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.
Rho
Edwin H
EH
Department of Anesthesiology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
Perkins
William J
WJ
Lorenz
Robert R
RR
Warner
David O
DO
Jones
Keith A
KA
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006162:Guanylate Cyclase / Q000502:physiology*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D012137:Respiratory System / Q000187:drug effects*; D013050:Spectrometry, Fluorescence; D013552:Swine; D013873:Thionucleotides / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D020030:Nitric Oxide Donors; D013873:Thionucleotides; D014665:Vasodilator Agents; C083763:8-bromoguanosino-3',5'-cyclic monophosphorothioate; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D002118:Calcium