Raj Renu R, Subramani Sathya
Department of Physiology, Christian Medical College, Vellore, Tamil Nadu, India.
PLoS One. 2016 Jun 30;11(6):e0158551. doi: 10.1371/journal.pone.0158551. eCollection 2016.
Phenylephrine (PE) causes vasoconstriction through alpha adrenergic receptors. PE-induced vasodilatation has also been reported earlier in pre-constricted vessels. Here we demonstrate in spiral strips of goat arteries that addition of PE can decrease tone even from base-line levels (i.e. not pre-constricted) and show that this process requires nitric oxide (NO) and alpha adrenergic stimulation, but is cGMP-independent. Under control conditions, PE caused vasoconstriction, but under conditions where NO levels are higher, as with L-Arginine or sodium nitroprusside, PE decreased vessel tension. L-Arginine/PE combination was not able to decrease tension when alpha adrenoceptors were blocked with Phentolamine or endothelial nitric oxide synthase (eNOS) was blocked with Nω-Nitro-L-arginine (L-NNA). Propranolol, a beta blocker, was unable to prevent the reduction in tension by the L-Arginine/PE combination. Adrenaline and noradrenaline (and not isoproterenol) also reduced vessel tension in the presence of L-Arginine. Even when NO levels were not enhanced, relieving NO from having to stimulate the enzyme soluble guanylyl cyclase (sGC) (either by using sGC blockers, namely ODQ or methylene blue, or by enhancing cGMP levels (with sildenafil) which by negative feedback probably inhibits sGC) led to PE-induced reduction of vascular tension. PMA-phorbol myristate acetate-an agonist which stimulates Protein Kinase C was able to prevent the ability of PE to reduce vascular tension in a high NO environment. Our conclusion is that PE reduces vascular tension through alpha adrenoceptors if there is excess NO availability to activate a putative pathway. Though the reduction of vessel tone by PE is dependent on NO, it is independent of cGMP. Prior treatment with PMA or PE itself can prevent further PE-induced reduction of tension in a high NO environment. The results here suggest, counter-intuitively, that alpha blockers may be of help in the treatment of septic shock where nitric oxide levels are high.
去氧肾上腺素（PE）通过α肾上腺素能受体引起血管收缩。此前也有报道称，在预先收缩的血管中，PE可诱导血管舒张。在此，我们在山羊动脉螺旋条中证明，添加PE即使从基线水平（即未预先收缩）也能降低张力，并表明这一过程需要一氧化氮（NO）和α肾上腺素能刺激，但不依赖于环磷酸鸟苷（cGMP）。在对照条件下，PE引起血管收缩，但在NO水平较高的情况下，如使用L-精氨酸或硝普钠时，PE可降低血管张力。当用酚妥拉明阻断α肾上腺素能受体或用Nω-硝基-L-精氨酸（L-NNA）阻断内皮型一氧化氮合酶（eNOS）时，L-精氨酸/PE组合无法降低张力。β受体阻滞剂普萘洛尔无法阻止L-精氨酸/PE组合引起的张力降低。在存在L-精氨酸的情况下，肾上腺素和去甲肾上腺素（而非异丙肾上腺素）也能降低血管张力。即使NO水平未升高，通过使用可溶性鸟苷酸环化酶（sGC）阻滞剂（即ODQ或亚甲蓝）或通过提高cGMP水平（使用西地那非，通过负反馈可能抑制sGC）来解除NO对sGC的刺激，也会导致PE诱导的血管张力降低。佛波酯肉豆蔻酸酯（PMA）——一种刺激蛋白激酶C的激动剂——能够在高NO环境中阻止PE降低血管张力的能力。我们的结论是，如果有过量的NO可用于激活一条假定的途径，PE可通过α肾上腺素能受体降低血管张力。虽然PE引起的血管张力降低依赖于NO，但不依赖于cGMP。预先用PMA或PE本身处理可在高NO环境中阻止PE进一步诱导的张力降低。此处的结果反直觉地表明，α受体阻滞剂可能有助于治疗一氧化氮水平较高的感染性休克。
