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 wil d-type (wt) and cGMP kinase I-deficient (cGKI(-/-)) mice. Low concentration s of NO and ACh decreased the spontaneous myogenic tone in wt but not in cG KI(-/-) arteries. However, contractions of cGKI(-/-) arteries and aortic ri ngs were reduced by high concentrations (10 mu mol/L) of 2-(N,N-diethylamin o)-diazenolate-2-oxide (DEA-NO). Iberiotoxin, a specific blocker of Ca2+-ac tivated 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 isolate d from wt cGKI(+/+) mice. These results suggest that low physiological conc entrations of NO decrease vascular tone through activation of cCKI, whereas high concentrations of DEA-NO relax vascular smooth muscle independent of cGKI and BKCa. NO-stimulated, cGKI-independent relaxation was antagonized b y the inhibition of soluble guanylyl cyclase or cAMP kinase (cAK). DEA-NO i ncreased cGMP to levels that are sufficient to activate cAK. cAMP-dependent relaxation was unperturbed in cGKI(-/-) vessels. In conclusion, low concen trations 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.