INTRODUCTION:

Natriuretic peptide is defined as type of peptide which is responsible to promote natriuresis process (means elevation in sodium excretion via kidney)^1,2, it includes five subclasses: (1) Atrial natriuretic peptide (ANP): also known as atrial natriuretic factor (ANF), this peptide is produced from cardiac atria^3,4, the essential job for this peptide is to elevate the renal sodium excretion which is resulted with decreasing of expanded extracellular fluid (ECF) volume. There are many conditions that activate production of ANP, for example; when atrial volume receptors stretch the walls of atria, the existence of Endothelin, hypernatremia^5,6, and increase stimulation of sympathetic β-adrenoceptors.

ANP has different physiological functions, in renal: it increases natriuresis process via certain mechanisms, it works to increase glomerular filtration rate (GFR), or it can interact with NKCC2 via guanosine 3',5'-cyclic monophosphate (cGMP) dependent phosphorylation of

ENaC and result in lowering sodium reabsorption in two areas: the thick ascending limb and cortical collecting duct, or it can prevent secretion of angiotensin and aldosterone by inhibiting renin enzyme.^7,8 In cardiac: works as inhibitor for hypertrophy in case of heart failure and fibrosis, this occurred by inactivation calcium influx which is happened via norepinephrine.^9,10 In Adipose tissue: works to release free fatty acids, also increase releasing of serum glycerol and nonesterified fatty acids by i.v. infusion of ANP, as well as act to elevate intracellular cGMP that is responsible of phosphorylation process for hormone-sensitive lipase and perilipin A, this occurred by action of cGMP-dependent protein kinase-I (cGK-I).In immune system: it acts to regulate innate immunity and modulate production of pro-inflammatory markers.^11,12 (2) Brain natriuretic peptide (BNP): also recognized as B-type natriuretic peptide, the stimulator of production this peptide in heart ventricles is the elevation in ventricular blood volume. BNP has different physiological functions, in renal: inactivation renin–angiotensin–aldosterone system. In Adrenal: decreasing aldosterone production zona glomerulosa which is in adrenal cortex. In cardiac: prevents maladaptive hypertrophy. (3) Natriuretic peptide precursor C (CNP) which is a human protein encoded by the NPPC gene^13-15, this protein works as diuretic, and vasodilator agent, incorporates in body fluid homeostasis. (4) Dendroaspis natriuretic peptide (DNP) and (5) Urodilatin.

The degradation of natriuretic peptides is done by action of neutral endopeptidase, which is exists in lungs, kidneys and brain.¹⁶

EXPERIMENTAL EVIDENCES:

In a study was carried out in 1990 to investigate the renal and endocrine effects when prolonging ANP in patients with heart failure , they found an increment by two folds in urine flow and four folds in excretion in sodium.¹⁶ Other study was performed to explain the hemodynamic, renal and endocrine effects of atrial natriuretic peptide infusion in severe heart failure, they concluded that there was an elevation in cardiac output with lowering in pulmonary capillary wedge pressure, serum renin and pulmonary vascular resistance.^17,18 A third one is done in order to study the hemodynamic, renal and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure.^19,20 Also there is a relationship among plasma aldosterone and ANP production, when aldosterone is decreased; the ANP production will be increased. Several researches indicated that BNP has different effects compared to ANP, it increases heart congestion.²¹ Using the therapeutic approach that blocks natriuretic peptides in chronic heart failure patients is reduced due to painful administration, where they are injected i.v. infusion continuously. So because of previous reason, it is necessary to develop an orally dosage form that prevents metabolism rout of endogenously natriuretic peptides.

