Hypotension, autonomic failure, and cardiac hypertrophy in transgenic miceoverexpressing the alpha(1B)-adrenergic receptor

alpha (1)-Adrenergic receptors (alpha (1A), alpha (1B), and alpha (1D)) are regulators of systemic arterial blood pressure and blood flow. Whereas vas oconstrictory action of the alpha (1A) and alpha (1D) subtypes is thought t o be mainly responsible for this activity, the role of the alpha (1B)-adren ergic receptor (alpha (1B)AR) in this process is controversial, We have gen erated transgenic mice that overexpress either wild type or constitutively active alpha (1B)ARs. Transgenic expression was under the control of the is ogenic promoter, thus assuring appropriate developmental and tissue-specifi c expression. Cardiovascular phenotypes displayed by transgenic mice includ ed myocardial hypertrophy and hypotension. Indicative of cardiac hypertroph y, transgenic mice displayed an increased heart to body weight ratio, which was confirmed by the echocardiographic finding of an increased thickness o f the interventricular septum and posterior wall. Functional deficits inclu ded an increased isovolumetric relaxation time, a decreased heart rate, and cardiac output. Transgenic mice were hypotensive and exhibited a decreased presser response. Vasoconstrictory regulation by alpha (1B)AR was absent a s shown by the lack of phenylephrine-induced contractile differences betwee n ex vivo mesenteric artery preparations. Plasma epinephrine, norepinephrin e, and cortisol levels were also reduced in transgenic mice, suggesting a l oss of sympathetic nerve activity, Reduced catecholamine levels together wi th basal hypotension, bradycardia, reproductive problems, and weight loss s uggest autonomic failure, a phenotype that is consistent with the multiple system atrophy-like neurodegeneration that has been reported previously in these mice. These results also suggest that this receptor subtype is not in volved in the classic vasoconstrictory action of alpha (1)ARs that is impor tant in systemic regulation of blood pressure.