Abstract
We have shown recently that intracisternal administration of endothelin-(ET)1 and ET-3 evokes increases in gastric motor function and arterial blood pressure. The aim of our study was to investigate whether the dorsal vagal complex (DVC) is a medullary site of action for the gastric motor and cardiovascular effects of ET-1 and to identify the ET receptor subtype through which these effects are mediated. ET-1 (0.1–40 pmol/site) and ET-3 (1 and 100 pmol/site) were microinjected into the DVC of α-chloralose anesthetized rats, while monitoring intragastric pressure, contractile activity of greater curvature longitudinal and pyloric circular smooth muscle, arterial blood pressure and heart rate. ET-1, at doses of 0.1 to 40 pmol, increased intragastric pressure and, at doses of 10 and 40 pmol, increased pyloric contractile activity and arterial blood pressure. The increases in gastric motor function, but not the hypertension, induced by ET-1 (10 pmol) in the DVC were completely abolished by bilateral vagotomy. Spinal cord transection prevented increases in arterial blood pressure evoked by ET-1 (40 pmol). Because only the highest dose of ET-3 (100 pmol), microinjected into the DVC, increased intragastric pressure and pyloric contractile activity and no consistent changes in cardiovascular functions were noted, we hypothesized that the gastric motor and hypertensive responses to endothelins in the DVC are mediated via ETA receptors. This was supported by the observation that a selective ETA receptor antagonist, cyclo(-d-Trp-d-Asp-Pro-d-Val-Leu) (BQ-123; 400 pmol), microinjected into the DVC 15 min before ET-1 (10 pmol) or ET-3 (100 pmol), completely blocked the gastric motor and cardiovascular responses to endothelins. We conclude that endothelins act in the brainstem at the level of the DVC to increase intragastric pressure and gastric contractile activity via a vagally mediated pathway and that both the gastric motor and hypertensive effects of endothelins in the DVC are mediated through ETA receptors.
Footnotes
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Send reprint requests to: Dr. Zbigniew K. Krowicki, Department of Pharmacology, LSU Medical Center, 1901 Perdido Street, New Orleans, LA 70112.
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↵1 This work was supported by the LSU Neuroscience Center of Excellence incentive grant to Z.K.K. and, in part, by the Public Health System Grant DK-42714 to P.J.H. Preliminary reports of this study were presented at the symposium of the International Union of Pharmacology-Gastrointestinal Section in Pecs, Hungary (Dig. Dis. Sci.41: 445, 1996) and at the 26th Annual Society for Neuroscience Meeting in Washington, D.C. (Soc. Neurosci. Abstr.22: 396, 1996).
- Abbreviations:
- BQ-123
- cyclo(d-Trp-d-Asp-Pro-d-Val-Leu)
- DVC
- dorsal vagal complex
- ET
- endothelin
- L-GLU
- l-glutamate
- MAP
- mean arterial pressure
- nTS
- nucleus of the solitary tract
- Received August 23, 1996.
- Accepted April 24, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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