The α_1D-adrenoreceptor antagonist BMY 7378 reverses cardiac hypertrophy in spontaneously hypertensive rats

Objective:The α_1D-adrenoreceptor (α_1D-AR) is involved in angiotensin II-induced vascular remodeling and hypertension. Whether α_1D-AR plays a role in hypertension-associated cardiac hypertrophy is unclear. Here we investigated effects of BMY 7378, a selective α_1D-AR antagonist, on cardiac status in aged spontaneously hypertensive rats (SHR).Methods:Male SHR were studied during the phase of developing hypertension (5 and 10 weeks old) and once hypertension was established (20 and 30 weeks old) to assess the evolution of cardiac hypertrophy. Age-matched WKY rats were studied as controls. Thirty-week-old SHR were treated for 4 weeks with BMY 7378 (10mg/kg per day, o.a.), or captopril (angiotensin-converting enzyme inhibitor, 40mg/kg per day, o.a.) (as a positive control). Blood pressure and cardiac function were measured in vivo, cardiac hypertrophy by histology, and α_1D-AR protein expression by immunofluorescence.Results:By 30 weeks of age, SHR exhibited significant hypertension and cardiac hypertrophy. BMY 7378 and captopril decreased blood pressure and improved hemodynamic parameters and cardiac function in treated SHR vs. untreated SHR (P<0.05). Histology showed increased cardiomyocyte size, fibrosis, and left ventricular hypertrophy in SHR hearts. BMY 7378 ameliorated fibrosis and cardiac hypertrophy, but had no effect on cardiomyocyte size in SHR. Effects of BMY 7378 were associated with increased α_1D-AR protein expression in SHR.Conclusion:Our data indicate that pharmacological antagonism of α_1D-AR reduces blood pressure and associated cardiac hypertrophy in aged SHR. These findings suggest that the α_1D-AR plays a pathophysiological role in the development of hypertension and cardiac target organ damage in SHR.