Actions of galanin and some of its analogues on rat isolated gastric fundus*

Abstract

The study was undertaken to characterize the effects of porcine galanin (pGal) and some of its analogues on rat gastric fundus muscle strips. pGal, galantide (M15) and pGal(1-14)-[Abu8]SCY-I evoked reproducible concentration-dependent contractions in concentrations of 1-300, 3-1,000 and 100-3,000 nM, respectively, with EC50 values of 13, 70 and 187 nM. Hill's coefficient for pGal is 1.03, indicating an interaction of one pGal molecule with one receptor, fulfilling criteria of classical receptor theory. For M15 and pGal(1-14)-[Abu8]SCY-I, Hill's coefficients are significantly different from 1, namely 0.73 and 1.56, so that one drug molecule may not interact with one receptor. The stimulatory effects of pGal were not modified by dibenamine 10 microM or glybenclamide 1 or 10 microM. Diltiazem 0.1, 1 and 10 microM, papaverine 0.1, 10 microM or dibutyryl cAMP (dib cAMP) 100 and 300 microM, blocked the contraction to pGal in a concentration-dependent manner, indicating an important role for the influx of extracellular calcium ions and regulation by cAMP the pGal-evoked contraction. Diltiazem, dibutyryl cAMP and papaverine were not competitive antagonists of pGal in the stomach smooth muscle.

Effects of Diabetes mellitus on the Contractile Activity of Carbachol and Galanin in Isolated Gastric Fundus Strips of Rats

“…To identify the site(s) of abnormalities responsible for impaired muscle contraction to galanin we measured some pharmacodynamic parameters characterizing the interaction of the peptide with its receptor(s). Our results confirm that galanin, according to the principles of the classical receptor theory, contracts gastric fundus strips by a direct interaction with a specific receptor, as Hill's coefficients calculated from the concentration-contraction curves in the strips from control animals were not different from unity [20,33]. On the contrary, Hill's coefficients estimated from the concentration-contraction curves in STZ rats at 4 and 8 weeks were below unity, values indicating either a heterogeneity of binding sites or modifications in agonist-receptor interactions.…”

“…Additionally Lucas and Sardar [26] suggested that a decreased myogenic response of the terminal ileum to exogenous acetylcholine after 30 days of diabetes may result from changes in the myocytes involving a decrease in the number of muscarinic receptors. A similar hypothesis may apply in our experiments, since STZ-induced diabetes seems to suppress galanin receptors in gastric fundus strips, and the significant reductions in E max to galanin and decreases in the slopes of the appropriate concentration-response curves are not accompanied by changes in EC 50 [7,20]. Clearly appropriate radioligandbinding studies are needed to definitely estab-lish which of the mechanisms is ultimately responsible for the above-mentioned alterations.…”

“…The results of our experiments show that E max to both agents was uniformly decreased in the course of the disease, even though carbachol and galanin act via different intracellular mechanisms [20,25]. Therefore it seems unlikely that the abnormality is limited to an isolated receptor defect.…”

“…Galanin was added directly into the organ baths by cumulative additions -each concentration added when the effect of the preceding one had reached a steady state until maximum contraction occurred (i.e., when the contractile response could not be further increased by a higher concentration of peptide). We have previously shown that cumulative additions of galanin do not elicit tachyphylaxis [20]. Three minutes after the maximum contraction was reached, the tissues were washed out at a rate of 1.2 ml/s for 2-3 min until the length of the strips returned to the basal level.…”

New chimeric analogues of galanin: Synthesis and effects on the glucose-induced insulin secretion

“…M15 blocks the neuronal action of galanin in the central nervous system [6]. In gastrointestinal smooth muscles galantide acts as a full agonist of galanin [7,8].…”