Itaconimides derivatives induce relaxation in mesenteric artery and negative inotropism by inhibition of CA²⁺ influx

Background: The aim of this study was to evaluate the cardiovascular effects of N-phenyl-itaconimide (Imide-1), N-4-methyl-phenyl-itaconimide (Imide-2), N-4-methoxy-phenyl-itaconimide (Imide-3) and N-4-chloro-phenyl-itaconimide (Imide-4), and investigate the mechanisms of action involved in the observed responses.

Methods: The relaxant effect was investigated in rat superior mesenteric arteries by using isometric tension measurements. Additionally, in isolated atria were evaluated the heart rate and force of cardiac contraction and in vivo experiments was evaluated blood pressure and heart rate.

Results: Cumulative administration of itaconimides (3 × 10^-8 to 3 × 10^-4 M) in pre-contracted mesenteric artery rings with phenylephrine, 1 μM, induced endothelium-independent vasorelaxation. The itaconimides showed similar maximum efficacies. Additionally, Imide-3 induced vasorelaxation in rings exposed to a depolarizing-tyrode solution containing 60 mM KCl or 20 mM KCl similar to the control, suggesting the non-participation of K⁺ channels. Imide-3 attenuated Ca²⁺ influx in a concentration-dependent manner. As well, imide-3 reduced CaCl₂-induced contraction in nominally calcium-free medium, in the presence of cyclopiazonic acid (20 μM), phenylephrine (1 μM) and nifedipine (1 μM), indicating a reduction of Ca²⁺ influx by receptor-operated channels (ROC) and store-operated channels (SOC). The presence of SKF 96365 (10^-5 M), SOC blocker, did not significantly alter the vasorelaxant effect induced by imide-3. Moreover, imide-3 induced a negative inotropic effect. In vivo studies, in non-anesthetized normotensive rats, imide-3 lowered blood pressure and induced bradycardia.

Conclusions: These results suggest that itaconimides have concentration-dependent vascular effects and the vasorelaxation seems to be endothelium-independent. The vasodilatory effect induced by imide-3 may be due to a possible influence on the Ca_V and ROC. In addition, imide-3 is able to reduce force of cardiac contraction, blood pressure and promote bradycardia.