High Affinity Binding of Azasetron Hydrochloride to 5-Hydroxytryptamine3 Receptors in the Small Intestine of Rats

Abstract

-Monkey cerebral artery strips partially contracted with prostaglandin F2a responded to histamine with biphasic patterns of relaxation. The delayed and sustained relaxation was suppressed by cimetidine, whereas the phasic response was abolished by treatment with chlorpheniramine and NG nitro-L-arginine (L-NA), a nitric oxide (NO) synthase inhibitor. The inhibition by L-NA was reversed by L-arginine. D-NA was without effect. Endothelium denudation abolished the phasic relaxation. We hypothesized that endothelium-dependent, phasic relaxations caused by histamine are mediated by NO that is released by Hi-receptor stimulation, whereas the sustained relaxation is associated with the activation of H2-receptors in the smooth muscle of monkey cerebral arteries.Keywords: Histamine, Nitric oxide, Endothelium, Hi-receptor subtype, Cerebral artery (monkey)The complexity of vascular responses to histamine is based on its actions on histaminergic receptor subtypes, H1 and H2, in the endothelium and smooth muscle and on the release of chemical mediators, such as endothelium-derived relaxing factor (EDRF) and pros taglandins (PGs), from endothelial and subendothelial tissues (1 6). Histamine-induced relaxations mediated by EDRF have been reported in human, monkey and rabbit cerebral arteries (7, 8); human and monkey coronary arteries (9, 10); guinea pig pulmonary arteries (11); human umbilical vessels (12); monkey pulmonary veins (13); and rat aortas (14). The participation of EDRF is postulated from evidence that the relaxation is dependent on the endothelium and is suppressed by treatment with oxyhemoglobin, methylene blue or anti oxidants. EDRF has been proposed to be nitric oxide (NO) or an unstable S-nitroso compound that releases the NO radical (15, 16). However, endothelium-depend ent relaxations are not always associated with NO or its analog (17, 18).We have reported that endothelium-dependent re laxations caused by histamine in monkey cerebral arter ies are significantly inhibited by methylene blue and chlorpheniramine, suggesting the involvement of the endothelial H1-receptor subtype in the release of EDRF (7). Despite this conclusion, whether NO was actually involved in the response could not be determined. Methylene blue has many actions other than the inhibi tion of soluble guanylate cyclase (19,20), whereas NO synthase inhibitors, including NG-monomethyl-L-argi nine, NG-nitro-L-arginine (L-NA), L-NA methylester, etc. (21), are selective in depressing the synthesis of NO. Thus, the role of NO can be evaluated more speci fically by the use of these inhibitors. In addition, the effectiveness of NO synthase inhibitors on the endo thelium-dependent relaxation has not been evaluated in cerebral arteries.Therefore, the present study was undertaken to eluci date the involvement of endothelium-derived NO in the histamine-induced relaxation of isolated monkey cere bral arteries, with special reference to the histaminergic receptor subtypes. MATERIALS AND METHODS PreparationJapanese monkeys (Macaca fuscata) of eith...

Losartan improves impaired nitric oxide synthase-dependent dilatation of cerebral arterioles in type 1 diabetic rats

“…We used ADP, acetylcholine and nitroglycerin to examine eNOS-dependent and -independent reactivity of cerebral arterioles in nondiabetic and diabetic rats. We and others (Ayajiki et al, 1992;Faraci, 1991;Mayhan, 1992b) have shown that ADP and acetylcholine, but not nitroglycerin, dilate cerebral arterioles via the synthesis/release of nitric oxide. Other investigators You et al, 1999), however, have suggested that relaxation of the rat middle cerebral artery to purines is related to the synthesis/release of nitric oxide and EDHF.…”

Chronic resveratrol treatment restores vascular responsiveness of cerebral arterioles in type 1 diabetic rats

“…ADP appears to dilate cerebral arterioles via the activation of NOS, presumably eNOS (3,15,30). However, some have suggested that relaxation of the rat middle cerebral artery to purines is related, in part, to the synthesis/release of nitric oxide and to Fig.…”

Neutrophil adhesion to histamine stimulated cultured endothelial cells is primarily mediated via activation of phospholipase C and nitric oxide synthase isozymes

“…Pathophysiological conditions such as vascular dilation [40], hyperemia [16,41], hypotension [42] and migraine [43] were reported to be mediated via the H 1 [15] or H 2 [16] receptor stimulated formation of NO. Inhibition of the endogenous and inducible nitric oxide synthase during histamine stimulation with a highly potent competitive inhibitor lead to a concentration dependent significant decrease of PMN adhesion within the first 30 min of stimulation.…”

“…Nitric oxide plays an important role in inflammatory responses and has also been proposed to be involved in the biochemical signaling pathway of histamine. Histamine stimulated synthesis of nitric oxide [14], can be mediated via the H 1 receptor [15] or the H 2 receptor [16], depending on the tissue and species under investigation.…”