Differential effects of soluble and particulate guanylyl cyclase on Ca(2+) sensitivity in airway smooth muscle.

Maximal relaxation of airway smooth muscle (ASM) in response to atrial natriuretic peptide (ANP), which stimulates particulate guanylyl cyclase (pGC), is less than that produced by nitric oxide (NO) and other compounds that stimulate soluble guanylyl cyclase (sGC). We hypothesized that stimulation of pGC relaxes ASM only by decreasing intracellular Ca(2+) concentration (Ca(2+)](i)), whereas stimulation of sGC decreases both Ca(2+)](i) and the force developed for a given Ca(2+)](i) (i.e., the Ca(2+) sensitivity) during muscarinic stimulation. We measured the relationship between force and Ca(2+)](i) (using fura 2) under control conditions (using diltiazem to change Ca(2+)](i)) and during exposure to ANP, diethylamine-NO (DEA-NO), sodium nitroprusside (SNP), and the Sp diastereoisomer of beta-phenyl-1,N(2)-etheno-8-bromoguanosine-3',5'-cyclic monophosphorothionate (Sp-8-Br-PET-cGMPS), a cell-permeant analog of cGMP. Addition of DEA-NO, SNP, or Sp-8-Br-PET-cGMPS decreased both Ca(2+)](i) and force, causing a significant rightward shift of the force-Ca(2+)](i) relationship. In contrast, with ANP exposure, the force-Ca(2+)](i) relationship was identical to control, such that ANP produced relaxation solely by decreasing Ca(2+)](i). Thus, during muscarinic stimulation, stimulation of pGC relaxes ASM exclusively by decreasing Ca(2+)](i), whereas stimulation of sGC decreases both Ca(2+)](i) and Ca(2+) sensitivity.