Paul M McKie, Alessandro Cataliotti, Guido Boerrigter, Horng C Chen, Fernando L Martin, and John C Burnett Jr

Transcription

1 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 CP

2 Disclosures The Mayo Foundation holds a patent for.

3 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

4 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

5 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

6 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 McKie PM. J Am Coll Cardiol. 2009;54:

7 Control peptide (%) Degradation by NEP ANP Minutes Dickey et al. J Biol Chem 2009

8 mm Hg ANP vs in Normal Canines MAP BL or ANP McKie et al. JACC ANP P< Post infusion (minutes) P<0.05 vs BL CP

9 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

10 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)

11 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 CP

12 mm Hg Mean Arterial Pressure Continuous ANG II infusion BL ANG II 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.

13 mmhg Mean Arterial Pressure BL ANG II or Continuous ANG II infusion Post or Infusion (minutes) P<0.05 vs BL, P<0.05 vs ANG II, 1-way ANOVA with Bonferroni s multiple-comparison test.

14 mmhg PCWP Continuous ANG II infusion BL ANG II 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.

15 µeq/min Urinary Sodium Excretion 1, Continuous ANG II infusion BL ANG II 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.

16 ml/min Glomerular Filtration Rate Continuous ANG II infusion BL ANG II 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.

17 ml/min Renal Blood Flow Continuous ANG II infusion BL ANG II 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.

18 ng/dl Aldosterone Continuous ANG II infusion BL ANG II 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.

19 pmol/ml Plasma cgmp Continuous ANG II infusion BL ANG II 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.

20 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

21 Conclusions Possesses pleiotropic blood pressure lowering actions while enhancing cardiorenal function Potential novel therapeutic agent in the treatment of acute or resistant hypertension

22 CP