Sub-acute effects of diazinon on biochemical indices and specific biomarkers in rats: Protective effects of crocin and safranal

In this study, the effects of crocin and safranal were studied against sub-acute toxicity of diazinon (DZN) on specific biomarkers, biochemical indices and enzymes levels in rats. Vitamin E (200 IU/kg), safranal at doses 0.025, 0.05 and 0.1 ml/kg and crocin at doses 50, 100 and 200 mg/kg were injected intraperitoneally three times per week alone or with DZN (20 mg/kg/day, orally) for 4 weeks. The parameters were evaluated at the end of 4 weeks. Diazinon did not change serum urea, creatinine, cholesterol, triglyceride, total and direct bilirubin levels. Total protein and albumin concentrations were decreased by diazinon. Crocin, safranal and vitamin E prevented the effect of diazinon on some biochemical indices and enzymes levels. The levels of serum TNF-α, direct 8-iso-prostaglandin F_2α and soluble protein-100 β (S100β) were increased significantly by diazinon. The augmentation of direct 8-iso-prostaglandin F_2α and S100β levels by diazinon was significantly decreased by crocin, safranal and vitamin E. TNF-α level was significantly decreased in diazinon plus crocin 50 and 100 mg/kg treated groups compared to the diazinon group. This study showed that vitamin E, safranal and crocin could prevent diazinon induced enzymes elevation and augmentation of some specific biomarkers.     

Curcumin attenuates fructose-induced vascular dysfunction of isolated rat thoracic aorta rings

Context: Consumption of high fructose is associated with metabolic abnormalities, insulin resistance, and hypertension. It is not known whether this hypertensive effect of fructose is related to metabolic abnormalities or due to the direct effect of fructose on blood vessels.

Objective: Here, we investigated the direct effect of fructose on rat isolated aorta and the possible protective effect of curcumin.

Materials and methods: The isolated rat thoracic aorta rings were used to measure the contractile responses to different concentrations of both phenylephrine and KCl, and the relaxant response to acetylcholine (Ach). The effect of curcumin (1?µM) alone or in combination with tempol (1?mM), a superoxide dismutase mimetic agent, and N-{[3(amino-methyl)-phenyl]-methyl} ethanimidamide dihydrochloride (1400?W), a specific inducible nitric oxide synthase (iNOS) inhibitor, (1?µM) on fructose-treated aorta was compared. The aortic rings were incubated with different treatments for 60?min before starting the experiment. Changes in the intracellular calcium in response to KCl and nitric oxide levels were also measured.

Results and discussion: Fructose strongly increased the contractile response of aortic rings to both phenylephrine and KCl (E_max was increased by 147.3% and 150.5%, respectively) but it did not affect the relaxant response to Ach. Curcumin significantly decreased the hyper responsiveness of arterial rings to both vasopressors (for phenylephrine, E_max decreased from 147.3% in fructose incubated aorta to 81%, and for KCl, E_max decreased from 150.5% in fructose-incubated aorta to 77.24% respectively). Curcumin also reduces the intracellular calcium level (85% reduction in intracellular calcium). A 1400?W was the only agent that potentiates the effect of curcumin.

Conclusion: Fructose has a direct deleterious effect on aortic vascular reactivity. Curcumin can partially protect against fructose-induced impairment in vascular contractility via an antioxidant effect and reduction of elevated intracellular calcium.     

Crocin exerts anti-inflammatory and anti-arthritic effects on type II collagen-induced arthritis in rats

Context: Rheumatoid arthritis (RA) is a common systemic auto-immune disease, which is characterized by chronic and symmetry synovial inflammation. Crocin has been reported to exhibit anti-inflammatory effects in animal models.

Objective: This study investigates the anti-inflammatory and anti-arthritic effects of crocin on type II collagen-induced arthritis (CIA) in Wistar rats.

