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EXPERIMENTAL STUDY

Beta-adrenoceptor stimulation attenuates the hypertrophic effect of alpha-adrenoceptor stimulation in adult rat ventricular cardiomyocytes

Matthias Schäfer, PhD^*, Klaus Pönicke, PhD, Ingrid Heinroth-Hoffmann, PhD, Otto-Erich Brodde, PhD^*, Hans Michael Piper, MD, PhD^* and Klaus-Dieter Schlüter, PhD^*

^* Physiologisches Institut, Justus-Liebig-Universität Giessen, Giessen, Germany
Institut fur, Pharmakologie und Toxikologie, Martin-Luther-Universität Halle, Halle, Germany

Manuscript received September 27, 1999; revised manuscript received July 17, 2000, accepted September 11, 2000.

Reprint requests and correspondence: Dr. Klaus-Dieter Schlüter, Physiologisches Institut, Aulweg 129, D-35392 Giessen, Germany
Klaus-Dieter.Schlueter{at}physiologie.med.unigiessen.de

OBJECTIVES

The study investigated whether ß-adrenoceptor antagonists augment the hypertrophic response of cardiomyocytes evoked by norepinephrine.

BACKGROUND

In adult ventricular cardiomyocytes, stimulation of - but not ß-adrenoceptors induces myocardial hypertrophy. Natural catecholamines, like norepinephrine, stimulate simultaneously - and ß-adrenoceptors. We investigated whether ß-adrenoceptor stimulation interferes with the hypertrophic response caused by -adrenoceptor stimulation.

METHODS

Adult ventricular cardiomyocytes isolated from rats were used as an experimental model. Hypertrophic parameters under investigation were stimulation of phenylalanine incorporation and protein mass, stimulation of ¹⁴C-uridine incorporation and RNA mass, and increases in cell shape.

RESULTS

Norepinephrine (0.01 to 10 µmol/liter) increased concentration-dependent phenylalanine incorporation; pEC₅₀ value was 5.9 ± 0.1 (n = 8). The ₁-adrenoceptor antagonist prazosin (0.1 µmol/liter) suppressed norepinephrine-induced increase in rate of protein synthesis. Conversely, propranolol (1 µmol/liter) and the ß₁-adrenoceptor selective antagonists CPG 20712A (300 nmol/liter) or atenolol (1 µmol/liter) augmented increases in phenylalanine incorporation caused by norepinephrine. Addition of the ß₂-adrenoceptor antagonist ICI 118,551 (55 nmol/liter) did not influence the hypertrophic effect of norepinephrine. Atenolol augmented the norepinephrine-induced increases of all hypertrophic parameters investigated (i.e., protein mass, uridine incorporation, RNA mass, cell volume, and cross-sectional area). In the presence of norepinephrine, inhibition of ß₁-adrenoceptors increased the amount of protein kinase C- and - isoforms translocated into the particulate fraction. The effect of pharmacological inhibition of ß₁-adrenoceptors could be mimicked by Rp-cAMPS (adenosine-3', 5'-cyclic phosphorothiolate-Rp). The inhibitory effect of ß₁-adrenoceptor stimulation on the -adrenoceptor-mediated effect persisted in cardiomyocytes isolated from hypertrophic hearts of rats submitted to aortic banding.

CONCLUSIONS

In isolated ventricular cardiomyocytes from rats, ß₁-adrenoceptor stimulation attenuates the hypertrophic response evoked by ₁-adrenoceptor stimulation.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   EDTA = ethylenediaminete acid   EGTA = ethylene glycol-bis(ß-aminoethyl ether) N,N,N',N'-tetraacetic acid   FCS = fetal calf serum   PKA = cyclic-AMP-dependent protein kinase   PKC = protein kinase C   PMA = phorbol myristate acetate   PMSF = phenylmethylsulfonyl fluoride   Rp-cAMPS = adenosine-3', 5'-cyclic phosphorothiolate-Rp   SDS–PAGE = sodium dodecyl sulfate–polyacrylamide gel electrophoresis

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