Protein kinase Cs and tyrosine kinases in permissive action of prostacyclin on cerebrovascular regulation in newborn pigs

The involvement of protein kinase C (PKC) and protein tyrosine kinase (PTK) in hypercapnia-induced cerebral vasodilation in newborn pigs was investigated with closed cranial windows using the PKC stimulator phorbol 12-myristate 13-acetate (PMA), and the PTK inhibitors, genistein and herbimycin A. The influence of prostaglandin I-2 was eliminated using the prostaglandin cyclooxygenase inhibitor, indomethacin. Changes in pial arteriolar diameters in response to hypercapnia [partial pressure of arterial CO2 similar or equal to 9.3 kPa (70 torr)] were analyzed. Genistein (40 mu g/mL), herbimycin A (10 mu M), or PMA (1 mu M) did not affect cerebral vasodilation to hypercapnia when applied topically, Indomethacin (5 mg/kg i.v.) treatment blocked the dilation to hypercapnia and attenuated hypercapnia-induced increase in cortical cAMP. Genistein and herbimycin A restored the response to hypercapnia to indomethacin-treated piglets. PMA also restored the pial arteriolar dilation and the cAMP response to hypercapnia to indomethacin-treated piglets. One-hour exposure to 10 mu M PMA, to down-regulate PKC, blocked vasodilation to hypercapnia but did not inhibit vasodilation to sodium nitroprusside. After prolonged (2 h) topical exposure of indomethacin-treated piglets to 10 mu M PMA, neither genistein nor iloprost could restore dilation to hypercapnia. These results indicate that PKC stimulation and/or PTK inhibition may permit hypercapnia-induced vasodilation. These data further suggest that PKC is downstream from PTK in the regulatory pathway, Because previous data showed prostaglandin I-2 at subdilator concentrations can also return dilation to hypercapnia to piglets treated with indomethacin, prostaglandin I-2 could provide its permissive input by activating PKC and/or inhibiting PTK.