Alpha-1 Adrenoceptor–Angiotensin II Type 1 Receptor Cross-Talk and Its Relevance in Clinical Medicine

The two most relevant clinical trials investigating the efficacy of multiple neurohormonal drug combinations in the treatment of chronic congestive heart failure are the Valsartan Heart Failure Trial and the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity-added studies. The Valsartan Heart Failure Trial study randomized patients with congestive heart failure to the angiotensin receptor blocker (ARB) valsartan versus placebo, in addition to baseline angiotensin-converting enzyme inhibitor (ACE-I) therapy. Overall, valsartan was found to significantly reduce the combined morbidity and mortality end point compared with placebo, mainly due to a reduction in heart failure admissions. However, a subgroup analysis showed that patients receiving triple therapy with valsartan, an ACE-I and a β-adrenoceptor blocker, appeared to do worse. These findings led to speculation that "triple therapy" with ARB, ACE-I, and nonselective β-blocker might be harmful, possibly due to excessive neurohormonal inhibition. In contrast, in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity-added study, the "triple therapy" combination of ARB, ACE-I, and β-adrenoceptor blocker was proven safe and beneficial. We propose that the discrepancy in outcomes observed in these two trials is related to the interaction between the α1-adrenoceptor and the angiotensin II type-1 receptor, and it is not just an inherent adverse event related to "triple therapy."