Natriuretic peptides and cardiovascular damage in the metabolic syndrome. Molecular mechanisms and clinical implications

Natriuretic peptides are endogenous antagonists of vasoconstrictor and salt- and water-retaining systems in the body's defence against blood pressure elevation and plasma volume expansion, through direct vasodilator, diuretic and natriuretic properties. In addition, natriuretic peptides may play a role in the modulation of the molecular mechanisms involved in metabolic regulation and cardiovascular remodelling. The metabolic syndrome is characterized by visceral obesity, hyperlipidaemia, vascular inflammation and hypertension, which are linked by peripheral insulin resistance. Increased visceral adiposity may contribute to the reduction in the circulating levels of natriuretic peptides. The dysregulation of neurohormonal systems, including the renin-angiotensin and the natriuretic peptide systems, may in turn contribute to the development of insulin resistance in dysmetabolic patients. In obese subjects with the metabolic syndrome, reduced levels of natriuretic peptides may be involved in the development of hypertension, vascular inflammation and cardio vascular remodelling, and this may predispose to the development of cardiovascular disease. The present review summarizes the regulation and function of the natriuretic peptide system in obese patients with the metabolic syndrome and the involvement of altered bioactive levels of natriuretic peptides in the pathophysiology of cardiovascular disease in patients with metabolic abnormalities

The Natriuretic Peptide System: A Single Entity, Pleiotropic Effects

In the modern scientific landscape, natriuretic peptides are a complex and interesting network of molecules playing pleiotropic effects on many organs and tissues, ensuring the maintenance of homeostasis mainly in the cardiovascular system and regulating the water-salt balance. The characterization of their receptors, the understanding of the molecular mechanisms through which they exert their action, and the discovery of new peptides in the last period have made it possible to increasingly feature the physiological and pathophysiological role of the members of this family, also allowing to hypothesize the possible settings for using these molecules for therapeutic purposes. This literature review traces the history of the discovery and characterization of the key players among the natriuretic peptides, the scientific trials performed to ascertain their physiological role, and the applications of this knowledge in the clinical field, leaving a glimpse of new and exciting possibilities for their use in the treatment of diseases

Natriuretic peptides and cardio-renal disease

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Physiology of the endocrine, cardiorespiratory and nervous systems in pinnipeds: Integrative approach and biomedical considerations

Thesis (Ph.D.) University of Alaska Fairbanks, 1997This thesis explored several aspects of the hormonal and cardiovascular physiology in pinnipeds (seals and sea lions). Plasma concentrations of the vasoactive hormones angiotensin II (Ang II), arginine vasopressin (AVP, the antidiuretic hormone) and atrial natriuretic peptide (ANP) were studied in six species of seals and sea lions. Resting levels of AVP, ANP and Ang II in these pinnipeds were similar to those reported for other vertebrate species, including humans. Age-related differences were found in the concentrations of these hormones in seals and sea lions. Geographic differences in hormone concentrations were found in Steller sea lions and harbor seals. To address the endocrine and cardiovascular responses to breath-holding (apnea) in marine mammals, heart rates and plasma levels of Ang II, AVP and ANP were studied in Weddell seal (Leptonychotes weddellii) and northern elephant seal (Mirounga angustirostris) pups during periods of spontaneous breathing (eupnea) and apnea. Ang II, AVP, and ANP, as well as the autonomic nervous system, were found to contribute differently to the control of heart rate in seal pups, depending whether the respiratory system was in eupnea or apnea. Because of changes in seals of different ages, it appeared that the integration of cardiorespiratory and hormonal function is not fully mature at birth, but develops post-natally, probably simultaneously to the development of diving behavior. These studies also suggested that the factors affecting cardiorespiratory function, including hormones, may differ by species. Plasma concentrations of AVP, ANP and Ang II were measured during food limitation and fasting in captive Steller sea lions (Eumetopias jubatus) and compared to levels in free-ranging conspecifics. The results suggest that Steller sea lions have a remarkable capacity to maintain hydrosmotic and endocrine balance during short-term food limitation and fasting. Hormonal studies did not provide conclusive evidence that Steller sea lions in Alaskan waters are currently affected by long-term food limitation

Central nitrergic system regulation of neuroendocrine secretion, fluid intake and blood pressure induced by angiotensin-II

