Knockout of the α1A/C-adrenergic receptor subtype:: The α1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure

alpha1-adrenergic receptors (ARs) play a major role in blood pressure regulation. The three alpha1-AR subtypes (A/C, B, and D) stimulate contraction of isolated arteries, but it is uncertain how different subtypes contribute to blood pressure regulation in the intact animal. We studied the role of the alpha1A/C subtype by using gene knockout. alpha1A/C knockout (KO) mice were viable and overtly normal. The LacZ reporter gene replaced a1A/C coding sequence in the KID, and beta-galactosidase staining was present in resistance arteries and arterioles, but not in the thoracic aorta or its main branches. By tail cuff manometer and arterial catheter in conscious mice, a1A/C KO mice were hypotensive at rest, with an 8-12% reduction of blood pressure dependent on a1A/C gene copy number. A61603, an alpha1A/C-selective agonist, caused a pressor response that was lost in the KO and reduced but significant in heterozygous mice with a single copy of the a1A/C. A subtype-nonselective agonist [phenrylephrine (PE)] caused a pressor response in KO mice, but the final arterial pressure was only 85% of wild type. The baroreflex was reset in the KO, and heart rate variability was decreased. After baroreflex blockade with atropine, PE increased blood pressure but did not change heart rate. Cardiac and vascular responses to the beta-AR agonist isoproterenol were unchanged, and the arterial lumen area was not altered. We conclude that the alpha1A/C-AR subtype is a vasopressor expressed in resistance arteries and is required for normal arterial blood pressure regulation. alpha1A/C-selective antagonists might be desirable anti hypertensive agents.