SP 04-1 THE ROLE OF NATRIURETIC PEPTIDES IN THE PATHOGENESIS OF CARDIOVASCULAR DISEASES.

The burden of cardiovascular diseases (CVD) in general and heart failure (HF) in particular continues to increase worldwide. CVD are major contributors to death and morbidity and recognized as important drivers of healthcare expenditure. Chronic overactivity of the renin-angiotensin-aldosterone system (RAAS) plays a key role in human hypertension and HF pathophysiology. RAAS is fundamental in the overall regulation of cardiovascular homeostasis through the actions of hormones, which regulate vascular tone, and specifically blood pressure through vasoconstriction and renal sodium and water retention. Drugs inhibiting key components of the RAAS have become a cornerstone of contemporary cardiovascular drug therapy. Nowadays there is a high priority for the development of innovative therapeutic agents that better control blood pressure, have a therapeutic potential in HF and enhance current therapies for CVD. The enhancement of the biological activities of the natriuretic peptides (NP) via inhibition of their degradation is one of the novel strategies.Natriuretic peptide system includes primarily three well-characterized peptides with structural similarity: atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). These three peptides are involved in the maintenance of cardio-renal homeostasis and all have cardio-renal protective properties. Atrial natriuretic peptide and BNP are synthetized mainly by the cardiomyocytes in response to cardiac stretch, whereas CNP is mainly produced by endothelial cells in response to cytokines and endothelium-dependent agonists. B-type natriuretic peptide is also produced by cardiofibroblasts where it elicits its antifibrotic actions in the heart. All NP function via the second messenger cGMP. All three peptides are cleared by the clearance receptor (NPR-C), not linked to a guanylate cyclase. The NP are also cleared from the circulation via enzymatic degradation by neutral endopeptidase (NEP). Natriuretic peptides play key role in the regulation of electrolytes and water balance homeostasis, blood pressure levels through diuretic, natriuretic, vasorelaxant effects, along with the ability to inhibit the RAAS and the sympathetic nervous system. They modulate systemic vascular resistance by inhibiting the contraction of vascular smooth muscle cells through cGMP-dependent kinases. Apart from increased volume overload and myocytes stress hormonal stimuli are involved in the control of NP release.Besides hemodynamic functions, new properties of NP have been recently discovered related to the interaction with cellular growth and proliferation at the vascular level. Natriuretic peptides preserve vascular health in endothelial and vascular smooth muscle cells by interfering with the key mechanisms of atherosclerosis (proliferation, angiogenesis, apoptosis, and inflammation). Natriuretic peptides exert antihypertrophic and antifibrotic actions within the heart.There is a growing body of evidence that dysregulation of the NP system exists in CVD. Hypertension and HF are considered as NP deficiency state. During the evolution of HF the heart increases its production and release of ANP and BNP in order to compensate the increased water retention. Elevated circulating levels of such hormones have been associated with worsening of HF and poor prognosis. Recent studies have reported that in patients with congestive HF and high plasma BNP levels there is actually a lack of mature BNP. Studies have confirmed that altered processing of BNP occurs in HF and hence a relative deficiency of this protective hormone. The presence of shorter, less biologically active precursors and multiple degraded forms of BNP was also demonstrated. These data explain the blunting of the expected physiological responses to apparently high levels of BNP. Patients with advanced HF may actually be in a state of NP deficiency.Similar to HF, patients with essential hypertension may also have NP deficiency state. Studies suggested that a deficiency of bioactive BNP may be present in the early stages of hypertension thus favoring its progression. It was revealed that BNP system was not activated and ANP system was lower in pre-hypertensives than in normotensive subjects. Altered processing pathway of pro-BNP to mature BNP also occurs in hypertension. This impaired processing of the NP may result in reduced blood pressure-lowering effects of NP and leads to hypertension progression, more severe CVD and overt HF. Besides single-nucleotide polymorphisms of the ANP and BNP gene as well as the NP clearance receptor have been identified.In summary there is the existence of a deficiency state of biologically active cardiac NP in hypertension and HF. As a result of their cardiovascular properties NP are currently viewed as active players in the process of cardiovascular remodeling and in the natural history of hypertension and HF. Manipulation of this system is a logical pursuit and represents a new therapeutic opportunity for CVD. Current NP-augmenting strategies include the design of a number of synthetic NP and inhibition of neprilysin.A key component of the NP system is the NEP (neprilysin). This membrane-bound metallopeptidase is widely expressed, but is most abundant in the kidney. Neprilysin serves as the principal mechanism for enzymatic removal of the native NPs with susceptibility to degradation greatest for CNP>ANP>BNP. Importantly, many other substrates for neprilysin exist, some of them with opposing physiological actions. These include endothelin-1, kinin peptides, opioid peptides, substance P, amyloid beta protein, gastrin. Neprilysin also hydrolyzes angiotensin-I to angiotensin-(1-7). Inhibition of NEP (NEPi) has been advanced as a potential therapeutic modality. NEP inhibition alone leads to an increase in circulating levels of both vasodilators as well as vasoconstrictors. Neutral endopeptidase's ability to degrade multiple substrates means that the sole NEPi yields broader effects than anticipated and explains why NEPi is best combined with the inhibition of other vasoactive compounds. Angiotensin receptor blockers (ARB) do not disrupt bradykinin metabolism as much as ACE-inhibitors, and some patients with ACE-inhibitor-associated angioedema can be switched over to an ARB without the occurrence of angioedema. A novel class of drugs that combines the actions of NEP inhibitors and ARB, known as angiotensin receptor blockade with neutral endopeptidase inhibition (ARNi) was developed. LCZ696 is the first compound of this category. Novel ARNi-based therapeutic strategies are expected contribute to optimize control of CVD and of their outcomes.