Effects of the alpha2-adrenergic/DA2-dopaminergic agonist CHF-1024 in preventing ventricular arrhythmogenesis and myocyte electrical remodeling, in a rat model of pressure-overload cardiac hypertrophy.
Cardiac hypertrophy induces morpho-functional myocardial alterations favoring arrhythmogenesis, especially under specific conditions such as sympathetic stimulation. We analyzed whether the dopaminergic agent CHF-1024, given its effect in decreasing adrenergic drive and collagen deposition in hypertrophied hearts, can also reduce arrhythmia vulnerability. Eighty-one male Wistar rats with intrarenal aortic coarctation and 18 control animals were studied. Fifty-eight banded animals were treated with CHF-1024 at four different doses (6, 2, 0.67, or 0.067 mg/Kg/die). One month after aortic ligature, spontaneous and sympathetic-induced ventricular arrhythmic events (VAEs) were telemetrically recorded in conscious animals. After sacrifice, membrane capacitance (Cm) and action potential duration (APD) were measured in isolated left ventricular myocytes (patch-clamp). In all groups, spontaneous VAEs were negligible whereas they significantly increased during sympathetic activation (stress exposure). Banded untreated animals showed a higher number of stress-induced VAEs, longer action potentials, and larger values of Cm and cell width as compared with control group. The treatment with CHF-1024 exhibited an antiarrhythmic effect, abolished APD prolongation, and reduced cell width at all doses. The lowest dose also prevented Cm increase. In conclusion, we demonstrated that in this model of pressure-overload hypertrophy CHF-1024 reduces arrhythmogenesis and causes a recovery of cell excitable properties toward a normal phenotype.
Dipartimento di Biologia Evolutiva e Funzionale-Sezione Fisiologia, Università di Parma, Italy.
Roberta
R
Berni
Francesca
F
Cacciani
Massimiliano
M
Zaniboni
Monia
M
Savi
Leonardo
L
Bocchi
Silvia
S
Lapucci
Roberta
R
Razzetti
Fiorella
F
Pastore
Ezio
E
Musso
Donatella
D
Stilli
D000200:Action Potentials / Q000187:drug effects; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control*; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology*; D048429:Cell Size / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006352:Heart Ventricles / Q000166:cytology / Q000503:physiopathology; D008297:Male; D032383:Myocytes, Cardiac / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D013686:Telemetry; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*; D013997:Time Factors; D017725:Ventricular Pressure / Q000187:drug effects / Q000502:physiology*; D020257:Ventricular Remodeling
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D013764:Tetrahydronaphthalenes; C112301:CHF 1024