Hypertrophic responsiveness of cardiomyocytes to alpha- or beta-adrenoceptor stimulation requires sodium-proton-exchanger-1 (NHE-1) activation but not cellular alkalization.
The influence of the sodium-proton-exchanger-1 (NHE-1) inhibitor HOE694 on alpha- or beta-adrenoceptor mediated stimulation of protein synthesis was investigated in cultured ventricular cardiomyocytes from adult rat pre-treated with fetal calf serum to induce hypertrophic responsiveness to beta-adrenoceptor stimulation. Stimulation of alpha-adrenoceptors with phenylephrine (10 microM) in bicarbonate-free medium caused cellular alkalization (Delta pH(i): + 0.17 +/- 0.02, n = 5, P < 0.05). HOE694, an NHE-1 inhibitor, completely abolished this effect. [14C]phenylalanine incorporation into cellular protein mass increased in the presence of phenylephrine by 23+/-8%, and this effect was also abolished in the presence of HOE694. HOE694 (1 mciroM) neither influenced basal protein synthesis nor interfered with alpha-adrenoceptor mediated activation of ERK2. Phorbol myristate acetate, a direct stimulator of protein kinase C, mimicked the effect of alpha-adrenoceptor stimulation in regard to protein synthesis, but did not lead to cellular alkalization. Protein synthesis increased in the presence of isoprenaline, a beta-adrenoceptor agonist also. Again, HOE694 attenuated the stimulation of protein synthesis although isoprenaline did not cause cellular alkalization. In conclusion, the growth response to different hypertrophic stimuli, namely alpha- or beta-adrenoceptor stimulation, is attenuated in the presence of the NHE-1 inhibitor HOE694 and this inhibition is independent from cellular alkalization.
Schäfer
Matthias
M
Physiologisches Institut, Justus-Liebig Universität, Aulweg 129, D-35392, Giessen, Germany.
Schäfer
Claudia
C
Michael Piper
Hans
H
Schlüter
Klaus-Dieter
KD
D000704:Analysis of Variance; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000503:physiopathology*; D006146:Guanidines / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D008297:Male; D010649:Phenylalanine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000502:physiology*; D013450:Sulfones / Q000494:pharmacology*
D006146:Guanidines; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; D010649:Phenylalanine