Key result
Guanfacine increases osmolar clearance in normotensive and 1K-1C rats but not in spontaneously hypertensive rats.
Why the study?
Altered renal alpha 2a/d-adrenoceptor subtype gene and function have been correlated with hypertension, but its role in modulating renal solute excretion in hypertensive versus normotensive rats was unclear.
Does guanfacine infusion alter osmolar clearance differently in genetic versus acquired models of hypertension in rats?
Does guanfacine infusion alter osmolar clearance differently in genetic versus acquired models of hypertension in rats?
The alpha 2a/d-adrenoceptor subtype's ability to mediate osmolar clearance is defective in genetically hypertensive rats but intact in acquired hypertension, suggesting a causal role in the pathogenesis of hypertension.
The alpha 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 alpha 2a/d-adrenoceptor subtype gene-has also been correlated with hypertension in rats and man. 2. We hypothesized that as a consequence of the altered alpha 2a/d-adrenoceptor subtype gene previously shown in spontaneously hypertensive (SH) rats, the increase in osmolar clearance following stimulation of the renal alpha 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 alpha 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 alpha 2a/d-subtype would be intact as compared to the normotensive Wistar 1K-sham rats. 3. 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 alpha 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). 4. 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. 5. In summary, the ability of the alpha 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 alpha 2a/d-subtype gene and not secondary to the elevated blood pressure. The altered alpha 2a/d-subtype gene and function may therefore play a causal role in the pathogenesis of hypertension.
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Intengan et al. (1997) studied Hypertension. Guanfacine vs. Vehicle was evaluated on Urine flow, sodium excretion, and osmolar clearance. Guanfacine dose-dependently increased osmolar clearance in normotensive Wistar and 1K-1C rats, but this response was absent in spontaneously hypertensive rats.
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