Abstract:
Over 80% of ischemic stroke patients show an abrupt increase in arterial blood pressure (BP) immediately following ischemic stroke. Whether this post-stroke hypertension is beneficial or harmful remains controversial, perhaps in part because the underlying physiological basis is unclear. Although elevated BP is known to increase the risk of secondary stroke, opinions on an optimal therapeutic approach for post-stroke hypertension remain widely divided in the scientific literature. Thus, my thesis aimed to evaluate the underlying mechanisms and impact of treating post-stroke hypertension in normotensive, controlled and uncontrolled hypertensive rats. To investigate the dynamic cardiovascular response to stroke, adult Wistar and Spontaneously Hypertensive Rats (SHRs) were instrumented with telemeters to measure BP, intracranial pressure (ICP) and tissue oxygen (pO2) in the predicted penumbra. After recovery and a threeday baseline recording, ischemic stroke was induced via transient middle cerebral artery occlusion (MCAo), or sham surgery. Cardiovascular and other signals were then recorded for a further ten days, and the functional sensorimotor recovery assessed using the Cylinder and Sticky Dot tests. To prevent post-stroke hypertension, BP therapy was given for three days following MCAo to reduce BP to the pre-stroke baseline level in Controlled Wistar and SH rats, and to a normotensive (below baseline) level in Overcontrolled SHRs. Controlled SHRs (chronic BP treatment prior to stroke) received enalapril to normalise BP for four weeks before MCAo, with post-stroke hypertension prevented to the pre-stroke baseline with additional treatment. This study showed for the first time that the profound rise in BP after stroke is initiated immediately (within minutes) of MCAo in both Wistar and SHRs, concurrent with the fall in cerebral tissue oxygen. This rise in BP increased cerebral perfusion pressure (CPP) for ~3 days after stroke, while penumbral pO2 was maintained at baseline levels. While this may suggest that post-stroke hypertension helps enhance regional blood flow to the affected area, preventing post-stroke hypertension to the pre-stroke baseline did not worsen mortality, infarct size or the functional recovery from stroke, in normotensive Wistars, SHRs or Controlled SHRs. In contrast, treating BP to a normotensive level after stroke in SHRs, increased mortality and infarct size, and impaired the functional recovery from stroke. After stroke induction, the pathophysiological response to several cases of spontaneous terminal haemorrhage was observed, with severe intracranial hypertension associated with pronounced counterbalancing systemic increases in BP, consistent with a Cushing Response. My results show that the magnitude and time-course of post-stroke hypertension are remarkably similar in Normotensive, Uncontrolled and Controlled SHRs and serves to elevate CPP above baseline for several days after stroke. Preventing post-stroke hypertension does not appear to worsen prognosis after stroke, regardless of whether BP prior to stroke was normotensive, hypertensive or controlled hypertensive. The results identify that overtreatment of BP to normotensive levels in hypertensive rats had a pronounced detrimental impact (analogous to the potential inadvertent overtreatment of stroke patients with undiagnosed hypertension). These findings have important clinical implications for setting BP targets after stroke in mixed patient cohorts, where the true pre-stroke BP is often unknown.