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Introduction: Ligands of adenosine A1Rs are potential candidates for the development of drugs for the treatment of paroxysmal supraventricular tachycardia, angina pectoris, hypertriglyceridemia, type 2 diabetes mellitus, neuropathic pain, and heart failure. At the same time, there is a deficiency of drugs that can regulate the functions of A1 receptors. A number of A1-antagonists are at the various stages of clinical trials; other drugs are not very selective or are characterized by an insufficient breadth of their therapeutic action. Therefore, the search for new medicinal compounds for the prevention and treatment of A1-depended diseases among nitro derivatives of tetrazolo[1,5-a]pyrimidine and 1,2,4-triazolo[1,5-a]pyrimidine is of scientific interest. Materials and methods: The search for active compounds was carried out by in silico and in vitro methods. At the first stage, a computer forecast of A1-antagonistic activity was carried out using the Microcosm BioS software. At the second stage, the prediction results were verified in vitro in a model of isolated mouse atria. Results and discussion: Based on the results of the prediction by the method of maximum similarity to standards, the most active compounds III, VIII, and XVII were selected. After testing the prediction results by the isolated atria method, the compound VIII was characterized by A1-blocking effect in vitro at a concentration of 10 µmol/L. Conclusion: The most promising compound with A1-blocking effect in vitro was identified; it is a derivative of tetrazolo[1,5-a]pyrimidine under the code of VIII. It is of interest for us for further in-depth study of its pharmacological properties. [ABSTRACT FROM AUTHOR]

Homeostasis of vascular tone is intricately and delicately maintained systemically and locally, by autonomic nerves and hormones in the blood and by intimal vasoactive substances, respectively. The balance can be acutely or chronically interrupted secondary to many alterations, especially under pathological conditions. Excessive matricellular glycoprotein thrombospondin 1 (TSP1) levels in circulation have been found to play an important role in ischemia-reperfusion injuries of different organs, by acutely suppressing vasorelaxation and chronically remodeling vascular bed. Our laboratory has been interested in identifying new drug moieties, which can selectively and effectively counteract TSP1-induced vascular dysfunction, in order to address associated clinical complications. Preliminary studies using computational docking and molecular models revealed potential drug candidates for further evaluation via vascular functional bioassay to prove the antagonism using an ex vivo vascular model. Herein, we described an efficient screening method for the identification of active drug candidates, by adapting a multiwire myograph system to perform a protocol with different treatments, in the presence of pathological levels of TSP1. We discussed the promising pharmacological evaluation results and suggested suitable modification for versatile applications. We also described the necessity of pre-determination of optimal resting tension to obtain the maximal response, if the experimental test model is different from those with determined optimal resting tension.

Context: Salsola imbricata Forssk. (Chenopodiaceae) has folkloric repute for the treatment of various gastrointestinal and respiratory ailments. Objective: The present study investigates spasmolytic and bronchorelaxant effects of S. imbricata. Materials and methods: The crude aqueous-ethanol extract of the aerial parts of S. imbricata and its fractions, in cumulative concentrations (0.01–10 mg/mL), were tested on contractions of isolated rabbit jejunum and tracheal preparations. Furthermore, concentration response curves (CRCs) of Ca+2 and carbachol were constructed in the absence and presence of the extract. Standard organ bath methods were used. Results: The crude extract relaxed spontaneous, K+ (80 mM) and carbachol (1 μM)-induced contractions in jejunum preparations with respective EC50 values of 0.40 (0.35–0.46), 0.69 (0.60–0.79) and 0.66 (0.57–0.75) mg/mL. It shifted Ca+2 CRCs rightward in nonparallel manner. In isolated tracheal preparations, the crude extract caused relaxation of K+ (80 mM) and carbachol (1 μM)-induced contractions with EC50 values of 0.86 (0.75–0.98) and 0.74 (0.66–0.84) mg/mL, respectively. It displaced carbachol CRCs rightward with suppression of maximal response. In both tissues, pretreatment with propranolol (1 μM) caused rightward shift in inhibitory CRCs of the extract against carbachol-induced contractions. The ethyl acetate fraction was found more potent in relaxing smooth muscle contractions than the parent extract and its aqueous fraction. Discussion and conclusion: The results suggest that the spasmolytic and bronchorelaxant activities of S. imbricata are related to Ca+2 antagonistic and β-adrenergic agonistic effects, thus justifying some of the traditional uses of the plant.

