Dihydropyridine modulation of the chromaffin cell secretory response.
Prolonged perfusion of cat adrenal glands with Krebs-bicarbonate solutions containing nicotine, muscarine, or excess K rapidly increased the rate of catecholamine output proportional to the concentrations of secretagogue used. The secretory responses to nicotine or high K reached a peak and declined to almost basal rates of secretion after about 10 min of stimulation. The dihydropyridine Ca channel agonist Bay K 8644 potentiated markedly the secretory responses to 1 microM nicotine and to 17.7 mM K but not to higher concentrations of these secretagogues. The muscarinic response did not decrease with time and was modestly potentiated by Bay K 8644. Similar curves were obtained with 17.7 mM K plus Bay K 8644 and with 59 mM K alone. CGP28392, another agonist, was about 10 times less potent than Bay K 8644 in potentiating the secretory responses to 17.7 mM K. Bay K 8644 also potentiated the release of [3H]noradrenaline evoked by stimulation of cultured bovine adrenal chromaffin cells with 17.7 mM K or 2 microM nicotine but not with higher concentrations of K or nicotine. Dihydropyridine Ca channel antagonists reversed the effects of Bay K 8644 with the following order of potency: niludipine greater than nifedipine = nimodipine greater than nitrendipine. The secretory rates from intact chromaffin cells treated with the Ca ionophores X537A or A23187, or those evoked by Ca-EGTA buffers from digitonin-permeabilized cells, were not affected by Bay K 8644. These results are compatible with the following conclusions: Bay K 8644 selectively potentiates catecholamine secretory responses mediated through the activation of voltage-sensitive Ca channels; during nicotine or high-K stimulation, Ca gains access to the cell interior through a common permeability pathway, the Ca channel.(ABSTRACT TRUNCATED AT 250 WORDS)
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000818:Animals; D002415:Cats; D002463:Cell Membrane Permeability; D002837:Chromaffin Granules / Q000187:drug effects / Q000378:metabolism*; D002838:Chromaffin System / Q000378:metabolism*; D005260:Female; D008297:Male; D009116:Muscarine / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D009568:Nitrendipine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D010477:Perfusion; D011188:Potassium / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*
D011725:Pyridines; D009538:Nicotine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009116:Muscarine; C040525:CGP 28392; D009568:Nitrendipine; D011188:Potassium; D009638:Norepinephrine