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

Abstract

␣1-adrenergic receptors (ARs) play a major role in blood pressure regulation. The three ␣1-AR subtypes (A͞C, 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 ␣1A͞C subtype by using gene knockout. ␣1A͞C knockout (KO) mice were viable and overtly normal. The LacZ reporter gene replaced ␣1A͞C coding sequence in the KO, and ␤-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, ␣1A͞C KO mice were hypotensive at rest, with an 8 -12% reduction of blood pressure dependent on ␣1A͞C gene copy number. A61603, an ␣1A͞C-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 ␣1A͞C. A subtype-nonselective agonist [phenylephrine (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 ␤-AR agonist isoproterenol were unchanged, and the arterial lumen area was not altered. We conclude that the ␣1A͞C-AR subtype is a vasopressor expressed in resistance arteries and is required for normal arterial blood pressure regulation. ␣1A͞C-selective antagonists might be desirable antihypertensive agents.

Preservation of Base-line Hemodynamic Function and Loss of Inducible Cardioprotection in Adult Mice Lacking Protein Kinase Cϵ

“…Results are expressed as the means of three independent daily measurements with at least 15 of 20 successful analyses each (18). Echocardiographic studies were performed on conscious mice after training using a 15-MHz linear array transducer and commercially available imaging system (Acuson Sequoia c256, Mountain View, CA).…”

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

“…Although all three ␣ 1 -AR subtypes signal through the same G q/11 signaling pathway (11), ␣ 1 -AR subtypes can differ in their tissue distributions (1), cellular localization (12,13), activation of transcriptional responses (14), and association with intracellular proteins (15)(16)(17), suggesting that ␣ 1 -AR subtypes perform specific physiological functions. Furthermore, recent data obtained from both ␣ 1 -AR overexpressed (18 -21) and knockout mice (22)(23)(24)(25) indicate that ␣ 1 -ARs play important physiological roles in the cardiovascular system and central nervous system. However, attempts to pharmacologically isolate specific responses to particular subtypes have proven difficult because of the lack of highly ␣ 1B -AR-selective antagonists.…”

α1d Adrenoceptor signaling is required for stimulus induced locomotor activity

“…Therefore, we assessed locomotor activity in response to a novel cage environment. As shown in Figure 5a, activity associated with rearing behavior is significantly decreased in a1d À/À mice when compared to their wild-type littermates (F (1,22) ¼ 0.2526; P ¼ 0.0068, post hoc test). This reduction is maintained throughout the 30-min test session.…”

“…This technique has been applied to a number of adrenergic receptors (AR) including the b1, b2, b3, a2a, a2b, a2c, a1a/c and a1b. [19][20][21][22][23][24][25] Analysis of these receptor knockout mice has enabled investigators to assign specific functions to certain receptor subtypes. The main advantage of the gene-targeting method for a1 receptor analysis lies in its circumvention of nonspecific pharmacological compounds and drugs which may not readily cross the blood-brain barrier, such as prazosin.…”