The potential interplay of NO and CO. Established interactions that lead to physiological responses are shown in solid lines, and dashed lines indicate interactions where some experimental support exists. NOS catalyzes the formation of NO and citrulline from arginine. NO directly activates the soluble isoform of guanylate cyclase (sGC), leading to 400-fold increased activity. cGMP then activates a PKG cascade and cellular Ca2+ levels are lowered. In part, PKG potentiates calcium-activated potassium channels (KCa), and the resulting hyperpolarization inhibits voltage-gated Ca2+ channels (CaV). PKG also appears to directly inhibit CaV. HO catalyzes the formation of CO from iron protoporphyrin IX. Results from HO–/– mice suggest that CO action depends on NO. While CO has been shown to activate the α1β1 isoform of sGC, the activation is very weak compared with that of NO (14). The action of CO on KCa would also lead to a hyperpolarization and inhibition of CaV. Agonists such as acetylcholine (Ach) and phenylephrine act by increasing cellular Ca2+.