Isometric or isotonic transducers have traditionally been used to study the contractile/relaxation effects of drugs on isolated tissues. However, these mechanical sensors are expensive and delicate, and they are associated with certain disadvantages when performing experiments in the laboratory. In this paper, a method that uses an image sensor to measure the contractile effect of drugs on blood vessel rings and other luminal organs is presented. The new method is based on an image-processing algorithm, and it provides a fast, easy and non-expensive way to analyze the effects of such drugs. In our tests, we have obtained dose-response curves from rat aorta rings that are equivalent to those achieved with classical mechanic sensors.

Context:Salsola imbricataForssk. (Chenopodiaceae) has folkloric repute for the treatment of various gastrointestinal and respiratory ailments. Objective:The present study investigates spasmolytic and bronchorelaxant effects ofS. imbricata. Materials and methods:The crude aqueous-ethanol extract of the aerial parts ofS. imbricataand its fractions, in cumulative concentrations (0.01–10 mg/mL), were tested on contractions of isolated rabbit jejunum and tracheal preparations. Furthermore, concentration response curves (CRCs) of Ca+2and carbachol were constructed in the absence and presence of the extract. Standard organ bath methods were used. Results:The crude extract relaxed spontaneous, K+ (80 mM) and carbachol (1 μM)-induced contractions in jejunum preparations with respective EC50values of 0.40 (0.35–0.46), 0.69 (0.60–0.79) and 0.66 (0.57–0.75) mg/mL. It shifted Ca+2CRCs rightward in nonparallel manner. In isolated tracheal preparations, the crude extract caused relaxation of K+ (80 mM) and carbachol (1 μM)-induced contractions with EC50values of 0.86 (0.75–0.98) and 0.74 (0.66–0.84) mg/mL, respectively. It displaced carbachol CRCs rightward with suppression of maximal response. In both tissues, pretreatment with propranolol (1 μM) caused rightward shift in inhibitory CRCs of the extract against carbachol-induced contractions. The ethyl acetate fraction was found more potent in relaxing smooth muscle contractions than the parent extract and its aqueous fraction. Discussion and conclusion:The results suggest that the spasmolytic and bronchorelaxant activities ofS. imbricataare related to Ca+2antagonistic and β-adrenergic agonistic effects, thus justifying some of the traditional uses of the plant. [ABSTRACT FROM PUBLISHER]

Ethnopharmacological relevance Nymphaea lotus , which is widely distributed throughout tropical Africa, enjoys a number of ethnomedical uses in Nigeria. Traditionally, the rhizomes of N. lotus are used to cure diarrhoea. Aim of study This study aims to evaluate the antidiarrhoeal activity of the methanol rhizome extract of N. lotus plant in laboratory animals. Materials and methods The extract was screened for activity against castor oil-induced diarrhoea and magnesium sulphate-induced diarrhoea as well as effect on gastric transit time in mice. The effect of methanol rhizome extract of Nymphaea lotus on the perfused isolated tissue preparation was also determined. Results For castor oil-induced diarrhoea, the extract at doses of 200, 400 and 800 mg/kg produced significant reduction in the frequency of diarrhoea (at p<0.001, p<0.001 and p<0.01 respectively). The extract at 800 mg/kg produced a significant delay in onset of diarrhoea (p<0.05) comparable to loperamide (3 mg/kg). The frequency of magnesium sulphate-induced diarrhoea was also significantly reduced in the groups treated with 200, 400 and 800 mg/kg of the extract at p<0.001, p<0.001 and p<0.01 respectively. At doses of 200 mg/kg and 400 mg/kg, the protection produced was comparable to loperamide, 3 mg/kg. All treated groups produced significant reduction in the transit of charcoal meal along the intestinal tract at p<0.001. The extract at low concentration (4×10 −4 –6.4×10 −2 mg/ml) had contractile effect on the tone of contraction of the rabbit jejunum while at higher concentrations (8×10 −2 –512×10 −2 mg/ml) produced significant reduction in the tone and rate of spontaneous contraction of rabbit jejunum. The extract at lower concentrations (4×10 −4 –2×10 −2 mg/ml) has no effect on contraction of the guinea pig ileum while higher concentrations (4×10 −2 –512×10 −2 mg/ml) produced significant relaxant activity on guinea pig ileum. Conclusion This study has shown that the methanol rhizome extract of N. lotus has antidiarrhoeal properties thus justifying its use by the local population for this purpose. [ABSTRACT FROM AUTHOR]

