A new long-acting ANP with unique therapeutic effects to treat hypertension and hypertensive heart failure
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Systemic hypertension is a common characteristic in acute heart failure (HF). This increasingly common phenotype is frequently associated with renal dysfunction and requires renal enhancing therapies. In a canine model of HF and acute hypertension we defined the cardiorenal actions of M-atrial natriuretic peptide (MANP), a novel particulate guanylyl cyclase A receptor activator (pGC-A) developed at the Mayo Clinic, and nitroglycerin (NTG), a soluble guanylyl cyclase (sGC) activator. Compared to native ANP, MANP has more sustained renal enhancing, blood pressure lowering and aldosterone inhibiting action.
Based on the expression of the pGC-A receptor in the glomerulus, renal tubule and adrenal gland, compared to the more widespread expression of sGC in the renal vasculature, we hypothesized that MANP would have a more robust effect upon the glomerular filtration rate (GFR) and natriuretic actions and with greater aldosterone suppressing effects than sGC activation with NTG. To test these hypotheses, we used a canine model of combined HF and hypertension. Specifically, HF was induced by chronic (10 days) rapid right ventricular pacing (180 bmp), while hypertension was induced by continuous angiotensin II infusion (on day 11). We than characterized the cardiorenal and humoral actions of intravenous MANP (n=7), NTG (n=7), and vehicle (n=7) infusion.
The natriuretic peptides, specifically atrial natriuretic peptide (ANP), are increasingly recognized to play a fundamental role in blood pressure (BP) regulation. This role in BP regulation reflects the pluripotent cardiorenal actions of ANP, which include diuresis, enhancement of renal blood flow and glomerular filtration rate, systemic vasodilatation, suppression of aldosterone, and inhibition of the sympathetic nervous system. These actions of ANP, in addition to recent human studies demonstrating an association of higher plasma ANP with lower risk of hypertension, support the development of an ANP-based therapy for hypertension. M-ANP is a novel ANP-based peptide that is resistant to proteolytic degradation and possesses greater BP-lowering, renal function-enhancing, and aldosterone-suppressing properties than native ANP. In an animal model of hypertension, M-ANP lowers BP via multiple mechanisms, including vasodilatation, diuresis, and inhibition of aldosterone. Importantly, M-ANP enhances both glomerular filtration rate and renal blood flow despite reductions in BP. The pluripotent BP-lowering actions and concomitant enhancement of renal function associated with M-ANP are highly attractive characteristics for an antihypertensive agent and underscore the therapeutic potential of M-ANP. M-ANP currently is heading into clinical testing, which may advance this novel strategy for human hypertension.
M-atrial natriuretic peptide (ANP; M-ANP) is a novel next generation 40 amino acid peptide based on ANP, which is highly resistant to enzymatic degradation and has greater and more sustained beneficial actions compared with ANP. The current study was designed to advance our understanding of the therapeutic potential of M-ANP in a canine model of acute angiotensin II-induced hypertension with elevated cardiac filling pressures and aldosterone activation. We compare M-ANP with vehicle and equimolar human B-type natriuretic peptide, which possesses the most potent in vivo actions of the native natriuretic peptides. M-ANP significantly lowered mean arterial pressure and systemic vascular resistance. Importantly, despite a reduction in blood pressure, renal function was enhanced with significant increases in renal blood flow, glomerular filtration rate, diuresis, and natriuresis after M-ANP infusion. Although angiotensin II induced an acute increase in pulmonary capillary wedge pressure, M-ANP significantly lowered pulmonary capillary wedge pressure, pulmonary artery pressure, and right atrial pressure. Further, M-ANP significantly suppressed angiotensin II-induced activation of aldosterone. These cardiovascular and renal enhancing actions of M-ANP were accompanied by significant increases in plasma and urinary cGMP, the second messenger molecule of the natriuretic peptide system. When compared with human B-type natriuretic peptide, M-ANP had comparable cardiovascular actions but resulted in a greater natriuretic effect. These results suggest that M-ANP, which is more potent than ANP in normal canines, has potent blood pressure lowering and renal enhancing properties and may, therefore, serve as an ANP based therapeutic for acute hypertension.