豚鼠体内R-α-甲基组胺对组胺H3受体激活的血流动力学特征

McLeod R L, Gertner S B, Hey J A

Allergy, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.

Gen Pharmacol. 1996 Sep;27(6):1001-7. doi: 10.1016/0306-3623(95)02110-8.

The effect of R-alpha-methylhistamine, a histamine H1 receptor agonist, was studied on cardiovascular hemodynamics in bilateral vagotomized, anesthetized guinea pigs. 2. R-alpha-methylhistamine (100 micrograms/kg, IV) a dose that selectively activates histamine H3 receptors, produced hypotension and bradycardia. Total peripheral resistance (TPR) and rate pressure product (RPP) were also decreased at this dose. 3. Pretreatment with the ganglionic blocker hexamethonium (20 mg/kg, IV) blocked the blood pressure (BP), heart rate (HR), TPR, and RPP effects of R-alpha-methylhistamine (100 micrograms/kg, IV). Hexamethonium did not block the hypotensive and TPR lowering actions of the muscarinic agonist methacholine (1 and 3 micrograms/kg, IV). 4. Pretreatment with the alpha 1-adrenoceptor antagonist prazosin (0.5 mg/kg IV), blocked R-alpha-methylhistamine's (100 micrograms/kg, IV) effects on BP, TPR, and RPP. Prazosin did not antagonize the bradycardia effect of R-alpha-methylhistamine. 5. Pretreatment with the beta-adrenoceptor antagonist atenolol (1 mg/kg, IV) did not alter the BP, TPR, or RPP actions of R-alpha-methylhistamine. The HR effects of R-alpha-methylhistamine were blocked by atenolol. 6. The hemodynamic effects of R-alpha-methylhistamine were compared to the hemodynamic profile of the calcium channel blocker, verapamil (0.5 mg/kg, IV). Verapamil had little effect on TRP and had a greater cardiac depressant effect as evidenced by a significant reduction in HR and cardiac output (CO). 7. In summary, these results show that activation of prejunctional H3 receptors with R-alpha-methylhistamine decreases basal, BP, HR, TPR, and RPP in anesthetized guinea pigs. The fall in BP is mediated by a decrease in TPR. Furthermore, the inhibitory effects of R-alpha-methylhistamine on sympathetic control of the vasculature appears to impart a greater physiologic effect on the H3-histamine mediated hypotension than its inhibitory effects on sympathetic agents to the heart.

研究了组胺H1受体激动剂R-α-甲基组胺对双侧迷走神经切断、麻醉的豚鼠心血管血流动力学的影响。2. R-α-甲基组胺（100微克/千克，静脉注射），这一选择性激活组胺H3受体的剂量，导致低血压和心动过缓。在此剂量下，总外周阻力（TPR）和速率压力乘积（RPP）也降低。3. 用神经节阻滞剂六甲铵（20毫克/千克，静脉注射）预处理可阻断R-α-甲基组胺（100微克/千克，静脉注射）对血压（BP）、心率（HR）、TPR和RPP的影响。六甲铵不阻断毒蕈碱激动剂乙酰甲胆碱（1和3微克/千克，静脉注射）的降压和降低TPR的作用。4. 用α1肾上腺素能受体拮抗剂哌唑嗪（0.5毫克/千克，静脉注射）预处理可阻断R-α-甲基组胺（100微克/千克，静脉注射）对BP、TPR和RPP的影响。哌唑嗪不拮抗R-α-甲基组胺的心动过缓作用。5. 用β肾上腺素能受体拮抗剂阿替洛尔（1毫克/千克，静脉注射）预处理不改变R-α-甲基组胺对BP、TPR或RPP的作用。阿替洛尔可阻断R-α-甲基组胺对HR的作用。6. 将R-α-甲基组胺的血流动力学效应与钙通道阻滞剂维拉帕米（0.5毫克/千克，静脉注射）的血流动力学特征进行比较。维拉帕米对TRP影响很小，且具有更大的心脏抑制作用，表现为HR和心输出量（CO）显著降低。7. 总之，这些结果表明，用R-α-甲基组胺激活节前H3受体可降低麻醉豚鼠的基础血压、心率、TPR和RPP。血压下降是由TPR降低介导的。此外，R-α-甲基组胺对血管系统交感神经控制的抑制作用似乎对H3-组胺介导的低血压产生的生理影响比对其对心脏交感神经递质的抑制作用更大。