Central neuropeptide Y and the sigma ligand, JO 1784, reverse corticotropin-releasing factor-induced inhibition of gastric acid secretion in rats.
1. The central interactions between the sigma ligand, JO 1784, [(+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethylbut-3- en-1-ylamine hydrochloride], or neuropeptide Y (NPY) and corticotropin-releasing factor (CRF)-induced inhibition of gastric acid secretion were investigated in rats anaesthetized with urethane. Drugs were injected intracisternally (i.c.) or into specific hypothalamic nuclei. Gastric acid secretion was measured by the flushed technique under basal and pentagastrin (10 micrograms kg-1 h-1, i.v.) stimulated conditions. 2. Intracisternal injection of CRF (10 micrograms), bombesin (0.1 microgram) and human recombinant interleukin-1 beta (hIL-1 beta, 0.1 microgram) inhibited gastric acid response to pentagastrin by 72%, 56% and 62%, respectively. NPY (0.5 microgram) or JO 1784 (0.5 microgram) injected i.c. did not alter acid secretion but completely prevented the inhibitory effect of CRF. The antagonistic effect of NPY and JO 1784 against CRF was dose-related (0.01-0.5 microgram) and peptide-specific since NPY and JO 1784 did not alter the antisecretory action of bombesin or hIL-1 beta. 3. The putative sigma receptor antagonist, BMY 14802, (1 mg kg-1, s.c.) did not influence pentagastrin-stimulated acid secretion nor CRF-induced inhibition of gastric acid secretion; however, BMY 14802 administered s.c. 20 min before JO 1784 or NPY, abolished the antagonistic effect of both JO 1784 and NPY. 4. CRF (3 micrograms) microinjected into the hypothalamic paraventricular nucleus (PVN) and the lateral hypothalamus (LH) inhibited pentagastrin-stimulated gastric acid secretion by 61% and 51%; NPY (0.03 micrograms) or JO 1784 (0.03 micrograms) microinjected into the PVN had no effect by themselves but blocked CRF antisecretory action.There were more VPBs (220 +/- 75), a higher incidence of VT (60%) and more episodes of VT (11.5 +/- 6.0 compared to 0.7 +/- 0.3 episodes in the preconditioned dogs not given L-NAME); none of the animals survived reperfusion (incidence of VF 100%). The improvement in the severity of the degree of inhomogeneity which resulted from preconditioning was abolished by L-NAME administration.5. L-NAME itself elevated blood pressure (from 96 +/- 5 mmHg diastolic to 119 +/- 7 mmHg), reduced heart rate (from 155 +/- 7 to 144 +/- 4 beats min-') but did not change LVEDP, LVdP/dt,,,,, coronary blood flow, ST-segment elevation or the degree of inhomogeneity of conduction. When given 10 min before the prolonged coronary artery occlusion in dogs not subjected to preconditioning, L-NAME had no significant effect on the severity of arrhythmias except for more periods of VT (a mean of 11.7 +/- 4.7 episodes per dog).6. It is concluded from these studies that the generation of nitric oxide contributes to the marked antiarrhythmic effects of preconditioning in the canine myocardium, probably through elevation of cyclic GMP.
Gué
M
M
CURE/VA Wadsworth Medical Center, Department of Medicine, Los Angeles, CA.
Yoneda
M
M
Mönnikes
H
H
Junien
J L
JL
Taché
Y
Y
D000818:Animals; D001839:Bombesin / Q000494:pharmacology; D002934:Cinnamates / Q000494:pharmacology*; D002946:Cisterna Magna; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D009478:Neuropeptide Y / Q000494:pharmacology*; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010418:Pentagastrin / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D002934:Cinnamates; D003521:Cyclopropanes; D007375:Interleukin-1; D009478:Neuropeptide Y; D011619:Psychotropic Drugs; D011743:Pyrimidines; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; D003346:Corticotropin-Releasing Hormone; D010418:Pentagastrin; D001839:Bombesin; C065310:igmesine