Cardiovascular Responses And Mechanisms To Rat/mouse Hemokinin-1 And Human Hemokinin-1 In Anesthetized Rats

The mammalian tachykinins are a family of evolutionary conserved peptides that share a common C-terminal sequence, Phe-X-Gly-Leu-Met-NH2, including substance P (SP), neurokinin A (NKA) and neurokinin B (NKB). Recently, two novel mammalian undecapeptide tachykinins, rat/mouse hemokinin-1 (r/m HK-1) and human hemokinin-l(h HK-1), were designated from a new preprotachykinin gene (PPT-C) identified in mouse and human. However, there were lack of cardiovascular studies of r/m HK-1 and h HK-1 in anesthetized rats. The present study was designed to synthesize r/m HK-1, SP and h HK-1 (purified by high-performance liquid chromatography (HPLC)) and investigate the effect and mechanism of action of r/m HK-1 and h HK-1 in the modulation of cardiovascular activity in anesthetized rats by comparing it with that of SP. Our data showed that injection of r/m HK-1 (0.1, 0.3, 1, 3 and 10 nmol/kg) dose-dependently lowered SAP. This effect was significantly blocked by pretreatment with SR140333 (a selective NK₁ receptor antagonist) and NO synthase inhibitor L-NAME, respectively. However, the depressor response to r/m HK-1 was unaffected by bilateral vagotomy or muscarinic receptor blocker atropine. Compared to r/m HK-1, a dose of 3 nmol/kg SP caused biphasic changes in blood pressure. Our results showed that the mechanisms in the phase of depressor response after injection of SP were similar to r/m HK-1 except for that SR48968 (a selective NK₂ receptor antagonist) could only significantly blocked the depressor response induced by r/m HK-1. On the other hand, injection the same doses of r/m HK-1 could also dose-dependently increased HR. This effect was unaffected by any treatment we used here except for bilateral vagotomy and atropine. Meanwhile, injection of h HK-1 (0.1, 0.3, 1, 3 and 10 nmol/kg) lowered SAP dose-dependently, but the depressor effect of h HK-1 lower than the effect of r/m HK-1 in any doses. Intriguing that a dose of 10 nmol/kg of h HK-1 caused biphasic changes in SAP (depressor and pressor responses). The effect of lowed SAP was significantly blocked by pretreatment with SR140333 (a selective NK₁ receptor antagonist) and NO synthase inhibitor L-NAME, respectively. The tachycardia effect was significantly blocked by the treatment of bilateral vagotomy and atropine. In vitro studies, h HK-1 (10^-10—10^-7) caused Dose-respose curve of the vasorelaxation on the PE (0.1μM) precontracted rat aorta.The results suggest that the mechanism of the depressor response caused by h HK-1 was similar to r/m HK-1 in that it was inhibited by SR140333 and L-NAME, respectively, but that there was a component of the cardiovascular change induced by r/m HK-1 (but not SP and h HK-1) that was attenuated by SR48968 (a selective NK₂ receptor antagonist). The depressor response induced by r/m HK-1 and h HK-1 (i.v.) might be explained primarily by the action on endothelial NK₁ receptors to release endothelium-derived relaxing factor (NO) and this effect was not affected by vagal components. Furthermore, some differences between r/m HK-1, SP and h HK-1 in the modulation of cardiovascular responses in anesthetized rats suggest that the activation properties of SP, r/m HK-1 and h HK-1 are different. The lower vasorelaxation on the precontracted rat aorta induced by h HK-1 might be explained primarily by the scarce of the receptors on rat aorta. Therefore, we might conclude that the depressor response induced by h HK-1 was mainly from the relaxation of peripheral small arteries.