Materials and methods: The CIA rat model was established and randomly divided into five groups with or without crocin treatment (10, 20 or 40?mg/kg), which was started on day 21 after arthritis induction and persisted for 36 days. The symptoms and molecular mechanisms of CIA and crocin-treated CIA rats were compared and investigated.

Results: CIA rats presented severe RA symptoms, including high arthritis score, paw swelling, joint inflammation, bone erosion, chondrocyte death, cartilage destruction, enhanced expressions of matrix metalloproteinase (MMP) and pro-inflammatory cytokines. However, crocin could mitigate these symptoms. Crocin (40?mg/kg) exhibited the most efficient therapeutic function on CIA rats: the histological scores of joint inflammation, bone erosion, chondrocyte death, cartilage surface erosion, and bone erosion of CIA rats receiving 40?mg/kg crocin treatment were comparable to the normal rats. MMP-1, -3 and -13 protein expression levels of CIA rats with 40?mg/kg crocin treatment were decreased to levels similar to normal rats. Moreover, crocin could also inhibit the expression of TNF-α, IL-17, IL-6 and CXCL8 in serum and ankle tissues of CIA rats.

Conclusions: In summary, crocin exhibits therapeutic potential for RA, by mitigating the symptoms and inhibiting the pro-inflammatory factor expression.     

Improvement of cytotoxic and apoptogenic properties of crocin in cancer cell lines by its nanoliposomal form

Objective: Saffron Crocus sativus L. (Iridaceae) is known for anticancer properties. However, limited effort has been made to correlate these effects to the active ingredients of saffron. In the present study, cytotoxic effects of crocin, the major coloring compound in saffron, and its nanoliposomal form for better cellular delivery are investigated.

Methods: HeLa and MCF-7 cells were cultured and exposed to crocin (1, 2, and 4?mM) and liposomal crocin (0.5 and 1?mM). The 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was performed to assess cytotoxicity. Apoptotic cells were determined using propidium iodide (PI) staining of DNA fragmentation by flow cytometry.

Results: MTT assay revealed a remarkable and concentration-dependent cytotoxic effect of crocin on HeLa and MCF-7 cells in comparison with non-malignant cell line (L929). Crocin liposomal forms (IC₅₀ values after 48 h: 0.61, 0.64, and 1.2?mM) showed enhanced cytotoxic effect compared with the crocin (IC₅₀ after 48 h: 1.603?mM) in HeLa cells. Crocin and its liposomal form induced a sub-G1 peak in flow cytometry histogram of treated cells indicating apoptosis is involved in this toxicity. Liposomal encapsulation enhances apoptogenic effects of crocin on cancerous cells.

Conclusion: It might be concluded that crocin and its liposomes could cause cell death in HeLa and MCF-7 cells, in which liposomal encapsulation improved cytotoxic effects. They could be also considered as a promising chemotherapeutic agent in cancer treatment in future.     

The mechanism of protective effect of crocin against liver mitochondrial toxicity caused by arsenic III

In this study, we want to understand whether crocin could prevent mitochondrial damage caused by As III. For this purpose, we determined different mitochondrial toxicity endpoints caused by As III. We evaluated mitochondrial ROS formation, lipid peroxidation, mitochondrial membrane potential (MMP) collapse, mitochondrial outer membrane integrity and cytochrome c release. Our results showed that pretreatment with crocin at a concentration of 25?µg/ml significantly (p?相似文献   

Relaxant effects of the essential oil of Mentha pulegium L. in rat isolated trachea and urinary bladder

