Decreased blood pressure response in mice deficient of the α _1b -adrenergic receptor

Abstract

To investigate the functional role of different ␣ 1 -adrenergic receptor (␣ 1 -AR) subtypes in vivo, we have applied a gene targeting approach to create a mouse model lacking the ␣ 1b -AR (␣ 1b ؊͞؊). Reverse transcription-PCR and ligand binding studies were combined to elucidate the expression of the ␣ 1 -AR subtypes in various tissues of ␣ 1b ؉͞؉ and ؊͞؊ mice. Total ␣ 1 -AR sites were decreased by 98% in liver, 74% in heart, and 42% in cerebral cortex of the ␣ 1b ؊͞؊ as compared with ؉͞؉ mice. Because of the large decrease of ␣ 1 -AR in the heart and the loss of the ␣ 1b -AR mRNA in the aorta of the ␣ 1b ؊͞؊ mice, the in vivo blood pressure and in vitro aorta contractile responses to ␣ 1 -agonists were investigated in ␣ 1b ؉͞؉ and ؊͞؊ mice. Our findings provide strong evidence that the ␣ 1b -AR is a mediator of the blood pressure and the aorta contractile responses induced by ␣ 1 agonists. This was demonstrated by the finding that the mean arterial blood pressure response to phenylephrine was decreased by 45% in ␣ 1b ؊͞؊ as compared with ؉͞؉ mice. In addition, phenylephrine-induced contractions of aortic rings also were decreased by 25% in ␣ 1b ؊͞؊ mice. The ␣ 1b -AR knockout mouse model provides a potentially useful tool to elucidate the functional specificity of different ␣ 1 -AR subtypes, to better understand the effects of adrenergic drugs, and to investigate the multiple mechanisms involved in the control of blood pressure.

Is overall blockade superior to selective blockade of adrenergic receptor subtypes in suppressing left ventricular remodeling in spontaneously hypertensive rats?

“…The AR-a 1 can be further classified into AR-a 1A , AR-a 1B and AR-a 1D subtypes with AR-a 1B is found to be dominant in the myocardium of mice. 23,24 Wang et al 25 reported that cardiac expression of constitutively active AR-a 1B is detrimental in terms of cardiac hypertrophy and dysfunction after pressure overload and also that increased AR-a 1A mRNA expression is not a feature of the hypertrophic response to hypertension. Vecchione et al 26 found no occurrence of high blood pressure and LV remodeling in response to noradrenaline stimulation in AR-a 1B À/À mice.…”

Emerging Evidence for a Central Epinephrine-Innervated α1-Adrenergic System that Regulates Behavioral Activation and is Impaired in Depression

“…An a 1B -receptor deficient mouse strain had been generated (Cavalli et al, 1997) and had been reported to show 'normal' activity in a novel chamber or open field (Spreng et al, 2001); however, a second group did report a significant reduction in the open field activity with this strain (Knauber and Muller, 2000). In order to determine if there was compensation for the loss of the a 1B -receptor in the mutant mice, we challenged them with large doses of the stimulant, modafinil.…”

Mice expressing the α1B‐adrenergic receptor induces a synucleinopathy with excessive tyrosine nitration but decreased phosphorylation

“…The three a 1 -AR subtypes (a 1A , a 1B , a 1D ) have been classified via molecular cloning (Cotecchia et al 1988;Lomasney et al 1991;Perez et al 1991;Perez et al 1994). The most well characterized cardiovascular functions associated with a 1 AR stimulation include the contraction and growth of vascular smooth muscle cells and their regulation of blood pressure (Chen et al 1995;Leech and Faber 1996;Cavalli et al 1997;Hrometz et al 1999). In other a 1 AR-expressing tissues such as liver, kidney and heart, the receptors regulate metabolic processes (Kunos and Ishac 1987), sodium re-absorption (Jeffries and Pettinger 1989) and inotropy (Anyukovsky and Rosen 1991), respectively.…”