First-in-Human Study of MANP: A Novel ANP (Atrial Natriuretic Peptide) Analog in Human Hypertension

Hypertension ◽  
2021 ◽  
Author(s):  
Horng H. Chen ◽  
Siu-Hin Wan ◽  
Seethalakshmi R. Iyer ◽  
Valentina Cannone ◽  
S. Jeson Sangaralingham ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Human Study ◽  
Antihypertensive Agents ◽  
Blood Pressure Lowering ◽  
Human Hypertension ◽  
Peptide Analog ◽  
Pressure Lowering ◽  
Atrial Natriuretic

M-atrial natriuretic peptide (MANP) is a novel ANP (atrial natriuretic peptide) analog engineered to be an innovative particulate GC-A (guanylyl cyclase A) receptor activator. The rationale for its design was to develop a best-in-class GC-A activator with enhanced cGMP activating, natriuretic, aldosterone-suppressing, and blood pressure–lowering actions, compared with endogenous ANP, for the treatment of hypertension. Here, we report the first-in-human study on the safety, tolerability, neurohumoral, renal, and blood pressure–lowering properties of MANP in hypertension subjects. This was an open-label sequential single ascending dose design in which all subjects stopped all antihypertensive agents for 14 days before receiving a single subcutaneous injection of MANP. MANP was safe, well tolerated, activated cGMP, induced natriuresis, reduced aldosterone, and decreased blood pressure at or below the maximal tolerated dose. Thus, MANP has a favorable safety profile and produced expected pharmacological effects in human hypertension. Our results support further investigations of MANP as a potential future blood pressure–lowering, natriuretic and aldosterone-suppressing drug for hypertension especially resistant hypertension.

Atrial natriuretic peptide and adaptation of sodium urinary excretion in patients with chronic renal failure

1988 ◽  
Vol 75 (3) ◽  
pp. 243-249 ◽  
Author(s):  
Stanislas Czekalski ◽  
Catherine Michel ◽  
Jean-Claude Dussaule ◽  
Philippe Touraine ◽  
Francoise Mignon ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Failure ◽  
Chronic Renal Failure ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Sodium Excretion ◽  
Mean Blood Pressure ◽  
Group Iii ◽  
Sodium Load ◽  
Atrial Natriuretic

1. In order to examine the potential role of endogenous atrial natriuretic peptide (ANP) in modulating the increased sodium excretion per nephron in chronic renal failure, we studied healthy subjects with normal renal function (group I) and patients with moderate (group II) or severe chronic renal failure (group III) before, during and after administration of an intravenous sodium load. All subjects had been on a controlled diet containing 120 mmol of sodium per day for 5 days before the study. 2. Under basal conditions, plasma ANP and fractional excretion of sodium (FENa) were highest in group III. Both parameters increased in response to the sodium load in the three groups studied (P < 0.001). Changes with time differed from group to group (P < 0.05), the more marked response for both parameters being observed in group III. After adjustment with respect to plasma ANP (analysis of covariance), FENa was no longer modified in response to the sodium load, whereas adjustment of FENa with respect to mean blood pressure was without consequence on the significance of its change with time. This demonstrates that plasma ANP, but not mean blood pressure, represents the main factor producing variation in FENa during and after the sodium load. 3. These results suggest an important role for plasma ANP in promoting adaptation of short-term sodium excretion in response to an acute sodium load in patients with chronic renal failure who ingest a normal sodium intake.

Abstract 181: Overexpression of Arachidonic Acid Cytochrome P450 Expoxygenases Prevents the Development of High Blood Pressure via Enhancing Atrial Natriuretic Peptide in Spontaneously Hypertensive Rats

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Dao Wen Wang ◽  
Bin Xiao ◽  
Yong Wang ◽  
Xiaojun Xiong ◽  
Darryl C Zeldin
Keyword(s):  
Blood Pressure ◽  
Cytochrome P450 ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Spontaneously Hypertensive Rats ◽  
Hypotensive Effect ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Atrial Natriuretic

Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have potent vasodilatory and diuretic feature, and therefore potentially hypotensive effect. No in vivo studies, however, were performed to support it. This study investigated the hypothesis via overexpressing CYP epoxygense genes in spontaneously hypertensive rats (SHR). Recombinant adeno-associated virus vector (rAAV) was utilized to mediate long-term transfection of CYP2J2 and CYP2C11 genes, respectively, in adult SHR, and animal systolic blood pressure (SBP) was monitored using arterial caudilis indirect manometric method. Results showed that at 2 months the urinary excretion of stable hydrolysis metabolic product of 14, 15-EE, 14–15-DHET increased by 11 and 8.7 folds in rAAV-2J2 and rAAV-2C11 groups, respectively, compared with AAV-GFP-treated rats. (2) SBP in 2J2- and 2C11-treated rats decreased from 175.0 ± 2.8mHg to 163.5 ± 5.8mmHg and 161.2 ± 6.1 mmHg, respectively, ( p <0.01) at month 2, and it is 165.0 ± 4.7 mmHg and 173.0 ± 12.8 mmHg at month 6 after gene injection (~30mmHg and ~23mmHg lowerer than that in control animals, respectively, p <0.001). (3) Before the rats were sacrificed, cardiac function tests with Pressure-Volume System showed that maximum intracardiac pressure was 202.1 ± 30.0 & 209.1 ± 17.1mmHg in two gene-treated rats, respectively, significantly lower than control (241.2 ± 18.2mmHg, p <0.01) and cardiac output in treatment rats were significantly higher than control (p<0.05). (4) Interestingly, atrial natriuretic peptide (ANP) mRNA were up-regulated 6–14 folds respectively in myocardium of 2J2 and 2C11 groups; furthermore, C-type receptor mRNA of ANP was increased in heart, lung, kidney and aorta. (5) in cultured atrial cells (HLB2G5), exogenous EETs stimulated ANP production. In conclusions, for first time our data indicates overexpression of CYP2J2 or CYP2C11 could prevent development of hypertension in SHR, improve cardiac functions, which may involve up-regulating ANP expression and its receptors in target tissues, which suppresses collagen deposition and cardiovascular remodeling.

Atrial Natriuretic Peptide: Regulator of Chronic Arterial Blood Pressure

Physiology ◽  
2000 ◽  
Vol 15 (3) ◽  
pp. 143-149 ◽  
Author(s):  
Luis Gabriel Melo ◽  
Stephen C. Pang ◽  
Uwe Ackermann
Keyword(s):  
Blood Pressure ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Salt Intake ◽  
Gene Knockout ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Arterial Blood ◽  
Gene Knockout Mouse ◽  
Atrial Natriuretic

Recent findings in atrial natriuretic peptide (ANP) transgenic and gene knockout mouse models uncovered a tonic vasodilatory effect of this hormone that contributes to chronic blood pressure homeostasis. With elevated salt intake, ANP-mediated antagonism of the renin-angiotensin system is essential for blood pressure constancy, suggesting that a deficiency in ANP activity may underlie the etiology of sodium-retaining disorders.

scholarly journals Emerging Drug Classes and Their Potential Use in Hypertension

Hypertension ◽  
2019 ◽  
Vol 74 (5) ◽  
pp. 1075-1083 ◽  
Author(s):  
Michel Azizi ◽  
Patrick Rossignol ◽  
Jean-Sébastien Hulot
Keyword(s):  
Blood Pressure ◽  
Antihypertensive Drugs ◽  
Generic Drugs ◽  
Antihypertensive Agents ◽  
Uncontrolled Hypertension ◽  
Blood Pressure Lowering ◽  
Receptor Antagonists ◽  
Drug Classes ◽  
Pressure Lowering ◽  
Potential Use

Despite the availability of multiple antihypertensive drugs targeting the different pathways implicated in its pathophysiology, hypertension remains poorly controlled worldwide, and its prevalence is increasing because of the aging of the population and the obesity epidemic. Although nonadherence to treatment contributes to uncontrolled hypertension, it is likely that not all the pathophysiological mechanisms are neutralized by the various classes of antihypertensive treatment currently available, and, the counter-regulatory mechanisms triggered by these treatments may decrease their blood pressure–lowering effect. The development of new antihypertensive drugs acting on new targets, with different modes of action, therefore, remains essential, to improve blood pressure control and reduce the residual burden of cardiovascular risks further. However, the difficulties encountered in the conception, development, costs, and delivery to the market of new classes of antihypertensive agents highlights the hurdles that must be overcome to release and to evaluate their long-term safety and efficacy for hypertension only, especially because of the market pressure of cheap generic drugs. New chemical entities with blood pressure–lowering efficacy are thus being developed more for heart failure or diabetic kidney disease, 2 diseases pathophysiologically associated with hypertension. These include dual angiotensin II receptor-neprilysin inhibitors, soluble guanylate cyclase stimulators, nonsteroidal dihydropyridine-based mineralocorticoid receptor antagonists, as well as sodium-glucose cotransporter 2 inhibitors. However, centrally acting aminopeptidase A inhibitors and endothelin receptor antagonists have a dedicated program of development for hypertension. All these emergent drug classes and their potential use in hypertension are reviewed here.

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