Objectives We evaluated the relaxant activity of the essential oil of Mentha pulegium L. (EOMP) and pulegone in rat isolated tracheal and bladder smooth muscles. Methods Isometric contractions of isolated tracheal and bladder strips from male Wistar rats were induced by KCl (K60; 60 mm ) or acetylcholine (ACh; 10 µm ). EOMP and its majory compound pulegone were incubated, after contracting agent, with the tissues in cumulating concentrations. Key findings EOMP (3–300 µg/ml) inhibited the contractions induced by ACh and K60 in both tissues, but was more effective against the contractions induced by K60 in trachea (IC50 = 40.47 ± 3.27 µg/ml) compared with ACh. Its relaxant action rules out ganglia and NO participation. Pulegone (10^?7 to 10^?3 m ) inhibited the contractions induced by ACh and K60 in both tissues. EOMP concentration‐dependently inhibited the contractions evoked by addition of CaCl₂ in depolarised trachea, suggesting inhibition of extracellular calcium entry. Conclusions These findings suggests that EOMP induced relaxant responses in pre‐contracted smooth muscles of rat trachea and bladder, which are likely to be mediated via inhibition of calcium entry, mainly by its major compound, pulegone. These effects are coherent with the popular use of EOMP as an antispasmodic agent.     

The effect of Hypericum perforatum on isolated rat aorta

Context: Different Hypericum species such as Hypericum perforatum (HP) L. and Hypericum triquetrifolium Turra are well known and widely used traditional medicine in Turkey.

Objectives: We investigated the effect of standardized HP extract on endothelium and vascular function.

Materials and methods: After suspending the aortas with endothelium in organ baths containing Krebs solution, contractile and relaxant responses were assessed in the absence and presence of HP (0.05?mg/ml).

Results: Although there were significant reductions in the contractile responses to phenylephrine (1113.73?±?164.11; 477.40?±?39.94; p?<?0.05) and potassium chloride (745.58?±?66.73; 112.58?±?26.58; p?<?0.05), no differences in the relaxant responses to acetylcholine (94.61?±?2.65; 87.79?±?9.40) and sodium nitroprusside (108.82?±?5.06; 106.43?±?7.45) were observed.

Discussion and conclusion: These data suggest that even the high dose of HP intervention does not bring any harmful effect on endothelium and smooth muscle function; meanwhile it might be beneficial on some of diseases accompanied with increased vascular contraction.     

Relaxant effect of Curcuma longa on rat tracheal smooth muscle and its possible mechanisms

Context: Turmeric is a spice obtained from the root of Curcuma longa L. (Zingiberaceae) with anti-aging, anticancer, anti-Alzheimer’s disease, antioxidant and other medicinal properties.

Objective: The relaxant effect of C. longa on rat tracheal smooth muscle and its possible mechanisms were investigated in this study.

Materials and methods: The relaxant effects of four cumulative concentrations of hydro-ethanol extract of C. longa (6.25, 12.5, 25, 50?mg/mL) were studied on tracheal smooth muscle precontracted by methacholine or KCl in non-incubated or incubated with different substances including propranolol, diltiazem, L-NAME, glibenclamide, atropine, chlorpheniramine, indomethacin and papaverine. The duration of the study was 84?days.

Results: In non-incubated tracheal smooth muscle, the extract of C. longa showed significant concentration-dependent relaxant effects (p?C. longa and theophylline in both methacholine and KCl-induced contraction conditions. In tissues incubated with propranolol, diltiazem, L-NAME and glibenclamide on methacholine-induced contraction and in tissues incubated with atropine, chlorpheniramine, indomethacin and papaverine on KCl-induced contraction, the extract also showed significant concentration-dependent relaxant effects (p?50 values of C. longa between non-incubated (16.22?±?0.62) and incubated tissues (atropine: 13.03?±?0.55, chlorpheniramine: 12.94?±?0.68, indomethacin: 14.80?±?0.57 and papaverine: 16.16?±?1.42) were not significantly different.

Conclusions: Tracheal smooth muscle relaxant effects of C. longa, were comparable to those of theophylline, which could be due to the presence of methylxanthines or its possible interaction with non-adrenergic non-cholinergic nervous system.     

