (NOS) isoforms are inhibited, even a mild reduction in arterial blood pressure would compromise brain blood flow and tissue oxygenation.Exactly how NO mechanisms are involved in brain blood flow regulation are difficult to predict but may involve feedback processes linked to oxygen. In studies of the small int...

Relationship between Myogenic Reaction and Autoregulation of Cerebral Circulation

“…An assumption was made that blood loss does not affect C (this agrees with previous experimental data [5]). Due to this simplifi cation, coeffi cient C in numerator and denominator is reduced and only SBP values are required for calculation.…”

Transfer of nitric oxide by blood from upstream to downstream resistance vessels causes microvascular dilation

“…In test chambers, neither nitrite nor nitrate at physiological concentrations influence the NOsensitive microelectrode (5), nor do the electrodes respond to arginine and lysine at physiological and vasoactive supraphysiological concentrations (34,45) and do not detect signals from frozen and rewarmed intestinal tissue (5). In this study, as well as others using nitroarginine analogs and lysine to suppress L-arginine transport (1,34,45), the measured signal interpreted as NO is substantially decreased, but not driven to nearly undectable as is possible with in vitro preparations (13,24). We have suspected for some time that the residual [NO] after localized suppression of eNOS is due to NO from blood.…”

“…Fig. 2 indicate that there is indeed a signal interpreted by the microelectrode at a vasoactive [NO] within the vessel lumen as judged by in vivo studies by various laboratories (1,2,9,10,25,44,45). In Fig.…”

“…A key issue in this area is whether formation of nitrosothiols, particularly with hemoglobin, are so rapid and pervasive that NO made in vessel walls would be rapidly removed to and released at downstream locations. Direct measurements of in vivo vessel wall NO concentration ([NO]) by multiple laboratories indicate [NO] in the range of 300 -1,000 nM in a variety of tissues and small mesenteric arteries, of which a few are now referenced (1,2,10,25,46,47). In these studies, activation of endothelial nitric oxide synthase (eNOS) by appropriate receptor agonists increased the measured [NO], and suppression of nitric oxide synthases with nitroarginine compounds dramatically lowered the measured [NO], giving credence that a form of NO is measured by the microelectrode.…”

The Key Role of Nitric Oxide in Hypoxia: Hypoxic Vasodilation and Energy Supply–Demand Matching

“…O 2 regulates transcription of eNOS (11) and possibly nNOS (19). With prolonged hypoxia, NO levels progressively rise; in an ex vivo macrophage model iNOS mRNA was detected after 1.5 hours of hypoxia (9).…”