Effects of Akrinor and Its Constituents on Basal and Norepinephrine Increased Tone in Human Internal Mammary Arteries

Objectives: Akrinor is a widely used drug to treat intraoperative hypotension. The drug consists of three different compounds: norepinephrine, norephedrine and theophylline. However, compounds in Akrinor are covalently linked to each other and the mechanism of action is unclear. To estimate whether arterial vasoconstriction contributes to Akrinor’s blood pressure rising effects we measured the intrinsic effects of Akrinor and some of its constituents on tension of human arterial rings. In addition, we estimated the impact on vasoconstriction evoked by the natural agonist on α-AR, norepinephrine.

Methods: We used pieces of left and right mammary arteries (IMA) which stayed over during heart surgery. After excision, arteries were immediately placed into oxygenated, modified Tyrode's solution and transported to the laboratory in less than 10 minute. The adherent connective tissue was carefully dissected, and the artery was cut in up to eight rings of 3mm length. The IMA segments were mounted on wire hooks in the organ bath. Resting tension was increased stepwise from 2 up to 20 mN. KCl (100 mM) was applied and washed out six times to confirm proper function of the vessel rings.

Results: We observed a continuous decline in tension over time. Addition of theophylline did not affect tension. However, high concentrations of theophylline blunted vasoconstriction to subsequent norepinephrine challenge, conceivable by unselective block of PDE. As to be expected from an indirect sympathomimetic agent norephedrine increased tension in a concentration-dependent manner. Effects were clearly smaller than of norepinephrine. Sensitivity to subsequent norepinephrine exposure was not affected by pretreatment with norephedrine. In stark contrast, Akrinor did not evoke any vasoconstriction alone but shifted the concentration-response for subsequent norepinephrine challenge to the right (from -logEC₅₀ [M] of 6.18 ± 0.08 to 5.23 ± 0.05 p < 0.05 paired t-test n = 10/5 vs. 9/5).

Conclusion: Akrinor itself has no effect on tension of human IMA. At first glance, one would assume that concomitant PDE-inhibition by both constituents (theodrenaline and cafedrine) blunts vasoconstriction by norepinephrine and norephedrine. However, norepinephrine-induced vasoconstriction was preserved in the presence of Akrinor. A rightward-shift of the concentrations-response curve for norepinephrine suggests theodrenaline acts as a competitive antagonist at the level of α₁-adrenoceptor.