Cerebrovascular control: What's so base‐ic about it?

Amongst the myriad of mechanisms that interact to regulate cerebral blood flow (CBF), alterations in arterial gases, specifically the partial pressure of arterial carbon dioxide (), are of great importance. By nature, CO2 transportation contributes to the acid–base equilibrium within the intravascular space, as well as in the perivascular space. Consequently, such alterations in pH predicate cerebrovascular reactivity to CO2 (CVR). It remains to be determined whether the intrinsic control of the cerebral vasomotor tone is a direct result of intraluminal , bicarbonate [HCO3–], arterial pH or a combination of these. One way of investigating the influence of alterations in acid–base balance on cerebrovascular control is through examining CVR following high altitude ascent. Indeed, Fan et al. (2010) observed enhanced ventilatory and CO2 sensitivity following an ascent to high altitude, which was attributed to alterations in pH buffering capacity during hypercapnia. Specifically, high altitude exposure causes a reduction in bicarbonate availability as a result of renal compensation following respiratory alkalosis. With a reduction in bicarbonate bioavailability, there is a greater reduction in perivascular pH for a given change in , resulting in an augmented CVR response (Fan et al. 2010). Although their study highlights an important role of the bicarbonate buffering system in modulating CVR, limitations include the use of transcranial Doppler ultrasound that measures blood velocity rather than CBF per se, which may underestimate CVR during hypercapnia as a result of middle cerebral artery dilatation (Coverdale et al. 2014) . Additionally, a modified rebreathing protocol was used as the stimulus to increase , which may have contributed to intra-individual variability in the change in that was observed (Borle et al. 2017) . In a recent issue of The Journal of Physiology, Caldwell et al. (2021) report on the integrative relationship between , pH and cerebrovascular tone that was explored in the context of acute metabolic alkalosis. In a highly unique and technically challenging protocol, the previously identified limitations were addressed by obtaining CBF measurements (rather than cerebral blood velocity alone) via duplex Doppler ultrasonography of the extracranial vessels and manipulating via end-tidal forcing, which allows for to be controlled on an individual basis. CVR was measured through stepwise iso-oxic alterations in (−10, −5, +5, and +10 mm Hg), before and following an infusion of a hypertonic solution of sodium bicarbonate (NaHCO3–; 8.4%, 50 mEq 50 mL−1) delivered through venous catheterization. A radial arterial catheterization was performed allowing for direct measures of key variables such as , HCO3–, H+ and pH through repeated arterial blood sampling. This protocol successfully elevated arterial pH (7.41 ± 0.02 vs. 7.46 ± 0.03, P < 0.001) and [HCO3–] (26.1 ± 1.4 vs. 29.3 ± 0.9 mEq L−1; P < 0.001) to assess the direct influence of [HCO3–] on CVR. Interestingly, Caldwell et al. (2021) observed no difference in absolute CBF at each matched stage of following bicarbonate infusion despite pH being elevated. This finding suggests that in the setting of acute metabolic alkalosis, CBF is regulated by , rather than arterial pH. Additionally, Caldwell et al. (2021) report a greater resting CBF (∼7%) following bicarbonate infusion in the presence of an unaltered . This observation provides the first human evidence for a direct vasodilatory influence of HCO3– on cerebral vessels. One proposed mechanism to explain the direct vasodilatory influence of HCO3– is based on a previous study by Boedtkjer et al. (2016). Using an in vitro isolated vessel preparation of mouse basilar arteries, it was suggested that reductions in bicarbonate may directly cause vasoconstriction through an endothelium-dependent mechanism activated through the membrane bound receptor, receptor protein tyrosine phosphatase gamma (RPTPy). Activation of this receptor by bicarbonate is reported to alter calcium sensitivity in vascular smooth muscle cells; a notion that is supported by the lack of a vasomotor response to bicarbonate in RPTPy knockout mice. However, the vasomotor effects of bicarbonate were only present under reduced bicarbonate concentrations, with the RPTPy pathway being maximally activated at a bicarbonate concentration of 22 mm. This finding suggests that further increases in bicarbonate above resting concentrations do not promote vasodilatation, but rather that reductions in bicarbonate below 22 mm cause vasoconstriction (Boedtkjer et al. 2016). Of note, this notion is contrary to the direct vasodilatory role of bicarbonate observed by Caldwell et al. (2021) where an increasing [HCO3–] (post-infusion all >27.2 ± 1.3 mEq L−1) was reported to cause cerebral vasodilatation. These differences between studies could potentially be attributed to differential roles of RPTPy between species (mouse vs. human) or may even suggest the possibility of a separate, yet to be identified sensor of bicarbonate that explains the direct vasodilatory actions observed by Caldwell et al. (2021). Considering how fluid and ion transfer across the blood–brain and blood–cerebrospinal fluid barriers, the question arises as to what drives HCO3– transportation? As elegantly summarized