Intracellular signals involved in the stimulation of cardiomyocyte
glucose transport by the -adrenergic agonist phenylephrine.
Fischer, Y., J. Kamp, J. Thomas, S. P[diaeresis]opping, H. Rose, C.
Carp[acute]en[acute]e, and H. Kammermeier.
Institute of Physiology, Medical Faculty, RWTH Aachen, Pauwelsstr.
30, D-52057 Aachen, Germany, Solvay Deutschland GmbH., PH-FEBK1,
Hans-B[diaeresis]ockler-Allee 20, D-30173 Hannover, Germany,
I.N.S.E.R.M. U 317, Institut Louis Bugnard, Facult[acute]e de
M[acute]edicine, C.H.U., Rangueil, F-31054, Toulouse, France
APStracts 2:0390C, 1995.
This study examines the potential intracellular signals mediating the
stimulation of glucose transport by the -adrenergic agonist
phenylephrine in cardiomyocytes. Phenylephrine caused a rapid rise
(within 5?min) in the cytosolic calcium concentration by 30%.
However, other interventions inducing a similar calcium response were
ineffective in stimulating glucose transport (treatment with
angiotensin II, or vasopressin), or even inhibited the basal and
insulin-stimulated glucose transport by 20% (elevation of
extracellular calcium concentration). The stimulatory action of the
diacylglycerol analogue phorbol myristate acetate on glucose
transport was additive to both the fast (4?min), and the slow phase
(60?min) of phenylephrine-induced transport stimulation.
Phenylephrine had no influence on the cellular content of cAMP and
cGMP, and agents rising cAMP (isoprenaline), or cGMP (nitroprusside,
8- bromo-cGMP, atrial natriuretic peptide) did not stimulate glucose
transport. Wortmannin (an inhibitor of the phosphatidylinositol-3
-kinase) had no influence on the phenylephrine-dependent glucose
transport, but suppressed the action of insulin. In contrast, the
Na+/H+-exchange inhibitor amiloride (known to block the
phenylephrine-induced cytosolic alkalinization, or even to lower the
cellular pH) depressed the effect of phenylephrine by 50%, while the
basal and insulin-stimulated glucose transport rates were not or
little affected. However, raising the extracellular pH from 7.4 up to
8.4 failed to increase glucose transport. On the other hand, lowering
the pH from 7.4 to 6.8 decreased phenylephrine's stimulation of
glucose transport by 40%, whereas the basal and insulin-dependent
were not significantly altered. Monoamine-oxidase inhibitors (which
block the intracellular degradation of catecholamines), such as
clorgyline or tranylcypromine, and exogenously added catalase
decreased the overall effect of phenylephrine by 50%, and by 20%,
resp. This inhibition only affected the slow phase of the
catecholamine's action, while amiloride also depressed the fast
phase. We conclude that (i) the stimulation of cardiomyocyte glucose
transport by phenylephrine does not involve cAMP or cGMP, nor a
phosphatidylinositol-3-kinase; (ii) protein kinase C activation
cannot explain the full extent of stimulation; (iii) a calcium
release, or a cytosolic alkalinization might be required, but are not
sufficient to trigger phenylephrine's action. The slow phase of
transport stimulation is mediated by the monoamine-oxidase dependent
degradation of phenylephrine, and by the resulting hydrogen peroxide
formation.
Received 24 July 1995; accepted in final form 17 October 1995.
APS Manuscript Number C450-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 6 November 95