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

Ryan L. Hoiland, Hannah G. Caldwell, Jay M.R.J. Carr, Connor A. Howe, Benjamin Stacey, Tony Dawkins, Dennis J. Wakeham, Joshua C. Tremblay, Michael M. Tymko, Kurt J. Smith, Mypinder S. Sekhon, David B. MacLeod, Daniel J. Green, Damian Bailey, Philip Ainslie

    Allbwn ymchwil: Cyfraniad at gyfnodolynErthygladolygiad gan gymheiriaid

    Crynodeb

    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
    PaCO2. 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
    PaCO2 ; 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.
    Iaith wreiddiolSaesneg
    Rhif yr erthyglJP282427
    Tudalennau (o-i)1385-1403
    Nifer y tudalennau19
    CyfnodolynThe Journal of Physiology
    Cyfrol600
    Rhif cyhoeddi6
    Dyddiad ar-lein cynnar13 Rhag 2021
    Dynodwyr Gwrthrych Digidol (DOIs)
    StatwsE-gyhoeddi cyn argraffu - 13 Rhag 2021

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