Evaluation of Vasomera™, a Novel VPAC2-Selective Vasoactive Intestinal Peptide Agonist, in Rats With Doxorubicin-Induced Cardiomyopathy: Evidence for Chronic Cardio-Protection.

Abstract

The natural vasoactive intestinal peptide (VIP) has been proposed as a therapeutic agent for heart failure triggering potent vasodilatation/inotropy via the activation of the G-protein-coupled VPAC1 and VPAC2 receptors; however, VIP's clinical utility is limited due to its short half-life and VPAC1-mediated side-effects. Vasomera™ is a novel long-acting biopolymer-based selective VPAC2-receptor agonist. Here, the chronic functional/geometrical effects of Vasomera when given daily to rats with doxorubicin-induced cardiomyopathy were evaluated.Sprague-Dawley rats were assigned to receive daily therapy with either Vasomera (9 mg/kg/day SQ; n = 15) or placebo (n = 10), and had heart failure induced via doxorubicin (3 mg/kg IP on M-W-F for 2 weeks; 18 mg/kg total); treatments started prior to HF induction (5 days) and continued until the end of the study. LV function/geometry were evaluated (via echocardiography) prior to the start of dosing, as well as weekly both during/after (for up to 3 weeks) HF induction. Animals were terminally studied in order to evaluate LV mechano-energetics.Doxorubicin lead to marked LV dysfunction/remodeling, characterized by depressed systolic function (e.g., FS: -18 ± 4 %, P < 0.05), myocardial dilatation (e.g., LVIDd: +12 ± 2, P < 0.05), and wall-thinning (WT: -15 ± 5 %, P < 0.05). Daily Vasomera therapy prevented doxorubicin-induced myocardial wasting/wall-thinning (WTs: +1 ± 4%, N.S.), ameliorating ventricular dysfunction (e.g., FS, -8 ± 2%, P < 0.05) and dilatation (LVIDd: +3 ± 3, N.S.). Vasomera treatment also tended to preserve the LV- to body-weight ratio (-2.4 ± 2.0% vs. time-controls, N.S.), when compared to un-treated animals (-7.5 ± 3.0% vs. time-controls, P = 0.1). Terminally, Vasometra-treated animals tended to have lower LV filling pressures (EDP: 13 ± 1 vs. 9 ± 1 mmHg).Daily treatment with Vasomera, a novel VPAC2 agonist, attenuated doxorubicin-induced myocardial remodeling/dysfunction in rats. In particular, Vasomera treatment prevented myocardial wall-thinning/muscular wasting. Moreover, acute Vasomera administration (IV) to rats with doxorubicin-induced cardiomyopathy, dose-dependently decreased myocardial loading and energetic demand, while improving LV systolic/diastolic function in a load-independent manner. The natural vasoactive intestinal peptide (VIP) has been proposed as a therapeutic agent for heart failure triggering potent vasodilatation/inotropy via the activation of the G-protein-coupled VPAC1 and VPAC2 receptors; however, VIP's clinical utility is limited due to its short half-life and VPAC1-mediated side-effects. Vasomera™ is a novel long-acting biopolymer-based selective VPAC2-receptor agonist. Here, the chronic functional/geometrical effects of Vasomera when given daily to rats with doxorubicin-induced cardiomyopathy were evaluated. Sprague-Dawley rats were assigned to receive daily therapy with either Vasomera (9 mg/kg/day SQ; n = 15) or placebo (n = 10), and had heart failure induced via doxorubicin (3 mg/kg IP on M-W-F for 2 weeks; 18 mg/kg total); treatments started prior to HF induction (5 days) and continued until the end of the study. LV function/geometry were evaluated (via echocardiography) prior to the start of dosing, as well as weekly both during/after (for up to 3 weeks) HF induction. Animals were terminally studied in order to evaluate LV mechano-energetics. Doxorubicin lead to marked LV dysfunction/remodeling, characterized by depressed systolic function (e.g., FS: -18 ± 4 %, P < 0.05), myocardial dilatation (e.g., LVIDd: +12 ± 2, P < 0.05), and wall-thinning (WT: -15 ± 5 %, P < 0.05). Daily Vasomera therapy prevented doxorubicin-induced myocardial wasting/wall-thinning (WTs: +1 ± 4%, N.S.), ameliorating ventricular dysfunction (e.g., FS, -8 ± 2%, P < 0.05) and dilatation (LVIDd: +3 ± 3, N.S.). Vasomera treatment also tended to preserve the LV- to body-weight ratio (-2.4 ± 2.0% vs. time-controls, N.S.), when compared to un-treated animals (-7.5 ± 3.0% vs. time-controls, P = 0.1). Terminally, Vasometra-treated animals tended to have lower LV filling pressures (EDP: 13 ± 1 vs. 9 ± 1 mmHg). Daily treatment with Vasomera, a novel VPAC2 agonist, attenuated doxorubicin-induced myocardial remodeling/dysfunction in rats. In particular, Vasomera treatment prevented myocardial wall-thinning/muscular wasting. Moreover, acute Vasomera administration (IV) to rats with doxorubicin-induced cardiomyopathy, dose-dependently decreased myocardial loading and energetic demand, while improving LV systolic/diastolic function in a load-independent manner.