Microwave assisted synthesis and anti-lipase activity of some new fluorine-containing benzimidazoles.

In this study, a new series of fluorine containing benzimidazoles (4a-l) and bisbenzimidazoles (6a-c, 8) were synthesized by the reaction of o-phenylenediamines with iminoester hydrochlorides (3a-l, 7) in methanol under microwave irradiation. The structures of these newly synthesized compounds were identified by IR, (1)H-NMR, (13)C-NMR, mass spectroscopy and elemental analysis data. The synthesized compounds were screened for their pancreatic lipase activities. Our results indicate that the compounds 6a, 6b and 6c can serve as an anti-lipase agent. The compounds 6b and 6c inhibited pancreatic lipase activity by 84.03% and 97.49% at a concentration of 3 µg/mL, respectively.

Rapid synthesis and lipase inhibition activity of some new benzimidazole and perimidine derivatives.

This study presents a synthesis of new series of some benzimidazole, bisbenzimidazole and perimidine derivatives via microwave technique, which, leads to the good product yields and short reaction times. The structure of newly synthesized compounds was confirmed by 1H-NMR and 13C-NMR spectra. These compounds were screened for their lipase inhibition activity. Then, all compounds were evaluated with regard to pancreatic lipase activity, and some of the 2-substituted perimidines, bisperimidine and bisbenzimidazole derivatives showed lipase inhibition at various concentrations.

G protein-coupled estrogen receptor1 (GPER1) may mediate Rho-kinase (ROCK-2) up-regulation in coronary endothelial cells.

OBJECTIVE: Effect of estrogenic compounds and 17ß-estradiol (E2), which induces endothelial cell motility, was investigated on ROCK-2 expression in rat coronary vascular endothelial cells (CVEC). METHODS: The CVEC were isolated from the heart of Wistar rats by collagenase (0.04%) and incubated with E2 (1-100 nM), estrogen receptor α (ERα) agonist: propyl pyrazole triol (PPT, 10 nM); ERß agonists: (2,3-bis(4-hydroxyphenyl)-propionitrile, DPN, 10 nM) and E2-conjugate with bovine serum albumin (E2-BSA, 1 nM); and GPER1 agonist: G1 (100 nM). Furthermore, the effect of combination of E2 with estrogen receptors (ERs) antagonist and GPER1 agonist, ICI-182780 (10 µM), physiological estrogen antagonists: progesterone (P4, 10-100 nM) and testosterone (T, 10-100 nM); transcription inhibitor: actinomycin-D (1 µg/ml); GPER1 antagonist: G-15 (100 nM), superoxide dismutase, (SOD, 500 U/ml); Gi/o protein inhibitor: pertussis toxin (PTX, 100 µg/ml); and epidermal growth factor receptor (EGFR) blocker: AG-1478 (10 µM) was tested. After 24h incubation, ROCK-2 and GPER1 protein expressions were detected in the CVEC by Western-blotting. RESULTS: E2, ICI-182780, and G1 but not E2-BSA significantly up-regulated ROCK-2 expression, which was suppressed by actinomycin-D, PTX, AG-1478, and G-15. However, PPT and DPN had no effects on the ROCK-2 expression. ICI-182780, P4, T or SOD did not antagonize the E2 action. GPER1 expression was demonstrated in the CVEC. CONCLUSIONS: Estrogens could up-regulate ROCK-2 in the rat CVEC through GPER1 and EGFR transactivation.

Exercise training enhances flow-mediated dilation in spontaneously hypertensive rats.

This study investigated the effect of exercise training on the flow-mediated dilation (FMD) in gastrocnemius muscle arteries from spontaneously hypertensive rats (SHR). SHR and WKY rats were divided into sedentary and exercised groups. After swimming exercise for eight weeks, the isolated arteries were mounted on pressurized myograph and FMD responses examined. The role of nitric oxide (NO), prostaglandins (PGs) and endothelium derived hyperpolarizing factor (EDHF) on FMD were assessed by obtaining dilation responses in the presence and absence of pharmacological antagonists. N(omega)-nitro-L-arginine methyl ester (L-NAME), indomethacin (INDO) and tetraethylamonium (TEA) were used to inhibit nitric oxide synthase, cyclooxygenase and EDHF-mediated responses, respectively. The FMD response was significantly blunted in arteries of SHR compared with WKY rats, and, improved by exercise training in SHR (SHR-ET) group. In SHR arteries, L NAME and TEA did not affect dilation responses to flow, while INDO led to a significant enhancement in this response. Although dilation response was not altered by L-NAME in arteries obtained from trained SHR, TEA caused a significant attenuation and INDO led to significant increases. These results demonstrate that exercise training improves FMD in SHR, and, this enhancement induced by exercise training occurs through EDHF-mediated mechanism(s).

