Etomidate and Thiopental Inhibit the Release of Endothelium-derived Hyperpolarizing Factor in the Human Renal Artery

1996 ◽  
Vol 84 (6) ◽  
pp. 1485-1488 ◽  
Author(s):  
Paul Kessler ◽  
Volker Lischke ◽  
Markus Hecker
Keyword(s):  
Nitric Oxide ◽  
Cytochrome P450 ◽  
Nitric Oxide Synthase ◽  
Renal Artery ◽  
Glyceryl Trinitrate ◽  
Sodium Nitroprusside ◽  
Ca Channel ◽  
Intravenous Anesthetics ◽  
Relaxant Response ◽  
Oxide Synthase

Background Endothelium-derived hyperpolarizing factor is thought to be a cytochrome P450-derived arachidonic acid metabolite that hyperpolarizes vascular smooth muscle cells by opening Ca(2+)-activated K+ channels (K+Ca channels). In the rabbit carotid artery both volatile and intravenous anesthetics inhibit the acetylcholine-stimulated release of endothelium-derived hyperpolarizing factor. Because the release of this factor may help to maintain vascular tone in humans under conditions of a failing nitric oxide synthesis, e.g., in atherosclerosis, the effects of two intravenous anesthetics, thiopental and etomidate, on the endothelium-derived hyperpolarizing factor-mediated relaxant response to acetylcholine were investigated in human isolated renal artery segments. Methods The segments were suspended in Krebs-Henseleit solution (37 degrees C) containing the cyclooxygenase inhibitor diclofenac (1 microM) and preconstricted with norepinephrine (6 microM). Relaxations caused by acetylcholine (1 microM) were compared in the presence and absence of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine (0.1 mM) in control segments and in segments exposed to etomidate or thiopental (0.03-0.3 mM). In addition, the effects of the two anesthetics on the relaxant response to the nitric oxide donors glyceryl trinitrate (3 microM) and sodium nitroprusside (0.1 microM) were examined. Results The relaxant response to acetylcholine, which was resistant to both nitric oxide synthase and cyclooxygenase blockade, was markedly reduced by the K+Ca channel antagonist tetrabutyl ammonium (3 mM) and the cytochrome P450 inhibitor clotrimazole (30 microM). Both etomidate and thiopental, at a concentration of 0.3 mM, selectively attenuated the relaxant response to acetylcholine in N(G)-nitro-L-arginine-treated segments, but did not affect relaxations elicited by glyceryl trinitrate or sodium nitroprusside. Conclusions Etomidate and thiopental inhibit the endothelium-derived hyperpolarizing factor-mediated relaxant response to acetylcholine in the human renal artery, an effect that appears to be attributable to the cytochrome P450-inhibiting properties of these anesthetics.

scholarly journals Contractile responsiveness of coronary arteries from exercise-trained rats

1997 ◽  
Vol 83 (2) ◽  
pp. 434-443 ◽  
Author(s):  
Janet L. Parker ◽  
Mildred L. Mattox ◽  
M. Harold Laughlin
Keyword(s):  
Nitric Oxide ◽  
Coronary Artery ◽  
Nitric Oxide Synthase ◽  
Exercise Training ◽  
Sodium Nitroprusside ◽  
Coronary Arteries ◽  
Internal Diameter ◽  
Relaxation Responses ◽  
Proximal Coronary Artery ◽  
Oxide Synthase

