Distribution of Endothelin-1-Receptor Subtypes in Rat Portal Vein

Abstract

Endothelin-1 (ET-1), a potent vasoactive peptide, was first isolated from cultured porcine endothelial cells. Subsequent studies revealed the existence of two additional related peptides, ET-2 and ET-3, and at least two distinct ET-receptor subtypes, ETA (selective for ET-1) and ETB (nonselective for ET isopeptides). These isopeptides and receptors are widely distributed in many tissues and are involved in numerous biological responses. The aim of this study was to identify the eventual distribution of the two distinct endothelin-receptor subtypes in isolated endothelium-denuded rat portal vein rings (PVRs) and strips (PVSs). BQ-123 (0.6, 1, and 6 microM) and PD-145065 (0.06, 0.1, 0.6, and 6 microM) were used to differentiate the subtypes because they are selective antagonists for ETA and nonselective antagonists for ETA-ETB receptors, respectively. To characterize the ET receptors further, sarafotoxin-S6c (a selective ETB-receptor agonist) and IRL-1038 (a selective ETB-receptor antagonist) were used. In PVRs, cumulative additions of ET-1 (0.1-100 nM) caused graded and slow contractions and potentiated spontaneous rhythmic contractions. The EC50 values and maximal response to 100 nM of ET-1 were 2.72 nM and 0.75 g, respectively (n = 7). PVSs showed ET-1 EC50 values very similar to those of PVRs, but Emax values to 100 nM of ET-1 were significantly lower (Emax = 0.33 g; n = 7). Moreover, ET-1 clearly increased the amplitude and frequency of spontaneous contractions in both types of specimens, although these were greater in the PVSs. Thirty-minute incubation with the selective ETA-receptor antagonist BQ-123 blunted ET-1-induced effects in PVS specimens but only weakly antagonized ET-1-induced contractions in PVRs. In contrast, the nonselective ETA-ETB-receptor antagonist PD-145065 significantly shifted the ET-1 concentration-response curve to the right in PVRs and partially inhibited ET-1 effects in PVSs. Moreover, sarafotoxin-S6c (0.1-100 nM) contracted PVRs and PVSs in a similar manner to ET-1; its effects were antagonized by IRL-1038 only at the PVR level. The differences observed in PVR and PVS specimens in response to agonists and antagonists of ET confirmed the great heterogeneity of endothelin-sarafotoxin receptors. In our experimental models, functionally ETB-like (or non-ETA) receptors seem mostly to mediate vasoconstriction.

Orchidectomy enhances the effects of phenylephrine in rat isolated portal vein

“…Previously, we reported indirect evidence that ET, through either ET A or ET B receptors, contracts the rat portal vein 27 . Other studies suggest that ET released from the rat portal vein endothelium has a potent venoconstrictor effect on the venous bed through ET A and/or ET B receptors 51–53 . However, the orchidectomy‐induced enhancement of the R max to PE in the rat portal vein did not change vessel responsiveness to exogenous ET.…”

Endothelin Receptors in Gastrointestinal Smooth Muscle

“…Incubation with BQ-123, 6 µM, moderately antagonized the ET-1-induced contractions in portal vein rings. Sarafotoxin S6c (0.1-100 nM) contracted portal vein rings and longitudinal strips in a similar manner to ET-1 [72]. These suggest that both ET A and ET B receptors are involved in the contraction of portal vein rings and longitudinal strips.…”

“…In the hepatobiliary system, ET causes contraction of the portal vein, hepatic stellate cells, the gallbladder and common bile duct [41][42][43][44][71][72][73][74][75][76][77][78][79][80][81]. On the other hand, ET inhibits carbachol-induced contraction in the sphincter of Oddi [82] ( Table 3).…”

Endothelin-1 induced bronchial hyperresponsiveness in the rabbit: an ETA receptor-mediated phenomenon

“…Although the focus of the research to date on the endothelins (ET) has been on their effects and potential pathophysiological relevance in the cardiovascular system (Yanagisawa et al 1988;Filippelli et al 1996), they produce an array of activities in a variety of other systems (Yanagisawa and Masaki 1989a;Yanagisawa and Masaki 1989b). In fact, the ET family exerts several effects in the pulmonary system (Pons et al 1992;Hay et al 1993b), including contraction of human airways and vascular smooth muscle (Henry et al 1990;Brink et al 1991) and stimulation of prostanoids release from human bronchus (Hay et al 1993c); these effects are mediated via an interaction with specific ET membrane receptors.…”