FIGURE 17–8 Generation of endothelin-1 (ET-1) in the vascular endothelium, and its direct and indirect effects on smooth muscle cells mediated by ETA and ETB receptors. ANG II, angiotensin II; ANP, atrial natriuretic peptide; Arg, arginine; BigET-1, proET-1; ECE, endothelial-converting enzyme; NO, nitric oxide; PreproET-1, precursor of BigET-1; PGI2, prostaglandin I2.
ETs exert widespread actions in the body. In particular, they cause potent dose-dependent vasoconstriction in most vascular beds. Intravenous administration of ET-1 causes a rapid and transient decrease in arterial blood pressure followed by a sustained increase. The depressor response results from release of prostacyclin and nitric oxide from the vascular endothelium, whereas the pressor response is due to direct contraction of vascular smooth muscle. ETs also exert direct positive inotropic and chronotropic actions on the heart and are potent coronary vasoconstrictors. They act on the kidneys to cause vasoconstriction and decrease glomerular filtration rate and sodium and water excretion. In the respiratory system, they cause potent contraction of tracheal and bronchial smooth muscle. ETs interact with several endocrine systems, increasing the secretion of renin, aldosterone, AVP, and ANP. They exert a variety of actions on the central and peripheral nervous systems, the gastrointestinal system, the liver, the urinary tract, the reproductive system, eye, skeleton, and skin. ET-1 is a potent mitogen for vascular smooth muscle cells, cardiac myocytes, and glomerular mesangial cells.
The signal transduction mechanisms triggered by binding of ET-1 to its vascular receptors include stimulation of phospholipase C, formation of inositol trisphosphate, and release of calcium from the endoplasmic reticulum, which results in vasoconstriction. Conversely, stimulation of PGI2 and nitric oxide synthesis results in decreased intracellular calcium concentration and vasodilation.
The ET system can be blocked with receptor antagonists and by drugs that block endothelin-converting enzyme. ETA or ETB receptors can be blocked selectively, or both can be blocked with nonselective ETA-ETB antagonists.
Bosentan is a nonselective ET receptor blocker. It is active orally and blocks both the initial transient depressor (ETB) and the prolonged pressor (ETA) responses to intravenous ET. A newer dual endothelin receptor antagonist, macitentan, was developed by modifying the structure of bosentan. Additional ET receptor antagonists with increased selectivity include the ETA antagonists ambrisentan, with some ETA selectivity, and sitaxsentan, the most selective ETA antagonist.
The formation of ETs can be blocked by inhibiting endothelinconverting enzyme with phosphoramidon. Phosphoramidon is not specific for endothelin-converting enzyme, but more selective inhibitors including CGS35066 are available.
Physiologic & Pathologic Roles of Endothelin
A. Effects of Endothelin Antagonists
Systemic administration of ET receptor antagonists or endothelinconverting enzyme inhibitors causes vasodilation and decreases arterial pressure in humans and experimental animals. Intra-arterial administration of the drugs also causes slow-onset vasodilation in humans. These observations provide evidence that the ET system participates in the regulation of vascular tone under resting conditions. The activity of the system is higher in males than in females. It increases with age, an effect that can be counteracted by regular aerobic exercise.