Posttransplantation therapeutic rapamycin concentration protects nitric oxide-related vascular endothelial function: comparative effects in rat thoracic aorta and coronary endothelial cell culture.

OBJECTIVE: To investigate the potential effects of therapeutic dosages of the immunosuppression agent rapamycin on endothelial function with regard to nitric oxide (NO) synthesis in rat thoracic aorta in vivo and rat coronary endothelial cells in vitro. MATERIALS AND METHODS: Male Wistar rats were injected with rapamycin, 1.5 mg/kg/d intraperitoneally for 14 days. After the rats were sacrificed, the thoracic aortas were suspended in organ chambers and evaluated for endothelium-dependent and endothelium-independent vascular responses. RESULTS: Rapamycin administration resulted in increased relaxant responses to L-arginine and to greater concentrations of the calcium ionophore (A23187) in the aortas. However, potassium chloride, acetylcholine, sodium nitroprusside, and N(G)-nitro-L-arginine methyl ester responses remained unchanged. In addition, phenylephrine-induced contractions were significantly decreased in the aortas regardless of the presence of functional endothelium. In a series of in vitro experiments, isolated rat coronary endothelial cells were incubated with therapeutic concentrations of rapamycin (10 nmol/L). Nitrite accumulation in the supernatants revealed that rapamycin decreased nitrite release induced by interleukin-1beta but did not affect basal or A23187-stimulated nitrite levels. Western blot analysis demonstrated that rapamycin decreased inducible NO synthase protein expression in coronary endothelial cells. CONCLUSION: Posttransplantation therapeutic concentrations of rapamycin not only preserve vascular endothelial function mediated by NO synthesis but possibly interact in vivo with adrenergic receptors in favor of vasodilatory mechanisms.

Vascular endothelial dysfunction in cyclosporine-treated rat aortas is not associated with serum total homocysteine levels.

OBJECTIVES: Elevation of serum total homocysteine (tHcy) is considered to contribute to endothelial cell dysfunction, which is considered to be the initial event in posttransplant vascular disease. We sought to investigate whether an association existed between serum tHcy levels and vascular endothelial function during cyclosporine (CsA) treatment. MATERIALS AND METHODS: Endothelium-dependent and -independent relaxation responses (to acetylcholine [ACh] and sodium nitroprusside [SNP]) were determined on thoracic aortae from CsA-treated rats (5 mg kg/d, subcutaneously, for 14 days). A correlation analysis was performed between ACh responses and tHcy levels. RESULTS: CsA decreased the responses to ACh and the pD(2) values of the concentration-response curves compared with controls (P < .05). Responses to SNP and serum tHcy levels were unchanged among the groups. tHcy negatively correlated with the ACh pD(2) values among control (r = -0.69; P < .05) and vehicle (r = -0.73; P < .05) groups, indicating that the increase in tHcy was associated with decreased sensitivity to ACh. In CsA-treated rats, no association was observed between these parameters. Also, no correlation was noted between CsA concentrations and tHcy levels. CONCLUSION: These data suggested a possible link between serum tHcy and decreased vascular sensitivity to endothelium-dependent vasorelaxation in control aortae, but CsA-induced vascular endothelial dysfunction was not associated with an effect of the drug on homocysteine metabolism.

Antioxidant vitamins C and E ameliorate hyperglycaemia-induced oxidative stress in coronary endothelial cells.

