PREVENTION OF DIAZEPAM-INDUCED THROMBOPHLEBITIS WITH CREMOPHOR AS A SOLVENT

In 104 patients undergoing anaesthesia of short duration, twodifferent solvents, propylene glycol and cremophor, were comparedin a double-blind trial. Diazepam 10 mg in a coded solutionwas injected into a superficial vein of the hand using a small-gaugeneedle. The vein was examined after 14 days. The frequency ofthrombophlebitis with propylene glycol was 62.2% and with cremophor3.4% (P> 0.001). The frequency of pain on injection was alsoin favour of the new solvent (P < 0.001). The possibilityof anaphylactic reactions accredited to cremophor, however,restricts the use of the new injection.     

PLASMA VISCOSITY AND CREMOPHOR-CONTAINING ANAESTHETICS

The cremophor-containing anaesthetic agents, Althesin, propanididand diazepam, were added to plasma in vitro and administeredto patients. In vitro these anaesthetics, and cremophor alonein concentrations equal to those obtained in vivo, decreasedthe viscosity of plasma 45% at shear rate 11.5 s-¹. In 11 patientsgiven cremophor-containing anaesthetics to induce anaesthesia,plasma samples obtained 5 min after injection showed a meandecrease in viscosity of 42% compared with the pre-inductionvalues. The effect on viscosity after a single dose disappearedin 50 min. Triton x-100 added to plasma caused a decrease inviscosity similar to that of cremophor. The interaction in vitroof cremophor and Triton x-100 with concentrated urea was foundto be identical both in plasma and dextran. This suggests thatcremophor acts by increasing the sheet of structured water aroundthe protein molecules, thereby preventing the aggregation ofsproteins.     

The effects of cremophor EL in the anaesthetized dog

The effects of cremophor EL were studied in 13 anaesthetized, paralyzed and ventilated dogs. Twenty per cent cremophor EL in a dose of 4.3 +/- 0.92 ml was infused at a rate of 30 ml X hr-1. In seven dogs, thoracopulmonary compliance, heart rate, systemic arterial pressure (SAP), pulmonary pressures (PAP, PCWP, RAP), cardiac output (CO) and platelet and white cell counts, were measured before the injection of cremophor EL, at the end of infusion and 5, 10, 30 and 150 minutes after the end of infusion. In six dogs, SAP, CO, and blood volume were measured before the injection of cremophor EL, at the end of infusion and 10, 30, 90 and 150 minutes after the end of infusion. Plasma histamine and catecholamines were assayed before the injection of cremophor EL and 2, 5, 10, 30, 90 and 150 minutes after starting the infusion. Cremophor EL induced a marked, sustained and significant decrease in SAP at the end of infusion and at 5, 10 and 30 minutes after the completion of the infusion (-68, -71, -70 and -43 per cent respectively), in PCWP, RAP and CO (-78 per cent at the end of infusion, -32 per cent 150 minutes after the end of infusion). Heart rate and systemic vascular resistance did not vary significantly. Pulmonary vascular resistance increased at the end of infusion, five and ten minutes after the end of infusion (+734, +548 and +439 per cent respectively). Plasma volume decreased 10 and 30 minutes after the end of infusion (-28 and -30.5 per cent respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravenous sedation and regional analgesia

A double-blind study of 229 patients with the use of intravenous diazepam as compared with a placebo to produce sedation during local analgesia showed that significantly improved sedation occurred when diazepam was used. The diazepam was dissolved in cremophor and this reduced the pain of intravenous injection of the diazepam. One patient who received Cremophor only, showed a moderately severe allergic reaction. It is suggested that a small test dose should always be given before giving any drug which is dissolved in Cremophor.     

Cremophor EL stimulates mitotic recombination in uvsH//uvsH diploid strain of Aspergillus nidulans

Cremophor EL is a solubilizer and emulsifier agent used in the pharmaceutical and foodstuff industries. The solvent is the principal constituent of paclitaxel's clinical formulation vehicle. Since mitotic recombination plays a crucial role in multistep carcinogenesis, the study of the recombinagenic potential of chemical compounds is of the utmost importance. In our research genotoxicity of cremophor EL has been studied by using an uvsH//uvsH diploid strain of Aspergillus nidulans. Since it spends a great part of its cell cycle in the G2period, this fungus is a special screening system for the study of mitotic recombination induced by chemical substances. Homozygotization Indexes (HI) for paba and bi markers from heterozygous B211//A837 diploid strain were determined for the evaluation of the recombinagenic effect of cremophor EL. It has been shown that cremophor EL induces increase in mitotic crossing-over events at nontoxic concentrations (0.05 and 0.075% v/v).     