<p>Abstract</p> <p>Background</p> <p>Nitric oxide (NO) synthesis has been described in several circumventricular and hypothalamic structures in the central nervous system that are implicated in mediating central angiotensin-II (ANG-II) actions during water deprivation and hypovolemia. Neuroendocrine and cardiovascular responses, drinking behavior, and urinary excretions were examined following central angiotensinergic stimulation in awake freely-moving rats pretreated with intracerebroventricular injections of Nω-nitro-L-arginine methyl ester (L-NAME, 40 μg), an inhibitor of NO synthase, and L-arginine (20 ug), a precursor of NO.</p> <p>Results</p> <p>Injections of L-NAME or ANG-II produced an increase in plasma vasopressin (VP), oxytocin (OT) and atrial natriuretic peptide (ANP) levels, an increase in water and sodium intake, mean arterial blood pressure and sodium excretion, and a reduction of urinary volume. L-NAME pretreatment enhanced the ANG-II response, while L-arginine attenuated VP and OT release, thirst, appetite for sodium, antidiuresis, and natriuresis, as well as pressor responses induced by ANG-II.</p> <p>Discussion and conclusion</p> <p>Thus, the central nitrergic system participates in the angiotensinergic responses evoked by water deprivation and hypovolemia to refrain neurohypophysial secretion, hydromineral balance, and blood pressure homeostasis.</p

A Cross-Talk between the Renin-Angiotensin and Adrenergic Systems in Cardiovascular Health and Disease

It is well accepted that a number of cardiovascular (CV) and renal diseases are characterized by the long-term activation of both the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS), which also contribute to the pathophysiology of structural and functional CV abnormalities as well as to the final clinical outcome. Moreover, there is a growing body of conclusive evidence that these systems do not operate independently, but interact at different levels throughout the CV system. The mediation of renin release from juxtaglomerular epithelioid (JGE) cells in kidney by SNS is well established and accepted. On the other hand, in recent years it became evident that RAS, by its main effect or angiotensin II (Ang II), induces SNS activity in various organs and tissues. Thus, there is a growing effort to clarify pathophysiological mechanisms of interaction and a more evident mutual potentiation of these two systems in different pathological states. Since it became evident that a high salt (HS) intake, which is a major risk factor for hypertension development, has a deleterious impact on vascular and endothelial functions (even in the absence of blood pressure changes), it became necessary to investigate and clarify the effect of HS loading on major regulating systems—RAS and SNS—precisely in healthy individuals. The present review aimed to summarize the interactions between the RAS and SNS in health and diseases (e.g. cardiovascular, renal), with a special focus on these two systems’ interaction during HS intake in a healthy normotensive population

Effect of the renal natriuretic peptide, ularitide, alone or combined with Vasopeptidase inhibitor, Omapatrilat, on experimental volume overloadinduced congestive heart failure in rats (Ularitide/ Omapatrilat in Congestive Heart Failure)

Introduction: Ularitide is a synthetic form of renally derived natriuretic peptide (NP), urodilatin. Omapatrilat (OMA) is a Vasopeptidase inhibitor (VPI), acting by dual inhibition of both angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP), which degrades the NPs. Ularitide and OMA underwent evaluation for the management of hypertension and heart failure (HF).Aim: This study aimed to address the effect of ularitide and OMA in aortocaval fistula (ACF) – induced congestive heart failure (CHF) in rats under various conditions of compensation (of clinical severity).Experimental protocol: Volume-overload CHF was induced in male albino rats by creating an infrarenal ACF. One week after fistula induction, ACF rats were randomized to compensated (Com) and decompensated (Decom) ACF groups and each further subdivided into ACF, ularitide and OMA/ularitide treated ACF groups. Sham was used as control. All treatment protocols were started one week after infrarenal ACF induction and continued for further two weeks. Three weeks after shunt induction, all animals were underwent assessment of cardiorenal and humoral functions. Renal outcome was measured by glomerular filtration rate (GFR), fractional excretion of sodium (FNa), absolute urinary sodium excretion (UNaV), urine volume, plasma cystin C level and urinary cyclic 30, 50-guanosine monophosphate (cGMP). The humoral function was assessed by plasma renin activity (PRA), angiotensin II (Ang II), Aldosterone, and cGMP. Cardiac outcome was assessed by plasma atrial natriuretic peptide (ANP), N-terminal pro–brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) while total and relative heart, lung and liver weights were recorded.Results: Induction of AC shunt was associated with deteriorated renal and excretory functions, activation of renin angiotensin aldosterone system (RAAS), elevated ANP with renal resistance to ANP, (NT-proBNP) and (cTnT), pulmonary and systemic congestion and marked cardiac hypertrophy. These changes were exacerbated in Decom-ACF. Ularitide treatment of ACF rats was associated with natriuresis, diuresis, enhanced GFR with RAAS inhibition. This effect was evident in Com-ACF, maximized by OMA but attenuated in Decom-ACF, restored by OMA treatment. Ularitide/OMA treatment had antihypertrophic, decongestant effect with preserved renal function, resulted in a marked improvement of animals’ survival.Conclusion: OMA potentiates the cardiorenal actions of ularitide in ACF-induced Com CHF and restoring its effect in Decom ACF, by simultaneously inhibiting ACE and NEP. OMA and ularitide could provide an effective therapeutic strategy for CHF.Keywords: Congestive heart failure; Aorto-caval fistula; Ularitide; Omapatrilat; Renin-angiotensin system; Vasopeptidase inhibitio

