Renal a2-Adrenergic Receptors and Hypertension

I N 1964 Oj-adrenergic receptors were first described pharmacologically using the in vitro melanocyte granule dispersion technique in Rana pipiens. The goal of these studies was to assess the intrinsic activity on o^-adrenergic receptors of methyldopa's neurotransmitter metabolites and other catecholamines. Publication of this description was delayed for 13 years, 1 until the evidence for a receptor agonist mechanism of centrally acting antihypertensive drugs became apparent. These observations provided the basis for a functional classification of a,-adrenergic and o^-adrenergic receptors 2 that was analogous to Ahlquist's 3 original classification of a-adrenergic and /8-adrenergic receptors. The existence of adrenergic receptors in organs and tissues usually has been demonstrated by a physiological or biochemical response. However, renal c^-adrenergic receptors were first demonstrated by using radioligand binding techniques. 4 Even with the demonstration of increased renal a 2-adrenergic receptor density in genetically hypertensive rats 5 " 7 several years later, there was essentially no characterization of either physiological or biochemical effects of renal a 2-adrenergic receptor activation. The lack of clearly defined physiological effects of renal a 2-adrenergic receptor activation has limited investigation on the pathophysiological role of altered a 2-adren-ergic receptor regulation in genetic rat hypertension. Some investigators, including DiBona and Sawin, whose article is published in this issue of Hypertension* have taken the approach of infusing an ctj-adrenergic receptor selective blocking agent into the kidney of genetically hypertensive rats. Because they did not see any effects of o^-adrenergic receptor blockade on vascular resistance or sodium retention, they concluded that altered ctj-adrenergic receptor regulation could not contribute to the pathogene-sis of genetic hypertension. These observations are of considerable interest and have been made by investigators who have already made important contributions to our understanding of renal adrenergic receptor control mechanisms. Nevertheless, given the complexity of these mechanisms, these findings warrant careful consideration. Several years ago we started on the same approach as that of DiBona and Sawin 8 by infusing yohimbine into the renal artery during activation of renal sympathetic nerves in the anesthetized dog. Our results were also negative, so we elected to develop and characterize biochemical and physiological test systems that would allow qualitative and partially quantitative expression of a^-adrenergic receptor effects in the kidney. Oj-Adrenergic receptors mediate, in many tissues, inhibition of adenylate cyclase and thus reduce cyclic adenosine 3',5'-monophosphate (cAMP) formation and effects induced by this nucleotide. A number of hormones can selectively activate adenylate cyclase in different …