The effect of medicinal electroapplication of the biologically active agent "Pelamine" from the ELAV-8 device on microcirculation in the rabbit ear

The study was the first to study the effect of pulsed electric currents from the ELAV–8 device and the biologically active substance "Pelamine" on microcirculation in the rabbit ear. It was found that pulsed currents from the ELAV-8 device with a frequency of 100 Hz, as well as the biologically active agent "Pelamine" injected into the rabbit's paravertebral region by means of pulsed currents, have a vasodilatory effect on the vascular bed of the rabbit's ear. At the same time, transdermal administration of the biologically active agent "Pelamine" with the help of currents from the ELAV-8 device has a more prolonged effect on vasodilation. Key words: Microcirculation, rabbit ear, paravertebral region, vascular diameter, "Pelamine", ELAV-8 device.

528 Advanced echocardiographic assessment in outpatients with advanced heart failure undergoing periodical levosimendan infusion

Aims The long-term clinical effects of Levosimendan in patients (pts) with heart failure and reduced ejection fraction (HFrEF) are mainly mediated by its long-acting metabolite, OR-1896, whose half-life is much longer (81 h vs. 1–1.5 h), although with similar inotropic and vasodilatory effect. Echocardiographic data are still lacking, expecially in the chronic setting. Global longitudinal strain (GLS) and left ventricular myocardial work index (LVMWI) are novel non-invasive methods for left ventricle (LV) function evaluation that consider myocardial deformation and afterloads using LV strain combined with the non-invasive estimation of LV pressure. The aim of this study was to perform an echocardiographic assessment in pts with advanced HFrEF before and after infusion of Levosimendan in a chronic setting, using GLS and LVMWI. Methods and results 6 pts with ischaemic HFrEF were prospectively enrolled in the study. Echo-data were collected from all patients using a Vivid E95 system (GE Healthcare), before and after the end of infusion (24–48 h). Moreover, 4 pts underwent another echo evaluation 96 h after the infusion to assess the long term effect of OR-1896. Although mean end-diastolic volume decreased after 24–48 h, increased after 96 h, as reported in Table 1. As to the Ejection Fraction (EF), strain-parameters and stroke volume (SV) remain unchanged before and after the infusion. Similarly LVMWI-derived parameters also remain overall unchanged (Table 1). Conclusions In pts with ischaemic HFrEF undergoing periodical infusion of Levosimendan, we very preliminary observed a reduction of LV size short after the infusion, which interestingly do not persist after 96 h. The other considered echocardiographic parameters (EF, SV, strain-derived parameters) did not show significant differences before and after the infusion. An explanation is that Levosimendan improves LV congestion but not the contractile force in pts with advanced HFrEF, whose myocardial performance is too compromised. Therefore the haemodynamic benefits observed chronically in pts with Levosimendan might be due to the initial decongestion and its vasodilatory effect, and it may not persist in mid-term, depending on basal myocardial conditions. Larger studies should be conducted to conferm these findings.

Comparative study of vasodilatation after intra-arterial nicardipine or dantrolene infusion in animal model of cerebral vasospasm

Intra-arterial (IA) infusions of calcium channel blockers (CCBs) have been widely applied in treating medically refractory vasospasm. However, surprisingly little is known regarding their vasodilatory duration. This study was undertaken to compare attributes of nicardipine and dantrolene, focusing on efficacy and capacity for sustained vasodilation. In New Zealand white rabbits (N=22), vasospasm was individually provoked through experimentally induced subarachnoid hemorrhage and confirmed via conventional angiography, grouping animals by IA-infused drug (nicardipine vs dantrolene). Controls received normal saline. After chemoangioplasty, follow-up angiography was performed at intervals of 1-3 hours for 6 hours to compare vasospastic and dilated (ie, treated) arterial diameters. Drug efficacy, duration of action, and changes in mean arterial pressure (relative to baseline) were analyzed by group. Compared with controls, effective vasodilation was evident in both nicardipine and dantrolene test groups after IA infusion. Vasodilatory effects of nicardipine peaked at 1 hour, returning to former vasospastic states at 3 hours. In dantrolene recipients, vasodilation endured longer, lasting >6 hours. This outcome suggests that IA dantrolene infused alone or together with a conventional CCB infusion may be a new means of prolonging vasodilatory effect. Further research is needed to assess durations of IA-infused vasodilatory drug based on perfusion status.

