P-368: Role of CYP and K+ channels in moderating renal vasoconstrictor responses

The activity of large conductance (100-250pS), Ca2+- activated K+ channels (BK) is modified by vasoactive hormones via second messengers, EETs and 20-HETE, generated by cytochrome P450 (CYP). We compared the effects of inhibition of CYP and K+ channels on vasoconstrictor responses to angiotensin II (AII) and the endoperoxide mimetic, U46619, which differ in their requirement for extracellular Ca2+. In the rat isolated perfused kidney, inhibition of CYP with 17-ODYA gradually elevated basal perfusion pressure (PP) without influencing vasoconstrictor responses to AII whereas those to U46619 (30-300ng) were increased several-fold. Inhibition of K+ channels with 1mM TEA enhanced constrictor responses to AII and U46619; viz, PP was increased by 10±5, 81±21 and 155±21 mmHg compared to 2±1, 21±9 and 62±10 mmHg in the control group by 30, 100 and 300 ng U46619, respectively. The inhibitor of BK, charybdotoxin (20nM), but not the inhibitor of small conductance Ca2+-activated K+ channels (15pS), apamin, also enhanced vasoconstrictor responses (U46619>AII). Bolus administration of TEA and charybdotoxin, but not apamin, produced dose-dependent vasoconstriction when PP was elevated to 94±17mmHg from 66±9mmHg by U46619. Thus, 1, 2.5 and 5mg TEA increased PP by 12±4, 29±5 and 49±14 mmHg, respectively, compared to 5±5, 12±5 and 22±7 mmHg, respectively, when PP was elevated to 91±8 mmHg by increasing flow. Similar results were obtained using AII as the constricting agent. These results show that blockade of K+ channels enhances renal vasoconstrictor responses to AII and the thromboxane mimic and that release of CYP-derived eicosanoids moderate constrictor responses.