Studies on the release of endogenous renal dopamine and assessment of the renal dopamine prodrug gludopa in normal man

The diverse experimental approaches into the actions of dopamine in the periphery have demonstrated the amine to possess various interesting features. By activation of distinct receptors it is capable of producing systemic and renal vasodilatation and of modulating sympatho-adrenal outflow. By a combination of haemodynamic and direct tubular effects it is actively natriuretic, and influences hormonal release from the kidney and adrenal cortex.A physiological function in the kidney is strongly suggested by the prod¬ uction and excretion of large amounts of free dopamine, by the close relation¬ ship between dopamine excretion and sodium output in the urine, and by the characterisation of a widespread distribution of dopamine receptors. Such observations do not however, prove that endogenous dopamine has physiological So 3 significance and more compelling evidence accrues when an inhibitor of dopamine can be shown to alter some parameter of normal function. Such studies have been approached using either dopamine receptor antagonists or dopa decarboxylase inhibitors to block dopamine synthesis, and a number of animal models have been utilised, notably in man, dog and rat.It can be concluded for the present studies and from other reported work that dopamine exerts independent action in the kidney, without the requisite mediation of other hormonal, neural or physical factors. More likely is a system of parallel influences, including dopamine, interacting in an array of negative and positive feedback loops, forming a highly complex control mechanism which maintains homeostasis and is able to respond rapidly to changes in the local and wider environment

Efferent Pathways in Sodium Overload-Induced Renal Vasodilation in Rats

Hypernatremia stimulates the secretion of oxytocin (OT), but the physiological role of OT remains unclear. the present study sought to determine the involvement of OT and renal nerves in the renal responses to an intravenous infusion of hypertonic saline. Male Wistar rats (280-350 g) were anesthetized with sodium thiopental (40 mg. kg(-1), i.v.). A bladder cannula was implanted for collection of urine. Animals were also instrumented for measurement of mean arterial pressure (MAP) and renal blood flow (RBF). Renal vascular conductance (RVC) was calculated as the ratio of RBF by MAP. in anesthetized rats (n = 6), OT infusion (0.03 mu g . kg(-1), i.v.) induced renal vasodilation. Consistent with this result, ex vivo experiments demonstrated that OT caused renal artery relaxation. Blockade of OT receptors (OXTR) reduced these responses to OT, indicating a direct effect of this peptide on OXTR on this artery. Hypertonic saline (3 M NaCl, 1.8 ml . kg(-1) b.wt., i.v.) was infused over 60 s. in sham rats (n = 6), hypertonic saline induced renal vasodilation. the OXTR antagonist (AT; atosiban, 40 mu g . kg(-1) . h(-1), i.v.; n = 7) and renal denervation (RX) reduced the renal vasodilation induced by hypernatremia. the combination of atosiban and renal denervation (RX+AT; n = 7) completely abolished the renal vasodilation induced by sodium overload. Intact rats excreted 51% of the injected sodium within 90 min. Natriuresis was slightly blunted by atosiban and renal denervation (42% and 39% of load, respectively), whereas atosiban with renal denervation reduced sodium excretion to 16% of the load. These results suggest that OT and renal nerves are involved in renal vasodilation and natriuresis induced by acute plasma hypernatremia.Fundacao de Amparo a Pesquisa do Estado de Goias (FAPEG)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Fed Goias, Ctr Neurosci & Cardiovasc Physiol, Inst Biol Sci, Dept Physiol Sci, Goiania, Go, BrazilUniv Fed Uberlandia, Fac Phys Educ, Inst Biol Sci, BR-38400 Uberlandia, MG, BrazilUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilUniv Fed Goias, Inst Biol Sci, Mol Biol Lab, Goiania, Go, BrazilUniv Fed Goias, Inst Biol Sci, Dept Biochem & Mol Biol, Goiania, Go, BrazilUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilFundacao de Amparo a Pesquisa do Estado de Goias (FAPEG): 2012/0055431086Fundacao de Amparo a Pesquisa do Estado de Goias (FAPEG): 2009/10267000352CNPq: 477832/2010-5CNPq: 483411/2012-4Web of Scienc