Corboz M R, Mutter J C, Rivelli M A, Mingo G G, McLeod R L, Varty L, Jia Y, Cartwright M, Hey J A
Pulmonary and Peripheral Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Pulm Pharmacol Ther. 2007;20(2):149-56. doi: 10.1016/j.pupt.2006.03.012. Epub 2006 May 6.
Nasal congestion, one of the major disease features of rhinitis, is induced by the filling of venous sinusoids causing mucosal engorgement with resultant obstruction of nasal airflow. The only available drugs that directly target the underlying vascular features driving nasal obstruction are the sympathomimetic alpha-adrenoceptor agonists due to their vasoconstrictor action. However, standard decongestants are nonselective alpha-adrenoceptor agonists, which have the potential for side-effects liabilities such as hypertension, stroke, insomnia and nervousness. In the present study, the effects of nonsubtype selective alpha(2)-adrenoceptor agonists BHT-920 and PGE-6201204 were evaluated in several isolated nasal mucosa contractile bioassays including dog, pig and monkey, and in a real-time tissue contractility assay using isolated pig nasal explants for BHT-920. The decongestant activity of PGE-6201204 was evaluated in vivo in a cat model of experimental congestion. Our results showed that alpha(2)-adrenoceptor agonists (1) contract nasal mucosa of different species, (2) exert a preferential vasoconstrictor effect on the capacitance vessels (veins and sinusoids), and (3) elicit decongestion. In conclusion, a selective alpha(2)-adrenoceptor agonist causing constriction preferentially in the large venous sinusoids and veins of nasal mucosa and producing nasal decongestion is expected to show efficacy in the treatment of nasal congestion without the characteristic arterio-constrictor action of the standard nonselective sympathomimetic decongestants.
鼻充血是鼻炎的主要疾病特征之一，它是由静脉血窦充血导致黏膜肿胀，进而阻碍鼻气流而引起的。由于其血管收缩作用，目前唯一直接针对导致鼻阻塞的潜在血管特征的药物是拟交感神经α-肾上腺素能受体激动剂。然而，标准减充血剂是非选择性α-肾上腺素能受体激动剂，具有高血压、中风、失眠和紧张等副作用风险。在本研究中，在包括狗、猪和猴在内的几种离体鼻黏膜收缩生物测定中，以及在使用离体猪鼻外植体对BHT-920进行的实时组织收缩测定中，评估了非亚型选择性α(2)-肾上腺素能受体激动剂BHT-920和PGE-6201204的作用。在实验性充血的猫模型中体内评估了PGE-6201204的减充血活性。我们的结果表明，α(2)-肾上腺素能受体激动剂(1)使不同物种的鼻黏膜收缩，(2)对容量血管(静脉和血窦)发挥优先的血管收缩作用，(3)引起鼻充血减轻。总之，一种选择性α(2)-肾上腺素能受体激动剂，优先在鼻黏膜的大静脉血窦和静脉中引起收缩并产生鼻充血减轻，有望在治疗鼻充血方面显示疗效，而没有标准非选择性拟交感神经减充血剂的典型动脉收缩作用。
