Exploring new drugs for heart failure: the case of urocortin.

Over the past decade, clinical development of natriuretic peptide analogues as drug therapy for acute heart failure has sparked a wide range of interests to seek other endogenous vasoactive peptide systems that are operative as adaptive responders in human heart failure. With rapid advances in the molecular understanding of heart failure pathogenesis, several novel neurohormonal systems have been identified and more are under study. Bringing a potential therapeutic concept from bench to bedside today often involves a prerequisite set of animal and human studies. However, much of the attention in recent years has focused on identifying what the best clinical end-points should be or what the sample size should be in order to power statistical significance. Sometimes the fundamental mechanisms of action are overlooked with the rush to clinical implications. Opportunities to refine our thinking in the exploitation of such neurohormonal agonists/antagonists can be easily missed. Davis and colleagues have extended our understanding of a new neurohormone and its pathophysiological role in heart failure. Urocortin is actually a group of peptides belonging to the corticotrophin-releasing factor (CRF) family, with other members including urocortin 1, urocortin 2, and urocortin 3. It is interesting to point out that the urocortin system has been conserved throughout evolution in vertebrates all the way back to the amphibian sauvagine. Such evolutionary conservation usually suggests that the peptide subserves an important adaptive role. This system appears to release corticosteroids in response to stress, at the same time contributing to some ‘cardioprotective’ properties. Other neurohormones such as angiotensin II, arginine vasopressin, natriuretic peptides, and norepinephrine similarly share .600 million years of history and serve important adaptive responses to protect the heart and circulation, thus ensuring survival. The urocortins act on specific G-protein-coupled receptors that subserve important homeostatic physiological functions: urocortin 1 acts on both CRF1 receptors in the central nervous system and CRF2 receptors in the myocardium, whereas urocortin 2 and urocortin 3 act selectively for specific CRF2 receptors found in the myocardium and arteriolar vessels. CRF2deficient mice demonstrate elevated blood pressure. Reports to date suggest that urocortin has a complex role in volume and pressure homeostasis. Based on existing data, these peptides are still considered primarily as vasodilators. Neurohormones such as urocortin stabilize haemodynamic alterations in heart failure and hypertension, and are attractive pathways to drug development. However, there are several fundamental gaps that have to be filled. First and foremost, is there a direct association between the neurohormonal system and the disease state? Identification of CRF2 receptors in the myocardium and certain blood vessels provides the first evidence of their involvement in cardiac diseases, with urocortin 2 and urocortin 3 expression abundant in the myocardium. In animal experiments, the expression of endogenous cardiac urocortin is increased in response to ischaemia–reperfusion damage, and the addition of exogenous urocortin is associated with reduction of myocardial cell death during ischaemia–reperfusion damage. Furthermore, gene expression of urocortin has been demonstrated in human myocytes derived from both dilated and hypertrophic cardiomyopathy, and elevated levels of circulating urocortin can be found in patients with heart failure. Taken together, the role of urocortin in heart failure pathophysiology appears convincing. Secondly, does modification of an observed pathophysiological mechanism directly relate to improvement in disease? If improvement is determined by resolution of haemodynamic alterations, the answer is affirmative. The group from Christchurch in particular has systematically studied all three urocortin infusions in normal and experimental heart failure animal models, normal humans, and now humans with heart failure. Consistently, they all produce substantial and prolonged cardiac vasodilatory and inotropic effects, and the reverse effects were seen when receptors were competitively antagonized. However, short-term administration of urocortin 1 did not show any significant haemodynamic or neurohormonal effects either in normal subjects or in patients with heart failure. In contrast to the report of Davis and colleagues, short-term urocortin 2 infusion caused flushing in all eight male patients with stable heart failure, consistent with its vasodilatory The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. * Corresponding author. Tel: þ1 216 444-3410; fax: þ1 216 636-0063. E-mail address: [email protected] † doi:10.1093/eurheartj/ehm340