Nitric oxide contributes to cerebrovascular shear‐mediated dilatation but not steady‐state cerebrovascular reactivity to carbon dioxide

Abstract

Cerebrovascular CO2 reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear‐mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)‐dependency of CVR and cSMD. Eleven volunteers underwent a steady‐state CVR test and transient CO2 test of cSMD during intravenous infusion of the NO synthase inhibitor NG‐monomethyl‐l‐arginine (l‐NMMA) or volume‐matched saline (placebo; single‐blinded and counter‐balanced). We measured cerebral blood flow (CBF; duplex ultrasound), intra‐arterial blood pressure and PaCnormalO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$. Paired arterial and jugular venous blood sampling allowed for the determination of trans‐cerebral NO2− exchange (ozone‐based chemiluminescence). l‐NMMA reduced arterial NO2− by ∼25% versus saline (74.3 ± 39.9 vs. 98.1 ± 34.2 nM; P = 0.03). The steady‐state CVR (20.1 ± 11.6 nM/min at baseline vs. 3.2 ± 16.7 nM/min at +9 mmHg PaCnormalO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$; P = 0.017) and transient cSMD tests (3.4 ± 5.9 nM/min at baseline vs. −1.8 ± 8.2 nM/min at 120 s post‐CO2; P = 0.044) shifted trans‐cerebral NO2− exchange towards a greater net release (a negative value indicates release). Although this trans‐cerebral NO2− release was abolished by l‐NMMA, CVR did not differ between the saline and l‐NMMA trials (57.2 ± 14.6 vs. 54.1 ± 12.1 ml/min/mmHg; P = 0.49), nor did l‐NMMA impact peak internal carotid artery dilatation during the steady‐state CVR test (6.2 ± 4.5 vs. 6.2 ± 5.0% dilatation; P = 0.960). However, l‐NMMA reduced cSMD by ∼37% compared to saline (2.91 ± 1.38 vs. 4.65 ± 2.50%; P = 0.009). Our findings indicate that NO is not an obligatory regulator of steady‐state CVR. Further, our novel transient CO2 test of cSMD is largely NO‐dependent and provides an in vivo bioassay of NO‐mediated cerebrovascular function in humans. Key points Emerging evidence indicates that a transient CO2 stimulus elicits shear‐mediated dilatation of the internal carotid artery, termed cerebral shear‐mediated dilatation. Whether or not cerebrovascular reactivity to a steady‐state CO2 stimulus is NO‐dependent remains unclear in humans. During both a steady‐state cerebrovascular reactivity test and a transient CO2 test of cerebral shear‐mediated dilatation, trans‐cerebral nitrite exchange shifted towards a net release indicating cerebrovascular NO production; this response was not evident following intravenous infusion of the non‐selective NO synthase inhibitor NG‐monomethyl‐l‐arginine. NO synthase blockade did not alter cerebrovascular reactivity in the steady‐state CO2 test; however, cerebral shear‐mediated dilatation following a transient CO2 stimulus was reduced by ∼37% following intravenous infusion of NG‐monomethyl‐l‐arginine. NO is not obligatory for cerebrovascular reactivity to CO2, but is a key contributor to cerebral shear‐mediated dilatation.

Clinical assessments of cerebrovascular health: is there a neED(D) for cerebral shear‐mediated dilatation?

“…6 from Hoiland et al . 2022). However, during the transient test, cSMD in the ICA was reduced by 37% following l ‐NMMA infusion (Fig.…”

“…The most notable finding by Hoiland et al . (2022) is the presence of a 37% reduction in shear‐mediated dilatation of the ICA following global NO synthase inhibition during the transient CO 2 test, while reductions in ICA dilation and CVR were absent during the steady‐state CO 2 test. As the authors suggest, these findings highlight the transient CO 2 test of cSMD as a measure of NO‐dependent cerebrovascular endothelial function.…”

“…This study presents novel evidence that the transient CO 2 test of cSMD offers an NO‐dependent measure of cerebrovascular endothelial function in healthy young men (Hoiland et al . 2022). To increase clinical relevance, steps must be taken to apply transient cSMD to other subject groups, such as healthy and clinical populations of both sexes.…”

“…Recently, an increasing number of laboratories have assessed an alternative measure of cerebrovascular function by utilizing a shear-mediated test of cerebral vascular function (cSMD), but whether cSMD could serve as a bioassay of NO-mediated cerebrovascular endothelial function is unknown. The recent work by Hoiland et al (2022) published in The Journal of Physiology addressed these gaps in the literature. The mechanistic studies performed by this group are necessary to extend our understanding of cerebrovascular function and establish sensitive and reliable methods to assess the integrity of cerebrovascular mechanisms that reflect concomitant changes in cerebrovascular endothelial function.…”

Hypnotizability-Related Cerebral Blood Flow

“…The cerebrovascular changes induced by increased or decreased CO2 cannot be reliably studied without concomitant assessment of arterial blood pressure [37]. It has also been shown, however, that NO release is not obligatory for cerebrovascular reactivity to CO2, whereas transient increases in CBF induced by increases in blood pressure mostly rely on NO release [38]. Cerebral autoregulation, in fact, stabilizes blood flow by buffering steady state increase in cerebral perfusion pressure, but cannot compensate for brief elevations in blood pressure and consequent increases in CBF [39,40].…”