Choice and concentration of contractile agent influence responses of rat aorta to vascular relaxant drugs

Concentration-response (relaxation) curves to diltiazem, forskolin, isobutylmethylxanthine (IBMX), procaterol, isoprenaline and sodium nitrite were obtained on isolated ring preparations of rat aorta contracted either submaximally or maximally with noradrenaline or KCl. Diltiazem was more potent on KCl-contracted than on noradrenaline-contracted preparations whether the preparations were submaximally or maximally contracted. The other relaxant drugs were at least 20-fold less potent against KCl than against noradrenaline, but only on maximally contracted preparations. On submaximally-contracted preparations there was no potency difference between preparations contracted with these two contractile agents. Increasing the KCl concentration had a marked influence on the location of the concentration-response (relaxation) curves to all the drugs except diltiazem. This influence was different for drugs that act via cyclic AMP and those that act via cyclic GMP. It is concluded that both the choice of contractile agent (noradrenaline or KCl) and the concentration (especially of KCl) influence relaxant responses of rat aorta to vasodilator drugs.     

依降钙素在SHR股动脉介导的收缩和舒张反应

INTRODUCTION The primary physiological function of calcitonin, apeptide hormone secreted from C-cells of the thyroidgland, is to modulate plasma Ca~(2 ) concentrations via itsactions on bone and kidney. The hypocalcemic effectof calcitonin is mainly caused by inhibition of osteoclasticbone resorption which is mediated by cyclic AMP-dependent protein kinase (PKA). Calcitonin can beused for treatment of metabolic bone disorders including     

藏红花素对糖尿病大鼠胸主动脉环舒缩功能的影响

目的:探究藏红花素对链脲佐菌素(STZ)诱导的糖尿病大鼠胸主动脉环舒缩功能的影响及其可能的机制.方法:雄性SD大鼠腹腔注射STZ诱导糖尿病模型,另设正常对照组.模型形成12周后,取正常组和模型组大鼠胸主动脉制成胸主动脉环,观察不同浓度藏红花素对胸主动脉环张力的影响并探究其可能的影响机制.结果:糖尿病状态下大鼠胸主动脉环舒张功能减弱,藏红花素能呈剂量依赖性舒张正常组内皮完整的胸主动脉环,且高于模型组,降低胸主动脉环的收缩张力,而L-硝基精氨酸(NLA)能减弱其舒血管效应.结论:藏红花素能改善糖尿病大鼠胸主动脉舒缩功能,其机制可能与内皮功能和一氧化氮有关.     

Effects of portal hypertension on responsiveness of rat mesenteric artery and aorta.

1. We have examined the effects of pre-hepatic portal hypertension on the responsiveness of rat small mesenteric arteries and aorta. Rats were made portal hypertensive by creating a calibrated portal vein stenosis, or sham-operated. 2. In rat mesenteric arteries, there was no significant difference between portal hypertensive and sham-operated animals in the contractile potency of noradrenaline (NA), but the maximum contractile responses to NA, U46619 and KCl were significantly increased in vessels from portal hypertensive animals. This altered maximum contractile response was not due to alterations in smooth muscle mass. 3. In rat mesenteric arteries, there were no significant differences between portal hypertensive and sham-operated animals in endothelium-dependent relaxations to acetylcholine (ACh). The difference between portal hypertensive and sham-operated rats in the maximum response to U46619 was maintained following a combination of methylene blue (1 microM) and NG-monomethyl-L-arginine (100 microM), suggesting that any differences in endothelial function do not explain differences in the response to vasoconstrictors. 4. In rat aorta, there were no significant differences between portal hypertensive and sham-operated animals in the contractile response to NA or KCl or in the endothelium-dependent relaxations to ACh. 5. In pithed rats, there was no difference between portal hypertensive and sham-operated animals in the pressor potency of NA. 6. It is concluded that portal hypertension produces an increase in the contractile response to the vasoconstrictors NA, U46619 and KCl in rat mesenteric arteries but not in the aorta. This suggests that the diminished responsiveness to vasoconstrictors reported in portal hypertensive rats in vivo is not due to a diminished responsiveness at the level of the vascular smooth muscle.     

