Dihydropyridine BAY-K-8644 activates chromaffin cell calcium channels

Abstract

Douglas and Rubin suggested that "the role of acetylcholine as a transmitter at the adrenal medulla is to cause some brief change in medullary cells which allows Ca ions to penetrate them and trigger the catecholamine ejection process". The Ca2+-channel blocking agents, verapamil, nifedipine and nitrendipine, have been used widely to investigate the properties of slow Ca2+ channels in a variety of tissues, including the adrenomedullary chromaffin cell. Recently, small modifications to the nifedipine molecule produced a derivative, BAY-K-8644 (methyl-1,4-dihydro-2, 6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate), that in contrast to the Ca2+-channel blocking agents, stimulated cardiac and vascular smooth muscle contractility. We have tested whether this compound behaves as a Ca2+-channel activator at the chromaffin cell membrane as shown by Schramm et al. in smooth muscle cells. The experiments described here strongly suggest that it does so.

Differential antagonism by Bay k 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle

“…This positive inotropic effect was not modified by the Padrenoceptor antagonist, nadolol. Therefore, the positive inotropic effect of Bay k 8644 does not seem to involve the release of catecholamines, although Bay k 8644 has been found to potentiate catecholamine release evoked by K+ in adrenomedullary chromaffin cells (Garcia et al, 1984). In the previous studies (Schramm et al, 1983a,b) the positive inotropic effect of Bay k 8644 (measured as an increase in left ventricular pressure in the guinea-pig isolated perfused heart) reached a maximum at 10-6 M, and it was less at 10-5 M than at 10-6 M. In keeping with these observations, in the present experiments the maximum positive inotropic effect of Bay k 8644 was attained at 106 M and the effect became less at 10-5 M. Thus, it is tempting to speculate that this phenomenon reflects the action of Bay k 8644 as a partial calcium agonist.…”

Chromogranin A: current status as a precursor for bioactive peptides and a granulogenic/sorting factor in the regulated secretory pathway

“…It is especially important in studying the biological activities of CGA-derived peptides. Many of the proposed actions of CGA peptides involve modulation of secretory processes mediated by L-type calcium channel operation [138][139][140]. Potent non-peptide inhibitors of L-type calcium-dependent voltage channels have been identified as low-molecular weight contaminants extractable from plasticware frequently used in peptide purification [141].…”

“…Chromostatin is a fragment of chromogranin A (CGA- (124)(125)(126)(127)(128)(129)(130)(131)(132)(133)(134)(135)(136)(137)(138)(139)(140)(141)(142)(143) in the cow) which represents a special case of potential extracellular processing of CGA. Simon and co-workers described an inhibitory effect of purified chromogranin A on catecholamine release from the adrenal medulla.…”

Tumor promoters potentiate the adrenomedullary secretion induced by acetylcholine and excess K possibly by stimulating phorbol ester receptors.

“…On the other hand, the responses to histamine (0.5 mM) or Ca (0.5 mM) reintroduction during exposure to a medium lacking divalent cation (DOUGLAS and RUBIN, 1963;SORIMACHI and NISHIMURA, 1984) were little affected by TPA (55±11 % in case of histamine, N=3, and 52±17% of the preceding controls in case of Ca reintroduction, N= 3). These results raise the possibility that TPA somehow activates voltage-dependent Ca channels as does dihydropyridine BAY-K-8644 (GARCIA et al, 1984). Even if this is so, however, mode of action of TPA appeared to be different from that of K-8644, since the responses to Ca (0.5 mM) reintroduction were greatly increased in the presence of K-8644 (20±7 times increase, N=3).…”