Parker, Janet L., Mildred L. Mattox, and M. Harold Laughlin.Contractile responsiveness of coronary arteries from exercise trained rats. J. Appl. Physiol. 83(2): 434–443, 1997.—The purpose of this study was to determine whether exercise training alters vasomotor reactivity of rat coronary arteries. In vitro isometric microvessel techniques were used to evaluate vasomotor properties of proximal left anterior artery rings (1 ring per animal) from exercise-trained rats (ET; n = 10) subjected to a 12-wk treadmill training protocol (32 m/min, 15% incline, 1 h/day, 5 days/wk) and control rats (C; n = 6) restricted to cage activity. No differences in passive length-tension characteristics or internal diameter (158 ± 9 and 166 ± 9 μm) were observed between vessesls of C and ET rats. Concentration-response curves to K+ (5–100 mM), prostaglandin F2α(10−8–10−4M), and norepinephrine (10−8–10−4) were unaltered ( P > 0.05) in coronary rings from ET rats compared with C rats; however, lower values of the concentration producing 50% of the maximal contractile response in rings from ET rats ( P = 0.05) suggest that contractile sensitivity to norepinephrine was enhanced. Vasorelaxation responses to sodium nitroprusside (10−9-10−4M) and adenosine (10−9-10−4M) were not different ( P > 0.05) between vessels of C and ET rats. However, relaxation responses to the endothelium-dependent vasodilator acetylcholine (ACh; 10−10-10−4M) were significantly blunted ( P < 0.001) in coronary rings from ET animals; maximal ACh relaxation averaged 90 ± 5 and 46 ± 12%, respectively, in vessels of C and ET groups. In additional experiments, two coronary rings (proximal and distal) were isolated from each C ( n = 7) and ET ( n = 7) animal. Proximal coronary artery rings from ET animals demonstrated decreased relaxation responses to ACh; however, ACh-mediated relaxation of distal coronary rings was not different between C and ET groups. N G-monomethyl-l-arginine (inhibitor of nitric oxide synthase) blocked ACh relaxation of all rings. l-Arginine (substrate for nitric oxide synthase) did not improve the blunted ACh relaxation in proximal coronary artery rings from ET rats. These studies suggest that exercise-training selectively decreases endothelium-dependent (ACh) but not endothelium-independent (sodium nitroprusside) relaxation responses of rat proximal coronary arteries; endothelium-dependent relaxation of distal coronary arteries is unaltered by training.

scholarly journals Formation of Transient Oxygen Complexes of Cytochrome P450 BM3 and Nitric Oxide Synthase under High Pressure

2003 ◽  
Vol 85 (5) ◽  
pp. 3303-3309 ◽  
Author(s):  
Stéphane Marchal ◽  
Hazel Mary Girvan ◽  
Antonius C.F. Gorren ◽  
Bernd Mayer ◽  
Andrew William Munro ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
High Pressure ◽  
Cytochrome P450 ◽  
Nitric Oxide Synthase ◽  
P450 Bm3 ◽  
Cytochrome P450 Bm3 ◽  
Oxide Synthase ◽  
Oxygen Complexes

scholarly journals Stopped-flow kinetic studies of electron transfer in the reductase domain of neuronal nitric oxide synthase: re-evaluation of the kinetic mechanism reveals new enzyme intermediates and variation with cytochrome P450 reductase

2002 ◽  
Vol 367 (1) ◽  
pp. 19-30 ◽  
Author(s):  
Kirsty KNIGHT ◽  
Nigel S. SCRUTTON
Keyword(s):  
Nitric Oxide ◽  
Electron Transfer ◽  
Cytochrome P450 ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Stopped Flow ◽  
Cytochrome P450 Reductase ◽  
P450 Reductase ◽  
Oxide Synthase ◽  
Reductase Domain

The reduction by NADPH of the FAD and FMN redox centres in the isolated flavin reductase domain of calmodulin-bound rat neuronal nitric oxide synthase (nNOS) has been studied by anaerobic stopped-flow spectroscopy using absorption and fluorescence detection. We show by global analysis of time-dependent photodiode array spectra, single wavelength absorption and NADPH fluorescence studies, that at least four resolvable steps are observed in stopped-flow studies with NADPH and that flavin reduction is reversible. The first reductive step represents the rapid formation of an equilibrium between an NADPH-enzyme charge-transfer species and two-electron-reduced enzyme bound to NADP+. The second and third steps represent further reduction of the enzyme flavins and NADP+ release. The fourth step is attributed to the slow accumulation of an enzyme species that is inferred not to be relevant catalytically in steady-state reactions. Stopped-flow flavin fluorescence studies indicate the presence of slow kinetic phases, the timescales of which correspond to the slow phase observed in absorption and NADPH fluorescence transients. By analogy with stopped-flow studies of cytochrome P450 reductase, we attribute these slow fluorescence and absorption changes to enzyme disproportionation and/or conformational change. Unlike for the functionally related cytochrome P450 reductase, transfer of the first hydride equivalent from NADPH to nNOS reductase does not generate the flavin di-semiquinoid state. This indicates that internal electron transfer is relatively slow and is probably gated by NADP+ release. Release of calmodulin from the nNOS reductase does not affect the kinetics of inter-flavin electron transfer under stopped-flow conditions, although the observed rate of formation of the equilibrium between the NADPH-oxidized enzyme charge-transfer species and two-electron-reduced enzyme bound to NADP+ is modestly slower in calmodulin-depleted enzyme. Our studies indicate the need for significant re-interpretation of published kinetic data for electron transfer in the reductase domain of neuronal nitric oxide synthase.

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