Anesthesiologic efficacy of propanidid as a liposome dispersion. An experimental study with rats]

BACKGROUND. Propanidid, an ultra-short-acting i.v. anaesthetic agent, was widely used in the 1960s. Reports of anaphylactoid reactions in patients associated with release of histamine following administration of the drug, however, led to withdrawal of this useful anaesthetic. Since the adverse side effects of the former solution could be attributed to the solvent cremophor, attempts have recently been made to produce a propanidid solution without addition of the solvent. We report on comparative investigations employing a new liposomal solution (B. Braun, Melsungen, FRG) and the conventional cremophor preparation with regard to anaesthetic properties, haemodynamic side effects, and electroencephalographic effects (EEG). METHODS. Sprague-Dawley rats (n = 46) were implanted with venous and arterial lines and epidural EEG electrodes during chloral-hydrate anaesthesia. The following day, arterial blood pressure (ABP), heart rate (HR), and EEG were monitored in awake animals and then after induction of anaesthesia by a bolus of the respective propanidid preparation, followed by an infusion period of 15 min in six different experimental groups. Animals of groups L-60, L-90, L-120, or C-60, C-90, or C-120 groups received 60, 90, or 120 mg.100 g-1.h-1 of the liposomal (L) or cremophor (C) preparation. During anaesthesia, the corneal reflex and nociception to tail-clamping were also tested. At termination of the infusion, blood samples were drawn for determination of plasma propanidid concentrations. RESULTS. Both preparations were similarly effective in induction and maintenance of anaesthesia in a dose-dependent manner; both similarly lowered ABP and HR. The corneal reflex and nociceptive responses to tail clamping were also comparably suppressed. However, whereas the liposomal preparation was well tolerated at higher dose levels, the cremophor preparation caused considerable dose-dependent mortality of 11%, 86%, and 86% in animals in groups C-60, C-90, and C-120, respectively. Both preparations were found to induce a burst-suppression pattern in the EEG associated with clonic seizures, with a lower incidence with the liposomal preparation (22% and 50% in groups L-90 and L-120) as compared to the cremophor preparation (100% and 89% in groups C-90 and C-120). A remarkable variability in propanidid plasma concentrations was found at the end of the infusion period, although no differences were observed between both preparations. Discontinuation of infusion of propanidid resulted in rapid awakening (less than 5 min), irrespective of whether the liposomal or conventional preparation was employed. CONCLUSION. The present findings demonstrate largely identical anaesthetic potencies of a new liposomal solution as compared to the conventional cremophor preparation of propanidid. The liposomal preparation, however, was superior as far as tolerance and incidence of clonic seizures was concerned. The present findings should prompt further studies on the suitability of liposomal propanidid as a short-acting anaesthetic agent in patients.     

Anästhesie mit Propanidid in liposomaler Zubereitung Eine experimentelle Studie am Schwein

