The consequences of cerebral ischemia were studied in three different strains (BDF, CFW, and BALB/C) of mice. The different strains exhibited significant differences in susceptibility to 24-h focal ischemia. Following middle cerebral artery occlusion (MCAO), infarct volumes (mm3) were 5 +/- 3 in BDF, 15 +/- 5 in CFW, and 23 +/- 3 in BALB/C mice (p < 0.05). MCAO plus ipsilateral common carotid artery occlusion (CCAO) resulted in infarct volumes of 15 +/- 9 in BDF, 38 +/- 10 in CFW, and 72 +/- 12 in BALB/C mice (p < 0.05). In addition, MCAO plus CCAO produced death by 24 h in 42% of CFW and 67% of BALB/C mice, but not in any BDF mice (p < 0.05). CCAO alone produced multifocal hemispheric infarctions in 36% of BALB/C mice but not in the other two strains. Brains of all mouse strains subjected to sham surgery were free of any ischemic injury. Arterial blood pressures, blood gases, and blood cell profiles were relatively similar for the three mouse strains. However, carbon black studies of the cerebrovascular anatomy revealed an incomplete circle of Willis (i.e., a significant decrease in the frequency of patent posterior communicating arteries) for BALB/C compared with BDF mice (p < 0.05), with CFW mice being intermediary. Based on these anatomical data, BALB/C mice also were evaluated following transient global brain ischemia produced by bilateral CCAO. BALB/C mice exhibited a > 85% reduction in cortical microvascular perfusion and EEG power within 1 min of bilateral CCAO. Also, hippocampal neuronal CA1 damage and mortality over 7 days were related to the duration of global brain ischemia (p < 0.05). These data demonstrate a significant difference between mouse strains in their sensitivity to cerebral ischemia that appears to be related, at least in part, to the functional vascular anatomy at the level of the posterior communicating arteries. In particular, we point out the potential usefulness of BALB/C mice as a sensitive and reproducible model of focal and global ischemia.

Background-Numerous pathological mediators of cardiac hypertrophy (eg, neurohormones, cytokines, and stretch) have been shown to activate p38 MAPK. The purpose of the present study was to examine p38 MAPK activation and the effects of its long-term inhibition in a model of hypertensive cardiac hypertrophy/dysfunction and end-organ damage. Methods and Results-In spontaneously hypertensive stroke-prone (SP) rats receiving a high-salt/high-fat diet (SFD), myocardial p38 MAPK was activated persistently during the development of cardiac hypertrophy and inactivated during decompensation. Long-term oral treatment of SFD-SP rats with a selective p38 MAPK inhibitor (SB239063) significantly enhanced survival over an 18-week period compared with the untreated group (100% versus 50%). Periodic echocardiographic analysis revealed a significant reduction in LV hypertrophy and dysfunction in the SB239063-treatment groups. Little or no difference in blood pressure was noted in the treatment or vehicle groups. Basal and stimulated (lipopolysaccharide) plasma tumor necrosis factor-␣ concentrations were reduced in the SB239063-treatment groups. In vitro vasoreactivity studies demonstrated a significant preservation of endothelium-dependent relaxation in animals treated with the p38 MAPK inhibitor without effects on contraction or NO-mediated vasorelaxation. Proteinuria and the incidence of stroke (53% versus 7%) were also reduced significantly in the SB239063-treated groups. Conclusions-These results demonstrate a crucial role for p38 MAPK in hypertensive cardiac hypertrophy and end-organ damage. Interrupting its function with a specific p38 MAPK inhibitor halts clinical deterioration. (Circulation. 2001;

1 The eect of carvedilol on renal function, structure and expression of TGFb and the matrix proteins ®bronectin, collagen I and collagen III, was evaluated in spontaneously hypertensive strokeprone (SHR-SP) rats fed a high fat, high salt diet. 2 Carvedilol treatment for 11 to 18 weeks did not alter systolic blood pressure in SHR-SP rats, however, it resulted in a signi®cant reduction in heart rate. 3 Carvedilol treatment reduced renal ®brosis and total, active and chronic renal damage to levels approaching those of WKY rats on a normal diet. 4 Urinary protein excretion was higher in SHR-SP rats (51+10 mg day 71 ) than WKY rats (18+2 mg day 71) and this was further increased when SHR-SP rats were fed a high fat, high salt diet (251+120 mg day 71). Treatment with carvedilol resulted in signi®cantly lower urinary protein excretion (37+15 mg day 71). 5 The expression of TGFb mRNA was signi®cantly higher in SHR-SP rats compared to WKY rats and a further increase was observed when rats were fed a high fat, high salt diet. Renal TGFb expression was signi®cantly reduced by treatment with carvedilol. The expression of ®bronectin and collagen I and collagen III mRNA showed a pattern similar to that observed with TGFb mRNA expression. Collagen I mRNA expression followed a pattern similar to renal ®brosis. 6 These data indicate that carvedilol can provide signi®cant renal protection in the absence of any antihypertensive activity and that the mechanisms involved in this action may include reduced expression of pro®brotic factors such as TGFb.

These data indicate that carvedilol provides remarkable cardioprotection, by suppressing severe hypertension-induced cardiac remodeling and myopathies at doses that do not reduce systemic blood pressure.

No abstract