Abstract Wed176: 6-Nitrodopamine potentiates the positive chronotopic and inotropic effect induced by noradrenaline in the rat isolated heart

Introduction: 6-Nitrodopamine (6-ND) has potent positive chronotropic and inotropic effects in the rat isolated right atrium and at 10fM causes remarkable potentiation of the positive chronotropic effects induced by dopamine, noradrenaline, and adrenaline. Cyclic AMP plays a fundamental role in the positive inotropic effect of classical catecholamines, and cyclase-associated proteins (CAP-1 and CAP-2) were identified as 6-ND receptors in human cardiomyocytes. Hypothesis: 6-ND as a modulator of the positive chronotropic and inotropic effects induced by noradrenaline. Methodology: Adult male Wistar rats were injected with heparin (1000 IU/kg) and euthanasia was performed by isoflurane overdose. Following exsanguination, the chest was opened, and the heart was rapidly excised, the ascending aorta was cannulated, and the heart was mounted in a non-recirculating Langendorff apparatus. The hearts were allowed to equilibrate for at least 10 min, the effects of a one-minute infusion (100 µL/min) 6-nitrodopamine (0.01, 0.1, or 1 pM final concentration) were evaluated. Paired t-test was used for statistical analysis. Results: At 0.01 and 0.1 pM, 6-ND had no chronotropic and/or inotropic effect. However, at 1 pM, 6-ND infusion significantly increased the heart rate (HR), left ventricular developed pressure (LVDP), dP/dt max , and rate pressure product (RPP). Bolus injection of noradrenaline at 1 pmol had no effect on heart rate frequency (Fig. 1A), LVDP (Fig. 1B), dPdt(max) (Fig. 1C) and RPP (Fig. 1D). One-min infusion of 6-nitrodopamine (0.001 pM) alone did not alter any of these parameters either. However, infusion of 6-nitrodopamine (0.01 pM) significantly increased the heart rate frequency (Fig. 1A), LVDP (Fig. 1B), dP/dt(max) (Fig. 1C), and RPP (Fig. 1D) when noradrenaline (1 pmol) was injected at the end of the infusion (1 min). Conclusion: 6-ND is a major modulator heart inotropism and has therapeutic potential in the management of acute and chronic heart failure.