Regulation of Cerebral Blood Flow in Untreated Mild-to-Moderate Hypertension

T he regulation of cerebral blood flow (CBF) is complex and influenced by multiple factors, most notably cerebral perfusion pressure (CPP, mean arterial pressure (MAP)-intracranial pressure), partial pressure of carbon dioxide (pCO2), arterial oxygen content, and cerebral metabolism. The individual relationships between these factors and CBF have been extensively studied. How the factors interrelate and whether perturbations in one influence others is, however, poorly understood. In some disease states such as severe head injury or subarachnoid hemorrhage, regulation to CPP may be abolished yet reactivity to oxygen and CO2 may be preserved. Understanding CBF responses to blood pressure (BP) changes is particularly important given the role of hypertension and its control in medical care. Under normal conditions, CBF remains constant despite fluctuations in MAP. This autoregulation of CBF is mediated by changes in cerebrovascular resistance (CVR): when MAP falls, arterioles dilate to reduce CVR, and when MAP increases, arterioles constrict to increase CVR. Cerebral vasoreactivity is altered in chronic hypertension due to vascular remodeling/ hypertrophy and impairment of endothelium-dependent relaxation. Autoregulatory limits are shifted to higher levels. The lower limit, which on average is at a MAP of 120 mm Hg compared to 70 mm Hg in normotensive controls,1 is variably and unpredictably affected by chronic antihypertensive drug treatment. Thus acute reductions in BP that would be safe in normotensive individuals may reduce CBF and precipitate cerebral ischemia in those with chronic hypertension. The most direct way to determine how much vascular reserve is present is to lower BP and see whether CBF falls. A noninvasive, indirect alternative is to measure linear blood flow velocity with transcranial Doppler to assess whether the cerebral vessels are able to dilate in response to CO2 inhalation, and from that infer how much vascular reserve is available to accommodate a reduction in BP. In this issue of American Journal of Hypertension, Claassen and colleagues2 used this latter technique to explore the effect of antihypertensive medication on CBF reactivity to hypercarbia in 11 newly diagnosed, untreated, mildly to moderately hypertensive subjects before and 1–2 weeks and 3–4 months after beginning losartan/hydrocholorothiazide. The hypothesis was that early after instituting treatment, dilation to hypercarbia would be limited. After prolonged treatment, autoregulatory limits would have adjusted to the new BP and dilation to hypercarbia would return to normal. Unexpectedly, the authors found preserved cerebral vasodilation to hypercarbia at all three time points. There are a number of potential explanations for this finding: the magnitude of the change was too small to be detected, treatment shifted the autoregulatory curve downward, or BP was not lowered far enough. The authors state that they had 90% power to detect changes in cerebrovascular reactivity of 1.5%/mm Hg, making the first explanation unlikely. Losartan has been shown to shift the autoregulatory curve to higher pressures,3 which should have impaired CO2 reactivity even more. This leaves the possibility that the BP change was not great enough. In dogs, CBF responses to changes in arterial CO2 are attenuated with mild hypotension (MAP 100) and abolished with severe hypotension (MAP 50).4 What is the clinical relevance of finding impaired global CO2 reactivity in otherwise normal hypertensive subjects? Although impaired CO2 reactivity in the setting of focal arterial disease increases the risk of stroke, the same cannot be said for global impairment in the absence of focal arterial disease. On the other hand, the deleterious effects of chronically elevated BP and the benefits of BP control in hypertension are clear. Thus unless a relationship between impairment in global CO2 reactivity and stroke can be demonstrated for a particular subgroup of individuals, BP reduction should remain the goal of medical care.