AkrinorTM, a Cafedrine/ Theodrenaline Mixture (20:1), Increases Force of Contraction of Human Atrial Myocardium But Does Not Constrict Internal Mammary Artery In Vitro

Abstract

Background: Intraoperative hypotension is a common problem and direct or indirect sympathomimetic drugs are frequently needed to stabilize blood pressure. AkrinorTM consists of the direct and the indirect sympathomimetic noradrenaline and norephedrine. Both substances are covalently bound to the phosphodiesterase (PDE) inhibitor theophylline, yielding theodrenaline and cafedrine, respectively. We investigated pharmacodynamic effects of AkrinorTM and its constituents on contractile force and tension in human atrial trabeculae and internal A. mammaria rings.Methods: Isometric contractions were measured in human atrial trabeculae at 1 Hz and 37°C. CGP 20712A and ICI 118,551 were used to elaborate β1- and β2-adrenoceptor (AR) subtypes involved and phenoxybenzamine to estimate indirect sympathomimetic action. PDE-inhibition was measured as a potentiation of force increase upon direct activation of adenylyl cyclase by forskolin. Human A. mammaria preparations were used to estimate intrinsic vasoconstriction and impact on the noradrenaline-induced vasoconstriction.Results: Clinically relevant concentrations of AkrinorTM (4.2–420 mg/l) robustly increased force in human atrial trabeculae (EC50 41 ± 3 mg/l). This direct sympathomimetic action was mediated via β1-AR and the effect size was as large as with high concentrations of calcium. Only the highest and clinically irrelevant concentration of AkrinorTM increased the potency of forskolin to a minor extent. Norephedrine has lost its indirect sympathomimetic effect when bound to theophylline. Increasing concentrations of AkrinorTM (4.2–168 mg/l) alone did not affect the tension of human A. mammaria interna rings, but shifted the noradrenaline curve rightward from -logEC50 6.18 ± 0.08 to 5.23 ± 0.05 M.Conclusion: AkrinorTM increased cardiac contractile force by direct sympathomimetic actions and PDE inhibition, did not constrict A. mammaria preparations, but shifted the concentration-response curve to the right, compatible with an α-AR antagonistic effect or PDE inhibition. The pharmacodynamic profile and potency of AkrinorTM differs from noradrenaline and norephedrine in vitro. We anticipate metabolism of theodrenaline and cafedrine resulting in a different pharmacodynamic profile of AkrinorTM in vivo.

Regulation of APD and Force by the Na+/Ca2+ Exchanger in Human-Induced Pluripotent Stem Cell-Derived Engineered Heart Tissue

“…Human preparations were pre-stretched to a 50% length, giving the maximum force, and paced at a frequency of 1 Hz with 5 ms electrical pulses 10% above the threshold intensity. The tissue samples were pretreated for 90 min with the irreversible α-adrenoceptor blocker phenoxybenzamine (6 µM) [ 13 ]. The compound effects were measured after an equilibration period of 30 min.…”

Muscarinic Receptor Activation Reduces Force and Arrhythmias in Human Atria Independent of IK,ACh

“…Therefore, tissues were incubated with 3 mM cocaine for 90 minutes to increase release of norepinephrine. 14 Trabeculae were washed from released catecholamines and force development was stabilized over additional 30 minutes. Force was recorded using Chart Pro for Windows version 5.51 analysis program (ADI Instruments, Castle Hill, NSW, Australia).…”

In VitroNegative Inotropic Effect of Low Concentrations of Bupivacaine Relates to Diminished Ca2+ Sensitivity but Not to Ca2+ Handling or β-Adrenoceptor Signaling

“…Phenoxybenzamine is an unselective α-adrenoceptor antagonist and increases release of noradrenaline. 13 Trabeculae were washed from released catecholamines and left to stabilize during an additional period of 30 min. In a first set of experiments, the negative inotropic effect of bupivacaine was analyzed by increasing concentrations in a cumulative manner.…”

“…A system for rapid solution changes allowed application of drugs in the close vicinity of the cells (Cell Micro Controls, USA; ALA Scientific Instruments, USA). Currents were measured in the whole cell configuration of the single electrode voltage clamp technique as described elsewhere 13 using the EPC-7 patch-clamp amplifier (List Electronics, Germany) and the ISO 2 software (MFK, Germany) for data acquisition and analysis. Borosilicate glass pipettes had a tip resistance of 2 to 4 MΩ.…”