Background. Propanidid was widely used as a short-acting i.v. anaesthetic until it was withdrawn due to severe haemodynamic side effects. It was presumed that anaphylactoid reactions with massive histamine release were caused by the solvent cremophor rather than by propanidid itself. A new liposomal preparation of propanidid was examined in this animal study and compared with propanidid in cremophor solution and with propofol. Methods. Eighteen pigs were randomly assigned to one of the following groups: Group 1 (n=6): Propanidid in liposomal preparation (PropaLip; Braun Melsungen, Germany). Anaesthesia was induced with 60 mg/kg, followed by continuous infusion of 400 mg/kg·h. Group 2 (n=6): Propanidid in cremophor solution (PropaCrem; Sombrevin, Gedeon Richter, Budapest) 15 mg/kg, 100 mg/kg·h. Group 3 (n=6): Propofol (Disoprivan, Zeneca, Plankstadt, Germany) 5 mg/kg, 20 mg/kg·h. After induction and tracheal intubation, the animals were ventilated with 50% oxygen in air. Basic monitoring included noninvasive blood pressure measurements, electrocardiographic monitoring, and capnography. In a short surgical procedure, arterial and pulmonary artery catheters were placed via the right carotid artery and right internal jugular vein, respectively. As soon as the animals responded to a pain stimulus a second anaesthetic induction was performed, followed by a 60-min continuous infusion of the agent studied with invasive haemodynamic monitoring including arterial and pulmonary arterial pressures and cardiac output. Blood samples were taken for the measurement of serum levels of adrenaline, noradrenaline, cortisol, aldosterone, adrenocorticotropic hormone, and histamine. Results. Intubation conditions and quality of anaesthesia were best in propofol animals, followed by PropaCrem animals. In spite of the large dose of 410 mg/kg·h, resulting in a volume load of as much as 16.4 ml/kg·h, the PropaLip animals showed evidence of poor anaesthetic quality. In group 1 we recorded the highest increases in heart rate (91 vs. 115/min), cardiac output (5.4 vs. 7.7 l/min), plasma catecholamine levels, and histamine concentrations (124–268 ng/ml). Conclusions. In our animal study, propanidid in liposomal preparation failed to show promise as a new anaesthetic agent. Our results are discussed in view of a drug targeting the cells of the reticuloendothelial system, especially the liver, where liposomes are eliminated from the blood. This may result in the transport of propanidid to one of its major places of inactivation.     

INTERACTIONS OF DIISOPROPYL PHENOL (ICI 35 868) WITH SUXAMETHONIUM,VECURONIUM AND PANCURONIUM IN VITRO

In vitro studies were performed using the rat phrenic nerve-hemidiaphragmpreparation to investigate possible interactions between diisopropylphenol and its solvent, cremophor, with three neuromuscularblocking drugs. Cumulative concentration curves were constructedfor the neuromuscular blockers and linear regression analysesperformed. Differences in the calculated effective concentrationto produce a 50% decrease in twitch height (EC₅₀) and slopeshowed that diisopropyl phenol potentiated the action of suxamethonium,vecuronium (Org NC 45) and pancuronium. Cremophor potentiatedthe action of suxamethonium but antagonized the action of thenon-depolarizing neuromuscular blockers. The possible mechanismsof action are discussed. ^*Present address: Department of Anaesthesia, Free University,Amsterdam, the Netherlands.     

COMPARISON OF THE EFFECT OF DIISOPROPYL PHENOL (ICI 35 868) AND THIOPENTONE ON RESPONSE TO SOMATIC PAIN

The response to somatic pain with sub-hypnotic doses of ICI35 868 (dusopropyl phenol in cremophor) and thiopentone wascompared using tibial pressure algesimetry. Studies were alsoearned out following recovery from larger doses of both drugs.The patients underwent minor gynaecological procedures usingonly one of the two i.v. agents and nitrous oxide in oxygen.The studies confirmed the known antanalgesic action of thiopentoneand demonstrated that dusopropyl phenol has an analgesic actionwhich is an attractive feature in an i v anaesthetic agent.     

Anaesthesia with ICI 35,868 monitored by the cerebral function analysing monitor (CFAM)

Ten patients who received bolus doses of the cremophor formulation of ICI 35,868 were monitored using the Cerebral Function Analysing Monitor (CFAM). Visual inspection of the traces obtained showed an easily recognizable pattern which was associated with an increasing depth of anaesthesia. Statistical analysis showed a high correlation between venous blood levels of the drug and changes recorded by the CFAM, although there was marked inter-patient variation. It is suggested that this variation is due to the effect of a time-lag between changes in drug concentration in the brain and venous blood.     

REACTIONS TO INTRAVENOUS INJECTIONS OF DIAZEPAM

Local reactions during and after i.v. injection of two differentformulations of diazepam were studied. Two-thirds of the patientsfelt pain during the injection. Verified or probable thrombophlebitisoccurred with increasing frequency following operation, indicatinga late onset. One month after discharge, 29% of those who hadreceived diazepam in glycoferol-alcohol-benzoic acid complainedof tender injection sites, compared with only 10% of the patientswho received diazepam in cremophor EL. The difference is significant,indicating an influence of the solvent system     

