Hypoxia modulates cyclic AMP activation of BK_Ca channels in rat pulmonary arterial smooth muscle

The signal transduction mechanisms defining the role of cyclic nucleotides in the regulation of potassium channel activity in pulmonary vascular smooth muscle are currently an area of great interest. Normally, signaling mechanisms that elevate cyclic AMP (cAMP) open potassium channels. Modulation of the large-conductance, calcium- and voltage-activated potassium (BK_Ca) channel is important in the regulation of pulmonary arterial pressure, and inhibition (closing) of the BK_Ca channel has been implicated in the development of pulmonary vasoconstriction. Accordingly, studies were done to determine the effect of cAMP-elevating agents on BK_Ca channel activity under normoxic and hypoxic conditions using patch-clamp studies in pulmonary arterial smooth muscle cells (PASMC) of the fawn-hooded rat (FHR). Forskolin (10 μM; n = 4), a stimulator of adenylate cyclase and an activator of cAMP-dependent protein kinase (PKA), and CPT-cAMP (100 μM; n = 3), a membrane-permeable derivative of cAMP, opened BK_Ca channels in single FHR PASMC under normoxic conditions. Exposure of FHRs to 4 weeks of 10% O ₂ (hypoxia) significantly attenuated the effect of both forskolin (n = 7) and CPT-cAMP (n = 14) on BK_Ca channel activity in PASMC. These results suggest that this phenomenon may serve as a physiological mechanism to cause hypoxic vasoconstriction in the pulmonary circulation via modulation of BK_Ca channels.