Cardiorenal Enhancing and Aldosterone Suppressing Actions of a Novel Designer Natriuretic Peptide in Experimental Hypertension with Ventricular Pressure Overload Paul M McKie, Alessandro Cataliotti, Guido Boerrigter, Horng C Chen, Fernando L Martin, and John C Burnett Jr Cardiorenal Research Laboratory, Division of Cardiovascular Diseases Mayo Clinic, Rochester, MN, United States Research supported by the National Institute of Health, Mayo Foundation, and the Sarnoff Cardiovascular Foundation CP1286268-2
Disclosures The Mayo Foundation holds a patent for.
Atrial Natriuretic Peptide ArgGly Gly Phe ANP Ser Leu Arg Arg Ser Met Ser Asp Cys Arg S S Ile Cys Asn SerPhe Gly Gly Arg Tyr AlaGln Ser Gly Leu N 2 H COOH First described member of the cardiac natriuretic peptide family Released in response to: myocardial stretch hormones (i.e. angiotensin) sympathetic nervous system Activates the GC-A receptor and leads to generation of the second messenger molecule cgmp Potter L et al. Endocrine Reviews 27 (1): 47-72, 2006
Pleiotropic Actions of ANP and Cardiorenal Homeostasis Kidney Adrenal gland Vessels Central nervous system glomerular filtration blood flow renin release collecting duct sodium reabsorption aldosterone synthesis and release salt and water appetite vasodilatation capillary permeability sympathetic activity Cataliotti A et al. Trends in Cardiovascular Medicine. 17(1):10-4, 2007
Common genetic variants associated with higher circulating ANP may contribute to lower BP and reduced risk of hypertension. Newton-Cheh C. Nat Genet. 2009;41:348-53
ArgGly Gly Phe Ser Leu Arg Arg Ser N 2 H Met Ser Asp Cys Arg S S Ile Cys Asn SerPhe Gly Gly Arg Tyr AlaGln Ser Gly Leu Arg ProThr Novel Mayo developed 40 amino acid natriuretic peptide Ala ArgArg Glu AspLys Gln GlyTrp Ala COOH 1 Dickey DM. J Biol Chem. 2009. 2 McKie PM. J Am Coll Cardiol. 2009;54:1024-32.
Control peptide (%) Degradation by NEP ANP Minutes Dickey et al. J Biol Chem 2009
mm Hg ANP vs in Normal Canines 150 140 MAP 130 120 110 100 BL or ANP McKie et al. JACC. 2009. ANP P<0.001 30 60 90 120 Post infusion (minutes) P<0.05 vs BL CP1304700-2
Objective and Hypothesis Determine the cardiorenal actions of in a large animal model of acute hypertension We hypothesized that would have potent blood pressure lowering, renal enhancing, and aldosterone suppressing properties in the presence of acute hypertension
Methods Studies were performed in anesthetized dogs Acute hypertension was induced by a continuous angiotensin II infusion (20 ng/kg/min) This model is characterized by: Increased pulmonary capillary wedge pressure Decreased cardiac output Reduction in renal blood flow Activation of aldosterone Intravenous (n=6) vs. (n=6)
Protocol or vehicle infusion (30 min) Post or vehicle infusion (120 minutes) Baseline ANG II or 30, 60, 90, 120 min Continuous Angiotensin II Infusion CP1202357-1
mm Hg Mean Arterial Pressure 170 160 150 140 130 120 110 Continuous ANG II infusion BL ANG II 30 60 90 120 or Post or Infusion (minutes) P<0.05 vs BL, P<0.05 vs ANG II, 1-way ANOVA with Bonferroni s multiple-comparison test.
mmhg Mean Arterial Pressure 170 160 150 140 130 120 110 BL ANG II or Continuous ANG II infusion 30 60 90 120 Post or Infusion (minutes) P<0.05 vs BL, P<0.05 vs ANG II, 1-way ANOVA with Bonferroni s multiple-comparison test.
mmhg PCWP 10 8 6 4 2 0 Continuous ANG II infusion BL ANG II 30 60 90 120 or Post or Infusion (minutes) P<0.05 vs BL, P<0.05 vs ANG II, 1-way ANOVA with Bonferroni s multiple-comparison test.
µeq/min Urinary Sodium Excretion 1,000 800 600 400 200 0 Continuous ANG II infusion BL ANG II 30 60 90 120 or Post or Infusion (minutes) P<0.05 vs BL, P<0.05 vs ANG II, 1-way ANOVA with Bonferroni s multiple-comparison test.
ml/min Glomerular Filtration Rate 70 60 50 40 30 20 10 0 Continuous ANG II infusion BL ANG II 30 60 90 120 or Post or Infusion (minutes) P<0.05 vs BL, P<0.05 vs ANG II, 1-way ANOVA with Bonferroni s multiple-comparison test.
ml/min Renal Blood Flow 300 250 200 150 100 Continuous ANG II infusion BL ANG II 30 60 90 120 or Post or Infusion (minutes) P<0.05 vs BL, P<0.05 vs ANG II, 1-way ANOVA with Bonferroni s multiple-comparison test.
ng/dl Aldosterone 60 50 40 30 20 10 0 Continuous ANG II infusion BL ANG II 30 60 90 120 or Post or Infusion (minutes) P<0.05 vs BL, P<0.05 vs ANG II, 1-way ANOVA with Bonferroni s multiple-comparison test.
pmol/ml Plasma cgmp 70 60 50 40 30 20 10 0 Continuous ANG II infusion BL ANG II 30 60 90 120 or Post or Infusion (minutes) P<0.05 vs BL, P<0.05 vs ANG II, 1-way ANOVA with Bonferroni s multiple-comparison test.
Summary In a model of acute angiotensin II induced hypertension infusion: Reduced MAP and PCWP Reduced SVR Enhanced diuresis and natriuresis Inhibited aldosterone activation Enhanced GFR and RBF
Conclusions Possesses pleiotropic blood pressure lowering actions while enhancing cardiorenal function Potential novel therapeutic agent in the treatment of acute or resistant hypertension
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