Mechanisms of NO/cGMP-dependent vasorelaxation.
Both cGMP-dependent and -independent mechanisms have been implicated in the regulation of vascular tone by NO. We analyzed acetylcholine (ACh)- and NO-induced relaxation in pressurized small arteries and aortic rings from wild-type (wt) and cGMP kinase I-deficient (cGKI(-/-)) mice. Low concentrations of NO and ACh decreased the spontaneous myogenic tone in wt but not in cGKI(-/-) arteries. However, contractions of cGKI(-/-) arteries and aortic rings were reduced by high concentrations (10 micromol/L) of 2-(N:, N-diethylamino)-diazenolate-2-oxide (DEA-NO). Iberiotoxin, a specific blocker of Ca(2+)-activated K(+) (BK(Ca)) channels, only partially prevented the relaxation induced by DEA-NO or ACh in pressurized vessels and aortic rings. DEA-NO increased the activity of BK(Ca) channels only in vascular smooth muscle cells isolated from wt cGKI(+/+) mice. These results suggest that low physiological concentrations of NO decrease vascular tone through activation of cGKI, whereas high concentrations of DEA-NO relax vascular smooth muscle independent of cGKI and BK(Ca). NO-stimulated, cGKI-independent relaxation was antagonized by the inhibition of soluble guanylyl cyclase or cAMP kinase (cAK). DEA-NO increased cGMP to levels that are sufficient to activate cAK. cAMP-dependent relaxation was unperturbed in cGKI(-/-) vessels. In conclusion, low concentrations of NO relax vessels by activation of cGKI, whereas in the absence of cGKI, NO can relax small and large vessels by cGMP-dependent activation of cAK.
Sausbier
M
M
Institut für Pharmakologie und Toxikologie der TU München, München, Germany.
Schubert
R
R
Voigt
V
V
Hirneiss
C
C
Pfeifer
A
A
Korth
M
M
Kleppisch
T
T
Ruth
P
P
Hofmann
F
F
D000109:Acetylcholine; D000818:Animals; D001011:Aorta; D000242:Cyclic AMP / Q000032:analysis; D006152:Cyclic GMP / Q000032:analysis / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000172:deficiency*; D006834:Hydrazines; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D009569:Nitric Oxide / Q000494:pharmacology*; D009589:Nitrogen Oxides; D010455:Peptides / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
D006834:Hydrazines; D009589:Nitrogen Oxides; D010455:Peptides; D009569:Nitric Oxide; C064719:iberiotoxin; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D000242:Cyclic AMP; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D000109:Acetylcholine