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Renal α 2a/d ‐adrenoceptor subtype function: Wistar as compared to spontaneously hypertensive rats
Author(s) -
Intengan H D,
Smyth D D
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701198
Subject(s) - medicine , endocrinology , renal artery , kidney , blood pressure , renal function , renal blood flow , agonist , stimulation , furosemide , excretion , spontaneously hypertensive rat , receptor
The α 2a/d ‐adrenoceptor subtype in the rat kidney modulates solute excretion (osmolar clearance). Since the kidney plays a role in chronic regulation of blood pressure, altered renal function may be implicated in the development of hypertension. A second alteration ‐ that of the α 2a/d ‐adrenoceptor subtype gene ‐ has also been correlated with hypertension in rats and man. We hypothesized that as a consequence of the altered α 2a/d ‐adrenoceptor subtype gene previously shown in spontaneously hypertensive (SH) rats, the increase in osmolar clearance following stimulation of the renal α 2a/d ‐subtype would be attenuated in SH rats as compared to normotensive Wistar rats. In contrast, based on the theory that such functional unresponsiveness of the α 2a/d ‐subtype would be genetically determined, we further hypothesized that in one kidney‐one clip (1K‐1C) rats, the response to stimulation of the renal α 2a/d ‐subtype would be intact as compared to the normotensive Wistar 1K‐sham rats. Male rats were unilaterally nephrectomized under ether anaesthesia. In the 1K‐1C rats, a silver clip (diameter 0.254 mm) was also placed around the left renal artery. On the experimental day, rats were administered pentobarbitone (50.0 mg kg −1 , i.p.). The carotid artery and jugular vein were cannulated for blood pressure monitoring and saline infusion. The ureter was catheterized for urine collection. A 31 gauge needle was advanced into the renal artery for infusion of the α 2a/d ‐selective agonist, guanfacine (vehicle, 1.0, 3.0 and 10.0 nmol kg −1 min −1 in Wistar and SH rats; vehicle and 10.0 nmol kg −1 min −1 in Wistar 1K‐sham and 1K‐1C rats). In Wistar rats, guanfacine dose‐dependently increased urine flow and sodium excretion. An increase in osmolar clearance but not free water clearance was also observed. However, in SH rats guanfacine failed to alter urine flow, sodium excretion, osmolar and free water clearance. In contrast, in both Wistar 1K‐sham and 1K‐1C rats, guanfacine increased urine flow rate. Again, this response was due solely to an increase in osmolar clearance. At these doses, guanfacine did not alter blood pressure or creatinine clearance during the experiment. In summary, the ability of the α 2a/d ‐adrenoceptor subtype to mediate an increase in osmolar clearance was absent in a genetic model of hypertension, the SH rats. This effect was intact in an acquired model of hypertension (1K‐1C rats). This suggested a defective modulation of solute excretion in SH rats which was probably due to alteration of the α 2a/d ‐subtype gene and not secondary to the elevated blood pressure. The altered α 2a/d ‐subtype gene and function may therefore play a causal role in the pathogenesis of hypertension.