© 2000 American Heart Association, Inc.
Integrative Physiology |
Mechanisms of NO/cGMP-Dependent Vasorelaxation
From the Institut für Pharmakologie und Toxikologie der TU München (M.S., V.V., C.H., A.P., T.K., P.R., F.H.), München, Germany; Institut für Physiologie der Universität Rostock (R.S.), Rostock, Germany; and Abteilung Pharmakologie für Pharmazeuten, Universitätskrankenhaus Eppendorf (M.K.), Hamburg, Germany.
Correspondence to Franz Hofmann, Institut für Pharmakologie und Toxikologie der TU München, Biedersteiner Str 29, 80802 München, Germany. E-mail pharma{at}ipt.med.tu-muenchen.de \ © 2000 American Heart Association, Inc.
Abstract—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 µmol/L) of 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA-NO). Iberiotoxin, a specific blocker of Ca2+-activated K+ (BKCa) channels, only partially prevented the relaxation induced by DEA-NO or ACh in pressurized vessels and aortic rings. DEA-NO increased the activity of BKCa 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 BKCa. 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.
Key Words: cGMP-dependent protein kinase I • arteries • K+ channels
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