by Caldwell et al. (2021), the current five proposed mechanisms are: (i) the buffering capacity of interstitial fluid by brain cells mostly by interconversion of CO2 and HCO3– intracellularly and across their membranes; (ii) the production of lactic acid within brain cells including the buffering of the hydrogen ion (H+) in the extracellular fluids by the CO2/HCO3– system; (iii) the exchange between the removal of lactate– and H+ with the addition of HCO3–; (iv) the removal of excess ions from the brain due to the interstitial and cerebrospinal fluid circulation; and, lastly, (v) the exchange of H+ and HCO3– across the choroid plexus or blood–brain barrier. The latter two pathways are highlighted by Caldwell et al. (2021) to justify the occurrence of HCO3– in their study design model. Even if [HCO3–] directly affected the vascular smooth muscle tone to increase CBF in the study by Caldwell et al. (2021), it should be noted that this vasodilatory response was insufficient to affect cerebrovascular responsiveness to acute steady-state changes in . Indeed, Caldwell et al. (2021) demonstrated that total CBF was acutely regulated by rather than intraluminal arterial pH and also that the CVR responses were a consequence of alterations in the buffering capacity following the NaHCO3– infusion. Caldwell et al. (2021) illustrated the compensatory buffering response throughout respiratory acidosis and alkalosis by comparing the absolute change in arterial [HCO3–], [H+] and pH for a given matched change in between pre- and post-cerebrovascular CO2 reactivity stages. They interpretated a smaller change in arterial pH in the hypo- and hypercapnic ranges compared to the pre-CVR to indicate an increase in the buffering capacity. Interestingly, when indexing arterial [H+] following NaHCO3– infusion, Caldwell et al. (2021) reported that relative hypocapnic CVR was higher, whereas relative hypercapnic CVR was lower. These results suggest an alteration in the buffering capacity between and arterial H+/pH consequent to the infusion only during hypercapnia. Although speculative, it is possible that a shear stress mediated vasodilatory response could have increased the bioavailability in nitric oxide concurrent with the CO2 induced vasodilatory response. They also speculated on differences in acid–base buffering capacity during hypo- and hypercapnic CVR. They interpreted that the acute regulation of CBF by is the result of the changes in arterial [H+]/pH induced by the alterations in that consistently relate to changes in the relationship between CBF and [H+]/pH. Although these latter results further improve the understanding of cerebrovascular control, the influence of acid–base balance on cerebrovascular control turns out to be not so basic after all. In this context, the potential limitations of the study should be highlighted. As acknowledged by Caldwell et al. (2021), one important limitation is linked to the sample characteristics. Only young men (age 25 ± 6 years, height 181 ± 4 cm, weight 78 ± 11 kg) were included, which limits the ability to relate these findings to women. Additionally, the order of trials was not randomized, which may have further influenced the observed results as a result of an order effect, if present. There are a number of clinical implications that could emanate from these findings. One such exemplar is the reduction in CBF experienced by end-stage renal disease patients undergoing haemodialysis. Haemodialysis causes reductions in CBF (∼7–12%) that are linked to cognitive dysfunction and brain structural abnormalities (Sprick et al. 2020). One of the goals of haemodialysis is correction of metabolic acidosis, a hallmark of end-stage renal disease. This correction is accomplished through the infusion of supraphysiological concentrations of bicarbonate in the dialysate (typically 32–39 mmol L–1). Based on the direct cerebrovascular dilatory effects of bicarbonate reported (∼7 %), it would be of interest to explore whether the bicarbonate rich dialysate may be one mechanism opposing intradialytic reductions in CBF. In conclusion, Caldwell et al. (2021) report the novel finding that , rather than arterial pH, mediates CVR in the setting of acute metabolic alkalosis. Additionally, a direct vasodilatory effect of bicarbonate has been observed for the first time in humans. These findings have important implications for advancing our understanding of acid–base balance in cerebrovascular physiology, although the mechanism responsible for mediating this bicarbonate-induced cerebral vasodilatation remains to be clarified. Future directions should include assessing the role of the influence of bicarbonate on cerebrovascular control in females, as well as elucidating the sensor and transducer of cerebrovascular dilatation in response to bicarbonate. No competing interests declared. AD, GA and JS were responsible for the conception and design of the work. AD, GA and JS were responsible for the analysis and interpretation of data for the work. AD, GA and JS were responsible for drafting the work and revising it critically for important intellectual content. AD, GA and JS approved the final version of the manuscript submitted for publication. All of the authors agree to be accountable for all aspects of the work. No funding was received.

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