Positive Inotropic Effects of Akrinor® in Human Atrial Tissue: Relevant PDE Inhibition at Clinically Used Concentration

Objectives: Akrinor^® is a widely used drug to treat intraoperative hypotension. The drug consists of three different compounds: norepinephrine, norephedrine and theophylline. Norepinephrine and norephedrine are expected to exert sympathomimetic actions. Theophylline should inhibit PDE and therefore sensitize for cAMP-dependent positive inotropic interventions, like catecholamines. However, theophylline in Akrinor^® is covalently linked to norepinephrine and norephedrine. It is not known if the potency of theophylline to inhibit PDE is preserved in such a formulation. Therefore, we have measured whether clinically used concentrations of Akrinor^® inhibit PDE in human heart muscle.

Methods and Results: We used human atrial trabeculae from patients who underwent cardiac surgery. All patients were in stable sinus rhythm. Trabeculae were paced at 1 Hz and isometric force generation was measured. To exclude direct or indirect sympathomimetic effects by norepinephrine or norephedrine, all experiments were performed in the presence of the β-adrenoceptor antagonist CGP20712A (300 nM). First, we tested whether Akrinor^® increased force generation under unstimulated conditions. In time-matched controls (TMC) force declined within 20 minutes from 4.8 ± 0.9 to 3.8 ± 0.8 mN (n = 13/8 numbers of trabeculae/number of patients). 42 mg/L Akrinor^®, a concentration expected in humans after intravenous injection of a single ampoule of Akrinor^® did not increase force compared with TMC. Only 10-fold higher concentrations of Akrinor^® evoked a small positive inotropic effect from 2.6 ± 0.8 to 3.3 ± 1.0 mN (n = 5/4, p < 0.005 when delta force was compared with TMC). To evaluate whether Akrinor sensitizes heart muscle for subsequent stimulation of cAMP generation we used the direct activator of adenylyl cyclase forskolin (FSK). Muscles were exposed to cumulatively increasing concentrations of FSK to construct concentration-response-curves (0.1–30 µM). In the TMC -logEC50 amounted to 5.35 ± 0.04 M. 42 mg/l Akrinor^® shifted the concentration response by ∼0.25 log unit (n = 11/6, p < 0.05). For comparison, the maximum shift by unbound theophylline was 0.7 log unit (n = 10/7).

Conclusion: Clinically used concentrations of Akrinor^® inhibit PDE in human heart muscle. However, the effect size seems moderate and is restricted to situations when cAMP generation is stimulated. We expect that covalently bound theophylline in Akrinor^® can augment positive inotropic effects of catecholamines.