OBJECTIVE: Vitamins C and E have protective features in many disease states associated with enhanced oxidative stress. The aim of this study was to investigate whether vitamin(s) C and/or E modulate hyperglycaemia-induced oxidative stress by regulating enzymatic activities of prooxidant, i.e. NAD(P)H oxidase and/or antioxidant enzymes, namely endothelial nitric oxide synthase (eNOS), superoxide dismutase, catalase and glutathione peroxidase, using coronary microvascular endothelial cells (CMEC). METHODS: CMEC were cultured under normal (5.5 mM) or high glucose (22 mM) concentrations for 7 days. The enzyme activities were determined by specific assays. The levels of O(2) (-) and nitrite were measured by cytochrome c reduction and Griess assays respectively. RESULTS: Hyperglycaemia did not alter eNOS activity or overall nitrite generation, an index of NO production. However, it increased NAD(P)H oxidase and antioxidant enzyme activities (p < 0.05). Specific inhibitors of NAD(P)H oxidase, i.e. phenylarsine oxide (0.1-3 microm) and 4-(2-aminoethyl)benzenesulfonyl fluoride (5-100 microm) and vitamins C and E (0.1-1 microm) significantly reduced prooxidant and antioxidant enzyme activities in CMEC exposed to hyperglycaemia (p < 0.01). The differences in enzyme activities were independent of increases in osmolarity generated by high glucose levels as investigated by using equimolar concentrations of mannitol in parallel experiments. CONCLUSIONS: Vitamins C and E may protect CMEC against hyperglycaemia-induced oxidative stress by concomitantly regulating prooxidant and antioxidant enzyme activities.

Investigation of the hypothalamo-pituitary-adrenal axis (HPA) by 1 microg ACTH test and metyrapone test in patients with primary fibromyalgia syndrome.

Primary fibromyalgia syndrome (PFS) is characterized by widespread chronic pain that affects the musculoskeletal system, fatigue, anxiety, sleep disturbance, headache and postural hypotension. The pathophysiology of PFS is unknown. The hypothalamic-pituitary-adrenal (HPA) axis seems to play an important role in PFS. Both hyperactivity and hypoactivity of the HPA axis have been reported in patients with PFS. In this study we assessed the HPA axis by 1 microg ACTH stimulation test and metyrapone test in 22 patients with PFS and in 15 age-, sex-, and body mass index (BMI)- matched controls. Metyrapone (30 mg/kg) was administered orally at 23:00 h and blood was sampled at 08:30 h the following morning for 11-deoxycortisol. ACTH stimulation test was carried out by using 1 microg (iv) ACTH as a bolus injection after an overnight fast, and blood samples were drawn at 0, 30 and 60 min. Peak cortisol level (659.4 +/- 207.2 nmol/l) was lower in the patients with PFS than peak cortisol level (838.7 +/- 129.6 nmol/l) in the control subjects (p < 0.05). Ten patients (45%) with PFS had peak cortisol responses to 1 microg ACTH test lower than the lowest peak cortisol detected in healthy controls. After metyrapone test 11-deoxycortisol level was 123.7 +/- 26 nmol/l in patients with PFS and 184.2 +/- 17.3 nmol/l in the controls (p < 0.05). Ninety five percent of the patients with PFS had lower 11-deoxycortisol level after metyrapone than the lowest 11-deoxycortisol level after metyrapone detected in healthy controls. We also compared the adrenal size of the patients with that of the healthy subjects and we found that the adrenal size between the groups was similar. This study clearly shows that HPA axis is underactivated in PFS, rather than overactivated.

Endotoxin-induced vascular hyporesponsiveness in rat aorta: in vitro effect of aminoguanidine.

The current study was designed to evaluate the endotoxin-induced alterations of the mechanisms involved in Ca(2+)handling within the rat thoracic aorta and further to examine whether in vitro inhibition of inducible nitric oxide synthase (iNOS) by aminoguanidine would account for this effect or not. Endothelium denuded aortic rings from rats injected with lipopolysaccharide (LPS) (5 mg kg(-1), i.p. 18 h prior to functional studies) or saline were mounted in isolated organ baths. Various experimental conditions were studied on paired rings of the same animal which were incubated in the presence or absence of aminoguanidine (100 microM). Phenylephrine contractility in Ca(2+)-containing buffer or in Ca(2+)-free buffer, contractions induced by K(+)depolarization and CaCl(2)in depolarized muscle and by caffeine exposure were significantly decreased in LPS-treated rings and were reversed by aminoguanidine exposure. Aminoguanidine also improved the contractions recorded while switching the Ca(2+)-free buffer to Ca(2+)-containing buffer. We conclude that endotoxin induces a generalized contractile defect in vascular smooth muscle including impairment in the influx of extracellular Ca(2+)and release of Ca(2+)from intracellular stores. An increase in iNOS activation leading to excessive nitric oxide synthesis, possibly non-endothelial in origin, may account for this defect.

Aprotinin impairs endothelium-dependent relaxation in rat aorta and inhibits nitric oxide release from rat coronary endothelial cells.

