Stimulation of the brain, seizures, and hypoxia lead to rapid increases in cerebral blood flow and are associated with elevated levels of perivascular potassium (K+). These increases in K+ are comparable to those that cause dilation of pial arterioles when K+ is topically applied to these vessels. When extracellular K+ surpasses 15 mEq/L, smooth muscle cells depolarize, leading to increased calcium (Ca++) entry and subsequent contraction and vasoconstriction. Thus, the extracellular concentration of K+ has a dual effect on smooth muscle function, which is attributed to its impact on Na+/K+-ATPase, K+ conductance, and the K+ concentration gradient.

The regulation of cerebral vessels is also influenced by carbon dioxide (CO2). Elevated levels of CO2 in arterial blood (PaCO2) result in significant cerebral vasodilation, as demonstrated by a two-fold increase in cerebral blood flow with inhalation of 7% CO2. Conversely, cerebral blood flow decreases with reduced PaCO2 due to hyperventilation. CO2 affects arteriolar resistance by altering the pH around the blood vessels. Regardless of the level of PaCO2 or bicarbonate (HCO3-) concentration, changes in pH show an inverse relationship with pial vessel diameter and blood flow. Acidosis triggers pronounced vasodilation of brain arterioles through localized release of Ca++ from the endoplasmic reticulum, leading to activation of large conductance BKCa channels. This subsequent hyperpolarization stabilizes vascular smooth muscle cells and counteracts vasoconstriction.

When intracranial pressure increases, such as in the presence of a brain tumor, systemic blood pressure also rises. This response, known as Cushing's phenomenon, is initiated by ischemic stimulation of vasomotor regions in the medulla. Cushing's phenomenon aids in maintaining cerebral blood flow in conditions like expanding intracranial tumors.

Carbon dioxide diffuses into vascular smooth muscle either from brain tissue or the lumen of blood vessels, while the blood-brain barrier prevents H+ from reaching arteriolar smooth muscle. Consequently, cerebral vessels dilate when the concentration of H+ in cerebrospinal fluid increases. However, these vessels only exhibit minimal dilation in response to an increase in H+ concentration in arterial blood. In individuals with endothelial dysfunction (e.g., diabetes, hypertension), the chemical regulation of cerebral blood flow by PaCO2 is impaired. The precise roles of H+ and nitric oxide (NO) in response to changes in PaCO2 remain unclear.

Potassium concentration also impacts cerebral blood flow. Hypoxia, brain stimulation, and seizures prompt rapid increases in cerebral blood flow and perivascular K+ levels. These K+ increases are similar to those observed during pial arteriolar dilation caused by topical application of K+ to these vessels. However, the elevation in K+ concentration is not sustained throughout the entire period of cerebral stimulation. Therefore, only the initial increase in cerebral blood flow can be attributed to the release of K+.
With regard to K+ , stimuli such as hypoxia, electrical stimulation of the brain, and seizures elicit rapid increases in cerebral blood flow, and they are associated with increases in perivascular K+ . The increments in K+ are similar to those that produce pial arteriolar dilation when K+ is applied topically to these vessels. When extracellular K+ exceeds 15 mEq/L, smooth muscle cells depolarize, and Ca++ entry is increased to cause contraction and vasoconstriction. Thus the extracellular [K+] has a dual effect on smooth muscle function that is derived from its actions on Na+/K+-ATPase, K+ conductance, and the K+ concentration gradient.
The cerebral vessels are also regulated by CO2. Increases in arterial blood CO2 tension (PaCO2) elicit marked cerebral vasodilation; for example, inhalation of 7% CO2 increases cerebral blood flow twofold. Conversely, decreases in PaCO2, caused by hyperventilation, diminish cerebral blood flow. CO2 evokes changes in arteriolar resistance by altering perivascular pH. When PaCO2 and the HCO3 − concentration are independently changed, pial vessel diameter and blood flow are inversely related to pH, regardless of the level of PaCO2 or [HCO3 −]. Acidosis initiates a marked vasodilation of brain arterioles. The vasodilation is mediated by a very localized release of Ca++ from the endoplasmic reticulum (Ca++ “sparks”). This local Ca++ signal activates large conductance BKCa channels; the ensuing hyperpolarization stabilizes the vascular smooth muscle cell and opposes vasoconstriction.
Elevationinintracranialpressure,causedbyabraintumor,resultsinanincreaseinsystemicbloodpressure.Thisresponse,calledCushing’s phenomenon, isevokedbyischemicstimulationofvasomotorregionsinthemedulla.Cushing’sphenomenonhelpsmaintaincerebralbloodflowinconditionssuchasexpandingintracranialtumors.
Carbon dioxide diffuses into vascular smooth muscle from brain tissue or from the lumen of blood vessels, whereas H+ in blood is prevented from reaching arteriolar smooth muscle by the blood-brain barrier. Hence, cerebral vessels dilate when the [H+] of cerebrospinal fluid is increased, but these vessels dilate only minimally in response to an increase in the [H+] of arterial blood. Chemical regulation of cerebral blood flow by PaCO2 is impaired in humans with endothelial dysfunction (e.g., diabetes, hypertension); the relative roles of H+ and NO in response to changes of PaCO2 are not clear.
Potassium concentration also affects cerebral blood flow. Hypoxia, electrical stimulation of the brain, and seizures elicit rapid increases in cerebral blood flow and in perivascular [K+]. The increases in [K+] are similar in magnitude to those that produce pial arteriolar dilation when K+ is applied topically to these vessels. However, the increase in [K+] is not sustained throughout the period of cerebral stimulation. Thus only the initial increase in cerebral blood flow can be attributed to the release of K+ .