Comparison of the effects of nitric oxide synthase inhibition and guanylate cyclase inhibition on vascular contraction in vitro and in vivo in the rat

We have investigated the differences between the nitric oxide synthase inhibitor (NOSI), L-NMMA, and the guanylate cyclase inhibitors (GCI), methylene blue and LY 83583, in their abilities to increase vasoconstrictor responses in vitro and in vivo. In rat small mesenteric arterial rings, 1 h exposure to the NOSI, L-NMMA (100 μM), and the GCI, methylene blue (10 μM), alone or in combination with L-NMMA, caused a significant reduction in the maximum relaxation to ACh in mesenteric arteries pre-contracted with the thromboxane mimetic U46619 (10 μM). Hence, both NOSI and GCI inhibit endothelium-dependent relaxations to ACh in rat small mesenteric artery. However, 1 h exposure to L-NMMA and L-NNA (both 100 μM), but not methylene blue (10 μM), significantly increased the contractile response to U-46619 (10 μM) in rat small mesenteric artery. It was decided to investigate further this difference between NOSI and methylene blue. In rat small mesenteric arterial rings, L-NMMA (10 μM) and LY 83583 (1–10 μM) significantly increased the contractile response to KCl (40 mM) or to noradrenaline (10 μM), when administered during the contraction. However, methylene blue (1–10 μM) increased the contractile response to KCl but not noradrenaline. In rat aortic rings, L-NMMA (100 μM), methylene blue (1–10 μM) and LY 83583 (1–10 μM) significantly increased the contractile response to KCl (40 mM) or to noradrenaline (1 μM). In the pithed rat preparation, L-NMMA (40.3 μmol kg^–1, i.v.) significantly increased the pressor response both to bolus injection of noradrenaline (3.13 nmol kg^–1) and to spinal pressor nerve stimulation. However, methylene blue (3.13–15.6 μmol kg^–1) or LY 83583 (4.0–40.0 μmol kg^–1), failed to affect pressor responses to either NA or pressor nerve stimulation. Hence, there are differences between NOSI and GCI in their abilities to increase vasoconstrictor responses, especially when comparing responses in vitro and in vivo. This suggests that nitric oxide has actions in addition to activation of guanylate cyclase to modulate vasoconstrictor responses, presumably by membrane hyperpolarisation, and that this action may be more important in vivo. Received: 2 May 1997 / Accepted: 19 June 1997     

Protective effect of thymoquinone,the main component of Nigella Sativa,against diazinon cardio-toxicity in rats

Several studies have shown that oxidative stress and cell damage can occur at very early stages of diazinon (DZN) exposure. The present study was designed to determine the beneficial effect of thymoquinone (Thy), the main component of Nigella sativa (black seed or black cumin), against DZN cardio-toxicity in rats. In the present experimental study, 48 male Wistar rats were randomly divided into six groups: control (corn oil gavages), DZN gavages (20?mg/kg/day), Thy gavages (10?mg/kg/day) and Thy?+?DVN gavages (2.5, 5 and 10?mg/kg/day). Treatments were continued for 28 days, then the animals were anesthetized by ether and superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), lactate dehydrogenize (LDH) and glutathione peroxide (GPX) activity was evaluated. In addition, glutathione (GSH) and malondialdehyde (MDA) the heart tissue and creatinephosphokinase-MB (CPK-MB) and troponin (TPI) levels and cholinesterase activity in the blood were evaluated. DZN-induced oxidative damage and elevated the levels of the cardiac markers CK-MB, TPI, MDA and LDH and decreased SOD, CAT and cholinesterase activity and GSH level compared with the control group. Treatment with Thy reduced DZN cardio-toxicity and cholinesterase activity. The success of Thy supplementation against DZN toxicity can be attributed to the antioxidant effects of its constituents. Administration of Thy as a natural antioxidant decreased DZN cardio-toxicity and improved cholinesterase activity in rats through the mechanism of free radical scavenging.     

