The Cardiovascular Effects Of Rat/Mouse Hemokinin-1 And The Structure Activity Relationship Study Of Human Hemokinin-1

Rat/mouse hemokinin-1 (r/m HK-1) has been identified as a member of the tachykinin family and its effect in central cardiovascular response remains unknown. In the present study, an attempt has been made to investigate the effects and mechanisms of action of r/m HK-1 on mean arterial pressure (MAP) and heart rate (HR) after intracerebroventricular (i.c.v.) injections in anesthetized rats by comparing it with that of substance P (SP). R/m HK-1 injected i.c.v. induced dose-dependent biphasic (depressor and pressor) responses, in which the depressor response is mediated by the activation of tachykinin NK1 receptors firstly, then release NO to inhibit sympathetic excitability within the brain. The pressor response is primarily via the activation of tachykinin NK1 receptors leading to the stimulation of sympathetic nerves. Moreover, r/m HK-1 produced a dose-dependent tachycardia response, in which the tachykinin NK1 receptors, sympathetic and NO are involved in this effect. In contrast, SP (10 nmol/kg, i.c.v.) only induced pressor response and the mechanisms involved in this effect are similar to that of r/m HK-1. Additionally, SP could also produce tachycardia response and its mechanisms are different from that of r/m HK-1. SP regulate the tachycardia mainly through the tachykinin NK1 receptors and sympathetic, while NO do not play a major role. The differences between SP and r/m HK-1 in the central cardiovascular response may uncover the novel regulatory mechanisms for tachykinins encoded by the newly identified TAC4 gene in central effects.Tachykinin plays pharmacological activity through the activation of tachykinin receptors. In their interactions, only amino acid side chains form a suitable conformation to fit with the receptor, tachykinin can active the receptor. Thus, once the amino acid sequence of tachykinin changed, the selection and affinity of the receptors all changed. In this study, we investigate the change of affinity between ligands and receptors and the change of pharmacological activity of h HK-1 in the condition of h HK-1 amino acid sequence altered. In experiment, the analgesic effects of h HK-1 carboxy-terminal fragments(h HK-1 (2-11), h HK-1(3-11), h HK-1 (4-11), h HK-1(5-11), h HK-1(6-11), h HK-1(7-11), h HK-1(8-11)) and amino-terminal fragments(h HK-1 (1-7), h HK-1(1-9)) were compared with those of h HK-1 in conscious mouse. The results show that h HK-1 and h HK-1(4-11) (10 nmol, i.c.v.) induced a potent analgesic effect, reach to 90% and 51% respectively. However, the analgesic effect to equimolar doses of h HK-1 (2-11), h HK-1 (3-11), h HK-1(5-11), h HK-1(6-11) were sharply decreased. The h HK-1 carboxy-terminal fragments (h HK-1 (7-11) and h HK-1 (8-11)) and the amino-terminal fragments (h HK-1 (1-7) and h HK-1(1-9)), did not elicit any significant analgesic effect. In general, T1, K3, Q6 plays a very important role in the h HK-1 structure. The COOH-terminal pentapeptide of h HK-1 is necessary for the activation of the receptor, while the regions of NH2-terminal sequence convey the selective information of receptors.