Koga Motokazu, Mizuno Yusuke, Watanabe Itaru, Kawakami Hiromasa, Goto Takahisa
Department of Anesthesiology and Critical Care Medicine, Division of Bio-Functional Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Department of Anesthesiology and Critical Care Medicine, Division of Bio-Functional Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
J Appl Physiol (1985). 2014 Aug 15;117(4):383-91. doi: 10.1152/japplphysiol.00861.2013. Epub 2014 Jun 19.
Pulmonary hypertension (PH) is associated with significant morbidity and mortality. Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase activating peptide (PACAP) have pulmonary vasodilatory and positive inotropic effects via receptors VPAC1 and VPAC2, which possess a similar affinity for both peptides, and PAC1, a PACAP-preferring receptor. VIP is a promising option for PH treatment; however, various physiological effects of VIP have limited its clinical use. We investigated the effects of VPAC1 and VPAC2 selective agonists VIP and PACAP to explore more appropriate means of treatment for PH. We examined hemodynamic changes in right ventricular systolic pressure (RVSP), systemic blood pressure (SBP), total pulmonary resistance index (TPRI), total systemic resistance index, and cardiac index (CI) in response to their agonists with monocrotaline (MCT)-induced PH and explored involvement of VIP/PACAP expression and receptors in PH. Sprague-Dawley rats were divided into the MCT group (administered MCT 60 mg/kg) and control group. In MCT-induced PH, decreased VIP and PACAP were associated with upregulation of VPAC1, VPAC2, and PAC1 in lung tissues. Intravenous injection of VPAC2-selective agonist BAY 55-9837 and VIP, but not [Ala(11,22,28)]VIP, improved the CI. The decrease in SBP with VPAC2 agonist was significantly less than that in the control. Although they decreased SBP, these agonists hardly affected RVSP in the control. Activation of VPAC2 receptor with BAY 55-9837 effectively improved RVSP, TPRI, and CI in MCT-induced PH, suggesting a VPAC2 agonist as a possible promising treatment for PH.
肺动脉高压（PH）与显著的发病率和死亡率相关。血管活性肠肽（VIP）和垂体腺苷酸环化酶激活肽（PACAP）通过受体VPAC1和VPAC2产生肺血管舒张和正性肌力作用，这两种受体对这两种肽具有相似的亲和力，还有PAC1，一种对PACAP更具选择性的受体。VIP是治疗PH的一个有前景的选择；然而，VIP的各种生理效应限制了其临床应用。我们研究了VPAC1和VPAC2选择性激动剂VIP和PACAP的作用，以探索更合适的PH治疗方法。我们检测了用野百合碱（MCT）诱导的PH大鼠在给予其激动剂后右心室收缩压（RVSP）、体循环血压（SBP）、总肺阻力指数（TPRI）、总体循环阻力指数和心脏指数（CI）的血流动力学变化，并探讨了VIP/PACAP表达及其受体在PH中的作用。将Sprague-Dawley大鼠分为MCT组（给予60 mg/kg MCT）和对照组。在MCT诱导的PH中，肺组织中VIP和PACAP的减少与VPAC1、VPAC2和PAC1的上调有关。静脉注射VPAC2选择性激动剂BAY 55-9837和VIP，但不是[Ala(11,22,28)]VIP，可改善CI。VPAC2激动剂引起的SBP下降明显小于对照组。虽然这些激动剂降低了SBP，但在对照组中它们几乎不影响RVSP。用BAY 55-9837激活VPAC2受体可有效改善MCT诱导的PH大鼠的RVSP、TPRI和CI，提示VPAC2激动剂可能是一种有前景的PH治疗方法。
