Regulation of coronary vascular tone via redox modulation in the α₁-adrenergic-angiotensin-endothelin axis of the myocardium

Abstract

We hypothesized that alpha(1)-adrenoceptor stimulation of cardiac myocytes results in the production of an endothelin (ET)-releasing factor that stimulates the coronary vasculature to release ET and, by manipulating the redox state of cardiac and vascular cells, may influence the extent of alpha(1)-adrenergic-ET-1 vasoconstriction. Dihydroethidium (DHE) and dichlorodihydrofluorescein (DCF) intensities were increased by phenylephrine stimulation in isolated rat cardiac myocytes, which were enhanced by the mitochondrial electron transport chain complex I inhibitor rotenone (DHE: 20.4 +/- 1.2-fold and DCF: 25.2 +/- 0.9-fold, n = 8, P < 0.01, respectively) but not by the NADPH oxidase inhibitor apocynin. Olmesartan, an angiotensin II type 1 receptor antagonist, and enalaprilate did not change DHE and DCF intensities by phenylephrine. Next, we measured the vasoconstriction of isolated, pressurized rat coronary arterioles (diameter: 74 +/- 8 microm) in response to supernatant collected from isolated cardiac myocytes. The addition of supernatant from phenylephrine-stimulated myocytes to a 2-ml vessel bath (n = 8 each) caused volume-dependent vasoconstriction (500 microl: -14.8 +/- 2.2%). Olmesartan and TA0201, an ET type A receptor antagonist, converted vasoconstriction into vasodilation (8.5 +/- 1.2% and 10.5 +/- 0.5%, P < 0.01, respectively) in response to supernatant from phenylephrine-stimulated myocytes, which was eliminated with catalase. Vasoconstriction was weakened using supernatant from phenylephrine with rotenone-treated myocytes. Treatment of arterioles with apocynin to myocyte supernatant converted vasoconstriction into vasodilation (7.8 +/- 0.8%, P < 0.01). These results suggest that alpha(1)-adrenergic stimulation in cardiac myocytes produces angiotensin I and H(2)O(2) and that angiotensin releases ET-1 through NADPH oxidase in coronary arterioles. Thus, coronary vasoconstriction via the alpha-adrenergic-angiotensin-ET axis appears to require redox-mediated signaling in cardiac and vascular cells.

Nicotinamide Adenine Dinucleotide Phosphate Reduced Oxidase 5 (Nox5) Regulation by Angiotensin II and Endothelin-1 Is Mediated via Calcium/Calmodulin-Dependent, Rac-1-Independent Pathways in Human Endothelial Cells

“…Vascular Noxes are expressed in a cell-specific manner, with endothelial cells expressing mainly Nox2 and Nox4; vascular smooth muscle cells, Nox1, Nox2 and Nox4; and adventitial fibroblasts, Nox2 and Nox4 (19–21). Regulation of vascular Noxes, through de novo protein synthesis of Nox homologues (22,23) and phosphorylation of NADPH oxidase regulatory subunits (24,25), is multifactorial, involving physical factors (stretch, pressure), chemical factors (pH, O 2 ) and vasoactive agents (angiotensin II (Ang II), endothelin-1 (ET-1), aldosterone and growth factors) (26,27). …”

Coronary endothelial dysfunction after cardiomyocyte-specific mineralocorticoid receptor overexpression

“…These communications may have a strong physiological relevance, for example to adapt coronary perfusion to increased metabolic demands (4), but may also be important in pathological conditions, for example by contributing to trigger endothelial dysfunction (26). Importantly, cardiac myocytes have been shown to trigger the release of endothelin from endothelial cells, especially in response to ␣-adrenergic stimulation (12,29). Since endothelin may per se induce endothelial dysfunction, it is possible that this peptide, as well as angiotensin II, may contribute to the alterations of coronary relaxations that we observed.…”

Selective Enhancement of Contractions to α1-adrenergic Receptor Activation in the Aorta of Mice With Sickle Cell Disease

“…18 However, such expression of endothelin-1 may not explain the enhanced renal vasoconstrictive response after renal ischemic injury; 14 it is thus possible that α1-adrenergic mechanisms may be involved in such settings. Interestingly, endothelin-1 is induced in some vascular beds by α1-adrenergic pathways, 19 and α1-adrenergic activity may condition the response to endothelin-1, thereby raising the possibility that there may be cross talk between α1-adrenergic mechanisms and endothelin-1 observed in SCD.…”