Received for publication April 21, 2005.
Revised October 12, 2005.
Accepted for publication October 12, 2005.

The impact of blunted beta-adrenergic responsiveness on growth regulatory pathways in hypertension

Abstract

The effects of vasodilator hormones acting through receptors linked to adenylyl cyclase are impaired in the hypertensive state. This has been ascribed to impaired receptor-G-protein coupling. However, these receptors also act via effectors not linked to adenylyl cyclase activation. These "alternate" mechanisms may be especially important in growth regulation and might be unaffected (or enhanced) with GPCR-G-protein uncoupling. Therefore we assessed the effects of beta-adrenergic activation on 1) regulation of PI3 kinase and ERK activation- two tyrosine kinase-dependent enzymes linked to cell growth and 2) microarray analysis in vascular smooth muscle cells from spontaneously hypertensive rats. Isoproterenol-stimulated phosphorylation of ERK 1/2 was impaired in SHR. The effect of forskolin was unaltered. In contrast, both vasopressin and angiotensin 2- mediated stimulation of ERK activation was enhanced in SHR. Also, beta adrenergic-mediated inhibition of PI3 kinase activity was attenuated in SHR (whereas the effect of forskolin remained intact). In microarray studies, the effect of isoproterenol to regulate transcription of was significantly impaired in SHR (as was the effect of forskolin). In total, these data support the hypothesis that the blunted vasodilator effects of hormones linked to adenylyl cyclase activation are an index of a more generalized impairment in modulating growth regulatory pathways. Further, these studies support the hypothesis that the blunting of beta adrenergic responses relating to increased GRK2 expression reflects a "generalized uncoupling" of beta-adrenergic-mediated responses and do not support the concept of "enhanced coupling" of "alternate" pathways of beta-adrenergic growth regulatory pathways in the hypertensive state.

Key words: Adrenergic, Gs family, cAMP, MAP Kinase, Regulation of gene expression

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