The role of prostanoids in the mediation of responses to KC-404, a novel cerebrovasodilator.

The purpose of this study was to characterize the nature of the response to KC-404 in the cerebral microcirculation of the newborn pig. Pial arterioles were observed directly using a closed cranial window in chloralose-anesthetized piglets. Topical application of 100, 300, 1000, 3000 and 10,000 ng/ml of KC-404 produced concentration-dependent increases in pial arteriolar diameter. Diameters were 168 +/- 18, 190 +/- 19 and 238 +/- 21 mu for control, 100 ng/ml and 10,000 ng/ml of KC-404, respectively. Responses to KC-404 (3-isobutyryl-2-isopropylpyrazolo-[1,5a]-pyridine) were blocked by indomethacin (5 mg/kg i.v.). Moreover, KC-404, topically applied to the cerebral cortex, produced small but significant increases in cortical subarachnoid cerebrospinal fluid levels of 6-keto-prostaglandin (PG) F1 alpha and PGE2, whereas thromboxane B2 levels were unchanged. Similar to topical application, i.v. KC-404 (0.5 mg/kg) produced pial arteriolar dilation without significantly altering arterial blood pressure. Intravenous KC-404 also increased cerebrospinal fluid levels of 6-keto-PGF1 alpha and PGE2, whereas thromboxane levels were unchanged. Further, topically applied KC-404 (1 microgram/ml) potentiated dilator responses to PGE2 and PGI2, whereas responses to isoproterenol were unchanged. These data indicate that KC-404 is a potent dilator of cerebral arterioles in newborn pigs. These data also suggest that KC-404 produces cerebral vasodilation predominantly by potentiating prostanoid-mediated dilation.