Dopamine-Mediated Disinhibition in the CA1 Region of Rat Hippocampus via D3 Receptor Activation

Abstract

Levosimendan enhances cardiac contractility primarily via Ca²⁺ sensitization, and it induces vasodilation through the activation of ATP-sensitive potassium channels and large conductance Ca²⁺-activated K⁺ channels. However, the concentration-dependent hemodynamic effects of levosimendan and its metabolites (R)-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide (OR-1896) and (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (OR-1855) have not been well defined. Thus, levosimendan (0.03, 0.10, 0.30, and 1.0 μmol/kg/30 min; n = 6) was infused as four escalating 30-min i.v. doses targeting therapeutic to supratherapeutic concentrations of levosimendan (C_max, ∼62.6 ng/ml); metabolites were infused at one-half log-unit lower doses and responses compared to dobutamine (β₁-agonist) and milrinone (phosphodiesterase 3 inhibitor). Peak concentrations of levosimendan, OR-1896, and OR-1855 at the end of the high dose were 323 ± 14, 83 ± 2, and 6 ± 2 ng/ml, respectively (OR-1855 rapidly metabolized to OR-1896; peak = 82 ± 3 ng/ml). Levosimendan and OR-1896 produced dose-dependent reductions in blood pressure and peripheral resistance with a rank potency, based on ED₁₅ values, of OR-1896 (0.03 μmol/kg) > OR-1855 > levosimendan > milrinone (0.24 μmol/kg); an ED₁₅ for dobutamine could not be defined. Only dobutamine produced increases in pulse pressure (30 ± 5%) and rate-pressure product (34 ± 4%). All of the compounds, with the exception of OR-1855, elicited dose-dependent increases in dP/dt with a rank potency, based on ED₅₀ values, of dobutamine (0.03 μmol/kg) > levosimendan > OR-1896 > milrinone (0.09 μmol/kg), although only levosimendan produced sustained increases in cardiac output (9 ± 4%). Thus, levosimendan and OR-1896 are hemodynamically active at sub- to supratherapeutic concentrations (whereas the effects of OR-1855 in the rat are thought to be predominantly mediated by conversion to OR-1896) and produce direct inotropic effects and also direct relaxation of the peripheral vasculature, which clearly differentiates them from dobutamine, which does not elicit K⁺ channel activation, suggesting a more balanced effect on the cardiac-contractile state and K⁺ channel-mediated changes in vascular resistance.