Vasodilator prostaglandins (PG's) moderate vasoconstriction and promote renin release but blood vessels and glomeruli also produce a vasoconstrictor thromboxane (Tx).
The aim of this research is to define the homeostatic functions of Tx in the normal kidney and in models of chronic renal failure and renal hypertension. PG and TxB2 release from the kidney and glomerulus will be studied in vivo from measurements in urine and proximal tubular fluid and in vitro from release of radiolabeled arachidonate metabolites from isolated interlobular, afferent and efferent arterioles. Macula densa regulation of glomerular TxA2 production will be studied from release of TxB2 and PG's into early proximal tubular fluid during graded perfusion of the loop of Henle. The pre- and post-glomerular vascular resistances and the individual determinants of glomerular ultrafiltration of Munich-Wistar rats will be calculated from micropuncture and capillary micropressure recordings. The role of TxA2 will be determined by administration of specific TxA2 antagonists or synthesis inhibitors. The first hypothesis is that vascular TxA2 synthesis is regulated by AII and modulates its systemic and renal actions. Since inhibition of TxA2 stimulates renin release, the second hypothesis is that endogenous TxA2 production regulates negative feedback inhibition of renin release by AII. Since macula densa stimulation by hyperchloremia releases TxA2, the third hypothesis is that TxA2 coordinates the macula densa inhibition of renin release, increases in pre- and post-glomerular vascular resistances and fall in GFR. Progresive renal damage in rat models of reduced renal mass and renovascular hypertension has been related to increased glomerular capillary pressure, which is normally stabilized by the tubuloglomerular feedback (TGF) response. Since TxA2 modulates TGF, the next hypothesis is that TxA2 regulates PGC and TGF in remanant nephrons of rats with reduced renal mass and interacts with AII in the contralateral kidney of rats with 2 kidney, 1 clip hypertension. This research will provide novel insights into the role of this powerful endogenous vasoconstrictor system in normal homeostasis and in models of common renal and vascular diseases.
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