Beta-adrenergic signal transduction following carvedilol treatment in hypertensive cardiac hypertrophy.
OBJECTIVE
Treatment with the beta-blocker carvedilol leads to an improvement of outcome and ejection fraction in heart failure. These effects occur without affecting the number of beta-adrenergic receptors, as determined in right ventricular biopsies from patients with heart failure. This study was aimed at investigating the effects of carvedilol on beta-adrenergic signal transduction alterations in a model of left ventricular pressure overload, which is characterized by sympathetic activation and a desensitized beta-adrenergic signal transduction.


METHODS
Transgenic rats with overexpression of renin [TG(mREN2)27] were treated with carvedilol (30 micrograms/kg) or held under control conditions and were compared with Sprague-Dawley rats. Myocardial beta-adrenoceptors (125I-labeled iodocyanopindolol binding), Gi alpha (pertussis toxin labeling), Gs alpha-activity (reconstitution into cyc--S49 membranes) and adenylyl cyclase activity were measured. Blood pressure and heart rate, increase in heart rate during sacrifice and pressure rate products were determined.


RESULTS
beta-Adrenoceptors were downregulated and Gi alpha-protein levels were significantly increased, producing a desensitization of basal, isoprenaline- and guanine nucleotide-stimulated adenylyl cyclase activity compared to controls. Carvedilol reduced heart rate, blood pressure and pressure rate product in TG(mREN2)27. Carvedilol did not restore biochemical alterations, but even further reduced beta-adrenoceptor numbers and adenylyl cyclase. It exhibited a two affinity state, guanine nucleotide-sensitive binding to cardiac beta-adrenergic receptors similar to isoprenaline but different from metoprolol.


CONCLUSIONS
Carvedilol did not restore beta-adrenergic signal transduction at concentrations producing antiadrenergic effects in vivo. This effect might be due to an atypical guanine nucleotide-dependent interaction with beta-adrenergic receptors. Thus, ancillary properties could explain the recently reported beneficial effects in patients with heart failure independent from an upregulation of beta-adrenergic receptors.
Böhm
M
M
Klinik III für Innere Medizin der Universität zu Köln, Germany. Michael.Boehm@Medizin.Uni-Koeln.De
Ettelbrück
S
S
Flesch
M
M
van Gilst
W H
WH
Knorr
A
A
Maack
C
C
Pinto
Y M
YM
Paul
M
M
Teisman
A C
AC
Zolk
O
O
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000032:analysis / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D030801:Animals, Genetically Modified; D001667:Binding, Competitive; D002227:Carbazoles / Q000627:therapeutic use*; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000378:metabolism; D000077261:Carvedilol; D005576:Colforsin / Q000494:pharmacology; D015536:Down-Regulation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009478:Neuropeptide Y / Q000378:metabolism; D037342:Pertussis Toxin; D011412:Propanolamines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D009478:Neuropeptide Y; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D010566:Virulence Factors, Bordetella; D000077261:Carvedilol; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases; D007545:Isoproterenol