Abstract—Studies on genetically manipulated mice suggest a role for -protein kinase C (PKC) in cardiac hypertrophy and in heart failure. The potential clinical relevance of these findings was tested here using a pharmacological inhibitor of PKC activity during the progression to heart failure in hypertensive Dahl rats. Dahl rats, fed an 8% high-salt diet from the age of 6 weeks, exhibited compensatory cardiac hypertrophy by 11 weeks, followed by heart failure at 17 weeks and death by the age of 20 weeks (123±3 days). Sustained treatment between weeks 11 and 17 with the selective PKC inhibitor V1-2 or with an angiotensin II receptor blocker olmesartan prolonged animal survival by 5 weeks (V1-2: 154±7 days; olmesartan: 149±5 days). These treatments resulted in improved fractional shortening (V1-2: 58±2%; olmesartan: 53±2%; saline: 41±6%) and decreased cardiac parenchymal fibrosis when measured at 17 weeks without lowering blood pressure at any time during the treatment. Combined treatment with V1-2, together with olmesartan, prolonged animal survival by 5 weeks (37 days) relative to olmesartan alone (from 160±5 to 197±14 days, respectively) and by 11 weeks (74 days) on average relative to saline-treated animals, suggesting that the pathway inhibited by PKC inhibition is not identical to the olmesartan-induced effect. These data suggest that an PKC-selective inhibitor such as V1-2 may have a potential in augmenting current therapeutic strategies for the treatment of heart failure in humans.