Dual excitatory and smooth muscle‐relaxant effect of β‐phenylethylamine on gastric fundus strips in rats

β‐Phenylethylamine (β‐PEA) is a trace amine with chemical proximity to biogenic amines and amphetamines. It is an endogenous agonist of trace amine‐associated receptors (TAARs) that acts as a neuromodulator of classic neurotransmitters in the central nervous system. At high concentrations, β‐PEA contracts smooth muscle, and a role for TAARs in these responses has been postulated. The high dietary intake of trace amines has been associated with such symptoms as hypertension and migraine, especially after the intake of foods containing such compounds. In gastrointestinal tissues, TAAR expression was reported, although the effect of β‐PEA on gastric contractile behaviour is unknown. Here, isolated strips that were obtained from the rat gastric fundus were stimulated with high micromolar concentrations of β‐PEA. Under resting tonus, β‐PEA induced contractions. In contrast, when the strips were previously contracted with KCl, a relaxant response to β‐PEA was observed. The contractile effect of β‐PEA was inhibited by 5‐hydroxytryptamine (5‐HT) receptor antagonists (i.e., cyproheptadine and ketanserin) but not by the TAAR₁ antagonist EPPTB. In gastric fundus strips that were previously contracted with 80 mmol/L KCl, the relaxant effect of β‐PEA intensified in the presence of 5‐HT receptor antagonists, which was inhibited by EPPTB and the adenylyl cyclase inhibitor MDL‐12,330A. The guanylyl cyclase inhibitor ODQ did not alter the relaxant effects of β‐PEA. In conclusion, β‐PEA exerted dual contractile and relaxant effects on rat gastric fundus. The contractile effect appeared to involve the recruitment of 5‐HT receptors, and the relaxant effect of β‐PEA on KCl‐elicited contractions likely involved TAAR₁.     

Crocin Attenuates Kindling Development and Associated Cognitive Impairments in Mice via Inhibiting Reactive Oxygen Species‐Mediated NF‐κB Activation

Crocin is a pharmacologically active carotenoid pigment mainly present in the stigmas of Crocus sativus L. (Iridaceae). It has been well explored in experimental animal models of cognitive impairments, depression, anxiety and epilepsy. This study was designed to understand the effect of crocin on pentylenetetrazol (PTZ)‐induced kindling development and its associated cognitive deficit in mouse. Crocin treatment at 5, 10 and 20 mg/kg p.o. doses showed a marked reduction in severity of PTZ‐induced seizures. There was an increase in novel object preference index and discrimination ratio in the crocin‐treated groups in the novel object recognition test. Its treatment also increased percentage spontaneous alternations in T‐maze test at all the tested doses. Histopathological examination by Nissl staining showed a reduction in dark neurons in the hippocampal pyramidal layer of crocin‐treated animals in contrast to vehicle control, indicating a decrease in neuronal damage. Biochemical estimations showed a significant increase in superoxide dismutase activity and reduced reactive oxygen species (ROS) in the hippocampus of crocin‐treated animals. Immunohistochemistry results revealed attenuation in the levels of nuclear factor‐κB (NF‐κB) and phosphorylated NF‐κB in the hippocampal sections of crocin‐treated animals. The results of this study concluded that crocin treatment increased seizure threshold, thus inhibiting PTZ‐induced kindling development and improving cognitive functions. The effect was found to be due to suppression of seizure‐induced ROS generation and its linked NF‐κB pathway‐associated neuronal damage.     

Investigation of the antimuscarinic and other actions of proadifen in-vitro

The possibility that proadifen (SKF 525A) antagonizes endothelium-dependent relaxations to acetylcholine (ACh) in isolated blood vessel preparations via a muscarinic receptor blocking action has been investigated. In phenylephrine-contracted rat isolated aortic ring preparations (with endothelium), proadifen (10–100 μm) shifts ACh relaxant curves to the right without affecting the maximal response, yet endothelium-dependent relaxations to ATP are unaffected. At lower concentrations, proadifen (1–10 μm) (i) antagonizes negative inotropic responses to ACh and ATP in guinea-pig left atria, (ii) antagonizes contractile responses to ACh and elevated [K⁺] in guinea-pig ileal preparations, (iii) displaces (?)-[³H]quinuclidinyl benzilate from muscarinic binding sites in membrane homogenates of guinea-pig ileal longitudinal muscle and (iv) reduces contractile responses to elevated K⁺] in rat aortic ring preparations. It is concluded that proadifen may possess (i) complex interactions with muscarinic receptors and (ii) Ca²⁺ entry blocking properties in concentrations 10–100 times lower than those reported to inhibit cytochrome P450-catalysed reactions.     

