TACHYKININ INHIBITION OF ACID-INDUCED GASTRIC HYPEREMIA IN THE RAT

1 Primary afferent neurones releasing the vasodilator, calcitonin gene -related peptide, mediate the gastric hyperaemic response to acid back -diffusion. The tachykinins neurokinin A (NKA) and substance P (SP) ar e located in the same neurones and are co-released with calcitonin gen e-related peptide. In this study we investigated the effect and possib le role of tachykinins in the acid-evoked gastric vasodilatation in ur ethane-anaesthetized rats. 2 Gastric acid back-diffusion, induced by p erfusing the stomach with 15% ethanol in the presence of 0.05 M HCl, i ncreased gastric mucosal blood flow by 60-90%, as determined by the hy drogen clearance technique. NKA and SP (0.14-3.78 nmol min(-1) kg(-1), infused intra-aortically) inhibited the gastric mucosal hyperaemic re sponse to acid back-diffusion in a dose-dependent manner, an effect th at was accompanied by aggravation of ethanol/acid-induced macroscopic haemorrhagic lesions. 3 The inhibitory effect of NKA (1.26 nmol min(-1 ) kg(-1)) on the acid-induced gastric mucosal vasodilatation was preve nted by the tachykinin NK2 receptor antagonist, MEN 10,627 (200 nmol k g(-1)) but left unaltered by the NK1 receptor antagonist, SR 140,333 ( 300 nmol kg(-1)) and the mast-cell stabilizer, ketotifen (4.6 mu mol k g(-1)). 4 Under basal conditions, with 0.05 M HCl being perfused throu gh the stomach, NKA (1.26 nmol min(-1) kg(-1)) reduced gastric mucosal blood flow by about 25%, an effect that was abolished by SR 140,333 b ut not MEN 10,627 or ketotifen. 5 SR 140,333, MEN 10,627 or ketotifen had no significant effect on basal gastric mucosal blood flow nor did they modify the gastric mucosal hyperaemic reaction to acid back-diffu sion. 6 The effect of M(A (1.26 nmol min(-1) kg(-1)) in causing vasoco nstriction and inhibiting the vasodilator response to acid back-diffus ion was also seen when blood flow in the left gastric artery was measu red with the ultrasonic transit time shift technique. 7 Arginine vasop ressin (AVP, 0.1 nmol min(-1) kg(-1)) induced gastric mucosal vasocons triction under basal conditions but was unable to inhibit the dilator response to acid back-diffusion. 8 These data show that NKA has two fu ndamentally different effects on the gastric circulation. Firstly, NKA reduces gastric blood flow by activation of NK1 receptors. Secondly, NKA inhibits the gastric hyperaemic response to acid back-diffusion th rough an NK2 receptor-mediated mechanism. These two tachykinin effects appear to take place independently of each other since they are media ted by different receptors. This concept is further supported by the i nability of AVP to mimic tachykinin inhibition of the gastric vasodila tor response to acid back-diffusion.