A dihydropyridine-resistant component in the rat adrenal secretory response to splanchnic nerve stimulation.
A study of the effects of dihydropyridine Ca2+ channel modulators on the release of catecholamines from perfused rat adrenal glands, evoked by electrical stimulation of their splanchnic nerves, is presented. Electrically mediated secretory responses were compared to chemically mediated responses (exogenous acetylcholine, nicotine, or high K+). Intensities of stimuli were selected to produce quantitatively similar secretory responses (between 100 and 200 ng per stimulus). The main finding of the study is that responses to transmural stimulation (300 pulses at 1 or 10 Hz) and to acetylcholine were inhibited only partially (about 50%) by isradipine, an L-type Ca2+ channel blocker. In contrast, responses to high K+ (17.5 mM for 2 min) were highly sensitive to isradipine (IC50 = 8.2 nM). Responses to nicotine were also fully inhibited by this drug. Bay K 8644 (an L-type Ca2+ channel activator) potentiated mildly the secretory responses to electrical stimulation at 10 Hz and to acetylcholine, but increased threefold the responses to K+ and nicotine. It is, therefore, likely that responses mediated by high K+ or nicotinic receptors are triggered by external Ca2+ gaining access to the internal secretory machinery through L-type, dihydropyridine-sensitive voltage-dependent Ca2+ channels. However, in addition to nicotinic receptors, the physiological stimulation of adrenal medulla chromaffin cells through splanchnic nerves has other components, i.e., muscarinic receptor stimulation or the release of cotransmitters such as vasoactive intestinal polypeptide. The poorer sensitivity to dihydropyridines of secretory responses triggered by electrical stimulation of splanchnic nerve terminals or exogenous acetylcholine speaks in favor of alternative Ca2+ pathways, probably some dihydropyridine-resistant Ca2+ channels, in modulating the physiological adrenal catecholamine secretory process.
López
M G
MG
Departamento de Farmacología, Universidad Autónoma de Madrid, Facultad de Medicina, Spain.
Shukla
R
R
García
A G
AG
Wakade
A R
AR
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D002395:Catecholamines / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D004351:Drug Resistance / Q000502:physiology; D004558:Electric Stimulation; D018738:Hexamethonium; D006584:Hexamethonium Compounds / Q000494:pharmacology; D017275:Isradipine; D008297:Male; D009431:Neural Conduction / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology; D013153:Splanchnic Nerves / Q000187:drug effects / Q000502:physiology*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002395:Catecholamines; D004095:Dihydropyridines; D006584:Hexamethonium Compounds; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D002104:Cadmium; D018738:Hexamethonium; D009538:Nicotine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000109:Acetylcholine; D011188:Potassium; D002118:Calcium; D017275:Isradipine