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 CaV and ROC. In addition, imide-3 is able to reduce force of cardiac contraction, blood pressure and promote bradycardia.

Antihypertensive potential of linalool and linalool complexed with ß-cyclodextrin: Effects of subchronic treatment on blood pressure and vascular reactivity.

Linalool (LIN) is a monoterpene alcohol present in some aromatic medicinal plants with biological activities that can impact cardiovascular diseases. This chemical class is highly volatile and ß-cyclodextrin (ß-CD) has been employed to improve the pharmacological properties of monoterpenes. Thus, the aim of this study was to evaluate the cardiovascular effects of LIN free focusing on the antihypertensive properties of this monoterpene and to study whether LIN, complexed in ß-cyclodextrin (LIN-ßCD) is able to improve the pharmacological activity of LIN. Spontaneously hypertensive rats (SHR) were randomly divided into 5 groups, each treated daily for 21 days, in the following manner: group 1 (vehicle solution); group 2 (captopril; 30 mg/kg/day); group 3 (LIN; 100 mg/kg/day); group 4 (LIN; 50 mg/kg/day) and group 5 (LIN/ß-CD; 50 mg/kg/day). Daily body weight measurements were conducted and mean arterial pressure and heart rate were measured every 5 days. The mesenteric artery from treated animals was tested for phenylephrine and sodium nitroprusside (SNP) sensitivity. The SHR treated with vehicle demonstrated progressive increase in mean arterial pressure and captopril, a positive control, induced a significant decrease. After 21 days of treatment, the blood pressure of the SHR treated by (-)-LIN (100 mg/kg) was significantly reduced. In addition, various important cardiovascular parameters improved, including: the treatment with LIN prevented the development of cardiac hypertrophy, increased levels of the anti-inflammatory cytokine (IL-10), increased vasodilator responsiveness and reduced sensitivity to the sympathetic agonist. Furthermore, the inclusion complex containing LIN in ß-CD produced a higher antihypertensive profile when compared with uncomplexed form. Taking together, our results suggested that LIN shown a potential antihypertensive effect and ß-CD may be an important tool to improve the cardiovascular activity of LIN and other water-insoluble compounds.