TY - JOUR

T1 - Influence of phorbol esters, and diacylglycerol kinase and lipase inhibitors on noradrenaline release and phosphoinositide hydrolysis in chromaffin cells

AU - JONES, J A

AU - OWEN, P J

AU - BOARDER, M R

PY - 1990/11

Y1 - 1990/11

N2 - 1We have investigated the modification of catecholamine efflux and inositol phosphate formation in cultured adrenal chromaffin cells by tetradecanoyl phorbol acetate (TPA) and inhibitors of diacylglycerol kinase (R 59 022) and diacylglycerol lipase (RG 80267), the two principal pathways of diacylglycerol metabolism.2TPA (1 nm to 1 μm) elicited a slow, calcium-dependent, sustained release of noradrenaline, which was partially blocked by the dihydropyridine calcium channel blocker (−)-202 791 and potentiated by the channel enhancer (+)-202 791.3R 59 022 enhanced noradrenaline efflux at 30 and 50 μm, while the lipase inhibitor RG 80267 failed to elicit release.4Neither R 59 022 nor RG 80267 affected bradykinin- or histamine-stimulated release, but both drugs substantially attenuated nicotine- and high K+-stimulated release.5Pretreatment for 10 min with TPA (but not the relatively inactive 4-methoxyTPA) or the non-phorbol protein kinase C stimulator mezerein potently inhibited bradykinin- and histamine-stimulated accumulation of total [3H]-inositol phosphate; inhibition of [3H]-inositol phosphate formation was also seen with 24 h TPA treatment.6Neither R 59 022 nor RG 80267, separately or together, affected bradykinin-stimulated [3H]-inositol phosphate formation.7Thus while the mechanism exists for inhibition of formation of inositol phosphates by stimulation of protein kinase C, these studies failed to show that this mechanism is activated by agonists acting on phospholipase C linked receptors.

AB - 1We have investigated the modification of catecholamine efflux and inositol phosphate formation in cultured adrenal chromaffin cells by tetradecanoyl phorbol acetate (TPA) and inhibitors of diacylglycerol kinase (R 59 022) and diacylglycerol lipase (RG 80267), the two principal pathways of diacylglycerol metabolism.2TPA (1 nm to 1 μm) elicited a slow, calcium-dependent, sustained release of noradrenaline, which was partially blocked by the dihydropyridine calcium channel blocker (−)-202 791 and potentiated by the channel enhancer (+)-202 791.3R 59 022 enhanced noradrenaline efflux at 30 and 50 μm, while the lipase inhibitor RG 80267 failed to elicit release.4Neither R 59 022 nor RG 80267 affected bradykinin- or histamine-stimulated release, but both drugs substantially attenuated nicotine- and high K+-stimulated release.5Pretreatment for 10 min with TPA (but not the relatively inactive 4-methoxyTPA) or the non-phorbol protein kinase C stimulator mezerein potently inhibited bradykinin- and histamine-stimulated accumulation of total [3H]-inositol phosphate; inhibition of [3H]-inositol phosphate formation was also seen with 24 h TPA treatment.6Neither R 59 022 nor RG 80267, separately or together, affected bradykinin-stimulated [3H]-inositol phosphate formation.7Thus while the mechanism exists for inhibition of formation of inositol phosphates by stimulation of protein kinase C, these studies failed to show that this mechanism is activated by agonists acting on phospholipase C linked receptors.

U2 - 10.1111/j.1476-5381.1990.tb14114.x

DO - 10.1111/j.1476-5381.1990.tb14114.x

M3 - Journal article

VL - 101

SP - 521

EP - 526

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 3

ER -