Neurohumoral stimulation is a key finding in syndromes such as chronic heart failure (CHF) or type-2 diabetes. In CHF, epidemiologic data support the notion that plasma norepinephrine (1) as well as brain-natriuretic peptide (BNP) (2) levels are reliable markers for outcome. Landmark studies have shown that patients with CHF benefit from angiotensin-converting-enzyme (ACE) inhibitors, betaadrenergic blockade as well as aldosterone antagonism. Concerning ACE inhibition, the inherent bradykininergic effects appear to be hemodynamically important in the CHF condition, rendering ACE inhibitors superior to angiotensin receptor blockers (3). Regarding the rationale for betaadrenergic blockade in CHF, the “Cardiac Insufficiency Bisoprolol Study II” (CIBIS II), amongst other studies, has shown a 34% mortality reduction in patients staged NYHA class III and IV when bisoprolol was added to standard of care therapy regardless of NYHA class (4;5). Even after the introduction of betaadrenergic blockade and ACE inhibition in CHF, an additional improvement in the prognosis of CHF patients has been achieved by aldosterone antagonism as shown by the “Randomized Aldactone Evaluation Study” (RALES) (6) and the “Eplerenone Post Acute Myocardial Infarction Efficacy and Survival Study” (EPHESUS) (7).

Beyond CHF, outcome-related research has tested the blockade of neurohumoral pathways in coronary artery disease as well: the “Heart Outcomes Prevention Evaluation Study” (HOPE) has proven a 26% reduction in cardiovascular deaths in patients with coronary artery disease without signs of CHF when treated with an ACE inhibitor (8).

More recently, an emerging body of data points at specific states of neurohumoral stimulation that are prevalent in type-2 diabetes and its precursor states such as obesity (9). As type-2 diabetes is tightly connected with obesity, obesity-related mechanisms of insulin resistance and neurohumoral stimulation become subject of research interest. Besides non-pharmacologic interventions such as increased physical activity and a low-caloric diet, medical interventions to influence appetite, and metabolic rate are investigated. The fact that the male-type obesity more significantly affects the incidence of diabetes has recently been influenced the criteria for metabolic syndrome issued by the “Third Report of the National Cholesterol Education Program’s Adult Treatment Panel” (ATP III). There, waist circumference is used instead of body-mass index (10). The established diagnosis of metabolic syndrome based on the ATP III criteria serves to predict the risk for type-2 diabetes (24 fold increased) and for atherosclerosis (3-4 fold increased) (11).

Neurohumoral mechanisms may offer some additional insights into the type-2-diabetes evolution. Among hypertensives treated either with losartan or atenolol in the LIFE study, the losartan-treated branch had a greater benefit in terms of type-2 diabetes prevention when compared to the atenolol-treated group while blood-pressure control was equal (12). That is, specific neurohumoral mechanisms such as the renin-angiotensin-aldosterone system (RAAS) may be intimately involved in diabetes evolution. Ongoing trials such as the “Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial“ (ONTARGET) will provide further evidence whether or not another drug class, the angiotensin II receptor blockers (ARB), is able to lower the incidence of type-2 diabetes (13). However, the big question for the foreseeable future remains: What actually does trigger states of neurohumoral stimulation seen in cardiovascular diseases such as CHF or type-2 diabetes? A better understanding of neurohumoral compensatory responses to prior dysregulations may help explain a number of puzzles, thereby facilitating adequate therapeutic or preventive measures.

Overall, in this chapter, we intend to highlight hormone actions with regard to hemodynamic actions as documented by alterations of systemic vascular resistance and cardiac output as well as non-hemodynamic effects such as inflammation and oxidative stress.