Endothelin in perinatal pharmacology.

Abstract

E ndothelin (ET) is a potent vasoconstrictor peptide that was initially isolated from the conditioned medium of the cultured porcine aortic endothelial cells.’ It contains 21 amino acidresidues including two intramolecular disulfide linkages. Subsequently, analysis of the human endothelin gene showed existence of three human endothelin genes, predicting the three distinct isotypes of ET designated ET-l, ET-2 and ET-3 (Fig l).’ Interestingly, an amino acid sequence very similar to ET was found in the sequence of a snake venom sarafotoxin S6b.3 Human, porcine, dog, and rat ET-1s have the identical amino acid sequences. It is now well-known that the cluster of the hydrophobic amino acid residues at the carboxy1 terminus of the peptide, particularly the terminal Trp21, aminoterminus carboxyl groups of Asp8 and GlulO and the aromatic group of Phel4 are very important in exerting the potent vasoconstriction.4,5 Further investigations have demonstrated widespread binding sites for ET-1 not only in vascular bed but also in lung, adrenal gland, nervous systems, and other organs.6 In addition, widespread transcription of ET-l mRNA was found in various tissues including neurons,7,8 suggesting a variety of physiological roles of ET. ET causes a slow-developing and long-lasting vasoconstriction in almost all arteries and veins.’ The concentration to induce vasoconstriction is very low, although ET exhibits different potencies depending on the vessel and species employed.1,g ET binds to a specific receptor on smooth muscle membrane and activates phospholipase C, producing phosphoinositol 1, 4, 5,-trisphosphate. The latter elicits the release of calcium ion from the caffeine-sensitive calcium store, inducing constriction. On the other hand, ET stimulates calcium channels of the smooth muscle membrane, inducing influx of exterior calcium ion in porcine coronary artery.“’ The activated influx of calcium ion prolongs the duration of intracellular calcium signal. However, several reports suggested no responsibility of extracellular calcium influx for endothelininduced vasoconstriction. There is still a controversy on this problem. ET elicits a constriction not only in vascular smooth muscle but also in nonvascular smooth muscle.g ET causes rhythmic contractions in nonpregnant human and rat uterine muscles. The contractile frequency increases. Concomitantly sustained tonic contraction appears. In the presence of dihydropyridine calcium antagonist, the increase in frequency of rhythmic contraction induced by ET is completely abolished whereas the sustained increase in tonic contraction is insensitive to external calcium ion.i1,12 This phenomenon is very similar to the oxytotin-induced contraction. Oxytocin stimulates both frequency and force of contractile activity in uterine smooth muscle. Oxytocin initiates spike discharges and increases the frequency. ET also elicits an increase in the number of spikes in a similar manner in rat portal vein.i3 However, WC have no information on uterine muscle. In case of oxytocin, these effects are highly dependent on the stage of gestation. We have no further information on the hormonal effect on the ET-induced contraction of uterine smooth muscle. In this connection, it is interesting that ET was detected in supra-optic and paraventricular nuclei and posterior lobe of pituitary.‘* Distribution of ET in this region is very similar to vasopressin. In addition, water deprivation depleted completely ET from the posterior lobe of pituitary, suggesting the role of ET in water balance.14 Oxytocin is also synthesized in the same region. However, neurons containing oxytocin are distinct from those of vasopressin. Recently Stojilbovic et ali5 demonstrated that ET releases luteinizing hormone (LH) and follicle-