Cannabinoids—A New Perspective in Adjuvant Therapy for Pulmonary Hypertension

Currently, no treatment can completely cure pulmonary hypertension (PH), which can lead to right ventricular failure and, consequently, death. Therefore, searching for new therapies remains important. Increased resistance in pulmonary circulation is mainly caused by the excessive contraction and proliferation of small pulmonary arteries. Cannabinoids, a group of lipophilic compounds that all interact with cannabinoid receptors, exert a pulmonary vasodilatory effect through several different mechanisms, including mechanisms that depend on vascular endothelium and/or receptor-based mechanisms, and may also have anti-proliferative and anti-inflammatory properties. The vasodilatory effect is important in regulating pulmonary resistance, which can improve patients' quality of life. Moreover, experimental studies on the effects of cannabidiol (plant-derived, non-psychoactive cannabinoid) in animal PH models have shown that cannabidiol reduces right ventricular systolic pressure and excessive remodelling and decreases pulmonary vascular hypertrophy and pulmonary vascular resistance. Due to the potentially beneficial effects of cannabinoids on pulmonary circulation and PH, in this work, we review whether cannabinoids can be used as an adjunctive therapy for PH. However, clinical trials are still needed to recommend the use of cannabinoids in the treatment of PH.

Treatment of In-Stent Stenosis Following Flow Diversion of Intracranial Aneurysms with Cilostazol and Clopidogrel

In-stent stenosis is a feared complication of flow diversion treatment for cerebral aneurysms. We present 2 cases of patients treated with pipeline flow diversion for unruptured cerebral aneurysms. Initial perioperative dual antiplatelet therapy (DAPT) consisted of standard aspirin plus clopidogrel. At 6-month follow-up cerebral angiography, the patients were noted to have developed significant in-stent stenosis (63% and 53%). The patients were treated with cilostazol and clopidogrel for at least 6 months. Subsequent angiography at 1-year post-treatment showed significant improvement of the in-stent stenosis from 63% to 34% and 53% to 21%. The role of cilostazol as treatment of intracranial in-stent stenosis has not been previously described. Cilostazol’s vasodilatory effect and suppression of vascular smooth muscle proliferation provides ideal benefits in this setting. Cilostazol plus clopidogrel may be a safe and effective alternative to standard DAPT for treatment of in-stent stenosis following flow diversion and warrants further consideration and investigation.

Study of the vasodilatory effect of extract from tissue culture biomass of Rauwolfia serpentina Benth.

Design of novel herbal drugs with a wide range of activity is an important object of pharmacology. Herbal remedies having antiarrhythmic, cardiotonic and vasodilatory effects are useful for treatment of heart arrhythmias. Vasodilating drugs are prescribed for medication of hypertension and migraine. Also they are a part of comprehensive treatment of various diseases such as disturbed peripheral blood circulation and atherosclerosis of arteries of extremities as well as problems with urination and potency. Search for novel herbal preparations with vasorelaxant activity in our view is a promising matter of current interest. This work is aiming in study of vasodilatory activity of methanol extract of strain K-27 tissue culture of Rauwolfia serpentina. Evaluation of vasodilatory activity extract of high-productive strain K-27 tissue culture of Rauwolfia serpentina has been carried out by the method of auxotonic mechanography of vascular smooth muscles. Strength and frequency of spontaneous contractions of portal vein as well as relaxation of aortic smooth muscles activated with phenylephrine were evaluation indicators of extract activity. In order to estimate working concentration of extract of strain K-27 tissue culture of Rauwolfia serpentina we have studied vascular activity at sequentially increasing concentrations of extract solution on the portal vein. Overlay of sequence of growing concentrations exhibited decrease in basal level of venous tone and dose-dependent suppression of phasic contractions with complete inhibition of spontaneous activity of portal vein at 1.44 mg/ml concentration and uprise of toxicity at higher concentrations. It has been shown dose-dependent relaxation of vascular preparations followed by development of α-adrenoceptor blocking effect and loss of sensibility to phenylephrine at the end of experiment. After discontinuing exposure with a substance the activating effect of phenylephrine remained not renewed during 30-50 minutes, at the same time contractile activity of aorta on the response to the other type activation (60 mM K+) took place. It was found that at the studied range of concentrations: 0.0288 μg/ml–28.8 μg/ml the extract of strain K-27 tissue culture of Rauwolfia serpentina has distinct vasodilatory effect. Also it was discovered α-adrenoceptor blocking effect of that extract, so it can find wide application in therapy as vasorelaxant and α-blocker, for instance in treatment of prostate diseases.