The relaxing effect of BDF 9148 on the KCl-contracted aorta isolated from normo- and hyper-tensive rats

BDF 9148, a positive cardiac inotrope, relaxes the rat isolated portal vein and the KCl-contracted rat aorta. The aims of our study were to determine the mechanism of action of BDF 9148, and to ascertain whether the relaxing effect of BDF 9148 was maintained in the presence of the hypertrophy associated with hypertension, by investigating the effects of BDF 9148 on the contractility and electrophysiology of aortae of Wistar Kyoto normotensive rats (WKY) and Spontaneously Hypertensive Rats (SHRs). High concentrations of veratridine contracted the quiescent rat aorta. BDF 9148 had no effect on the quiescent, but relaxed the KCl-contracted WKY and SHR aorta by a tetrodotoxin insensitive mechanism, and these relaxations decreased with age but were not greatly altered by hypertrophy. The verapamil relaxations of the KCl-contracted aorta were not altered by age or hypertrophy. The ability of KCl to depolarise the aorta was reversed by verapamil, but not by BDF 9148. On the contracted rat aorta, the relaxant responses to acetylcholine were abolished by removal of the endothelium but potentiated by IBMX (10^–6 M), and the responses to isoprenaline were inhibited by propranolol (10^–6 M) but potentiated by forskolin (10^–7 M). The relaxation responses of the KCl-contracted aorta to BDF 9148 were not altered by removal of the endothelium, or by propranolol, forskolin and IBMX. In summary, the effects of verapamil and BDF 9148 on the aorta are different, and thus it is unlikely that the relaxant responses to BDF 9148 on the aorta are due to calcium channel blocking activity. The mechanism of the relaxant effect of BDF 9148 on the aorta remains unknown, but we have shown the response is endothelium-independent, and not mediated by sodium channel opening, hyperpolarization, β-adrenoceptors, or by stimulating adenylate cyclase or guanylate cyclase. Received: 12 March / Accepted: 8 October 1997     

Chronic 17β-estradiol augments relaxant role of basal nitric oxide in blood vessels from rats with heart failure

The effects of chronic 17β-estradiol on endothelium-dependent relaxation to acetylcholine (ACh) and contraction to N ^G-nitro-l-arginine methyl ester (l-NAME), and endothelium-independent relaxation to sodium nitroprusside (SNP) were examined on blood vessels from rats with chronic heart failure (CHF). Two groups of ovariectomized female (50–60 days) rats were implanted with pellets containing 17β-estradiol (25 μg/day) or vehicle, and given ligation of the left main coronary artery 1 week later. Another group of ovariectomized rats was implanted with vehicle pellets, and sham-operated. After 7 weeks, thoracic aortic rings, pulmonary artery rings, and portal vein strips were prepared for in vitro studies. Relative to sham-operated rats treated with the vehicle, vessels from vehicle-treated, coronary-ligated rats had similar relaxation to ACh and SNP but reduced response to l-NAME that was significant (P<0.05) for the aorta and portal vein but not pulmonary artery. Treatment of ligated rats with 17β-estradiol augmented responses to l-NAME in the aorta, pulmonary artery and portal vein to values above those in sham-operated rat. 17β-Estradiol did not affect relaxation of any vessels to SNP and increased maximum relaxation to ACh only in the portal vein. Hence, 17β-estradiol enhances the relaxant role of basal nitric oxide in CHF. Received: 17 June 1998 / Accepted: 21 September 1998