These studies are designed to illuminate the actions of TxA2 in hypertension and integration of glomerular and tubular functions. Infusion of angiotensin II (Ang II) or Ang II-dependent models of hypertension, cause widespread release of TxA2 which mediates much of the systemic and renal vasoconstriction. To mimic the effects of widespread TxA2/PGH2 receptor activation, we propose to infuse the stable TxA2/PGH2 agonist, U-46,619, for 10 days into conscious rats. We have developed methods to measure BP and renal blood flow to analyze the mechanisms of hypertension and renal vasoconstriction in this new model. Preliminary studies have implicated central actions of TxA2/PGH2 expressed through the sympathetic nervous system, renal nerves and renin release. Moreover, endogenous release of TxA2 appears to promote the vasoconstriction while nitric oxide and a factor from activated platelets offset the response. Therefore, the first objective is to study the role of these systems in the development of hypertension, renal vasoconstriction and salt retention. In other preliminary studies, we perfused U-46,619 into the loop of Henle (LH) at a concentration equivalent to that of TxB2 that we measured in proximal tubular fluid; it enhanced chloride reabsorption and tubuloglomerular feedback responses (TGF) by a macula densa-mediated mechanism. We propose to explore the mechanism of action of TxA2/PGH2 on epithelial transport in isolated, perfused thick ascending limb segments from the rabbit. We will define the role of macula densa reabsorption, Ang II and adenosine in regulating the release of glomerular TxA2 in vivo (from proximal tubule appearance of TxB2) and characterize the segmental reabsorption and secretion of TxB2 to determine the origin of urinary TxB2. Further preliminary studies have shown not only that TxA2/PGH2 may mediate half of the actions of adenosine on the afferent arteriole, but also that TxA2 may release adenosine which can mediate up to 80% of the pre-renal vasoconstriction. Therefore, we propose to use selective agonists of adenosine type 1 and 2 receptors in micropuncture studies to define this interaction with TxA2 and their individual effects on the determinants of the single nephron glomerular filtration rate. Thus, we propose a progressive series of studies of TxA2 from conscious rats to single nephrons to explore its mechanism of action, its interaction with adenosine and the regulation of its release in the kidney.
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