Intracoronary gastrin 17 increases cardiac perfusion and function through autonomic nervous system, CCK receptors, and nitric oxide in anesthetized pigs

Abstract

The release of gastrointestinal hormones has been reported to modulate reflex cardiovascular responses caused by gastric distension, although the role played by gastrin 17 is as yet unknown. The present study was therefore planned to determine the primary in vivo effect of gastrin 17 on coronary blood flow and cardiac function and the involvement of autonomic nervous system, CCK1/2 receptors, and nitric oxide (NO). In 40 anesthetized pigs, gastrin 17 was infused into the left anterior descending coronary artery at constant heart rate and arterial blood pressure. In 35 of the 40 pigs, the mechanisms of the observed hemodynamic responses were analyzed by repeating gastrin 17 infusion after autonomic nervous system and NO blockade, and after specific CCK receptors agonists/antagonists administration. Intracoronary gastrin 17 administration caused dose-related increases of both coronary blood flow and cardiac function. The intracoronary co-administration of CCK33/pentagastrin and gastrin 17 potentiated the coronary effects observed when the above agents were given alone (P <0.05). The potentiation of the cardiac response was observed only with the co-administration of pentagastrin and gastrin 17 (P <0.05). Moreover, blockade of muscarinic cholinoceptors (intravenous atropine) and of α-adrenoceptors (intravenous phentolamine) did not abolish the hemodynamic responses to gastrin 17. The cardiac and vascular effects of the hormone were prevented by blockade of β-adrenoceptors (intravenous atenolol and butoxamine), CCK1/2 receptors (intracoronary lorglumide and CAM-1028), and NO synthase (intracoronary Nω-nitro-l-arginine methyl ester). In conclusion, gastrin 17 primarily increased coronary blood flow and cardiac function through the involvement of CCK receptors, β-adrenoceptors, and NO release.

Gastrin Protects Against Myocardial Ischemia/Reperfusion Injury via Activation of RISK (Reperfusion Injury Salvage Kinase) and SAFE (Survivor Activating Factor Enhancement) Pathways

“…The role of CCK2R in protecting against IRI is controversial. In the heart, gastrin 17 increases cardiac perfusion and function through CCK2R in anesthetized pigs 10. In the present study, we found that C1988, a selective inhibitor of CCK2R, abolished the gastrin‐induced cardioprotective effects; therefore, the potent cardioprotective role of gastrin in the I/R‐injured heart is likely mediated through CCK2R.…”

“…It is known that the cholecystokinin receptor has 2 subtypes, type 1 and type 2. The expression of CCK2R (CCKBR) is greater than CCK1R in both myocardium and coronary artery10 and has a 500‐ to 1000‐fold higher affinity for gastrin than CCK1R 25, 26. In the present study, the protective effect of gastrin was abolished in the presence of a CCK2R inhibitor, CI988 (Figure 7A–7E).…”

“…Gastrin has a 500‐ to 1000‐fold higher affinity for CCK2R than CCK1R 25, 26. CCK2R is highly expressed not only in the stomach and the gastrointestinal tract but also in the heart, brain, and kidney 8, 10, 41. Consequently, gastrin is thought to mediate its biological effects primarily through CCK2R, which is a 7‐transmembrane domain G protein–coupled receptor 42.…”

“…Plasma gastrin level is associated with decreased cardiovascular mortality risk, the opposite of that found with plasma cholecystokinin level 9. Gastrin and its receptor, CCK2R (also known as CCKBR), are highly and widely expressed in the heart 10, 11, 12. The intracoronary infusion of gastrin 17, the endogenous ligand of CCK2R, or the CCK2R agonist pentagastrin dose‐dependently increases coronary blood flow and myocardial contractility in anesthetized pigs 10.…”

“…Gastrin and its receptor, CCK2R (also known as CCKBR), are highly and widely expressed in the heart 10, 11, 12. The intracoronary infusion of gastrin 17, the endogenous ligand of CCK2R, or the CCK2R agonist pentagastrin dose‐dependently increases coronary blood flow and myocardial contractility in anesthetized pigs 10. It is of interest that plasma serum gastrin levels are increased in patients with myocardial infarction 13.…”