Fig. 2.

ET-induced VSM relaxation pathways. ET binds to ET_B1 receptor in endothelial cells or ET_A and ET_B2 receptors in VSM. ET_B1 may function in ET uptake. ET_B1 is also coupled to activation of PLCβ, hydrolysis of PIP₂, and release of IP₃ and diacylglycerol (DAG). IP₃ stimulates Ca²⁺ release from the endoplasmic reticulum (ER). Ca²⁺ stimulates eNOS, which converts L-arginine to L-citrulline and increases NO production. NO diffuses into VSM, stimulates guanylate cyclase (GC) and increases cGMP. cGMP causes VSM relaxation by decreasing [Ca²⁺]_i and the myofilament sensitivity to Ca²⁺. ET_B1 -mediated increase in endothelial Ca²⁺ also stimulates cyclooxygenases (COX) and prostacyclin (PGI₂) production. PGI₂ activates adenylate cyclase (AC) and increases cAMP, which causes VSM relaxation similar to cGMP. ET_B1 also increases the release of EDHF, which activates K⁺ channels and causes hyperpolarization, inhibition of Ca²⁺ influx, and VSM relaxation. Interrupted arrows indicate inhibition.