The Effect of a Neuronal Nitric Oxide Synthase Inhibitor on Neurovascular Regulation in Humans

Abstract

BACKGROUND: Neurovascular coupling (NVC) is a key process in cerebral blood flow regulation. NVC ensures adequate brain perfusion to changes in local metabolic demands. Neuronal nitric oxide synthase (nNOS) is suspected to be involved in NVC; however, this has not been tested in humans. Our objective was to investigate the effects of nNOS inhibition on NVC in humans. METHODS: We performed a 3-visit partially randomized, double-blinded, placebo-controlled, crossover study in 12 healthy subjects. On each visit, subjects received an intravenous infusion of either S-methyl-L-thiocitrulline (a selective nNOS-inhibitor), 0.9% saline (placebo control), or phenylephrine (pressor control). The NVC assessment involved eliciting posterior circulation hyperemia through visual stimulation while measuring posterior and middle cerebral arteries blood velocity. RESULTS: nNOS inhibition blunted the rapidity of the NVC response versus pressor control, evidenced by a reduced initial rise in mean posterior cerebral artery velocity (−3.3% [−6.5, −0.01], P =0.049), and a reduced rate of increase (ie, acceleration) in posterior cerebral artery velocity (slope reduced −4.3% [−8.5, −0.1], P =0.045). The overall magnitude of posterior cerebral artery response relative to placebo control or pressor control was not affected. Changes in BP parameters were well-matched between the S-methyl-L-thiocitrulline and pressor control arms. CONCLUSIONS: Neuronal NOS plays a role in dynamic cerebral blood flow control in healthy adults, particularly the rapidity of the NVC response to visual stimulation. This work opens the way to further investigation of the role of nNOS in conditions of impaired NVC, potentially revealing a therapeutic target.

Effects of phenylephrine on systemic and cerebral circulations in humans: a systematic review with mechanistic explanations

“…The systematic literature search yielded 2586 records. After removing 703 duplicates and two retracted papers, we screened 1881 records and finally identified 45 studies that met the eligibility criteria [3, 15–58]. Four additional studies were identified through PubMed and Google Scholar searches and screening relevant articles' reference lists [59–62].…”

“…Fifteen of the 49 eligible studies had been conducted in awake healthy subjects [15, 17, 18, 20, 30–32, 37, 39–41, 46, 47, 53, 58] and the remaining 34 studies in anaesthetised subjects [3, 16, 19, 21–29, 33–36, 38, 42–45, 48–52, 54–57, 59–62]. Among the latter, 31 involved patients undergoing various surgical procedures [3, 16, 19, 21–23, 25–29, 34–36, 38, 42–45, 48–52, 54, 55, 57, 59–62], two involved healthy volunteers [24, 33] and one involved patients with hyperdynamic sepsis or cardiac diseases [56].…”

“…Among the latter, 31 involved patients undergoing various surgical procedures [3, 16, 19, 21–23, 25–29, 34–36, 38, 42–45, 48–52, 54, 55, 57, 59–62], two involved healthy volunteers [24, 33] and one involved patients with hyperdynamic sepsis or cardiac diseases [56]. Phenylephrine was administered as follows: bolus in 21 studies [3, 15, 17, 19, 22, 23, 26, 34–38, 42, 44, 49–54, 62]; infusion in 26 studies [18, 20, 24, 25, 27–33, 39–41, 43, 45–48, 55–61]; and bolus followed by an infusion in two studies [16, 21]. The study characteristics and findings are summarised in the online Supporting Information Table S1.…”

“…These changes were significantly negatively correlated (slope = ‐0.69, r = ‐0.77, p < 0.001, Fig. 1c) [15, 18, 20, 30–32, 37, 39–41, 46]. Data from 23 studies in patients anaesthetised for surgical procedures showed a median MAP increase of 33.3% accompanied by a median heart rate decrease of 6.4%, with the changes being significantly negatively correlated (slope = ‐0.36, R = ‐0.59, p < 0.001, Fig.…”

“…Data from seven studies in awake healthy volunteers showed a median MAP increase of 18.6% with a median stroke volume decrease of 4.9%, the changes being negatively but not significantly correlated (slope = ‐0.56, r = ‐0.52, p = 0.12, Fig. 1e) [15, 20, 30, 32, 37, 39, 46]. Data from 10 studies in patients anaesthetised for surgery showed a median MAP increase of 33.3% with an associated median stroke volume decrease of 11.0%, the changes being negatively but not significantly correlated (slope = ‐0.20, r = ‐0.51, p = 0.08, Fig.…”