Vascular bed‐dependent roles of the peptide CGRP and nitric oxide in acid‐evoked hyperaemia of the rat stomach.

Abstract

1. Acid back-diffusion through a disrupted gastric mucosal barrier is known to increase gastric mucosal blood flow via a neural mechanism. The present study examined how the acid-evoked change in the gastric microcirculation compares with blood flow changes in the left gastric artery, one of the major arteries supplying the stomach, and whether the dilator mediators in the left gastric artery are identical to those in the gastric mucosa.2. The experiments were performed on rats anaesthetized with urethane. Blood flow in the left gastric artery was measured by the ultrasonic transit time shift technique, and blood flow in the gastric mucosa was assessed by the hydrogen gas clearance method. 3. Gastric acid back-diffusion evoked by perfusion of the stomach with 15% ethanol in 0-15 M HCI increased blood flow in the left gastric artery by a factor of 4 7, which was significantly larger than the 2-9-fold increase in blood flow through the gastric mucosa. Blood pressure and heart rate were not altered appreciably. 4. The acid-evoked hyperaemia in the left gastric artery was left unaltered by atropine and the substance P receptor antagonist RP-67 580. 5. The calcitonin gene-related peptide (CGRP) antagonist CGRP(8-37) had no effect on gastric blood flow but prevented the dilator action of CGRP and inhibited the acidevoked hyperaemia in the gastric mucosa to a larger degree than the hyperaemia in the left gastric artery. 6. Blockade of nitric oxide synthesis by NV-nitro-L-arginine methyl ester (L-NAME) caused constriction of the left gastric artery and the gastric mucosal microvessels. The acid-evoked vasodilatation in the gastric mucosa was blocked by L-NAME, whereas the dilator response in the left gastric artery was not significantly depressed. 7. The data show that the gastric hyperaemic response to acid back-diffusion results from dilatation of mucosal microvessels and extramural arteries. The dilator mechanisms, however, differ between the two vascular beds. CGRP and nitric oxide are important vasodilator mediators in the gastric mucosa but are of less relevance in the left gastric artery.

Visceral vasodilatation and somatic vasoconstriction evoked by acid challenge of the rat gastric mucosa: diversity of mechanisms.

“…The simultaneous increase in gastric mucosal blood flow is closely related to the back-diffusion of acid, because it is only after exposure to combined ethanol and HCl that blood flow through the stomach rises to a significant extent (Holzer et al 1991a). As reported and discussed previously (Holzer et al 1994), the acid-evoked rise of blood flow is seen both in the gastric microcirculation and in the arteries supplying the stomach, which is consistent with the organization of the gastrointestinal circulation and the fractional distribution of blood flow in this system (Granger, Richardson, Kvietys & Mortillaro, 1980;Guth & Leung, 1987). The increase in blood flow through the coeliac artery was small when expressed as percentage change, but in absolute terms it was sufficient to account for the increased blood flow to the stomach.…”

“…A catheter in the left jugular vein was used for the continuous infusion of saline (1P5 ml h-'), to avoid dehydration, and for the intravenous injection of drugs. The stomach, exposed by a midline laparotomy, was fitted with an inflow cannula placed in the forestomach and an outflow cannula inserted through the pylorus (Holzer et al 1991(Holzer et al a, 1994. The experimental media (for composition see Experimental protocol) were kept at room temperature (21-23°C) and perfused through the stomach at a rate of 0-7-0-8 ml min-'.…”

“…Acid-evoked changes in the laser Doppler flux readings were expressed as a percentage of the average flux recorded over a 3 min period immediately before exposure of the gastric mucosa to back-diffusing acid. Blood flow in discrete arteries was recorded continuously with the ultrasonic transit time shift technique which measures the net volume of blood flow with a factory-calibrated sensor (Barnes et al 1983;Burton & Gorewit, 1984;Holzer et al 1993Holzer et al , 1994. To this end, the terminal segment of the left gastric artery (LGA) close to its entry into the stomach, the coeliac and superior mesenteric artery close to their origin from the abdominal aorta, the left common carotid artery at the cervical level and the right femoral artery (FA) proximal to the superficial epigastric artery were separated from the surrounding tissue over a length of 4-5 mm under a binocular microscope.…”

“…To this end, specimens of the gastric corpus full thickness wall (100-200 mg wet weight) were excised at the end of the experiments and extracted, and their CGRP content was determined by radioimmunoassay . Experimental protocol The basic experimental protocol to study the effects of gastric acid challenge has been evaluated in previous studies (Holzer et al 1991(Holzer et al a, 1994. After set-up of the preparation an equilibration period of 15 min was allowed during which the stomach was perfused with saline.…”

“…A particular, yet unexplored feature of the acid-evoked hyperaemia in the rat stomach is that the vasodilator response takes place without any change in the systemic blood pressure (Holzer et al 1991a(Holzer et al , 1994. This haemodynamic characteristic raises the possibility that gastric vasodilatation in response to acid back-diffusion is balanced by constriction of other vascular beds.…”