Endothelin-1 induces vasoconstriction and nitric oxide release via endothelin ETB receptors in isolated perfused rat liver
Introduction
The endothelium participates in the regulation of vascular tone by synthesizing potent vasoactive substances such as endothelin-1, a vasoconstrictor, and nitric oxide (NO), a vasodilator (De Nucci et al., 1988). Endothelin receptors have been classified into two major subtypes, namely endothelin ETA (which is highly selective for endothelin-1) and ETB (non-isopeptide selective) (Sakurai et al., 1990). Endothelin ETA receptors are found predominantly on vascular smooth muscle cells and mediate contraction. In contrast, endothelial cells have endothelin ETB receptors which are thought to induce relaxation of vascular smooth muscle via nitric oxide production (Namiki et al., 1992; Hirata et al., 1993). The interaction between endothelin and NO is reportedly of importance in the regulation of vascular tone. Endothelin-1 and NO reportedly play a major role in regulating hepatic microcirculation, as with other organs (Zhang et al., 1994; Okumura et al., 1994).
Infusion of endothelin-1 into the intact perfused rat liver causes a profound, sustained increase in hepatic portal pressure and a transient increase in O2 consumption which is followed by a second phase characterized by a slow decrease (Gandhi et al., 1990; Tran-Thi et al., 1993). As in other organs, two specific endothelin receptors, ETA and ETB, have been identified in the liver. Housset et al. (1992)reported that Ito cells (hepatic stellate cells or fat-storing cells) express both endothelin ETA and ETB receptors, whereas Kupffer cells and sinusoidal endothelium express only endothelin ETB receptors. The identity of the endothelin receptor involved in mediating the endothelin-induced intrahepatic vasoconstriction and sinusoidal constriction is still in question. Rockey (1995)reported that the endothelin ETB receptor is a prominent mediator of Ito cell contraction in vitro and raised the possibility of a novel endothelin receptor subtype. Zhang et al. (1995)demonstrated that the endothelin-1-induced sinusoidal constriction is mediated by endothelin ETA receptors on Ito cells, and that endothelin-induced intrahepatic vasoconstriction resulted in part from presinusoidal constriction, which was mediated by endothelin ETB but not ETA receptors in isolated perfused rat liver.
Direct measurement of endothelin-1-induced NO is required to understand the role of endothelin and NO in the modulation of the intrahepatic microcirculation. However, such data are, to our knowledge, unavailable because of the short half-life of NO. Further, there are no studies that demonstrate which receptors mediate the endothelin-induced release of NO in the liver.
The present study was designed to (1) reconfirm the role of endothelin ETA and ETB receptors in endothelin-1-induced intrahepatic vasoconstriction in isolated perfused rat liver; (2) investigate which receptor is involved in mediating the endothelin-1-induced NO release; and (3) more closely examine the interaction between endothelin-1 and NO in regulating intrahepatic vasopressure and hepatic O2 consumption. To this end, we used a relatively specific endothelin ETA receptor antagonist, BQ-123 (cyclo(-d-Trp-d-Asp-Pro-d-Val-Leu)) (Ihara et al., 1992), an endothelin ETB receptor antagonist, BQ-788 (N-cis-2,6-dimethylpiperidinocarbonyl-l-γ-methylleucyl-d-1-methoxycarbonyltryptophanyl-d-norleucine) (Ishikawa et al., 1994), an endothelin ETB receptor agonist, IRL 1620 (Suc- [Glu9,Ala11,15]endothelin-1-(8–21)) (Takai et al., 1992), and NO-selective electrodes (Ichimori et al., 1994) to continuously monitor the endothelin-1-induced NO release in isolated perfused rat liver.
Section snippets
Measurement of portal pressure, oxygen consumption and nitric oxide from isolated perfused rat liver
Livers were taken from male Sprague-Dawley rats (310–340 g) under deep sodium pentobarbital (40 mg/kg i.p.) anaesthesia, using a standard technique described earlier (Oshita et al., 1992; Mittal et al., 1994). The perfusate with Krebs-Henseleit bicarbonate buffer (118 mM NaCl, 4.74 mM KCl, 1.18 mM KH2PO4, 1.18 mM MgSO4, 24.87 mM NaHCO3, and 2.54 mM CaCl2 at pH 7.4, 37°C and saturated with 95% O2/5% CO2) was pumped with a rotor pump (Gilson Minipuls III, Middleton, WI, USA) into the liver via a
Portal pressure, oxygen consumption and nitric oxide induced by endothelin-1 and IRL 1620
The baseline liver portal pressure, O2 consumption and NO current were 4.0±0.0 mmHg, 44.8±0.1 μl/g liver per min and 493.8±4.0 nmol, respectively (n=149). Infusion of endothelin-1 (0.01 nM) did not significantly change the portal pressure, O2 consumption, or nitric oxide current (Fig. 1Fig. 2). Portal pressure increased immediately after the addition of endothelin-1 (1 and 10 nM) and reached a maximum in approximately 5.5 min, then gradually decreased. O2 consumption decreased after the
Discussion
The use of NO-selective electrodes in the current study allowed us to obtain simultaneous real-time measurements of NO release, hepatic portal pressure and hepatic O2 consumption. l-NMMA infusion completely inhibited the NO response to endothelin-1. However, in the absence of l-NMMA, endogenous NO was released immediately after endothelin-1 induction; release reached a maximum after the increase in portal pressure peaked and thereafter gradually returned to its basal level. Therefore, it
Acknowledgements
We thank Mr. Eiichi Murakami (Intermedical Co.) and Mrs. Yaeko Oshikiri (Department of Anesthesiology) for their assistance.
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