Neurokinins Induce Relaxation of Human Pulmonary Vessels Through Stimulation of Endothelial NK1 Receptors

Abstract

The effects of neurokinins and neurokinin receptor selective agonists have been investigated on human intralobar pulmonary vessels. Substance P (SP) and [Sar(9) Met(O(2)) ]SP(11), a selective NK(1) receptor agonist, induced concentration-dependent relaxation of pulmonary vessels precontracted with phenylephrine. The mean negative log (M) EC (50) values for SP and [Sar (9) Met(O2))]SP(11) were 8.6 and 8.9, respectively, on arterial preparations and 8.9 and 8.6, respectively, on venous preparations. Relaxations to [Sar(9) Met(O(2) ) ]SP were abolished by the NK receptor antagonist SR140333. The relaxations to a second application of [Sar(9) Met(O (2)) ]SP were markedly reduced, suggesting a rapid desensitization of the NK(1) receptor. Such desensitization was not observed with acetylcholine. The selective NK receptor agonist, [Nle(10)]NKA, and the selective NK (3) receptor agonist, [MePhe(7)]NKB, caused neither contractions nor relaxations of pulmonary vessels. The NK(1) receptor-mediated relaxations were abolished by removing the endothelium or by a combination of -nitro-L-arginine and indomethacin, whereas each compound exerted a partial inhibitory effect. Similar results were observed with acetylcholine. Positive immunostaining for NK(1) receptors was only found in the endothelium. Reverse transcription-polymerase chain reaction detected messenger RNA for NK(1) receptors without any detection of messenger RNA for NK(2) or NK(3) receptors. In conclusion, human pulmonary arteries and veins express endothelial NK(1) receptors that mediate relaxation through a combination of cyclooxygenase and nitric oxide activities and are subjected to rapid tachyphylaxis.

Interaction of calcitonin gene related peptide (CGRP) and substance P (SP) in human skin

“…Physiologically, SP mediates vasodilation (Holzer, 1998) via activation of NK1 receptors (neurokinin 1-receptors) (Mechiche et al, 2003). NK1 receptors can be found on the walls of arterioles, capillaries and venules (Ruocco et al, 2001).…”

The effect of substance P on nitric oxide release in a rheumatoid arthritis model

“…As mentioned above [11], substance P induces NO production in some cell types. Andoh and Kuraishi [22] showed that intradermal SP caused increased NO generation in the skin, possibly through an action on the tachykinin receptors of the epidermal keratinocytes.…”

“…In addition to a direct action on vascular smooth muscle, SP controls vascular effector systems via the release of vasoactive messenger molecules, such as nitric oxide (NO) [11]. NO is recognised to be an important chemical messenger molecule involved in the regulation of a variety of physiological and pathophysiological actions, and has been implicated in a number of chronic human infl ammatory diseases including RA [12,13].…”

Expression of NK1 receptor at the protein and mRNA level in the porcine female reproductive system

“…The distribution of NK1 receptor in the oviduct and uterus resembles that described in other organs of laboratory animals. NK1 receptor was found in the vascular endothelium of the human urinary bladder (Burcher et al 2000) and lungs (Mechiche et al 2003). NK1 receptor was also found in the muscular membranes of the canine stomach and intestines (Mantyh et al 1988), as well as human colon (Korman et al 1989).…”