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

Publication ,  Journal Article
Hoiland, RL; Caldwell, HG; Carr, JMJR; Howe, CA; Stacey, BS; Dawkins, T; Wakeham, DJ; Tremblay, JC; Tymko, MM; Patrician, A; Smith, KJ ...
Published in: The Journal of physiology
March 2022

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${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ . 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 PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ ; 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.

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Published In

The Journal of physiology

DOI

EISSN

1469-7793

ISSN

0022-3751

Publication Date

March 2022

Volume

600

Issue

6

Start / End Page

1385 / 1403

Related Subject Headings

  • omega-N-Methylarginine
  • Physiology
  • Nitrogen Dioxide
  • Nitric Oxide Synthase
  • Nitric Oxide
  • Humans
  • Enzyme Inhibitors
  • Dilatation
  • Cerebrovascular Circulation
  • Carbon Dioxide
 

Citation

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Hoiland, R. L., Caldwell, H. G., Carr, J. M. J. R., Howe, C. A., Stacey, B. S., Dawkins, T., … Ainslie, P. N. (2022). Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide. The Journal of Physiology, 600(6), 1385–1403. https://doi.org/10.1113/jp282427
Hoiland, Ryan L., Hannah G. Caldwell, Jay M. J. R. Carr, Connor A. Howe, Benjamin S. Stacey, Tony Dawkins, Denis J. Wakeham, et al. “Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide.The Journal of Physiology 600, no. 6 (March 2022): 1385–1403. https://doi.org/10.1113/jp282427.
Hoiland RL, Caldwell HG, Carr JMJR, Howe CA, Stacey BS, Dawkins T, et al. Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide. The Journal of physiology. 2022 Mar;600(6):1385–403.
Hoiland, Ryan L., et al. “Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide.The Journal of Physiology, vol. 600, no. 6, Mar. 2022, pp. 1385–403. Epmc, doi:10.1113/jp282427.
Hoiland RL, Caldwell HG, Carr JMJR, Howe CA, Stacey BS, Dawkins T, Wakeham DJ, Tremblay JC, Tymko MM, Patrician A, Smith KJ, Sekhon MS, MacLeod DB, Green DJ, Bailey DM, Ainslie PN. Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide. The Journal of physiology. 2022 Mar;600(6):1385–1403.
Journal cover image

Published In

The Journal of physiology

DOI

EISSN

1469-7793

ISSN

0022-3751

Publication Date

March 2022

Volume

600

Issue

6

Start / End Page

1385 / 1403

Related Subject Headings

  • omega-N-Methylarginine
  • Physiology
  • Nitrogen Dioxide
  • Nitric Oxide Synthase
  • Nitric Oxide
  • Humans
  • Enzyme Inhibitors
  • Dilatation
  • Cerebrovascular Circulation
  • Carbon Dioxide