Verapamil inhibition of the intestinal effects of substance P

The undecapeptide substance P (SP) is contained in enterochromaffin cells and circulates in high concentrations in patients with carcinoid syndrome. We have previously reported that elevated SP levels, simulating those reported in patients with carcinoid syndrome, induce profound changes in intestinal water and electrolyte secretion, motility, and blood flow in a canine model. The purpose of this study was to attempt to block the effects of circulating carcinoid levels of SP on intestinal secretion and motility with the calcium channel blocker verapamil. In five dogs a chronic proximal jejunal Thiry-Vella loop was constructed, and after a 2-week recovery the loops were perfused with an isotonic test solution containing 14C-polyethylene glycol as a volume marker. Motor activity was measured by changes in intraluminal pressure and a motility index was calculated with computer-assisted planimetry and expressed as square millimeters per 5 minutes. After a 30-minute baseline period, SP was infused at 50 ng/kg/min for 90 minutes. SP circulating levels rose from a baseline of 6.2 +/- 1.3 pg/ml to a peak of 93.3 +/- 3.1 pg/ml during this infusion. Thirty minutes after the start of this SP infusion, a simultaneous infusion of verapamil (5.0 micrograms/kg/min) was begun at a separate site. During SP infusion there was a significant secretory response of water (-48 +/- 12 microliters/min), Na+ (-7.7 +/- 2.5 microEq/min), Cl- (-8.8 +/- 2.7 microEq/min) and K+ (-0.57 +/- 0.14 microEq/min), and hypermotility (motility index: 1479 +/- 138 mm2/5 min). When verapamil was added a reversal of secretion to net absorption was observed (water: + 116.9 +/- 15.6 microliter/min; Na+: + 13.8 +/- 2.1 microEq/min; Cl-: + 5.5 +/- 2 microEq/min; K+: + 0.38 +/- 0.9 microEq/min) (p less than 0.05). In addition, there was a reduction in motility (motility index: 853 +/- 92 mm2/5 min; p less than 0.05). These results confirm that SP has profound effects on both intestinal motility and secretion and that calcium channel blockade reduces these effects significantly.