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  • The present study was designed to clarify the

    2022-06-16

    The present study was designed to clarify the distribution and the function of the endothelin receptors in the guinea-pig urinary bladder. We found that endothelin-1 produced a clear tonic contraction via both N1-Methyl-ATP sale subtypes, the endothelin ETA and ETB receptor, and that sarafotoxin S6c also induced a small but significant contraction, thereby indicating the contribution of the endothelin ETB receptor as well as ETA receptor to the contraction.
    Materials and methods
    Results
    Discussion The present study demonstrated that both endothelin ETA and ETB receptors are present in the muscle layer of the guinea-pig urinary bladder, and that endothelin-1 produces contraction via both receptors. Addition of either BQ123 or BQ788 reduced the density of [125I]endothelin-1 binding in the muscle layer, and unlabelled endothelin-1 or a combination of BQ123 and BQ788 abolished this binding. These results indicate the presence of specific endothelin ETA and ETB receptors in the muscle layer of the guinea-pig bladder. The presence of endothelin-1 in the muscle layer suggests that endothelin-1 may be involved in the regulation of muscle tension within an autocrine system. Endothelin-1 caused contraction, and the contraction was significantly reduced by BQ123, but not by BQ788 alone. The different effect of BQ788 on the binding of [125I]endothelin-1 and on the contraction elicited by endothelin-1 may be due to the concentration of endothelin-1 used, 10−10 M for binding and higher than 3×10−9 M for contraction, which induced a significant contraction. Since the combination of BQ123 and BQ788 reduced the contraction more than BQ123 alone did, the endothelin ETB receptor may contribute to the contraction induced by endothelin-1. This concept was supported by the finding that the endothelin ETB receptor agonist, sarafotoxin S6c, produced a small but significant contraction, and that the contraction was abolished by BQ788. Thus, the endothelin ETB receptor as well as the ETA receptor may play a role in the regulation of muscle tension in the guinea-pig urinary bladder. The lack of antagonistic action of BQ788 alone on the contraction induced by endothelin-1 has been reported in various tissues where both subtypes of endothelin receptors are present. In the human bronchi, the contraction induced by endothelin-1 was not inhibited by BQ788 alone, but was inhibited by combined treatment with BQ123 and BQ788, or BQ928, a nonselective antagonist (Fukuroda et al., 1996). Himeno et al. (1998) suggested that heterodimerization of endothelin ETA and ETB receptors occurred in the rat pituitary, based on the finding that BQ788 inhibited [125I]endothelin-1 binding only when BQ123 was present. In the bladder of patients with benign prostatic hypertrophy, the density of endothelin receptors is reduced (Kondo et al., 1995). The expression of the endothelin ETB receptor is up-regulated in diabetic rabbit urinary bladder (Mumtaz et al., 1999) and the expression of both endothelin ETA and ETB receptors is increased in rabbits with partial bladder outlet obstruction (Khan et al., 1999). These results suggest that endothelin receptors in the urinary bladder play a role in the pathophysiology of bladder hypertrophy due to bladder outlet obstruction and diabetic cystopathy. In conclusion, endothelin-1 and both endothelin ETA and ETB receptors exist in the detrusor smooth muscle of the guinea-pig urinary bladder. Endothelin-1 plays a role in the regulation of muscle tension through an autocrine system via not only the endothelin ETA receptor but also the endothelin ETB receptor. A pathophysiological role of endothelin should be considered.
    Acknowledgments
    Introduction Endothelins (ETs) are a group of 21 amino acids vasoactive peptides which comprise three distinct isopeptides, termed endothelin-1 -2 and -3 which have different pharmacological profiles of pressor and vasoconstrictor activities (Yanagisawa et al., 1988). Biochemical characterization of the receptors in various tissues indicate the presence of, at least two types of ETs receptors, a finding that has been confirmed by cDNA cloning (Arai et al., 1990; Sakurai et al., 1990). Two receptor subtypes, ETA and ETB, can be distinguished according to their ligand specificities. ETA receptor has higher affinities to ET-1 and ET-2 than to ET-3, while ETB receptor is a non-isopeptide-selective receptor (Sakurai et al., 1990). In addition to their well-established vascular effects (Lovenberg and Miller, 1990) ETs have also been implicated in the control of several neuroendocrine and endocrine activities (Sakurai et al., 1990). In effect, ETs stimulate secretion of atrial natriuretic peptide from rat atrial myocytes (Fukuda et al., 1989), vasopressin from rat hypothalamus (Shichiri et al., 1989), and aldosterone biosynthesis and its release from zona glomerulosa cells in the adrenal cortex (Cozza et al., 1989). In the adrenal medulla ETs has been proposed as a modulator of the release of catecholamines from chromaffin cells (Yamaguchi, 1993).