Mechanism of blockade by (+)isradipine of adrenal catecholamine release.
Cat adrenal glands were perfused at a high rate with various modified Krebs solutions containing different concentrations of K+ but no Ca2+. Catecholamine release was tested by applying brief Ca2+ pulses (10 s of a solution containing 120 mM K+ and 2.5 mM Ca2+). Under polarizing conditions (10 min perfusion with 1.4 mM K+ with no Ca2+), the total catecholamines released by the Ca2+ pulse amounted to 5 micrograms; in depolarizing conditions (10 min perfusion with a solution containing 70 mM K+ but no Ca2+), secretion was somewhat less (4-4.5 micrograms). (+)Isradipine, a 1,4-dihydropyridine Ca2+ channel blocker, did not affect the secretory response under polarizing conditions at 10(-8) M; at 10(-6) M, the secretory response was halved. When present under depolarizing conditions (70 mM K+ in 0 Ca2+), (+)isradipine (10(-8) M) blocked catecholamine release by 90%. In contrast, the inorganic Ca2+ channel blocker, Co2+, inhibited secretion equally well under polarizing or depolarizing conditions. Since 45Ca2+ uptake into adrenal medullary chromaffin cells was also inhibited by (+)isradipine (10(-8) M) in a voltage-dependent manner, it seems likely that blocking effects of the drug on catecholamine release are associated with inhibition of Ca2+ entry into cells through L-type Ca2+ channels. The association of (+)isradipine to its receptor is very rapid under polarizing conditions; dissociation is very slow in depolarized cells and very rapid upon polarization of such cells. Since chromaffin cells are being depolarized during stressful situations to secrete catecholamines into the circulation, (+)isradipine is likely to bind better to dihydropyridine receptors in this state; in this manner, the ensuing blockade of adrenal secretion could serve as a protective mechanism of cardiovascular tissues against massive increases in circulating catecholamines. If this suggestion is correct this mechanism could have additional therapeutic value in the treatment of hypertensive patients with (+)isradipine.
Cárdenas
A M
AM
Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
Montiel
C
C
García
A G
AG
Michelena
P
P
Sánchez-García
P
P
D000311:Adrenal Glands / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D002415:Cats; D002838:Chromaffin System; D003864:Depression, Chemical; D005260:Female; D066298:In Vitro Techniques; D017275:Isradipine; D008297:Male; D008564:Membrane Potentials; D011725:Pyridines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002395:Catecholamines; D011725:Pyridines; D011978:Receptors, Nicotinic; D002118:Calcium; D017275:Isradipine