Department of Physiological Sciences, Federal University of Goiás, Goiânia, GO, 74690-900, Brazil.
Laboratory of Neural and Cardiovascular Physiology and Therapeutics, Department of Physiological Sciences, Federal University of Goiás, Goiânia, 74690-900, Brazil.
Peptides. 2018 Dec;110:1-9. doi: 10.1016/j.peptides.2018.10.005. Epub 2018 Oct 21.
Bj-PRO-7a and Bj-PRO-10c belong to a family of proline-rich oligopeptides (PROs) identified in Bothrops jararaca (Bj) crude venom. Previous studies have shown an antihypertensive effect evoked by theses peptides. However, the mechanisms underlying the direct effects on vessels and heart remain to be unraveled. Thus, we investigated the effect of the Bj-PRO-7a and Bj-PRO-10c in the aorta and coronary arteries and in cardiac contractility in normotensive (Wistar) and hypertensive (SHR) rats. Pre-constricted aortic rings were exposed to increasing concentrations of Bj-PROs in presence or absence of muscarinic type 1 receptor antagonist (Pirenzepine), nonselective muscarinic receptor antagonist (Atropine), nitric oxide synthase inhibitor (L-NAME), guanylyl cyclase inhibitor (ODQ), adenylyl cyclase inhibitor (MDL), or argininosuccinate synthetase inhibitor (MDLA). The effects of Bj-PROs in the cardiac contractility and coronary vasomotricity were evaluated using Langendorff perfused heart preparation. The rat hearts were perfused with Bj-PRO-7a or Bj-PRO-10c in absence or presence of L-NAME, ODQ or MDL. Both Bj-PROs induced endothelium-dependent vasorelaxation in aortic rings from Wistars and SHRs. These effects were inhibited by L-NAME, ODQ or MDL. Atropine and Pirenzepine blocked the vasorelaxant effect of Bj-PRO-7a in aorta from both strains. MDLA inhibited the Bj-PRO-10c-induced vasorelaxation in aortic rings from SHR, but not Wistar. The Bj-PRO-7a induced coronary vasodilation only in SHR. L-NAME, ODQ and MDL inhibited this effect. Bj-PRO-10c induced coronary vasodilatation in both strains, which was blocked by L-NAME, ODQ and MDL. Bj-PRO-7a decreased the dP/dt max in Wistar hearts and the dP/dt min in Wistar and SHR hearts. These effects were abolished by L-NAME. Bj-PRO-10c decreased dP/dt max and dP/dt min in hearts from normotensive and hypertensive animals, which were abolished in the presence of L-NAME, MDL and ODQ. In summary, the Bj-PROs induced endothelium-dependent vasorelaxation in rat thoracic aorta, coronary vasodilation and negative inotropic effects through mechanisms mediated by activation of nitric oxide pathway.
Bj-PRO-7a 和 Bj-PRO-10c 属于在巴西矛头蝮蛇（Bothrops jararaca）粗毒液中发现的富含脯氨酸的寡肽（PRO）家族。先前的研究表明，这些肽具有降压作用。然而，其对血管和心脏的直接作用的机制仍有待阐明。因此，我们研究了 Bj-PRO-7a 和 Bj-PRO-10c 在正常血压（Wistar）和高血压（SHR）大鼠的主动脉和冠状动脉中的作用以及对心肌收缩力的影响。预先收缩的主动脉环在存在或不存在毒蕈碱 1 型受体拮抗剂（哌仑西平）、非选择性毒蕈碱受体拮抗剂（阿托品）、一氧化氮合酶抑制剂（L-NAME）、鸟苷酸环化酶抑制剂（ODQ）、腺苷酸环化酶抑制剂（MDL）或精氨酸合成酶抑制剂（MDLA）的情况下，暴露于逐渐增加浓度的 Bj-PRO 中。使用 Langendorff 灌流心脏制备物评估 Bj-PRO 对心脏收缩力和冠状血管舒缩性的影响。在不存在或存在 L-NAME、ODQ 或 MDL 的情况下，用 Bj-PRO-7a 或 Bj-PRO-10c 灌流大鼠心脏。Bj-PRO-7a 和 Bj-PRO-10c 均诱导 Wistar 和 SHR 主动脉环的内皮依赖性血管舒张。这些作用被 L-NAME、ODQ 或 MDL 抑制。阿托品和哌仑西平阻断了两种品系主动脉中 Bj-PRO-7a 的血管舒张作用。MDLA 抑制了 SHR 主动脉环中 Bj-PRO-10c 诱导的血管舒张，但对 Wistar 没有影响。Bj-PRO-7a 仅在 SHR 中诱导冠状动脉扩张。L-NAME、ODQ 和 MDL 抑制了这种作用。Bj-PRO-10c 诱导两种品系的冠状动脉舒张，这种作用被 L-NAME、ODQ 和 MDL 阻断。Bj-PRO-7a 降低 Wistar 心脏的 dp/dt max 和 Wistar 和 SHR 心脏的 dp/dt min。这些作用被 L-NAME 消除。Bj-PRO-10c 降低了正常血压和高血压动物心脏的 dp/dt max 和 dp/dt min，在存在 L-NAME、MDL 和 ODQ 的情况下，这些作用被消除。总之，Bj-PRO 诱导大鼠胸主动脉内皮依赖性血管舒张、冠状血管舒张和负性变力作用，其机制涉及一氧化氮途径的激活。
