title: CHF-1024, a DA2/alpha2 agonist, blunts norepinephrine excretion and cardiac fibrosis in pressure overload.
abstract: We compared the effects of an ACE inhibitor, captopril, with those of a DA2-dopaminergic/alpha2-adrenergic receptor agonist (CHF-1024) on neuroendocrine activation and cardiac fibrosis in a model of pressure-overload hypertrophy. Interrenal aortic stenosis was performed in 89 rats, treated with CHF-1024 (0.33, 2 or 6 mg kg(-1) day(-1)), or captopril (1 g/L). Hemodynamic variables were recorded. Cardiac and renal weights, plasma aldosterone, renin activity and urinary catecholamine excretion were measured, as well as cardiac collagen. Blood pressure was lower in stenotic animals treated with CHF-1024 compared to vehicle (161 +/- 10 vs 219 +/- 10 mmHg, p < 0.01), but LV weight was similar. CHF-1024 elicited a marked dose-dependent attenuation of urinary norepinephrine excretion (1.80 +/- 0.18 in controls compared to 0.40 +/- 0.14 microg/24 h at the highest dose, p < 0.01) and of LV perivascular fibrosis. Captopril provoked a marked hypotension, reduced cardiac and body weights, plasma aldosterone concentration, dopamine excretion and perivascular collagen. The DA2/alpha2 agonist CHF-1024 effectively blunts adrenergic drive and cardiac fibrosis in a rat model of pressure overload.
authors.affiliation: Department of Cardiovascular Research, Istituto di Ricerche Farmcologiche-Mario Negri, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Masson
authors.forename: S
authors.initials: S
authors.lastname: Chimenti
authors.forename: M
authors.initials: M
authors.lastname: Salio
authors.forename: M
authors.initials: M
authors.lastname: Torri
authors.forename: F
authors.initials: F
authors.lastname: Limana
authors.forename: R
authors.initials: R
authors.lastname: Bernasconi
authors.forename: L
authors.initials: L
authors.lastname: Calvillo
authors.forename: D
authors.initials: D
authors.lastname: Santambrogio
authors.forename: N
authors.initials: N
authors.lastname: Gagliano
authors.forename: B
authors.initials: B
authors.lastname: Arosio
authors.forename: G
authors.initials: G
authors.lastname: Annoni
authors.forename: R
authors.initials: R
authors.lastname: Razzetti
authors.forename: S
authors.initials: S
authors.lastname: Bongrani
authors.forename: R
authors.initials: R
authors.lastname: Latini
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000704:Analysis of Variance; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001024:Aortic Valve Stenosis / Q000517:prevention & control*; D002216:Captopril / Q000494:pharmacology* / Q000627:therapeutic use; D002312:Cardiomyopathy, Hypertrophic / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D006977:Hypertension, Renal / Q000188:drug therapy; D008026:Ligation; D008297:Male; D009638:Norepinephrine / Q000652:urine*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000316:Adrenergic alpha-Agonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D013764:Tetrahydronaphthalenes; D002216:Captopril; C112301:CHF 1024; D009638:Norepinephrine