Affolter Jonathan T, McKee Sinéad P, Helmy Ahmed, Jones C Richard, Newby David E, Webb David J
Department of Medical Sciences, University of Edinburgh, Western General Hospital, United Kingdom.
Clin Pharmacol Ther. 2003 Jul;74(1):9-16. doi: 10.1016/S0009-9236(03)00065-1.
Diverse vascular effects have been ascribed to vasopressin, including the potential to cause vasodilation, vasoconstriction, and nitric oxide release. The objective of this study was to establish the pharmacodynamics, reproducibility, and nitric oxide dependence of the vasomotor actions of vasopressin in the forearm resistance vessels.
Blood flow in both forearms of 12 healthy men was measured with venous occlusion plethysmography. Continuous and discontinuous doses of 1 to 300 pmol/min vasopressin were administered by the intrabrachial route. For assessment of the contribution of nitric oxide, vasopressin was coadministered with a "nitric oxide clamp," a balanced coinfusion of 4 micromol/min L-N(G)-monomethylarginine (a nitric oxide synthase inhibitor) and 0.3 to 0.8 nmol/min sodium nitroprusside (an exogenous nitric oxide donor) to block endogenous nitric oxide production and restore normal basal blood flow, respectively.
Vasopressin produced a dose-dependent biphasic change in blood flow with a maximum reduction in percentage change in blood flow ratio of infused and control arms of 22% +/- 5% at 3 pmol/min (P <.01) and an increase of 80% +/- 30% at 300 pmol/min (P <.01). There were no significant differences in repeated responses obtained either within or between days. Repeated discontinuous dosing did not change the magnitude of the maximum vasoconstriction or vasodilation, but prolonged continuous infusion produced maximal vasodilation at 12 minutes that subsequently resulted in substantial tachyphylaxis (P =.04). Although there was no augmentation of vasoconstriction, the nitric oxide clamp abolished vasopressin-induced vasodilation (P <.05).
Intra-arterial vasopressin causes a reproducible dose-dependent biphasic change in forearm blood flow. Vasomotor responses are time-dependent with a modest delay to peak vasodilation and tachyphylaxis with prolonged sustained infusion. Nitric oxide release is a major contributor to vasopressin-induced vasodilation but does not directly oppose low-dose vasopressin-induced vasoconstriction.
血管加压素具有多种血管效应，包括引起血管舒张、血管收缩以及释放一氧化氮的潜力。本研究的目的是确定血管加压素在前臂阻力血管中的血管舒缩作用的药效学、可重复性及对一氧化氮的依赖性。
采用静脉阻断体积描记法测量12名健康男性双侧前臂的血流量。通过肱内途径给予1至300 pmol/min的血管加压素连续和间断剂量。为评估一氧化氮的作用，血管加压素与“一氧化氮钳夹”联合使用，即4 μmol/min的L-N(G)-单甲基精氨酸（一种一氧化氮合酶抑制剂）和0.3至0.8 nmol/min的硝普钠（一种外源性一氧化氮供体）平衡共输注，分别阻断内源性一氧化氮生成并恢复正常基础血流量。
血管加压素引起血流量呈剂量依赖性双相变化，在3 pmol/min时，输注臂与对照臂血流量比值变化百分比最大降低22%±5%（P<.01），在300 pmol/min时增加80%±30%（P<.01）。在同一天内或不同天之间获得的重复反应无显著差异。重复间断给药未改变最大血管收缩或舒张的幅度，但持续输注12分钟时产生最大血管舒张，随后出现明显快速耐受（P =.04）。尽管血管收缩未增强，但一氧化氮钳夹消除了血管加压素诱导的血管舒张（P<.05）。
动脉内注射血管加压素可引起前臂血流量可重复的剂量依赖性双相变化。血管舒缩反应具有时间依赖性，达到最大血管舒张有适度延迟，持续输注时间延长会出现快速耐受。一氧化氮释放是血管加压素诱导血管舒张的主要因素，但不直接对抗低剂量血管加压素诱导的血管收缩。