Objective: To establish a method of detecting the tension of isolated pregnant rat myometrium strips in the reproductive toxicity of drugs. Methods: SD rats were treated with drugs on the 6th-15th(GD6-15) of gestation, the uterine smooth muscle was taken on the 20th(GD20) of gestation and treated with different concentrations of oxytocin and magnesium sulfate solution to choose the best conditions for testing. Then the effect of different dosages of drugs on the activity of isolated uterus smooth muscle of pregnant rats were observed by RM-6240 BD biological signaling system. Results: 0.007 U/m L magnesium sulfate and 0.008 mol/m L oxytocin were selected as the best concentration. With the increase of drug dosage, the frequency and tension of pregnant uterine smooth muscle of each group all showed a rising trend. While after the treatment with magnesium sulfate, the amplitude, frequency and tension of uterine smooth muscle of each dose group tends to decrease, but no significant difference was found between each dose group and control group(P>0.05). Conclusion: A method for the determination of muscle tension from isolated uterus of pregnant rats was established, which could better reflect the toxicity of the test substances on pregnant rats’ uterine muscle and comprehensively evaluate the reproductive toxicity. [ABSTRACT FROM AUTHOR]

Isometric or isotonic transducers have traditionally been used to study the contractile/relaxation effects of drugs on isolated tissues. However, these mechanical sensors are expensive and delicate, and they are associated with certain disadvantages when performing experiments in the laboratory. In this paper, a method that uses an image sensor to measure the contractile effect of drugs on blood vessel rings and other luminal organs is presented. The new method is based on an image-processing algorithm, and it provides a fast, easy and non-expensive way to analyze the effects of such drugs. In our tests, we have obtained dose-response curves from rat aorta rings that are equivalent to those achieved with classical mechanic sensors. [ABSTRACT FROM AUTHOR]

Background: Aloe vera is used in traditional medicine to treat hypertension. The purpose of this study was to examine the effect of the aqueous extract of Aloe vera (compared to Na+ nitroprusside) on the contraction of the rat isolated thoracic aorta precontracted with 20 mM potassium chloride. Materials and Methods: In this study, 18 rings isolated from the thoracic aorta of 9 Wistar rats (250-300g) were divided into three groups. On the loaded tissue, a tension less than 2 g was applied which then was precontracted with potassium chloride (20mM) in organ bath containing the carbogen-Krebs solution. Changes in aorta contractility in response to cumulative application of vehicle (group I), extract (group II: 5-50 mg/ml) and Na+ Nitroprusside (group III: 0.0001-10 μM) were measured isometrically. Results: The results showed that although Aloe vera has a decreasing effect on the contraction induced by potassium chloride (20mM), this effect was less than the cumulative effect of Na+ nitroprusside (P<0.05). Conclusion: The possible antihypertensive mechanism of Aloe vera may be for reducing the contractility of vascular smooth muscle and this effect is weaker than the effect of nitroprusside. Hence, Aloe vera can be used as a potential drug for lowering the high blood pressure. [ABSTRACT FROM AUTHOR]