OBJECTIVE: Aprotinin, a non-specific serine protease inhibitor, reduces postoperative bleeding after coronary artery surgery. The mechanism of action for this 'blood-sparing' effect of aprotinin is only partially clarified. We therefore aimed to investigate the effect of aprotinin on the release of nitric oxide (NO), a vasodilator and antiaggregant factor, from rat coronary microvascular endothelial cells and on the NO-mediated endothelium-dependent relaxation of rat thoracic aorta. METHODS: Endothelium-intact and endothelium-denuded thoracic aortic rings from Wistar rats (250-300 g) were suspended in organ chambers. Contractile and relaxant responses in the absence and presence of aprotinin (125, 250 and 500 KIU/ml) were recorded via a mechanotransducer. Coronary microvascular endothelial cells (CMEC) were isolated on a Langendorff system by collagenase perfusion of the hearts from the same rats. Calcium ionophore- (1 microM) induced release of NO from confluent cells was determined spectrophotometrically by measuring its stable metabolites, nitrite and nitrate, via Griess reaction. RESULTS: Aprotinin selectively enhanced phenylephrine-induced contractions in endothelium-intact rat thoracic aortic rings, but not in the endothelium-denuded rings. The use of a nitric oxide synthesis inhibitor Nomega-nitro-L-arginine methyl ester (100 microM) on endothelium-intact rings produced a similar increase in phenylephrine-induced contractions. KCl-induced contractions remained unaltered. Aprotinin inhibited acetylcholine-, calcium ionophore- and L-arginine-induced endothelium-dependent relaxations, but not sodium nitroprusside-induced endothelium-independent relaxation. Aprotinin had no significant effect on basal nitrite-nitrate release from CMEC, while it inhibited calcium ionophore-induced total nitrite accumulation in the supernatants. CONCLUSION: Aprotinin selectively impairs endothelium-dependent relaxation as well as basal NO availability in rat thoracic aortic rings and inhibits NO release from rat CMEC. This effect of the drug may contribute to its 'blood-sparing' action and may also account for the increase in perioperative restenosis risk observed in clinical practice during aprotinin therapy.

Effect of dietary vitamin E supplementation on vascular reactivity of thoracic aorta in streptozotocin-diabetic rats.

The present study evaluated the effect of dietary vitamin E supplementation (1,000 mg/kg chow) on the alterations in vascular reactivity of streptozotocin-diabetic aorta of Wistar rats. After 12 weeks of treatment, thoracic aortic rings of rats were mounted in organ baths and contractile responses to phenylephrine and 5-hydroxytryptamine and relaxant responses to acetylcholine, calcium ionophore and sodium nitroprusside were assessed. Plasma vitamin E concentration as measured by HPLC was markedly decreased in diabetic rats and increased with dietary vitamin E supplementation. Induction of diabetes significantly impaired endothelium-dependent relaxations to acetylcholine and calcium ionophore in aortic rings, but did not change endothelium-independent relaxation to sodium nitroprusside. Vitamin E significantly improved the impaired endothelium-dependent relaxations, further it decreased the enhanced contractile response to phenylephrine and 5-hydroxytryptamine in diabetic rings. The mechanical denudation of endothelium or the chemical inhibition of endothelium-dependent relaxation with N(omega)-nitro-L-arginine methyl ester (100 micromol/l) significantly increased phenylephrine contractility in control rings and the rings of diabetic rats treated with vitamin E; such a difference was not observed in diabetic rats fed with normal diet. Liver and lung malondialdehyde concentrations, as an index of lipid peroxidation, were increased in diabetic rats and significantly decreased with vitamin E supplementation. It is concluded that dietary supplementation of vitamin E improved endothelial dysfunction in insulin-dependent model of uncontrolled diabetes, probably decreasing membranal lipid peroxidation.

Effect of nabumetone treatment on vascular responses of the thoracic aorta in rat experimental arthritis.

Nabumetone is a nonsteroidal anti-inflammatory (NSAI) drug which is known to cause less gastrointestinal damage than other NSAI drugs. This study was performed to evaluate whether nabumetone treatment might alter the vascular aberrations related to inflammation in a rat model of adjuvant-induced arthritis. Nabumetone treatment (120 or 240 mg x kg(-1) x day(-1), orally) was initiated on the 15th day of adjuvant inoculation and continued for 14 days. Arthritic lesions, vascular contractile and relaxant responses and gastroduodenal histopathological preparations were evaluated 29 days after adjuvant inoculation. The contractile responses of aortic rings to phenylephrine and KCl were increased in grade 2 arthritic rats. In grade 3 arthritis only the phenylephrine contractility was decreased. The relaxant responses to acetylcholine and sodium nitroprusside were decreased in grades 2 and 3. In healthy rats, nabumetone did not change the vascular responses. After treatment of arthritic rats with nabumetone, both the contractile and relaxant response of the aortic rings returned to normal, and arthritic score and paw swelling were reduced. Gastroduodenal histopathology did not show erosions or ulcers in any of the groups. In conclusion, nabumetone improved the systemic signs and vascular alterations in experimental arthritis without showing any gastrointestinal side effects.

