CARVEDILOL UPDATE .4. PREVENTION OF OXIDATIVE STRESS, CARDIAC REMODELING AND PROGRESSION OF CONGESTIVE-HEART-FAILURE

On May 29, 1997, the United States Food and Drug Administration grante d final approval for the use of carvedilol in the treatment of mild to moderate congestive heart failure. In this action, the United States joined 20 countries worldwide that have approved carvedilol (Coreg(R)/ Kredex(R)) for treatment of hypertension and congestive heart failure. Carvedilol is also approved for the treatment of angina in several co untries. Carvedilol (Fig. 1) is a chemically distinct and pharmacologi cally unique agent that possesses multiple pharmacological actions, in cluding: 1) nonselective B-adrenoceptor blockade, 2) alpha(1)-adrenoce ptor blockade, 3) potent antioxidant activity, and 4) regulation of ge nes involved in cardiovascular organ remodeling and apoptosis. Based o n this pharmacological profile, carvedilol is uniquely positioned to i nhibit several of the major congestive heart failure, including: 1) he modynamics: reduction of preload, afterload and heart rate; 2) neuroho rmonal: inhibition of the sympathetic nervous system, renin-angiotensi n system and endothelin; 3) oxidative stress: scavenging potentially t oxic oxygen radicals and restoring endogenous antioxidants; 4) genomic reformatting: suppression of several genes associated with pathologic al organ remodeling. Thus, carvedilol, through its multiple actions, h as the capacity to provide broad cardiovascular organ protection. As a result of these multiple actions, carvedilol, when used in conjunctio n with standard therapy for heart failure (i.e., diuretics, digoxin, a nd angiotensin-converting enzyme inhibitors), significantly reduced mo rbidity, mortality and hospitalization in patients with congestive hea rt failure of either ischemic or nonischemic (i.e., idiopathic dilated cardiomyopathy) origin, independent of disease severity (mild to mode rate) or left ventricular function (ejection fraction). The highly fav orable clinical outcomes from the large multicenter clinical trials co nducted with carvedilol in the United States and Australia/New Zealand merits a detailed update of the unique mechanisms of action of carved ilol, and a thorough review of the clinical trial results. Accordingly , we will highlight in this update our previous experimental findings with carvedilol as well as more recent data that shed light on the mec hanisms by which this drug produces its effects in congestive heart fa ilure. In addition, an update of the results from the large multicente r clinical trials, which formed the basis for the approval of the drug for the treatment of heart failure, will be presented.