Abstract: It was recently reported that the hexapeptide Ac-RYYRIK-ol binds with high affinity nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors and competitively antagonizes N/OFQ actions in the mouse vas deferens assay. Here we further describe the in vitro and in vivo pharmacological features of this NOP receptor ligand. In mouse brain homogenate the degradation half life of Ac-RYYRIK-ol (2.48 min) was significantly higher than that of the parent compound Ac-RYYRIK-NH2 (1.20 min). In the electrically stimulated mouse vas deferens, Ac-RYYRIK-ol (10–1000 nM) competitively antagonized the inhibitory effect of N/OFQ (pA2 =8.46), while in the isolated mouse colon the hexapeptide mimicked N/OFQ contractile effects thus behaving as a NOP receptor agonist (pEC50 =9.09). This latter effect was no longer evident in colon tissues taken from mice knock out for the NOP receptor gene (NOP−/−). In vivo in mice, similarly to N/OFQ, Ac-RYYRIK-ol (dose range 0.001–1 nmol) produced: i) pronociceptive effects after intracerebroventricular (i.c.v.) administration and antinociceptive actions when given intrathecally (i.t.) in the tail withdrawal assay; ii) inhibition of locomotor activity and iii) stimulation of food intake after supraspinal administration. Finally, in the forced swimming test, Ac-RYYRIK-ol was inactive per se, but reversed the antidepressant-like effects elicited by the NOP receptor selective antagonist UFP-101 ([Nphe1,Arg14,Lys15]N/OFQ-NH2). Thus, in all these in vivo assays Ac-RYYRIK-ol mimicked the actions of N/OFQ showing however higher potency. In conclusion, Ac-RYYRIK-ol displayed a complex pharmacological profile which is likely due to the low efficacy agonist nature of this novel ligand of the NOP receptor. The high potency, selectivity of action, and in vivo effectiveness make Ac-RYYRIK-ol a useful pharmacological tool for future studies in the field of N/OFQ and its NOP receptor. [Copyright &y& Elsevier]

Homeostasis of vascular tone is intricately and delicately maintained systemically and locally, by autonomic nerves and hormones in the blood and by intimal vasoactive substances, respectively. The balance can be acutely or chronically interrupted secondary to many alterations, especially under pathological conditions. Excessive matricellular glycoprotein thrombospondin 1 (TSP1) levels in circulation have been found to play an important role in ischemia-reperfusion injuries of different organs, by acutely suppressing vasorelaxation and chronically remodeling vascular bed. Our laboratory has been interested in identifying new drug moieties, which can selectively and effectively counteract TSP1-induced vascular dysfunction, in order to address associated clinical complications. Preliminary studies using computational docking and molecular models revealed potential drug candidates for further evaluation via vascular functional bioassay to prove the antagonism using an ex vivo vascular model. Herein, we described an efficient screening method for the identification of active drug candidates, by adapting a multiwire myograph system to perform a protocol with different treatments, in the presence of pathological levels of TSP1. We discussed the promising pharmacological evaluation results and suggested suitable modification for versatile applications. We also described the necessity of pre-determination of optimal resting tension to obtain the maximal response, if the experimental test model is different from those with determined optimal resting tension. [ABSTRACT FROM AUTHOR]

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We aimed to investigate factors contributing to ureteral responses and establish a reliable porcine model for studying ureteral contractility. Isolated ureteral strips from young (6-month old) and older (3-year old) pigs were mounted in organ baths and subjected to phenylephrine, 5-HT, carbachol and histamine. Ureteral strips developed bursts of contractile activity which was measured as area under the curve (AUC) and frequency. Phenylephrine and 5-HT-induced responses of proximal and distal ureters were obtained, in the presence and absence of indomethacin (10 μM) and L-NNA (100 μM), and the influence of an intact mucosa was examined. Phenylephrine and 5-HT-induced contractile responses were greater than those to carbachol in the porcine ureter. In fact, responses to carbachol were only present in ureters from older animals. Ureters suspended longitudinally had increased phenylephrine-induced contractions compared to those suspended circularly (p <.05). A greater amount of tissue strips developed spontaneous contractions from the proximal region compared to distal (83% vs 25%). There was an increase in maximum phenylephrine-induced responses in the distal ureter when compared to the proximal ureter (p <.05). In the presence of indomethacin, only 5-HT-induced contractions in the young animals were depressed (p <.05) while L-NNA did not affect any ureteral responses. The intact mucosa significantly decreased contractile responses to phenylephrine and 5-HT in the porcine ureter. The complexity of ureteral contractions depicting bursts of phasic activity requires AUC assessment. Porcine ureteral contractile properties, such as regional differences, influence of mucosa and lack of response to carbachol, are similar to those reported in the literature for human ureter. [ABSTRACT FROM AUTHOR]