Synthesis and Effects of Novel Dihydropyridines as Dual Calcium Channel Blocker and Angiotensin Antagonist on Isolated Rat Aorta

Four novel losartan analogues 5a-d were synthesized by connecting a dihydropyridine nucleus to imidazole ring. The effects of 5a and 5b on angiotensin receptors (AT1) and L-type calcium channels were investigated on isolated rat aorta. Materials and MethodsAortic rings were pre-contracted with 1 µM Angiotensin II or 80 mM KCl and relaxant effects of losartan, nifedipine, 5a and 5b were evaluated by cumulative addition of these drugs to the bath solution.ResultsThe results showed that compounds 5a and 5b have both L-type calcium channel and AT1 receptor blocking activity. Their effects on AT1 receptors are 1000 and 100,000 times more than losartan respectively. The activity of compound 5b on L-type calcium channel is significantly less than nifedipine but compound 5a has comparable effect with nifedipine. ConclusionFinally we concluded that these two new Compounds can be potential candidates to be used as effective antihypertensive agents

Synthesis and Effects of 4,5-Diaryl-2-(2-alkylthio-5-imidazolyl) Imidazoles as Selective Cyclooxygenase Inhibitors

Objective(s)In recent years highly selective COX-2inhibitors were withdrawn from the market because of an increased risk of cardiovascular complications. In this study we were looking for potent compounds with moderate selectivity for cox-2. So, four analogues of 4, 5-diaryl-2-(2-alkylthio-5-imidazolyl) imidazole derivatives were synthesized and their anti-inflammatory and anti-nociceptive activities were evaluated on male BALB/c mice (25-30 g). Molecular modeling and in vitro COX-1 and COX-2 isozyme inhibition studies were also performed. Materials and Methods2-(2-Alkylthio-5-imidazolyl)-4,5-diphenylimidazole compounds were obtained by the reaction of benzyl with 2-alkylthio-1-benzylimidazole-5-carbaldehyde, in the presence of ammonium acetate. Spectroscopic data and elemental analysis of compounds were obtained and their structures elucidated. Anti-nociception effects were examined using writhing test in mice. The effect of the analogues (7.5, 30, 52.5 and 75 mg/kg) against acute inflammation were studied using xylene-induced ear edema test in mice. Celecoxib (75 mg/kg) was used as positive control.ResultsAll four analogues exhibited anti-nociceptive activity against acetic acid induced writhing, but did not show significant analgesic effect (P< 0.05) compared with celecoxib. It was shown that analogues injected 30 min before xylene application reduced the weight of edematic ears. All analogues were found to have less selectivity for COX-2 in comparison to celecoxib. ConclusionInjected doses of synthesised analogues possesses favorite anti-nociceptive effect and also has anti-inflammatory effects, but comparing with celecoxib this effect is not significantly different. On the other hand selectivity index for analogues is less than celecoxib and so we expect less cardiovascular side effects for these compounds

Effects of aqueous saffron extract (Crocus sativus L.) on the acquisition and reinstatement of morphine-induced conditioned place preference in mice

Objective: In the present study, the effects of aqueous saffron extract (Crocus sativus L.) on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP) in mice were investigated. Materials and Methods: Subcutaneous administration of morphine (40 mg/kg for four days) produced place preference. Intraperitoneal administration of aqueous extract (40 and 80 mg/kg for four days) 30 min before the morphine administration decreased the acquisition of morphine CPP. In other groups of animal, following extinction of a place preference induced by morphine (40 mg/kg), single administration of morphine (10 mg/kg) reinstated the place reference. The aqueous extract (80 mg/kg) 30 min before this priming dose of morphine blocked morphine-induced reinstatement of place preference. Results: These results show that aqueous saffron extract can reduce the acquisition and reinstatement of morphine-induced conditioned place preference

A review of the effects of Berberis vulgaris and its major component, berberine, in metabolic syndrome

Metabolic syndrome (MetS), characterized by a cluster of metabolic abnormalities including hypertension, obesity, type 2 diabetes mellitus (T2DM) and dyslipidemia, is a well-known cardiovascular risk factor (CVRF). Cardiovascular disease (CVD) represents a massive healthcare burden worldwide. In recent years, with regard to the adverse effects of synthetic drugs, increasing attention has been paid by researchers to herbal medicines for a variety of disorders such as CVD. A large body of literature supports different pharmacological actions of Berberis vulgaris (B. vulgaris) and its active component, berberine (BBR), such as antidiabetic, antiobesity, hypotensive and hypolipidemic properties that could be interesting in the management of MetS associated with high CVD risk. Numerous preclinical in vitro and in vivo studies support all these effects. In this review, we evaluated the most related original articles to discover the role of B. vulgaris on various constituents of MetS and CVRF comprising dyslipidemia, obesity, high blood pressure and high blood glucose. This review suggests a potential role of B. vulgaris and BBR in the managing of MetS; nevertheless more investigations, especially reliable clinical trials, need to be accomplished to evaluate their effectiveness

Evaluation of nitric oxide or opioid receptors involvement in antinociceptive properties of silymarin

Objective: It has been shown that Silybum marianum or its extracts have hepatoprotective, antioxidant, anticancer, anti-inflammatory and anti-diabetic effects. Nitric oxide (NO) plays an important role in neurotransmission, neuroprotection, neurotoxicity and pathological pain, as a neurotransmitter or neuromodulator in the central nervous system. Therefore, this experiment was performed in order to assess the analgesic effects of single and multiple-dosed ip administration of silymarin and the probable role of nitric oxide or opioid receptors using tail flick assay. Results: Based on our results, only silymarin 100 mg/kg showed analgesic properties. Since naloxone did not change silymarin’s analgesic effects, it is concluded that opioid receptors are not involved. Although in the presence of L-arginine, analgesic effect of silymarin remained intact, but it is not possible to strongly determine the involvement of nitric oxide pathway here. Based on our results, the difference between anti nociceptive properties of single and multiple-dosed treatment of silymarin 100 mg/kg is not significant. Conclusion: It is concluded that silymarin exert its analgesic effects via other mechanisms. Inhibiting 5-lipooxygenase and neutrophil chemotaxis to inflammation location could be the probable ways of silymarin’s action

