| Carvedilol is a beta blocker which also has α 1-adrenergic blocking and free radical scavenging activities. The commercial drug is a racemic mixture of both R(+) and S(−) enantiomers, and is available in an oral preparation. It has been used for treatment of patients with hypertension, cardiac ischemia, and heart failure. Carvedilol is reported to improve left ventricular function, and to prevent the remodeling processes. However, there is little information about the use of carvedilol in veterinary medicine. The objectives of the present study were to study the physiological and pharmacological effects of carvedilol in dogs, and to determine if carvedilol has a protective effect against doxorubicin-induced cardiotoxicity. Results indicate that acute effects of intravenous carvedilol on cardiac function include increase in heart rate and velocity of fiber shortening at zero load (Vmax), shortening of PQ interval, and decrease in systemic and pulmonary arterial systolic pressures. Pharmacokinetic studies after an intravenous injection of carvedilol at 100 μg/kg showed that the plasma concentration curve was fitted by a two-compartment model. Half lives of distribution and elimination phases were 3.6 and 52 minutes respectively. The mean clearance was 24.3 ml/kg/min, and the mean volume of distribution was 1830 ml/kg. The increase in heart rate, in response to an infusion of 0.512 μg/kg/min of isoproterenol, was decreased approximately 50% by an oral dose of approximately 0.3125 mg/kg of carvedilol at the 1st, 2nd, and 4th hours after the last dose of carvedilol. The dose of isoproterenol required to increase heart rate 50% of the increase achieved when no carvedilol was given, increased proportionally with the amount of carvedilol given (0.15625, 0.3125, 0.625, and 1.25 mg/kg). The amount of isoproterenol, required to increase heart rate 50% of the maximal increase, increased to a maximum at the 4th hour after dosing with carvedilol. Protective effects of carvedilol on doxorubicin-induced cardiotoxicity were demonstrated. Dogs given doxorubicin and carvedilol maintained PEP/ET ratios, systemic blood pressures, and Vmax. Moreover, they also had decreases in tau and minimal QT prolongation, and had higher heart rate variability. The present study suggests that carvedilol protects the heart from doxorubicin by improving left ventricular function, decreasing energy required for contraction and relaxation, and preventing cardiac arrhythmias. |
