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

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 37C. CGP 20712A and ICI 118,551 were used to elaborate b1- and b2-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 b1-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 a-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

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

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 AkrinorTMin vivo

Ranolazine antagonizes catecholamine-induced dysfunction in isolated cardiomyocytes, but lacks long-term therapeutic effectsin vivoin a mouse model of hypertrophic cardiomyopathy

Aims Hypertrophic cardiomyopathy (HCM) is often accompanied by increased myofilament Ca2+ sensitivity and diastolic dysfunction. Recent findings indicate increased late Na+ current density in human HCM cardiomyocytes. Since ranolazine has the potential to decrease myofilament Ca2+ sensitivity and late Na+ current, we investigated its effects in an Mybpc3-targeted knock-in (KI) mouse model of HCM. Methods and results Unloaded sarcomere shortening and Ca2+ transients were measured in KI and wild-type (WT) cardiomyocytes. Measurements were performed at baseline (1 Hz) and under increased workload (30 nM isoprenaline (ISO), 5 Hz) in the absence or presence of 10 mu M ranolazine. KI myocytes showed shorter diastolic sarcomere length at baseline, stronger inotropic response to ISO, and drastic drop of diastolic sarcomere length under increased workload. Ranolazine attenuated ISO responses in WT and KI cells and prevented workload-induced diastolic failure in KI. Late Na+ current density was diminished and insensitive to ranolazine in KI cardiomyocytes. Ca2+ sensitivity of skinned KI trabeculae was slightly decreased by ranolazine. Phosphorylation analysis of cAMP-dependent protein kinase A-target proteins and ISO concentration-response measurements on muscle strips indicated antagonism at beta-adrenoceptors with 10 mu M ranolazine shifting the ISO response by 0.6 log units. Six-month treatment with ranolazine (plasma level > 20 mu M) demonstrated a beta-blocking effect, but did not reverse cardiac hypertrophy or dysfunction in KI mice. Conclusion Ranolazine improved tolerance to high workload in mouse HCM cardiomyocytes, not by blocking late Na+ current, but by antagonizing beta-adrenergic stimulation and slightly desensitizing myofilaments to Ca2+. This effect did not translate in therapeutic efficacy in vivo