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. 2014 Jan 2;3(1):e000206.
doi: 10.1161/JAHA.113.000206.

M-atrial natriuretic peptide and nitroglycerin in a canine model of experimental acute hypertensive heart failure: differential actions of 2 cGMP activating therapeutics

Paul M McKie  1 , Alessandro Cataliotti, Tomoko Ichiki, S Jeson Sangaralingham, Horng H Chen, John C Burnett Jr
Affiliations

M-atrial natriuretic peptide and nitroglycerin in a canine model of experimental acute hypertensive heart failure: differential actions of 2 cGMP activating therapeutics

Paul M McKie et al. J Am Heart Assoc. .

Abstract

Background: Systemic hypertension is a common characteristic in acute heart failure (HF). This increasingly recognized phenotype is commonly associated with renal dysfunction and there is an unmet need for renal enhancing therapies. In a canine model of HF and acute vasoconstrictive hypertension we characterized and compared the cardiorenal actions of M-atrial natriuretic peptide (M-ANP), a novel particulate guanylyl cyclase (pGC) activator, and nitroglycerin, a soluble guanylyl cyclase (sGC) activator.

Methods and results: HF was induced by rapid RV pacing (180 beats per minute) for 10 days. On day 11, hypertension was induced by continuous angiotensin II infusion. We characterized the cardiorenal and humoral actions prior to, during, and following intravenous M-ANP (n=7), nitroglycerin (n=7), and vehicle (n=7) infusion. Mean arterial pressure (MAP) was reduced by M-ANP (139 ± 4 to 118 ± 3 mm Hg, P<0.05) and nitroglycerin (137 ± 3 to 116 ± 4 mm Hg, P<0.05); similar findings were recorded for pulmonary wedge pressure (PCWP) with M-ANP (12 ± 2 to 6 ± 2 mm Hg, P<0.05) and nitroglycerin (12 ± 1 to 6 ± 1 mm Hg, P<0.05). M-ANP enhanced renal function with significant increases (P<0.05) in glomerular filtration rate (38 ± 4 to 53 ± 5 mL/min), renal blood flow (132 ± 18 to 236 ± 23 mL/min), and natriuresis (11 ± 4 to 689 ± 37 mEq/min) and also inhibited aldosterone activation (32 ± 3 to 23 ± 2 ng/dL, P<0.05), whereas nitroglycerin had no significant (P>0.05) effects on these renal parameters or aldosterone activation.

Conclusions: Our results advance the differential cardiorenal actions of pGC (M-ANP) and sGC (nitroglycerin) mediated cGMP activation. These distinct renal and aldosterone modulating actions make M-ANP an attractive therapeutic for HF with concomitant hypertension, where renal protection is a key therapeutic goal.

Keywords: cyclic GMP; heart failure; hypertension; natriuretic peptide; nitroglycerin.

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Figures

Figure 1.
Figure 1.
Mean arterial pressure (MAP) and mean pulmonary capillary wedge pressure (PCWP) during mild LV dysfunction (MLVD) clearance; MLVD and angiotensin II‐induced hypertension (MLVD+HTN); M‐ANP, NTG, or vehicle infusion; and 30, 60, 90, and 120 minutes after M‐ANP, NTG, or vehicle infusion. *P<0.05 vs MLVD and †P<0.05 vs MLVD+HTN, 2‐way ANOVA with pairwise comparison of individual timepoints within groups using the Tukey HSD method. ‡P<0.05 for M‐ANP vs vehicle at a specific time point, 2‐way ANOVA with Bonferroni posttests. P interaction <0.05 for the main effects of treatment and time between M‐ANP vs NTG for MAP and PCWP, 2‐way ANOVA. ANG II indicates angiotensin II; ANOVA, analysis of variance; HSD, honestly significant difference; M‐ANP, M‐atrial natriuretic peptide; NTG, nitroglycerin.
Figure 2.
Figure 2.
Renal blood flow, glomerular filtration rate, urine volume, and urinary sodium excretion during mild LV dysfunction (MLVD) clearance; MLVD and angiotensin II‐induced hypertension (MLVD+HTN); M‐ANP, NTG, or vehicle infusion; and 30, 60, 90, and 120 minutes after M‐ANP, NTG, or vehicle infusion. *P<0.05 vs MLVD and †P<0.05 vs MLVD+HTN, 2‐way ANOVA with pairwise comparison of individual timepoints within groups using the Tukey HSD method. ‡P<0.05 vs NTG at a specific time point, 2‐way ANOVA with Bonferroni posttests. P interaction <0.05 for the main effects of treatment and time between M‐ANP vs NTG for renal blood flow, glomerular filtration rate, urine volume, and urinary sodium, 2‐way ANOVA. ANG II indicates angiotensin II; ANOVA, analysis of variance; M‐ANP, M‐atrial natriuretic peptide; NTG, nitroglycerin.
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