Role of leukotrienes on coronary vasoconstriction in isolated hearts of arthritic rats: effect of in vivo treatment with CI-986, a dual inhibitor of cyclooxygenase and lipoxygenase.

In this study, coronary perfusion pressure and force of contraction were investigated in isolated hearts removed from arthritic rats by using the Langendorff method. A strong coronary vasoconstriction was determined in arthritic hearts which was associated with elevated levels of arachidonate 5-lipoxygenase (5-LOX) products, leukotriene B(4) (LTB(4)) and LTC(4) in coronary effluents. In vivo treatment with the dual inhibitor of cyclooxygenase (COX) and LOX, CI-986 (2 and 10 mg/kg/day) on days 14- 26 following adjuvant injection, prevented the coronary vasoconstriction and the increased production of LTB(4) and LTC(4). These results suggest that the coronary vasoconstriction in the isolated arthritic hearts is associated with an increased activity of the LOX system and CI-986 could have a preventive effect on constriction of coronary arteries.

Possible contribution of leukotrienes in the arrhythmogenic effects of digoxin on isolated guinea-pig hearts.

The effect of a leukotriene D4 (LTD4) receptor antagonist, L-648,051, was investigated in digoxin-induced cardiac toxicity in isolated guinea-pig hearts (Langendorff preparation). Digoxin infusion (25 microg.ml-1, 0.5 ml.min-1) increased perfusion pressure and contractile force initially, but decreased them later. The onset of first ventricular premature beats (VPBs) matched the increase phase, but the decrease phase was accompanied by ventricular tachycardia (VT) and fibrillation (VF). In the presence of L-648,051 (5 micromol. l-1), the initial phase was similar to that observed with digoxin alone, but the marked reduction was inhibited. This drug increased the concentration of digoxin required for VBSs and cardiac arrest, but it could not prevent the formation of VT and VF. The duration of VT was significantly decreased by L-648,051. It is concluded that the leukotriene receptor antagonist might have beneficial effects on digoxin-induced arrhythmias. Whether this effect depends on direct or indirect actions is uncertain.

Effects of MK-886, a leukotriene biosynthesis inhibitor, in a rabbit model of endotoxic shock.

Leukotrienes are one of the biological mediators that play a role in endotoxic shock. In this study, we investigated the effects of a leukotriene biosynthesis inhibitor, MK-886, in a rabbit model of endotoxic shock. Lipopolysaccharide (Escherichia coli serotype 055:B5) infusion (1 mg kg(-1) h(-1)) to rabbits caused a biphasic decline in arterial blood pressure and decreased the vasoresponsiveness to phenylephrine, potassium chloride, sodium nitroprusside and acetylcholine in abdominal aortic rings. Oral administration of MK-886 (3-(1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl(-2,2-+ ++dimethylpropanoic acid) (5 mg/kg) 3 h prior to lipopolysaccharide infusion significantly inhibited the decline in arterial blood pressure and enhanced the responsiveness to phenylephrine and acetylcholine, whereas the changes in sodium nitroprusside and potassium chloride responses were not significant. However, the pD2 (-log EC50) values for sodium nitroprusside in this group were higher than those of the group that received lipopolysaccharide alone. Neither the administration of the vehicle alone to endotoxemic rabbits, nor MK-886 administration to control animals, caused significant changes. These data suggest that MK-886 attenuates the hypotension and partially reverses the impaired vascular responsiveness observed in endotoxic shock.

Effect of vitamin E on vascular responses of thoracic aorta in rat experimental arthritis.

