Hypertension and Experimental Stroke Therapies

Abstract

Hypertension is an established target for long-term stroke prevention but procedures for management of hypertension in acute stroke are less certain. Here, we analyze basic science data to examine the impact of hypertension on candidate stroke therapies and of anti-hypertensive treatments on stroke outcome. Methods: Data were pooled from 3,288 acute ischemic stroke experiments (47,899 animals) testing the effect of therapies on infarct size (published 1978-2010). Data were combined using meta-analysis and meta-regression, partitioned on the basis of hypertension, stroke model, and therapy. Results: Hypertensive animals were used in 10% of experiments testing 502 therapies. Hypertension was associated with lower treatment efficacy, especially in larger infarcts. Overall, anti-hypertensives did not provide greater benefit than other drugs, although benefits were evident in hypertensive animals even when given after stroke onset. Fifty-eight therapies were tested in both normotensive and hypertensive animals: some demonstrated superior efficacy in hypertensive animals (hypothermia) while others worked better in normotensive animals (tissue plasminogen activator, anesthetic agents). Discussion: Hypertension has a significant effect on the efficacy of candidate stroke drugs: standard basic science testing may overestimate the efficacy which could be reasonably expected from certain therapies and for hypertensive patients with large or temporary occlusions. Keywords: acute stroke; animal models; brain ischemia; hypertension; neuroprotection INTRODUCTION Hypertension-the elevation of blood pressure-dramatically increases the risk of stroke, with an estimated 52% of all strokes attributable to hypertension. 1 Hypertension can be controlled and numerous interventions are used in the longterm management of hypertension to prevent both first-time strokes and their recurrence. 2 Less well understood is how to tackle high blood pressure within the first 24 to 48 hours after stroke and how the presence of hypertension affects the efficacy of neuroprotective treatments administered within this period. Lowering blood pressure is not without risks, and it is generally recommended that blood pressure only be lowered if extreme; nevertheless, there is no consensus on the optimal blood pressure thresholds to trigger initiation of treatment, rates of reduction and blood pressure targets, or how hypertension should be managed with concurrent therapies such as tissue plasminogen activator. [2][3][4] Clinical trials are ongoing. 5 By examining hypertension and anti-hypertensive treatments in experimental (animal) stroke models, we may develop a better understanding of how to manage hypertension in the acute stroke setting. Knowledge of hypertension in basic science is also important in its own right. The external validity of animal testing depends upon the ability to generalize to the clinical setting: it has been a frequent criticism of preclinical drug testing that the paradigm has failed to capture the impact of important comorbidit...

Contractile Responses in Spontaneously Hypertensive Rats after Transient Middle Cerebral Artery Occlusion

“…These rats were not subjected to stroke, but in combination with our results they suggest that risk factors for stroke have an effect on the vasocontractile receptor responses in cerebral arteries, since there was no change in the vasocontractile receptor responses in ischemic cerebral arteries from WKY rats (normotensive rats). This difference between hypertensive and normotensive rats supports the discrepancy in treatment efficacy between the strains after experimental stroke [2]; however, we also observed a discrepancy in the vasocontractile receptor responses in ischemic cerebral arteries from the normotensive rats in our study compared to previous studies. The endothelin-1-induced contractile response in ischemic cerebral arteries from normotensive rats is the same, but we did not observe any change in the contractile response to sarafotoxin 6c, as it has been shown before [19, 20].…”

“…The lack of risk factors such as hypertension incorporated into the preclinical stroke research could be one reason for the translational failure between preclinical and clinical studies. It has even been shown that several stroke treatments elicited lower efficacy or worse outcome in hypertensive compared to normotensive animals after experimental stroke [2]. Hypertension is a major risk factor for stroke, and about 77% of people who have a first stroke have a blood pressure higher than 140/90 mm Hg [1].…”

Pharmacological therapy of acute ischaemic stroke: Achievements and problems

“…Angiotensin II receptor blockers (ARBs) tended to be more effective than other classes of AH (review by O'Collins et al, 2013). The ARB candesartan administered after reperfusion in an animal model of stroke in rats (middle cerebral artery occlusion, MCAO) rapidly decreased BP, reduced the neurovascular damage and improved outcome (Fagan et al, 2006).…”

Animal Models of Stroke: Translational Potential At Present and In 2050

“…The selectively bred spontaneously hypertensive rat (SHR) has been extensively studied to assess the role of hypertension in stroke [35]. The SHR rat develops hypertension within the first few months of birth and exhibits elevated blood pressure that appears to be maximal at approximately 200 mmHg.…”