A single exposure to nitric oxide (NO) donors produces a long-lasting hyporesponsiveness to phenylephrine (HRP) in rat aorta rings. Here the authors investigate the role of the endothelial layer in the development of NO-induced HRP and the putative role of endothelium-derived vasoconstrictors in counteracting it. The NO donor S-nitrosoacetyl-D,L-penicillamine (SNAP) induced a dose-dependent reduction in the maximal effect (Emax) of phenylephrine. In rings without endothelium, Emax dropped to 60%, 25%, and 10% of control values 1 h after a 30-min incubation with SNAP (2, 20, and 200 μM, respectively). In contrast, the presence of endothelium prevented the HRP induced by 2 μM SNAP and significantly reduced the HRP elicited by 20 and 200 μM SNAP (Emax reductions of 50% and 65%, respectively), thereby characterizing the endothelium protective effect. Superoxide dismutase (SOD; 100 IU/mL), MnTBAP (a nonenzymatic SOD mimetic; 100 μM), captopril (10 μM), MK886 (a lipoxygenase inhibitor; 10 μM) and BQ 123 (endothelin receptor A antagonist; 1 μM) did not change the endothelium protective effect. Therefore, increased release of vasoconstrictors that would counteract NO-induced loss in phenylephrine responses cannot account for the protective effect of endothelium. In contrast, oxidation of sulphydryls with DTNB prevented the onset of SNAP-induced HRP. A better understanding of mechanisms by which the endothelial layer (or protein sulphydryl groups present in it) exerts its protective effect towards the NO-induced loss in physiological vasoconstriction is likely to be of value in cardiovascular conditions such as ischemia/reperfusion and septic shock.
Bibliographical noteFunding Information:
The authors wish to thank Dr. Giles A. Rae and J. E. da Silva-Santos for valuable suggestions regarding this study. They also thank Dr. Rae for the gift of BQ123. The authors are grateful to Adriane Madeira for expert technical assistance. This work was partially supported by CNPq, CAPES, and PRONEX, Brazil.
Copyright 2008 Elsevier B.V., All rights reserved.
- Nitric oxide