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1、Triphasic vascular responses to bradykinin in the mesenteric resistance artery of the ratHideki Nawa, Hiromu Kawasaki*, Akira Nakatsuma, Sachiko Isobe, Yuji KurosakiDepartment of Clinical Pharmaceutical Science, Graduate School of Natural Science and Technology, Okayama University, 1-1-1 Tsushima-na
2、ka, Okayama 700-8530, JapanReceived 14 May 2001; received in revised form 1 November 2001; accepted 6 November 2001AbstractThe vascular effects of bradykinin were studied in rat perfused mesenteric vascular beds with active tone. Bolus injections of bradykinin (11000 pmol) but not des-Arg9-bradykini
3、n (bradykinin B1receptor agonist) induced triphasic vascular responses: the initial sharp vasodilation followed by transient vasoconstriction and subsequent gradual vasodilation. The triphasic vascular responses to bradykinin were abolished by FR 172357 (3-bromo-8-2,6-dichloro-3-N-(E)-4-(N,N-dimethy
4、lcarbamoyl) cinnamidoacetyl-N-methylaminobenzyloxy-2- metylimidazo1,2-apyridine) (bradykinin B2receptor antagonist, 0.1 mM). Endothelium removal with sodium deoxycholate and Nw-nitro-L- arginine (300 mM) abolished the bradykinin-induced initial sharp vasodilation. Indomethacin (0.5 mM) and seratroda
5、st (thromboxane A2 receptor antagonist, 0.5 and 5 mM) abolished the bradykinin-induced second vasoconstriction. The bradykinin-induced third vasodilation was abolished by capsaicin (1 mM) and calcitonin gene-related peptide (CGRP)-(837) (CGRP receptor antagonist, 0.5 mM). These findings suggest that
6、 the bradykinin-induced initial sharp vasodilation is endothelium dependent, that endogenous thromboxane A2is involved in the second vasoconstriction, and that the third slow vasodilation is produced by activation of capsaicin-sensitive CGRP-containing nerves. D 2001 Elsevier Science B.V. All rights
7、 reserved.Keywords: Bradykinin; Vasodilation; Endothelium dependent; Thromboxane A2; CGRP (calcitonin gene-related peptide); Mesenteric resistance artery, (Rat)1. IntroductionBradykinin, an endogenous nonapeptide, has a wide variety of vascular effects. The action of bradykinin has been shown to be
8、mediated by the activation of two membrane receptors, denoted as bradykinin B1and B2receptors (Regoli andBarabe,1980;BurchandKyle,1992;Regolietal.,1998). Bradykinin preferentially acts through constitutive bradyki- nin B2receptors to cause a vascular effect (Berguer et al., 1993; Miyamoto et al., 19
9、99). Bradykinin induces endothe- lium-dependent vasorelaxation and vasoconstriction, which are mediated via activation of endothelial bradykinin B1and B2receptors (Drummond and Cocks, 1995; Ohlmann et al., 1997; Ihara et al., 2000). The main endothelium-dependent relaxing and contracting factors in
10、bradykinin-induced responses are nitric oxide (NO) and prostanoids, respectively (Lundgaard et al., 1997; Miyamoto et al., 1999; Ihara et al.,2000). Furthermore, bradykinin has a direct action on vas- cular smooth muscle, via its action on bradykinin B1and B2 receptors (Persson and Andersson, 1998).
11、 Activationofthese receptors leads to relaxation, contraction, or a biphasic res- ponse, depending on the organs or species (Persson and An- dersson, 1998; Bagate et al., 1999). It is generally accepted that peripheral vascular tone is maintained predominantly by the vasoconstrictor neurotrans- mitt
12、er,norepinephrine, released from perivascular adrenergic nerves. Neuropeptide Y and ATP, which are co-localized in perivascular adrenergic nerves and released along with nor- epinephrine when these nerves are stimulated, are also involved in the control of vascular tone (Lundberg et al., 1982). Evid
13、ence has accumulated that the resistance artery is innervated not only by adrenergic nerves but also by non- adrenergic noncholinergic (NANC) nerves (Kawasaki et al., 1988;TodaandOkamura,1992).Wepreviouslyreportedthat calcitonin gene-related peptide (CGRP) acts as the potential vasodilatortransmitte
14、rforNANCnervesintheratmesenteric resistanceartery(Kawasakietal.,1988).Bradykininhasbeen shown to release endogenous CGRP in the heart, lung and trachea (Geppetti et al., 1990; Hua et al., 1994; Schuligoi et0014-2999/01/$ - see front matter D 2001 Elsevier Science B.V. All rights reserved. PII: S0014
15、-2999(01)01513-8*Corresponding author. Tel./fax: +81-86-251-7970. E-mail address: Kawasakipheasant.pharm.okayama-u.ac.jp (H. Kawasaki) Journal of Pharmacology 433 (2001) 105113al., 1998). However, the role of CGRPin bradykinin-induced vascularresponsesofthemesentericresistancearteryremains unknown.
16、The present study was, therefore, designed to investigate the vascular effect of bradykinin in mesenteric resistance blood vessels of the rat.2. Materials and methods2.1. AnimalsMale Wistar rats, weighing 220350 g, were used in the present study. The animals were given food and water ad libitum. They were housed in the Animal Research Center of Okayama University at a controlled ambient temperature of 222 ?C with 5010%, relative humidity and
