**4. Metabolic control**

The mechanical stimuli of pressure and flow are generally thought to be important in setting the basal vascular tone so that metabolic influences are able to cause dilation or constriction depending on the needs of the cerebral tissue [24]. Metabolic control of vascular resistance is of particular importance in the cerebral circulation since cerebral tissue is extremely intolerant to ischemia [88]. As such, the cerebral circulation has a precise and highly localized coupling between the metabolic requirements of cerebral tissue and the magnitude of blood flow by controlling vascular resistance. There are numerous vasoactive metabolites that contribute to the control of cerebral vascular tone including adenosine, CO2, H+ , O2 and K+ . Increasing concentrations of adenosine, CO2, H+ , and K+ and decreased concentration of O2 result in relaxation of VSM and dilation of cerebral resistance vessels. Each metabolite is associated with a cascade of events that ultimately either alters intracellular Ca2+ concentration or Ca2+ sensitivity of the VSM and results in a change in vessel diameter. Although the effects of each metabolite have been well characterized the relative importance of each along with its interaction with each other and other parameters of tone remains an area of further investigation. The discussion below is summarized in **Figure 1**.

### **4.1 Adenosine**

Adenosine has been proposed as being the primary metabolite controlling metabolic regulation of cerebral vascular tone. It is a naturally occurring nucleoside produced as a byproduct of ATP metabolism; thus, its accumulation signals a need for increased blood flow to match the metabolic activity. This relationship with metabolism has widely implicated adenosine in local regulation of cerebral vascular tone during functional hyperemia, ischemia, or whenever PO2 becomes limited [89–91]. Adenosine has direct effects on the vasculature [92, 93] that can both vasodilate and hyperpolarize VSM and is therefore considered an EDHF [94]. There are four distinct subtypes of adenosine receptors; however, the A2A receptor appears to be of high importance in mediating vasodilation [95–97]. The A2A receptor is a purinergic P1 receptor that has been confirmed to be present in cerebral microvessels [98–101] on the VSM cells [102, 103]. It causes dilation in a concentration-dependent manner [101, 104] once bound to the A2A receptor by activation of adenylate cyclase [105] and therefore cAMP [106–108] which reduces cytosolic calcium and leads to vasodilation. The opening of KATP channels also occurs secondary to the increase in cAMP levels as a result of adenosine binding to its receptors on the cell membrane [109–112]. The contribution of opening KATP channels to dilation is likely substantial since during blockade of KATP channels with glibenclamide, adenosine-induced dilation was reduced by approximately 50% [113]. Although A2A receptors are generally considered the most important mediators of the effects of adenosine on vascular tone the A2B receptors are also proposed to cause dilation through similar mechanisms as A2A in addition to coupling to Gq proteins to produce Ca2+ mobilization by activation of phospholipase C and mitogen-activated protein kinase activation [98, 114, 115]. In addition to dilating the cerebral vasculature adenosine may also block vasoconstrictive signals in the parenchyma as evidenced by *in vitro* data from Gordon et al. [116]. When adenosine receptors are blocked with theophylline dilation was attenuated to arterial hypoxia [117]. Similarly the competitive adenosine receptor antagonist aminophylline causes a 20–30% decrease in CBF and cerebral oxygen delivery in normoxia [118].

### **4.2 PCO2**

Similar to many of the other metabolites discussed CO2 tends to increase under conditions of increased metabolism without adequate flow to eliminate it from the area of production and thus its accumulation leads to dilation of the vasculature. High sensitivity to PCO2 is unique to the cerebral circulation [119] causing approximately 3–6% increase and 1–3% decrease in flow per mmHg change in PaCO2 above or below eupnoeic PaCO2 respectively. This high sensitivity is seen throughout the arterial side of the vascular network including the large arteries in the neck [120] and large intracranial arteries [121–123] to the smallest pial arterioles [124] and parenchymal vessels [125–128]. There are likely several redundant mechanistic contributors to the sensitivity of the vasculature to PCO2 which may contribute to the debate as to whether the dilation is triggered by increased PCO2 or rather the accompanying increase H+ concentration from the carbonic anhydrase reaction. There is strong support that the change in PCO2 mediates at least in part alterations in cerebral vascular tone locally by changes in perivascular pH [107, 129–131] as evidenced by acidic and alkaline perfusate administered through an intracranial window. Experiments that have been able to alter pH and PCO2 independently have provided evidence of the dependence of altered pH to initiate a change in cerebral vascular tone [74]. In a cat pial arteriole cranial window preparation, lowering pH along with hypercapnia resulted in no difference in the magnitude of vasodilation when compared to acidic isocapnia [132]. Interestingly, vessel tone was unaltered in response to intraluminal CO2 change,

**29**

*Cerebral Vascular Tone Regulation: Integration and Impact of Disease*

suggesting that a change in superfusate pH is necessary to evoke a change in cerebral vascular tone [107, 133]. This is supported by the findings of unchanged CBF in humans [107] and animals [133] in response to changes in arterial pH, and highly localized pial arteriolar diameter changes in response to the application of acidic/ basic solution into the perivascular space [131]. Additionally, when pH is maintained as seen in an experiment with artificial CSF pretreated with sodium bicarbonate, pial vessel dilation is eliminated in response to intraluminal hypercapnia [107, 134] further supporting that a change in superfusate pH is necessary to alter the cerebral vascular

there is some evidence that bicarbonate ion may independently influence vascular tone. Having the ability to sense and react to multiple parameters associated with acidosis allows for control of tone in response to not only the pH but also the cause of the disturbance (accumulation of CO2 for instance). In isolated rat basilar arter-

