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 (K_Ca), and the resulting hyperpolarization inhibits voltage-gated Ca²⁺ channels (Ca_V). PKG also appears to directly inhibit Ca_V. 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 K_Ca would also lead to a hyperpolarization and inhibition of Ca_V. Agonists such as acetylcholine (Ach) and phenylephrine act by increasing cellular Ca²⁺.