CHEMISTRY:

The clinical studies suggested two prodrugs (candoxatril and ecadotril) which they are selective inhibitors of NEP for HF patient. Candoxatrilat is the active form of candoxatril that activated in liver, and S-thiorphan is the active form of ecadotril.²¹

PHRMACOLOGICAL CONSIDERATIONS:

The clinical trials are limited for ecadotril compared to candoxatril that has several trials. When infused candoxatril in mild heart failure patient, it is achieved diuresis and naturesis effects.²² In case of severe heart failure, it is recommended to reducing candoxatril dosage, because of insufficient renal perfusion.²³ In a research was founded to make a comparison of the short-term effects of candoxatril, and frusemide in the treatment of patients with chronic heart failure, in a double-blinded clinical trial for mild HF patients, it is used monotherapy which is an orally candoxatril 200-400mg, and the combined therapy is 20mg of frusemide, but these patients had advised to stop taking diuretic medications two weeks before start this trials, this because the diuretic effect via monotherapy of candoxatril as well as natriuresis, and kaluresis. Utilizing NEP inhibitors will lower systolic blood pressure and does not affect in heart rate and diastolic blood pressure. ^24,25 The trial used a negative prognostic factor for chronic HF which is the serum renin that exhibits an increment by two folds after first administration of frusemide, but the treatment with candoxatril did not show any changes in plasma renin levels. by using different techniques to prognoses heart failure development, such as Treadmill exercise capacity which is elevated by 12 ± 3.5 sec after administered candoxatril (200mg) twice daily, and 35 ± 3.1 sec after administered candoxatril (400mg) twice daily for nine days. Patients who treated by frusemide, the exercise capacity period is lowered by 30 ± 2.6 secs.²⁴ Another clinical trial was performed to the same previous patients, and they exhibited a reduction by 40% in pulmonary capillary wedge pressure by using candoxatril and 15% by using frusemide.²⁶ A randomized trial of ecadotril versus placebo in patients with mild to moderate heart failure was shown to be disappointingly negative clinical efficacy.^27,28 A research titled with “Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions”, and resulted when HF patient administered ecadotril, this will increase plasma ANP and reduce plasma renin as well as pulmonary capillary wedge pressure.²⁹

DISCUSSION:

The first approach of treatment heart failure is to prescribe diuretic medications plus antihypertensive agents as ACE inhibitors. In a clinical trial was carried out to assess the symptoms of moderate HF patients when increasing doses of diuretics and captopril, when suggested them to administer high doses of frusemide (120 mg) they are gotten well health and enhanced life quality.^30,31 A clinical research was titled as “. Untreated heart failure: clinical and neuroendocrine effects of introducing diuretics” had shown there was a reduction in exercise capacity when administered low doses to treat mild HF³². There are two interpreters for adverse effects that caused via diuretics in mild HF patients which are: the activation of the renin-angiotensin pathway, and reduction in cardiac output, the adverse effects that occurred in severe HF can be managed by results of taking diuretics, such as: reduction in congestion as well as lowering of fluid overload. by continuous studying on the behavior of natriuretic peptides in different heart disorders, it is documented that there is an elevation in plasma natriuretic peptides in case of left ventricular dysfunction, this will block stimulation of renin-angiotensin-aldosterone system (RAAS) as well as increase in salt and water retention.³³

CAVEATS:

The inhibition of RAAS system acts as a special advantage in administration NEP inhibitors compared to conventional diuretics to treat heart diseases. In case of mild heart failure, these drugs alter haemodynamic behavior in a better way compared to diuretics. The action of NEP inhibitors is related to the secretion rate of endogenous natriuretic peptides, so these medications will be most efficacious in patients with high peptide secretion. Targeted patients of diuresis are patients with high left ventricular preload because of high peptide secretion. Any condition (such as in dehydration) that may lower preload and resulted in reduce secretion of natriuretic peptide and their diuretic impaction, this help to prevent dehydration to be developed.^34,35

CONCLUSION:

Drug of choice in case of hypertension, heart failure, or diabetes with microalbuminuria is administration of ACE inhibitors, which prevent actions of Ang II and aldosterone. Another pharmacological group (vasopeptidase inhibitors (VPIs)) hat has an additional advantage which is enhancement of the NPS; VPIs are more effective in patients with cardio-renal disease and diabetes, under clinical trials, omapatrilat that inhibits both NEP and ACE, it was never marketed due to large limitation of chronic renal damage compared to ACE inhibitors.

ACKNOWLEDGEMENT:

The author is grateful to the Middle East University, Amman, Jordan, for the financial support granted to cover the publication fee of this research article.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 10.10.2020 Modified on 30.11.2020

Research J. Pharm. and Tech. 2021; 14(8):4491-4494.

DOI: 10.52711/0974-360X.2021.00780