Sodium-dependent inhibition by PN200-110 enantiomers of nicotinic adrenal catecholamine release.
1. Dimethylphenylpiperazinium (DMPP) or high K concentrations evoke catecholamine release from perfused cat adrenal glands; in both cases the secretory response was significantly enhanced in the absence of Na. Tetrodotoxin did not modify the nicotinic secretory response. 2. The (+)- and (-)-enantiomers of the dihydropyridine Ca channel blocker PN200-110 show a high degree of stereoselectivity in the inhibition of catecholamine secretion evoked by high K or by DMPP in the presence of Na, the (+)-enantiomer being 57 and 80 times more potent, respectively, than the (-)-enantiomer. Both, noradrenaline and adrenaline release were equally depressed by PN200-110. 3. The IC50 values for (+)- and (-)-PN200-110 for blockade of the secretory response induced by K or DMPP in the presence of Na are in the same range. In the absence of Na, (-)-PN200-110 did not affect DMPP-evoked secretion; however, the (+)-enantiomer partially inhibited it. 4. The results suggest that the physiological catecholamine release from chromaffin cells is preceded by Na entry through the nicotinic receptor-associated ionophore; this causes cell depolarization, opening of voltage-dependent, dihydropyridine-sensitive Ca channels and Ca entry into the cell. In the absence of Na, additional Ca influx through an alternative pathway (the nicotinic cholinoceptor ionophore?) might also activate secretion.
Cárdenas
A M
AM
Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid, Facultad de Medicina, Spain.
Montiel
C
C
Artalejo
A R
AR
Sánchez-García
P
P
García
A G
AG
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002395:Catecholamines / Q000378:metabolism*; D002415:Cats; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology; D004837:Epinephrine / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D017275:Isradipine; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology*; D010477:Perfusion; D011188:Potassium / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012964:Sodium / Q000502:physiology; D013237:Stereoisomerism
D002121:Calcium Channel Blockers; D002395:Catecholamines; D010069:Oxadiazoles; D011978:Receptors, Nicotinic; D004246:Dimethylphenylpiperazinium Iodide; D012964:Sodium; D011188:Potassium; D009638:Norepinephrine; D004837:Epinephrine; D017275:Isradipine