脊髓NO信号通路和ERK信号通路在吗啡依赖大鼠戒断反应中的作用

目的 评价脊髓NO信号通路和细胞外调节激酶(ERK)信号通路在吗啡依赖大鼠戒断反应中的作用.方法 鞘内置管成功的健康雄性SD大鼠90只,体重200～ 250 g,采用随机数字表法,将其随机分为9组(n＝10):正常对照组(C组)、吗啡依赖组(MD组)、吗啡戒断组(MW组)、L-N-硝基精氨酸甲酯组(L-NAME组)、7-硝基吲唑组(7-Ni组)、氨基胍组(AG组)、U0126组、克列莫佛组(cremophor组)和二甲基亚砜组(DMSO组).MD组、MW组、L-NAME组、7-Ni组、AG组、U0126组、cremophor组和DMSO组皮下注射吗啡10 mg/kg,2次/d,隔天每次增加10 mg/kg,至第6天末次注射50 mg/kg,建立吗啡依赖模型.末次注射吗啡后4h时,MW组、L-NAME组、7-Ni组、AG组、U0126组、cremophor组和DMSO组腹腔注射纳洛酮4 mg/kg激发吗啡戒断反应.给予纳洛酮前30 min时,L-NAME组、7-Ni组、AG组、U0126组、cremophor组和DMSO组分别鞘内注射L-N-硝基精氨酸甲酯400μg(溶于10μl生理盐水中)、7-硝基吲唑400 μg(溶于10μl克列莫佛中)、氨基胍400μg(溶于10 μl生理盐水中)、U0126 150μg(溶于10μl二甲基亚砜中)、克列莫佛10 μl和二甲基亚砜10 μl.注射纳洛酮后1h内观察大鼠戒断反应和痛觉异常反应,并进行评分,然后处死大鼠,取脊髓组织,分别采用免疫组化法和Western blot 法测定脊髓背角诱导型一氧化氮合酶(iNOS)、神经型一氧化氮合酶(nNOS)和磷酸化ERK(p-ERK)的表达.结果 与MD组比较,MW组、L-NAME组、7-Ni组、AG组、U0126组、DMSO组和crmophor组戒断反应评分和促诱发痛评分升高(P<0.05);与MW组比较,L-NAME组、7-Ni组、AG组和U0126组戒断反应评分和促诱发痛评分降低(P<0.05),DMSO组和cremophor组差异无统计学意义(P＞0.05);与C组和MD组比较,MW组脊髓背角nNOS和iNOS表达上调(P<0.05);与MW组比较,U0126组脊髓背角nNOS和iNOS表达下调(P<0.05).与C组比较,MD组和MW组脊髓背角p-ERK表达上调(P＜0.05);与MW组比较,L-NAME组、7-Ni组和AG组脊髓背角p-ERK表达下调(P<0.05).结论 脊髓NO信号通路和ERK信号通路的相互调节作用参与了吗啡依赖大鼠的戒断反应.     

A HAEMORHEOLOGICAL STUDY OF ALTHESIN

In 11 patients, induction of anaesthesia with a slow i.v. infusionof Althesin caused small but statistically significant reductionsin venous haematocrit and plasma viscosity. Whole blood viscositywas slightly reduced but this only attained statistical significanceat one (0.945 s^–1) of several shear rates tested. Redcell deformability remained unchanged. In vitro studies revealedthat when dilutional effects were eliminated, plasma viscositywas not reduced by the addition of cremophor or Althesin toplasma. The small reductions in haematocrit and plasma viscosityobserved in vivo are considered to be secondary effects of sedation. ^*Hedon Road Maternity Hospital, Hull. 48, Esplanade, Greenock, PA167JD.     

Cyclosporin A tubular effects contribute to nephrotoxicity: role for Ca2+ and Mg2+ ions.

