In a previous study, we showed that caffeine (CAFF) increases basal renin secretion by blocking intrarenal adenosine receptors and, when sympathetic activity is increased, augments renin release in part by blockade of brain adenosine receptors, leading to increased central sympathetic tone. The purpose of this study was to investigate the effects of CAFF treatment on neurohumoral status and heart performance in experimental heart failure. Two series of experiments were performed. First, the effects of CAFF (10 mg/kg +150 microg/min over 40 min) on heart performance (time-pressure variables) and neurohumoral status were studied in conscious, 9-month-old Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs), and spontaneously hypertensive heart failure (SHHF/Mcc-fa(cp) rats. Second, caffeine (0.1% in drinking water) was given for 10 days to 14-month-old SHHF/Mcc-fa(cp) rats, and cardiac performance, renal function, and neurohumoral status determined in vivo. CAFF infusion increased heart rate, left ventricular peak systolic pressure, and workload in hypertensive (SHRs and SHHF), but not in normotensive (WKY) animals and had no effects on cardiac contractility in all three strains. CAFF increased plasma renin activity (PRA), norepinephrine (NE), and epinephrine (E) levels in all three strains [treatment effect, p<0.001, 2F analysis of variance (ANOVA)], and these effects were greater in hypertensive (SHRs and SHHF) animals as compared with normotensive WKY rats (p<0.015). Ten-day CAFF treatment in 14-month-old SHHF did not change measured cardiac time-pressure variables, or hemodynamic or renal excretory function parameters that can affect renin secretion. However, CAFF treatment significantly increased renal renin secretion (71.1+/-19.2 vs. 9.5+/-5.8 ng Ang I/h/min/kg for caffeine and control group, respectively; p<0.01). In summary, acute administration of CAFF increases workload, but has no effects on cardiac contractility in conscious SHHF rats. The cardiac effects are accompanied by increased renin release and NE and E plasma levels. Moreover, this study provides the first evidence that short-term caffeine consumption increases renal renin secretion in heart failure, an effect most likely due to the blockade of intrarenal adenosine receptors. It is possible that long-term activation of neurohumoral mechanisms by CAFF could have adverse effects in heart failure.