Functional role of the renal A|2[subscript a/d]|-adrenoceptor subtype in normotensive and hypertensive rats

Thumbnail Image
Intengan, Hope D.
Journal Title
Journal ISSN
Volume Title
Clonidine is a mixed $\alpha\sb2$-adrenoceptor/imidazoline receptor agonist. Previous studies showed that, in the anesthetized rat, clonidine increased urine flow rate by increasing both osmolar (solute) and free water clearance. These renal effects of clonidine and other $\alpha\sb2$-adrenoceptor agonists were postulated to involve the stimulation of two distinct anatomical sites and/or receptors. The receptors mediating the renal effects of clonidine were investigated using male, uninephrectomized rats. Rats were anesthetized with pentobarbitone. Following a tracheotomy, the carotid artery and jugular vein were cannulated respectively for the measurement of blood pressure and saline infusion. The remaining kidney was exposed and the ureter was catheterized for the collection of urine. A 31 gauge needle was advanced into the renal artery for the infusion of the agonist of interest (or vehicle) directly into the kidney. If required, antagonists were administered as a slow intravenous bolus. A low infusion rate of clonidine (1.0 nmol/kg/min) increased urine flow rate by increasing free water and osmolar clearance. These renal effects were shown to be pharmacologically independent using prazosin (an $\alpha\sb1$-antagonist with relative selectivity for the $\rm\alpha\sb{2b}$-adrenoceptor subtype) and naltrexone (an opioid receptor antagonist). The free water response to clonidine was prazosin-sensitive/naltrexone-insensitive where as the osmolar response was prazosin-insensitive/naltrexone-sensitive. This was consistent with the renal effects of clonidine being mediated by two separable and distinct receptors. Based on the prazosin sensitivity of the increase in free water clearance, this response was postulated but not proven to involve the $\rm\alpha\sb{2b}$-subtype. The receptor mediating the clonidine-induced osmolar clearance was less clear. Moxonidine (an imidazoline receptor agonist) increased osmolar clearance but was insensitive to naltrexone indicating that imidazoline receptors were not involved in the osmolar response to clonidine. UK-14,304 is an $\alpha\sb2$-agonist that, at a low dose, selectively increased osmolar and not free water clearance. The osmolar response to UK-14,304 was also attenuated by naltrexone and unaffected by prazosin. Literature reports have speculated on the purported selectivity of UK-14,304 for the $\rm\alpha\sb{2a/d}$-subtype over other $\alpha\sb2$-subtypes. In the rat kidney, only the $\rm\alpha\sb{2a/d}$- and $\rm\alpha\sb{2b}$-adrenoceptor subtypes have been identified. A clearly selective $\rm\alpha\sb{2a/d}$-agonist, guanfacine, was used to test the hypothesis that the renal $\rm\alpha\sb{2a/d}$-adrenoceptor subtype mediated osmolar clearance. Guanfacine increased osmolar clearance but not free water clearance. As with clonidine and UK-14,304, this response was naltrexone-sensitive and prazosin-insensitive, RX-821002, an $\rm\alpha\sb{2a/d}$-selective antagonist, attenuated the osmolar response to guanfacine. These results supported the contention that the renal $\rm\alpha\sb{2a/d}$-adrenoceptor subtype mediated osmolar clearance. Further studies examined the renal function of the $\rm\alpha\sb{2a/d}$-adrenoceptor in hypertensive versus normotensive rats. Guanfacine consistently increased osmolar clearance when administered to the relevant, normotensive control rats. In contrast, the osmolar response to guanfacine was absent in a genetic model of hypertension (spontaneously hypertensive (SH) rats) while intact in an acquired model of hypertension (one kidney-one clip rats). These data suggested that the natriuretic function of the $\rm\alpha\sb{2a/d}$-subtype was defective in SH rats and that this defect was not secondary to elevated blood pressure. Decreased natriuretic activity of the $\rm\alpha\sb{2a/d}$-adrenoceptor subtype in SH rats would be consistent with this defect playing a causal role in the pathogenesis of hypertension.