1. Vascular contractile and relaxant responses were evaluated in isolated aortic rings of adjuvant-induced arthritic rats in comparison with control rats, and the effect of an antioxidant treatment on the development of the arthritis was investigated by vitamin E administration (100 mg/kg/day, i.m., for 26 days). 2. Arthritis was induced by an intradermal injection of Freund's complete adjuvant into rat paw. Vascular responses, arthritic lesions and serum copper levels were evaluated after 26 days from adjuvant inoculation. 3. Serum copper levels were significantly lower in arthritic rats than in the control. 4. The contractile response of aortic rings to phenylephrine (PE), but not to KCl, was increased in preparations from arthritic rats, which could be explained by an enhancement of intracellular calcium contents. 5. Acetylcholine (Ach)-mediated endothelium-dependent and sodium nitroprusside (SNP)-mediated endothelium-independent relaxations were not changed significantly in vascular preparations from arthritic rats. 6. In arthritic rats, vitamin E treatment improved arthritic lesions with an increase in copper levels. Despite this ameliorating effect, vitamin E treatment caused an increase in contractile response to PE and a decrease in the relaxant response to Ach and SNP in arthritic rats. 7. These data show that vitamin E provides ameliorating effects in improving systemic signs of experimental arthritis, but it fails to restore abnormalities in vascular function, indicating that adjuvant-induced alterations in vascular function may include mechanisms other than oxygen-free radical formation.

Effects of a lipoxygenase inhibitor on digoxin-induced cardiac arrhythmias in the isolated perfused guinea-pig heart.

1. The effects of a lipoxygenase inhibitor, BW A4C, on digoxin-induced arrhythmias and cardiac dynamics (contractile force, perfusion pressure, heart rate) were investigated in Langendorff-perfused isolated guinea-pig hearts. In the control group, arrhythmias were induced by 25 micrograms/ml digoxin at a perfusion rate of 0.5 ml/min. In the treated groups, BW A4C (1 and 0.3 microM) perfused continuously from 15 min prior to digoxin until cardiac arrest occurred. Digoxin exposure (microgram/g wet weight of heart) for the occurrence of arrhythmias and cardiac arrest were the parameters evaluated to assess cardiotoxicity. 2. Digoxin caused a marked increase in leukotriene B4 release in the coronary effluent, and was collected during tachyarrhythmias. BW A4C markedly inhibited the digoxin-induced elevation of LTB4. 3. BW A4C (1 and 0.3 microM) did not prevent the onset of ventricular fibrillation and ventricular tachycardia despite a slight delay in the occurrence of ventricular fibrillation and cardiac arrest at the 0.3 microM concentration. 4. Contractile force increased significantly after digoxin infusion which was concomitant with the time of onset of arrhythmias. In the presence of BW A4C, the contractile force increased, but not significantly. Perfusion pressure increased initially after digoxin infusion in the absence and the presence of BW A4C, but not significantly. 5. These findings show that the lipoxygenase inhibitor lacked any protective action on digoxin-induced arrhythmias despite its effective suppression of digoxin-induced elevation of LTB4 in coronary effluent.

Platelet aggregation and atrial natriuretic peptide.

1. Isolated human platelets were used to investigate the effect of atrial natriuretic peptide (ANP) on in vitro platelet aggregation induced by epinephrine, ADP, collagen and 5-hydroxytryptamine. As a direct stimulant of particulate guanylate cyclase, ANP is known to have no direct effect on platelets which contain soluble guanylate cyclase. 2. In our experiments ANP inhibited epinephrine- and partially ADP-induced aggregation in vitro and this effect was suggested to be the result of an interaction of the peptide with adenylate cyclase in platelets. However, the concentrations required to produce this effect were higher than those expected to be found in the circulation both physiologically and pathologically. 3. We therefore conclude that though the peptide may inhibit-aggregation via adenylate cyclase activation, it is unlikely that ANP may play a direct role in preventing platelets aggregating.

Effects of ketamine, thiopental sodium and propofol on muscle contractures in rat diaphragm in vitro.

The effects of commonly used intravenous anaesthetic agents ketamine, thiopental sodium and propofol on the caffeine-alone or halothane-plus-caffeine-induced muscle contractures were investigated to determine safety for use in patients susceptible to malignant hyperthermia (MH). The muscle strips from rat diaphragm were exposed to one of these anaesthetic agents prior to challenge with caffeine 8 mmol/l alone or halothane 3% plus caffeine 8 mmol/l together. None of the three agents induced contractures when added alone. Ketamine 100 mumol/l and thiopental sodium 300 mumol/l augmented neither caffeine-alone nor caffeine-with-halothane contractures significantly and these two agents appear to be safe for use in MH-susceptible patients. In contrast, propofol 150 mumol/l augmented these contractile responses significantly and may not be recommended for use in patients known to be susceptible to this anaesthetic complication.