Thiazide-type diuretics have been utilized since the 1950s for the treatment of hypertension. Although the mode of their antihypertensive action is not firmly established, thiazides are known to inhibit reabsorption of NaCl (and increase reabsorption of calcium) from the renal tubule, probably by inhibition of a Na-Cl electroneutral symporter in the distal nephron. Thus, considerable evidence has been advanced that their antihypertensive action is related, at least in the acute situation, to their natriuretic/chloriuretic action. We have developed and utilize 3H-metolazone to identify the pharmacological receptor for thiazide-type diuretics by ligand-binding technology. The current project is based on our finding that the thiazide receptor is increased in kidneys of hypertensive SHR animals, but not in either kidney from animals with 2 kidney-1 clip hypertension. The increased density of the thiazide receptor in SHR has the potential to be of exceptional importance, since overactivity of the thiazide-sensitive transporter would be expected to lead to increased sodium (and chloride) retention, and presumably to both systemic hypertension and hypercalciuria. Thus, the increase in the thiazide receptor in SHR could be not only cause of our contributory to the hypertension in this genetic form of hypertension, but also explain several other abnormalities in the SHR. We will test whether the increase the density of the thiazide receptor in the SHR could be a genotypic expression of, a phenotypic expression of, an innocent bystander to, or unrelated to the genetic hypertension by determining: (i) if the increase in density of the thiazide receptor in SHR genetically co-segregates with hypertension, abnormal calcium balance or metabolic acidosis; (ii) if the regulation of density of the thiazide receptor in SHR differs from that in WKY in response to altered activity of the renal nerves, adrenergic receptor blockade, adrenal steroid status or dietary calcium status; (iii) if pharmacological control of hypertension dissociates systemic hypertension from the increased density of the thiazide receptor, using different classes of antihypertensive agents. These experiments will test these questions: (a) is the increase in the density of the thiazide receptor in SHR causally related to, a secondary manifestation of, an innocent bystander to or unrelated to the hypertension; (b) what regulatory system accounts for the increased density of the thiazide receptor in the SHR; and is the abnormality in calcium balance and/or acid-base balance in SHR associated with an increased activity of the thiazide receptor in SHR?
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