Hegde S S, Chan P, Eglen R M
Institute of Pharmacology, Syntex Discovery Research, Palo Alto, CA 94304.
Eur J Pharmacol. 1994 Jan 4;251(1):43-51. doi: 10.1016/0014-2999(94)90441-3.
Selective histamine H3 receptor agonists, such as R-alpha-methylhistamine, have been shown to inhibit neurogenic sympathetic pressor responses in vivo. The objective of the present study was to test the hypothesis that R-alpha-methylhistamine would evoke an histamine H3 receptor mediated hypotensive response in an animal with intact sympathetic vascular tone. In pentobarbital anaesthetized rats, administration of R-alpha-methylhistamine (0.1-3 mg.kg-1, i.v.) had a biphasic effect on arterial pressure, consisting of a transient depressor response followed by a more long-lasting pressor response. The depressor response was antagonized by chlorpheniramine (selective histamine H1 receptor antagonist, 3 mg.kg-1, i.v.), but was unaffected by cimetidine (selective histamine H2 receptor antagonist, 3 mg.kg-1, i.v.) or thioperamide (selective histamine H3 receptor antagonist, 3 mg.kg-1, i.v.). The pressor response was unaltered by chlorpheniramine, cimetidine or thioperamide. In pithed rats, R-alpha-methylhistamine had a biphasic effect on arterial pressure which was qualitatively similar to that seen in anaesthetized rats with the exception that the pressor responses were much greater in magnitude and duration and were accompanied by significant increases in heart rate. On a pharmacological basis, the biphasic response in pithed rats was identical to that seen in anaesthetized rats inasmuch as the depressor response was antagonized by chlorpheniramine whereas the pressor response was resistant to histamine H1, H2 and H3 receptor antagonists. Combined alpha- and beta-adrenoceptor blockade (with phentolamine and nadolol) produced significant attenuation of the pressor and tachycardic responses to R-alpha-methylhistamine in pithed rats.(ABSTRACT TRUNCATED AT 250 WORDS)
选择性组胺H3受体激动剂，如R-α-甲基组胺，已被证明在体内可抑制神经源性交感神经升压反应。本研究的目的是检验以下假设：在具有完整交感神经血管张力的动物中，R-α-甲基组胺会引发组胺H3受体介导的降压反应。在戊巴比妥麻醉的大鼠中，静脉注射R-α-甲基组胺（0.1 - 3mg·kg-1）对动脉血压有双相作用，包括短暂的降压反应，随后是更持久的升压反应。氯苯那敏（选择性组胺H1受体拮抗剂，3mg·kg-1，静脉注射）可拮抗降压反应，但西咪替丁（选择性组胺H2受体拮抗剂，3mg·kg-1，静脉注射）或硫代哌酰胺（选择性组胺H3受体拮抗剂，3mg·kg-1，静脉注射）对其无影响。氯苯那敏、西咪替丁或硫代哌酰胺对升压反应无改变。在去脑大鼠中，R-α-甲基组胺对动脉血压有双相作用，其性质与麻醉大鼠相似，不同之处在于升压反应的幅度和持续时间更大，且伴有心率显著增加。基于药理学原理，去脑大鼠的双相反应与麻醉大鼠相同，因为氯苯那敏可拮抗降压反应，而升压反应对组胺H1、H2和H3受体拮抗剂有抗性。联合α和β肾上腺素能受体阻断（使用酚妥拉明和纳多洛尔）可显著减弱去脑大鼠对R-α-甲基组胺的升压和心动过速反应。（摘要截断于250字）
