Antihypertensive effect of carvacrol is improved after incorporation in ß-cyclodextrin as a drug delivery system.

Carvacrol (CARV), has been shown to possess various pharmacological properties, especially in the treatment of cardiovascular diseases. We evaluated the antihypertensive effect of the CARV free and encapsulation of CARV in ß-cyclodextrin (CARV/ß-CD), and whether CARV/ß-CD is able to improve the antihypertensive effects of CARV free in spontaneously hypertensive rats (SHR). The rats were randomly divided into four groups, each treated daily for 21 days and the mean arterial pressure and heart rate was measured every 5 days: group 1, Wistar-vehicle solution; group 2, SHR-vehicle; group 3, SHR-CARV 50 mg/kg/d; and group 4, CARV/ß-CD 50 mg/kg/d. After 21 days of treatment, the mesenteric artery from treated animals was tested for phenylephrine (Phe) and sodium nitroprusside (SNP) sensitivity. In addition, administration of CARV/ß-CD induced important antihypertensive activity when compared with the uncomplexed form, reducing the progression of arterial hypertension in SHR. Moreover, pharmacological potency to Phe in the SHR-CARV and CARV/ß-CD groups was increased, approaching values expressed in the Wistar-vehicle. Furthermore, CARV/ß-CD reduced the production of the pro-inflammatory mediator, IL-1ß, and increased anti-inflammatory cytokine, IL-10. Together, these results produced evidence that the encapsulation of CARV in ß-CD can improve cardiovascular activity, showing potential anti-inflammatory and antihypertensive effects.

Ru(II) based dual nitric oxide donors: electrochemical and photochemical reactivities and vasorelaxant effect with no cytotoxicity.

The synthesized complexes, cis-[Ru(NO)(NO2)(phen)2](PF6)2 (NONO2P) and cis-[Ru(NO)(NO2)(bpy)2](PF6)2 (NONO2B), were characterized by using elemental analysis, voltammetry and electronic and vibrational spectroscopy. Under electrochemical and photochemical stimulation in an aqueous medium, there are indications of the formation of complexes, which suggests that the nitro and nitrosyl groups are converted into nitric oxide. Both compounds do not show cytotoxic activity against human umbilical vein endothelial cells (HUVECs). The cis-[Ru(NO)(NO2)(phen)2](PF6)2 complex presented vasorelaxation activity in superior mesenteric arteries from Wistar rats: the biphasic concentration-response curve indicates two sites of action. In the presence of NO scavengers, we observed an impaired relaxing effect induced by NONO2P, suggesting that the vasorelaxant effect is due to NO production from this compound.

Vascular Dysfunction in Diabetes and Obesity: Focus on TRP Channels.

Transient receptor potential (TRP) superfamily consists of a diverse group of non-selective cation channels that has a wide tissue distribution and is involved in many physiological processes including sensory perception, secretion of hormones, vasoconstriction/vasorelaxation, and cell cycle modulation. In the blood vessels, TRP channels are present in endothelial cells, vascular smooth muscle cells, perivascular adipose tissue (PVAT) and perivascular sensory nerves, and these channels have been implicated in the regulation of vascular tone, vascular cell proliferation, vascular wall permeability and angiogenesis. Additionally, dysfunction of TRP channels is associated with cardiometabolic diseases, such as diabetes and obesity. Unfortunately, the prevalence of diabetes and obesity is rising worldwide, becoming an important public health problems. These conditions have been associated, highlighting that obesity is a risk factor for type 2 diabetes. As well, both cardiometabolic diseases have been linked to a common disorder, vascular dysfunction. In this review, we briefly consider general aspects of TRP channels, and we focus the attention on TRPC (canonical or classical), TRPV (vanilloid), TRPM (melastatin), and TRPML (mucolipin), which were shown to be involved in vascular alterations of diabetes and obesity or are potentially linked to vascular dysfunction. Therefore, elucidation of the functional and molecular mechanisms underlying the role of TRP channels in vascular dysfunction in diabetes and obesity is important for the prevention of vascular complications and end-organ damage, providing a further therapeutic target in the treatment of these metabolic diseases.

Inhibition of intracellular Ca2+ mobilization and potassium channels activation are involved in the vasorelaxation induced by 7-hydroxycoumarin.

Coumarins exhibit a wide variety of biological effects, including activities in the cardiovascular system and the aim of this study was to evaluate the vascular therapeutic potential of 7-Hydroxicoumarin (7-HC). The vascular effects induced by 7-HC (0.001 µM-300 µM), were investigated by in vitro approaches using isometric tension measurements in rat superior mesenteric arteries and by in silico assays using Ligand-based analysis. Our results suggest that the vasorelaxant effect of 7-HC seems to rely on potassium channels, notably through large conductance Ca2+-activated K+ (BKCa) channels activation. In fact, 7-HC (300 µM) significantly reduced CaCl2-induced contraction as well as the reduction of intracellular calcium mobilization. However, the relaxation induced by 7-HC was independent of store-operated calcium entry (SOCE). Moreover, in silico analysis suggests that potassium channels have a common binding pocket, where 7-HC may bind and hint that its binding profile is more similar to quinine's than verapamil's. These results are compatible with the inhibition of Ca2+ release from intracellular stores, which is prompted by phenylephrine and caffeine. Taken together, these results demonstrate a therapeutic potential of 7-HC on the cardiovascular system, making it a promising lead compound for the development of drugs useful in the treatment of cardiovascular diseases.

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.