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Platelet activating factor (PAF) is produced by the rat renal papilla from a neutral lipid, alkylacetylglycerol. Renal release of another neutral lipid, antihypertensive neutral renomedullary lipid, and PAF might account for normalization of blood pressure after unclipping in Goldblatt hypertensive rats. We studied the potential storage and release of hypotensive substances by the rat renal papilla in vitro. Rat kidneys were snap-frozen in liquid N2-cooled freon immediately after removal and the total lipids were extracted from pooled dissected papillae and partially separated by thin layer chromatography on silica gel with a hexane: ether: acetic acid (40:60:1) solvent system. Lipids eluted from four, contiguous silica gel zones were assayed in anesthetized spontaneously hypertensive rats. No hypotensive activity was found in the thin layer chromatography lipid fraction co-migrating with palmitylacetylglycerol or in any other neutral lipid fraction. In contrast, the Krebs medium obtained after 30-min incubation of freshly minced papillary tissue induced dose-related hypotension and bradycardia. The hypotensive activity was equivalent to 48 ± 9 ng prostaglandin E2 (PGE2)/mg wet papilla. Bradycardia induced by the incubation medium was correlated with decrements in blood pressure. In the same assays, nitroprusside caused tachycardia which was correlated with hypotension, and the bradycardia associated with PGE2-induced hypotension was significantly less than that induced by the incubation medium. The dose-related effects of the incubation medium were dramatically attenuated by indomethacin treatment of the papilla, suggesting that the hypotensive activity is dependent upon papillary cyclooxygenase activity. However, PGI2 elicited hypotension concomitant with tachycardia rather than bradycardia and PGE2 did not mimic the incubation medium-induced bradycardia. Therefore, the effects of the papillary incubation medium may be mediated by other cyclooxygenase metabolites. Production/release of hypotensive material by indomethacin-treated papillary tissue was potentiated by co-incubation with non-hypotensive quantities of PGE2, suggesting a potential role for PGE2 in the renal antihypertensive function. Increasing pressure on the papilla from 6 to 20mmHg during incubation did not increase release of non-prostanoid hypotensive substance(s). These results suggest that the formation and release of cyclooxygenase metabolites accounts primarily for the hypotensive activity released from rat renal papillae in vitro, and that prostaglandins might play a permissive role in the release of other renomedullary hypotensive substances.