Endothelin‐1 modulates vascular smooth muscle structure and vasomotion: Implications in cardiovascular pathology

Abstract

Endothelin-I modulates vascular smooth muscle tone by exerting potent vasoconstrictor actions through the ETA receptor subtype located on the membranes of vascular smooth muscle cells. This receptor subtype also mediates the growth-promoting actions of this peptide in vascular smooth muscle cells. The ETA receptor is distinct, however, from the endothelin receptor subtype located on the endothelium; the anatomically and functionally distinct ET, receptor mediates the release of the endothelium-derived factor nitric oxide, a labile substance which not only produces potent vasodilation but also possesses anti-mitogenic activity. This report describes the interaction between these two vasoactive factors i n the control of cardiovascular function. Under normal conditions the endothelium serves to modulate the contractile and proliferative actions of endothelin-I . However, many cardiovascular disorders (e.g., hypertension, atherosclerosis, vascular restenosis, subarachnoid hemorrhage, etc.) are associated with both abnormal endothelial cell function, resulting in an inability to synthesize and/or release nitric oxide, and elevated circulating levels of endothelin-I. Since the resultant loss/inhibition of nitric oxide will augment both the contractile and proliferative actions of endothelin-I, this has the potential to promote vasoconstriction and smooth muscle hyperplasidhypertrophy at the site of any such lesion. Since evidence i s accumulating that both endothelin-I and nitric oxide play pivotal roles in the control of both vascular smooth muscle tone and growth, any imbalance between these two counter-regulatory systems is likely to have profound pathological consequences within the cardiovascular system. 0 1993 Wiley-Liss, Inc.

In vivo pharmacological characterization of the non‐peptide endothelin receptor antagonist SB 209670

“…Indeed, the antagonism observed in vivo with 10 mg kg-' ( ± )-SB 209670 is indistinguishable from that observed with the same dose of (+)-SB 209670 endothelin-1 in hypertensive strains of rat w may be involved in the abnormal elevation o resistance (Douglas et al, 1992;19! 1994a (Spokes et al, 1989;Douglas & Hiley, 1991;Ohlstein & Douglas, 1993 are inhibited selectively by BQ-123 over a dose-range which does not attenuate the depressor actions of endothelin-l (Douglas et al, 1992). However, such a classification is now recognized as being an oversimplification.…”

Hemodynamic Effects of Tezosentan, an Intravenous Dual Endothelin Receptor Antagonist, in Patients With Class III to IV Congestive Heart Failure

“…8 ET A receptors are found in smooth muscle cells and mediate vasoconstriction and proliferation. 9 Under physiological conditions, ET B receptors, present in the brain, endothelium, and certain smooth muscle cells, play a role in endothelium-dependent vascular smooth muscle relaxation. 10 In experimental heart failure, ET B receptor expression is upregulated, and these receptors become capable of mediating vasoconstriction and participate in the development of cardiac fibrosis.…”

A role for endogenous endothelin-1 in neointimal formation after rat carotid artery balloon angioplasty. Protective effects of the novel nonpeptide endothelin receptor antagonist SB 209670.

“…The advanced occlusive atherosclerotic lesions observed in humans are characterized by a marked fibroproliferative response involving large numbers of intimal smooth muscle cells, macrophages, and T lymphocytes.1 Several neurohumoral factors, such as angiotensin II and norepinephrine, have been implicated in neointimal development.2 Like angiotensin II and norepinephrine, endothelin-1 is now recognized as playing an intrinsic role in the endogenous control of systemic hemodynamics. 3 Since levels of endothelin-1 are elevated in the human coronary sinus after PTCA, it has been suggested that endothelin-1 is involved in the pathogenesis of vascular restenosis. 4 In addition to its actions on vascular smooth muscle tonus, endothelin-1 is also a potent mitogen in several cultured cell lines of both cardiovascular and noncar-growth factors, the latter of which may be synergistic.…”