(with pH maintained at 7.4 and CO2 kept constant at 5%) through the binding of receptor protein tyrosine phosphatase through an endothelium-dependent response

a pH-independent mechanism [136]. If this is correct then the modest increase

opposing vasocontractile response to decreases in [HCO3

<sup>−</sup>]o has been shown to directly increase cerebral vascular tone

<sup>−</sup> may, therefore, stimulate soluble adenylate cyclase activity through

<sup>−</sup>] during hypercapnia may aid in the dilation response to CO2 but the

laxation caused by a reduction in pH [135]*.* Limiting vasorelaxation during acidosis is important to lessen the increase in capillary pressure associated with vasorelaxation of upstream arterioles. Hyper-relaxation may overload the capillaries leading to edema and damage thereby worsening the consequences of local inadequate perfusion*.*

The effects of oxygen are unique in that its availability is required for aerobic metabolism rather than a byproduct like some of the metabolic factors discussed. Therefore it is not surprising that its abundance leads to vasoconstriction and its relative shortage leads to dilation. Although its availability is tightly linked to that of

been able to discern its independent effect in the presence of otherwise constant conditions. Data from isolated arteries/arterioles suggest there is in fact an oxygen sensor independent of other vasoactive metabolic byproducts within the vascular wall itself [137–142]. Once the change in oxygen is sensed there are various mediators of hypoxic dilation including endothelial-derived NO [138, 141], prostanoids [137, 140, 141, 143], 20-HETE [141] and EDHF [139]; however, the contribution of each factor appears to be dependent on the severity of hypoxia [141]. In skeletal muscle, dilation from mild hypoxia (15% O2) was mostly NO-dependent, while moderate (10% O2) was mediated by a combination of increased PGI2 and decreased 20-HETE, and severe (0% O2) was almost entirely accounted for by an increase in PGI2 [141]. In all cases, there appears to be significant involvement by the endothelium to mediate the dilation, which is further supported by a reduction in hypoxic dilation when isolated vessels were exposed to indomethacin (an inhibitor of AA metabolism and thus the production of PGI2) [137, 144, 145] and to a lesser degree by L-NAME (an inhibitor of NO production from NOS) [145]. Therefore, PGI2 is likely a substantial contributor to hypoxic dilation with a lesser but likely still significant role for NO. Human studies measuring CBF with pcMRI, instead of isolated vessel diameter as in the aforementioned studies, with and without administration of L-NAME suggest that hypoxic dilation is highly dependent on NO, with no change from baseline observed in hypoxia when L-NAME was administered [146]. These differences may be

because of a species-specific response or differences in *ex vivo* and *in vivo* conditions.

and other metabolic byproducts in a physiological setting, studies have

through the carbonic anhydrase reaction,

<sup>−</sup>]o may limits the vasore-

*DOI: http://dx.doi.org/10.5772/intechopen.90404*

tone. In addition to its link with CO2 and H+

ies reduced [HCO3

[135]. HCO3

in [HCO3

**4.3 PO2**

PCO2 and H+

#### *Cerebral Vascular Tone Regulation: Integration and Impact of Disease DOI: http://dx.doi.org/10.5772/intechopen.90404*

suggesting that a change in superfusate pH is necessary to evoke a change in cerebral vascular tone [107, 133]. This is supported by the findings of unchanged CBF in humans [107] and animals [133] in response to changes in arterial pH, and highly localized pial arteriolar diameter changes in response to the application of acidic/ basic solution into the perivascular space [131]. Additionally, when pH is maintained as seen in an experiment with artificial CSF pretreated with sodium bicarbonate, pial vessel dilation is eliminated in response to intraluminal hypercapnia [107, 134] further supporting that a change in superfusate pH is necessary to alter the cerebral vascular tone. In addition to its link with CO2 and H+ through the carbonic anhydrase reaction, there is some evidence that bicarbonate ion may independently influence vascular tone. Having the ability to sense and react to multiple parameters associated with acidosis allows for control of tone in response to not only the pH but also the cause of the disturbance (accumulation of CO2 for instance). In isolated rat basilar arteries reduced [HCO3 <sup>−</sup>]o has been shown to directly increase cerebral vascular tone (with pH maintained at 7.4 and CO2 kept constant at 5%) through the binding of receptor protein tyrosine phosphatase through an endothelium-dependent response [135]. HCO3 <sup>−</sup> may, therefore, stimulate soluble adenylate cyclase activity through a pH-independent mechanism [136]. If this is correct then the modest increase in [HCO3 <sup>−</sup>] during hypercapnia may aid in the dilation response to CO2 but the opposing vasocontractile response to decreases in [HCO3 <sup>−</sup>]o may limits the vasorelaxation caused by a reduction in pH [135]*.* Limiting vasorelaxation during acidosis is important to lessen the increase in capillary pressure associated with vasorelaxation of upstream arterioles. Hyper-relaxation may overload the capillaries leading to edema and damage thereby worsening the consequences of local inadequate perfusion*.*