Cardiovascular effects of saffron and its active constituents: A review article

(Crocus sativus L.) Commonly known as saffron, is a perennial stem less herb of the iridaceae family, widely cultivated in Iran and other countries. It is used as a flavoring and coloring agent for many thousands of years. In traditional medicine, saffron has been used for various purposes including abortion, as a fever reducer, an analgesic, expectorant, antispasmodic, aphrodisiac, sedative, digestive and a carminative. Various pharmacological studies have been described that saffron and its constituents exhibit different beneficial properties, including antioxidant, anticancer, anticonvulsant, antiischemic, antigenotoxic, antidote, antiapoptotic, antitussive, antidepressive, sedative and hypnotic, hypolipidemic, antinociceptive and antiinflammatory effects. Research projects have also revealed that saffron also exhibits protective effects against cardiovascular diseases including cardiac ischemia, arrhythmia, hypertension and atherosclerosis. In this review article, the effects of saffron and its active constituents on cardiovascular system were introduced

Antihypertensive effect of auraptene, a monoterpene coumarin from the genus Citrus, upon chronic administration

Objective(s): Auraptene, a monoterpene coumarin from Citrus species, exhibits cardioprotective effects.In this study, the effects of auraptene administration were investigated on blood pressure of normotensive and desoxycorticosterone acetate (DOCA) salt induced hypertensive rats. Materials and Methods: Five weeks administration of auraptene (2, 4, 8 and 16 mg/kg/day) and nifedipine (0.25, 0.5, 1, 2 and 4 mg/kg/day) in different groups of normotensive and hypertensive rats (at the end of 3 weeks treatment by DOCA salt) was carried out and their effects on mean systolic blood pressure (MSBP) and mean heart rate (MHR) were evaluated using tail cuff method. Results: Our results indicated that chronic administration of auraptene (2, 4, 8 and 16 mg/kg/day) significantly reduced the MSBP in DOCA salt treated rats in a dose and time dependent manner. The percent of decreases in MSBP levels by the highest dose of auraptene (16 mg/kg) at the end of 4 th to 8 th weeks, were 7.00%, 10.78%, 16.07%, 21.28% and 27.54% respectively(

The Relaxant Activity of Safranal in Isolated Rat Aortas is Mediated Predominantly via an Endothelium-Independent Mechanism -Vasodilatory mechanism of safranal-

Objectives: Safranal is a pharmacologically active component of saffron and is responsible for the unique aroma of saffron. The hypotensive effect of safranal has been shown in previous studies. This study evaluates the mechanism for the vasodilatory effects induced by safranal on isolated rat aortas. Methods: To study the vasodilatory effects of safranal (0.2, 0.4 and 0.8 mM), we contracted isolated rat thoracic aorta rings by using 10-6-M phenylephrine (PE) or 80-mM KCl. Dimethyl sulfoxide (DMSO) was used as a control. The vasodilatory effect of safranal was also evaluated both on intact and denuded endothelium aortic rings. Furthermore, to study the role of nitric oxide and prostacyclin in the relaxation induced by safranal, we incubated the aortic rings by using L-NAME (10-6 M) or indomethacin (10-5 M), each for 20 minutes. Results: Safranal induced relaxation in endothelium-intact aortic rings precontracted by using PE or KCl in a concentration-dependent manner, with a maximum relaxation of more than 100%. The relaxant activity of safranal was not eliminated by incubating the aortic rings with L-NAME (EC50 = 0.29 vs. EC50 = 0.43) or with indomethacin (EC50 = 0.29 vs. EC50 = 0.35), where EC50 is the half maximal effective concentration. Also, the vasodilatory activity of safranal was not modified by endothelial removal. Conclusion: This study indicated that relaxant activity of safranal is mediated predominantly through an endothelium- independent mechanism

Effects of berberine on acquisition and reinstatement of morphine-induced conditioned place preference in mice

Objective: It has been shown that berberine, a major component of Berberis vulgaris extract, modulates the activity of several neurotransmitter systems including dopamine (Da) and N-methyl-D-aspartate (NMDA) contributing to rewarding and reinforcing effects of morphine. Drug craving and relapsing even after a long time of abstinence therapy are the most important problems of addiction. In the present study, we investigated the alleviating effects of berberine on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP) in mice. Materials and Methods: In male NMRI mice, the acquisition of CPP was established by 40 mg/kg of morphine sulphate injection and extinguished after the extinction training and reinstated by a 10 mg/kg injection of morphine.  The effects of different doses of berberine (5, 10, and 20 mg/kg) on the acquisition and reinstatement induced by morphine were evaluated in a conditioned place preference test. Results: The results showed that intraperitoneal administration of berberine (5, 10, and 20 mg/kg) did not induce conditioned appetitive or aversive effects. Injection of berberine (10 and 20 mg/kg) 2 h before the morphine administration reduced acquisition of morphine-induced CPP. In addition, same doses of berberine significantly prevented the reinstatement of morphine-induced CPP. Conclusion: These results suggest that berberine can reduce the acquisition and reinstatement of morphine-induced conditioned place preference and may be useful in treatment of morphine addiction