title: M-atrial natriuretic peptide and nitroglycerin in a canine model of experimental acute hypertensive heart failure: differential actions of 2 cGMP activating therapeutics.
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.
  
  
  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.
authors.affiliation: Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN.
authors.forename: Paul M
authors.initials: PM
authors.lastname: McKie
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cataliotti
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ichiki
authors.forename: S Jeson
authors.initials: SJ
authors.lastname: Sangaralingham
authors.forename: Horng H
authors.initials: HH
authors.lastname: Chen
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000804:Angiotensin II; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004285:Dogs; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D005996:Nitroglycerin / Q000494:pharmacology*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012079:Renal Circulation / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase; D013997:Time Factors
chemical_list: D020536:Enzyme Activators; D018160:Receptors, Cytoplasmic and Nuclear; D000804:Angiotensin II; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D005996:Nitroglycerin
keywords: cyclic GMP; heart failure; hypertension; natriuretic peptide; nitroglycerin