Mechanism of blockade by flunarizine of bovine adrenal catecholamine release.
How flunarizine, a class IV Ca2+ antagonist, affects the secretion of catecholamines in response to nicotinic receptor activation (10-s pulses with 100 microM dimethylphenylpiperazinium, DMPP) or direct depolarization of chromaffin cells (10-s pulses with 100 mM K+ and 2.5 mM Ca2+, 100 K+/2.5 Ca2+) was studied in bovine adrenal glands perfused with an oxygenated Krebs-Tris solution at 37 degrees C at a rate of 20 ml/min. Experimental protocols aimed to test voltage and time dependence of the flunarizine blocking effects on secretion are described. The DMPP pulses released an average of 217 micrograms catecholamines and the K+ pulses, an average of 117 micrograms. These responses were blocked by flunarizine concentration dependently; IC50s were 3.7 microM for DMPP and 1.1 microM for K+. Under polarizing conditions (60-s perfusion with a solution containing 5.9 mM K+ and nominally zero Ca2+), a 10-s pulse with 100 K+/2.5 Ca2+ released 117 +/- 26 micrograms of catecholamines (n = 12). Under depolarizing conditions (60-s perfusion with 118 K+/0 Ca2+ prior to the Ca2+ pulse), the pulse with 118 K+/2.5 Ca2+ released 307 +/- 36 micrograms of catecholamines (n = 14). Flunarizine blocked these secretory responses equally and concentration dependently with an IC50 of 3.4 microM under polarizing conditions and of 3.8 microM under depolarizing conditions. Thus, blockade by flunarizine of secretion was apparently not voltage-dependent. The blockade was, however, clearly dependent on the time of exposure of the adrenal medullary tissue to flunarizine.(ABSTRACT TRUNCATED AT 250 WORDS)
De la Fuente
M T
MT
Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
Guantes
J M
JM
Del Valle
M
M
Garcia
A G
AG
D000313:Adrenal Medulla / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005444:Flunarizine / Q000494:pharmacology*; D066298:In Vitro Techniques; D011188:Potassium / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism
D002395:Catecholamines; D011978:Receptors, Nicotinic; D004246:Dimethylphenylpiperazinium Iodide; D005444:Flunarizine; D011188:Potassium; D002118:Calcium