Impaired Release of Gallbladder Calcitonin Gene-Related Peptide in Human Gallstone Disease

Abstract

Calcitonin gene-related peptide (CGRP) is a neurotransmitter present in the peripheral ends of sensory neurons of the gut and may modulate reflexes of the enteric nervous system. We studied the release of CGRP in normal human gallbladders and in those containing gallstones to test the hypothesis that abnormalities of regulation of CGRP release participate in gallstone formation. Human gallbladder strips were obtained from histologically normal organs removed during liver surgery ( n = 8) or from patients operated upon for symptomatic cholelithiasis ( n = 14). After removal of the mucosa, muscle strips were superfused with oxygenated Kreb's buffer in an organ bath at 37°C. Pharmacologic agents were added to the superfusate and samples were collected at 2-min intervals for analysis. CGRP release was measured by a sensitive and specific radioimmunoassay and adjusted for tissue weight. In normal gallbladders, CGRP release was stimulated sixfold over basal by capsaicin (10 -5 M) to 363 ± 75 pg per gram of muscle per 2 min. This release was abolished by addition of somatestatin (SS) or the neural blocker tetrodotoxin (TTX). Lesser degrees of CGRP release were observed after nonspecific stimulation with K + or phosphodiesterase inhibition with caffeine. In gallbladders with gallstones, capsaicin-induced CGRP release was 74 ± 16 pg per gram of muscle per 2 min (20% of normal, P < 0.001). Release induced by caffeine and K + was also inhibited compared to normal gallbladder strips. Release of CGRP from diseased strips was abolished by TTX and inhibited by SS to degrees similar to normal tissue. CGRP release in normal human gallbladder muscle strips is increased by the sensory neuron stimulant capsaicin, the nonspecific stimulant K +, and phosphodiesterase inhibition by caffeine. This release is abolished by blockade of axonal transmission with TTX and by SS. CGRP content and release from gallbladders containing gallstones are inhibited. Whether these observations have significance in gallstone formation or are secondary processes remains to be seen.