Ecklonia cava Extract and Its Derivative Dieckol Promote Vasodilation by Modulating Calcium Signaling and PI3K/AKT/eNOS Pathway in In Vitro and In Vivo Models

Nitric oxide (NO), an endothelial-derived relaxing factor synthesized by endothelial nitric oxide synthase (eNOS) in endothelial cells, enhances vasodilation by modulating vascular tone. The calcium concentration critically influences eNOS activation in endothelial cells. Thus, modulation of calcium-dependent signaling pathways may be a potential therapeutic strategy to enhance vasodilation. Marine algae reportedly possess protective effects against cardiovascular disorders, including hypertension and vascular dysfunction; however, the underlying molecular signaling pathways remain elusive. In the present study, we extracted and isolated dieckol from Ecklonia cava and investigated calcium transit-enhanced vasodilation. Calcium modulation via the well-known M3 muscarinic acetylcholine receptor (AchM3R), which is linked to NO formation, was investigated and the vasodilatory effect of dieckol was verified. Our results indicated that dieckol effectively promoted NO generation via the PI3K/Akt/eNOS axis and calcium transients influenced by AchM3R. We also treated Tg(flk: EGFP) transgenic zebrafish with dieckol to assess its vasodilatory effect. Dieckol promoted vasodilation by enlarging the dorsal aorta diameter, thus regulating blood flow velocity. In conclusion, our findings suggest that dieckol modulates calcium transit through AchM3R, increases endothelial-dependent NO production, and efficiently enhances vasodilation. Thus, E. cava and its derivative, dieckol, can be considered as potential natural vasodilators.

Effects of Essential Oils and Some Constituents from Ingredients of Anti-Cellulite Herbal Compress on 3T3-L1 Adipocytes and Rat Aortae

Cellulite is associated with a complex array of adipocytes under the skin and vascular system. A herbal compress that was previously developed was proven to have an anti-cellulite effect in healthy volunteers within 2 weeks of treatment. However, its mechanism and ingredients responsible for reducing cellulite were not known. The purpose of this study was to investigate the activity of eight essential oils in, and two water extracts from, the ingredients of the herbal compress together with nine monoterpenoid constituents on the 3T3-L1 adipocytes. The vasodilatory effect on rat aortae was also studied. The adipocytes were induced by dexamethasone, 3-isobutyl-1-methylxanthine and insulin. At all concentrations tested, all essential oils, water extracts and their monoterpenoid constituents significantly inhibited lipid accumulation activity (p < 0.05) and decreased the amount of triglycerides when compared to untreated cells (p < 0.01). In addition, our results showed that the mixed oil distilled from the herbal compress mixed ingredients could relax the isolated rat aorta (EC50 = 14.74 ± 2.65 µg/mL). In conclusion, all essential oils, extracts and chemical constituents tested showed effects on adipogenesis inhibition and lipolysis induction on the cultured adipocytes with the mixed oil demonstrating vasorelaxation activity, all of which might be the mechanisms of the anti-cellulite effects of the herbal compress.

Diphlorethohydroxycarmalol Isolated from Ishige okamurae Exerts Vasodilatory Effects via Calcium Signaling and PI3K/Akt/eNOS Pathway

Nitric oxide (NO) is released by endothelial cells in the blood vessel wall to enhance vasodilation. Marine polyphenols are known to have protective effects against vascular dysfunction and hypertension. The present study is the first to investigate how diphlorethohydroxycarmalol (DPHC) isolated from Ishige okamurae affects calcium levels, resulting in enhanced vasodilation. We examined calcium modulation with the well-known receptors, acetylcholine receptor (AchR) and vascular endothelial growth factor 2 (VEGFR2), which are related to NO formation, and further confirmed the vasodilatory effect of DPHC. We confirmed that DPHC stimulated NO production by increasing calcium levels and endothelial nitric oxide synthase (eNOS) expression. DPHC affected AchR and VEGFR2 expression, thereby influencing transient calcium intake. Specific antagonists, atropine and SU5416, were used to verify our findings. Furthermore, based on the results of in vivo experiments, we treated Tg(flk:EGFP) transgenic zebrafish with DPHC to confirm its vasodilatory effect. In conclusion, the present study showed that DPHC modulated calcium transit through AchR and VEGFR2, increasing endothelial-dependent NO production. Thus, DPHC, a natural marine component, can efficiently ameliorate cardiovascular diseases by improving vascular function.