Spontaneous stroke in a genetic model of hypertension in mice.
OBJECTIVE
Hypertension is the most common risk factor for hemorrhagic stroke. An experimental model of stroke, the stroke-prone spontaneously hypertensive rat (SHRSP), which has been enormously useful in studies of cerebral circulation, has been used in >1000 papers. However, SHRSP usually have an ischemic or less commonly hemorrhagic stroke in the cortex, not in the brain stem, cerebellum, or basal ganglia, as in patients with hypertension. The goal of this study was to develop a model of hemorrhagic stroke in hypertensive mice.


METHODS
A genetic model of hypertensive mice, double transgenic mice (R+/A+) that overexpress both human renin (R+) and human angiotensinogen (A+), and nonhypertensive control mice were divided into 3 groups: (1) high-salt diet; (2) Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthases, in drinking water; and (3) high-salt diet and L-NAME.


RESULTS
All R+/A+ mice on high-salt diet and L-NAME died within 10 weeks, with hemorrhage in the brain stem, and several of the mice had hemorrhages in brain stem, cerebellum, and basal ganglia. No control mice on high-salt diet and L-NAME had hemorrhagic stroke. Arterial pressure in R+/A+ mice increased progressively during high-salt diet and L-NAME. In R+/A+ and control mice, high-salt diet or L-NAME alone did not increase arterial pressure.


CONCLUSIONS
We now describe the first model of spontaneous hemorrhagic strokes in hypertensive mice. The type and locations of stroke are reasonably similar to those observed in patients with hypertension.
Iida
Shinichiro
S
Cardiovascular Center, Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA.
Baumbach
Gary L
GL
Lavoie
Julie L
JL
Faraci
Frank M
FM
Sigmund
Curt D
CD
Heistad
Donald D
DD
D000808:Angiotensinogen / Q000235:genetics; D000821:Animal Feed; D000818:Animals; D001794:Blood Pressure; D001921:Brain / Q000473:pathology; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000235:genetics*; D020300:Intracranial Hemorrhages / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012083:Renin / Q000235:genetics; D012492:Salts / Q000494:pharmacology; D020521:Stroke / Q000209:etiology* / Q000235:genetics*
D012492:Salts; D000808:Angiotensinogen; D019001:Nitric Oxide Synthase; D012083:Renin; D019331:NG-Nitroarginine Methyl Ester