BACKGROUND: Cyclosporin A (CsA) nephrotoxicity has been attributed primarily to renal haemodynamic alterations caused by afferent arteriolar vasoconstriction. However, CsA nephropathy is also characterized by CsA-induced pre-glomerular disturbances and interstitial injury that may occur independently of haemodynamic changes. Given the high lipophilic activity of CsA, we hypothesized that direct tubular injury is likely to contribute to nephrotoxicity. METHODS: To investigate tubular toxicity of CsA, increasing concentrations of CsA (1, 2.5, 10, 25, 50 and 100 micro g/ml) and its vehicle (cremophor) were added to isolated rat proximal tubules (PT). Cell injury was assessed by lactate dehydrogenase (LDH) release. The role of Ca(2+) ions in tubular toxicity and the effect of calcium channel blockers on CsA toxicity were evaluated by measuring intracellular calcium using the fluorescent dye Fura-2 AM. The role of Mg(2+) ions was assessed using high extracellular Mg(2+) medium (2 mM). RESULTS: Whereas cremophor alone was not toxic to PT, CsA caused PT injury but only at the highest concentration (100 micro g/ml). After 90 min incubation, LDH was 22.5% in control PT and 41.9% in PT treated with 100 micro g/ml CsA (P < 0.001, n = 11). There was a transient increase in intracellular calcium ([Ca(2+)](i)) after CsA administration. A low calcium medium (100 nM) prevented CsA injury to renal tubules. However, verapamil, but not nifedipine, enhanced cell damage. Only nifedipine completely prevented [Ca(2+)](i) increases following CsA. Finally, a high Mg(2+) medium attenuated CsA-induced injury. CONCLUSION: We found that high CsA concentrations caused Ca(2+)- and Mg(2+)-dependent PT injury. Thus, low extracellular Ca(2+) and high Mg(2+) media attenuated CsA-induced tubular injury. Verapamil, but not nifedipine, enhanced CsA tubular toxicity. Therefore, CsA-induced tubular injury may contribute to CsA nephrotoxicity independently of haemodynamic disturbances.     

Onset Time for Alcuronium and Pancuronium after Cremophor-Containing Anaesthetics

Cremophor is a nonionic, surface-acting agent, previously shown to bind to proteins and biological membranes. The compound is used as a solvent for certain anaesthetics. The effects of this surfactant on the onset times for alcuronium and pancuronium were investigated. Both artery-to-muscle (A-M) and vein-to-muscle (V-M) onset times were determined after cremophor- and non-cremophor-containing induction agents. Circulatory effects of the surfactant were investigated by measuring the blood velocity of the brachial artery using pulsed Doppler ultrasound. A significant reduction in both A-M and V-M onset times was found for pancuronium after cremophor-containing anaesthetics. However, no difference was found for the onset times for alcuronium in the two induction groups. In contrast to alcuronium, there was no significant difference between A-M and V-M onset times for pancuronium. Arterial blood velocity was found to be practically the same after cremophor and non-cremophor induction agents. The possibility of a stronger affinity of pancuronium than alcuronium to intravascular binding sites is suggested. Cremophor might, due to its protein and membrane effects, interfere with pancuronium association to these sites.     

Acidosis and weight loss are induced by cyclosporin A in uninephrectomized rats

The effects of cyclosporin A (CyA, 50 mg/kg body weight) or its commercial vehicle (cremophor) on the acid-base regulation of uninephrectomized rats were assessed for 7 days and in non-nephrectomized rats for 15 days. CyA induced a marked systemic acidosis, accompanied by decreases in blood PCO₂ and plasma bicarbonate. Untreated uninephrectomized rats did not show the acidosis. In CyA-treated rats the urine pH decreased (control 6.65±0.06 vs. CyA 6.18±0.08; P<0.01) as well as urinary bicarbonate (non-nephrectomized rats 7.50±1.88 mM vs. uninephrectomy plus CyA 0.75± 0.06 mM; P<0.01), suggesting partial renal compensation of systemic acidosis. Titratable acidity increased in CyA-treated rats (control 21.6±1.2 vs. CyA 63.3±12.0 μEq/l; P<0.001). Phosphate, glucose, and osmolar clearances were not significantly altered in non-nephrectomized rats treated with CyA for 15 days. There was a striking decrease in body weight in CyA-treated rats (control 274.0±3.8 vs. CyA 225.0±5.1 g; P<0.01), but compensatory growth of the remaining kidney was not prevented by this drug or by its vehicle. In summary, CyA induced a severe metabolic acidosis in uninephrectomized rats that was not compensated by the remaining kidney, in spite of the well-preserved compensatory weight gain of this organ. Loss of body weight was significant in CyA-treated animals. Received: 6 May 1997 / Revised: 20 October 1998 / Accepted: 29 April 1999     

Effects of cyclosporine on the isolated perfused rat kidney

Although cyclosporine (CsA) has been shown to cause decreased renal function in humans, the mechanisms important in cyclosporine nephrotoxicity are not well understood. Investigations of cyclosporine nephrotoxicity in animal models have been complicated by systemic toxic effects not seen in humans. In the present study, the direct renal effects of cyclosporine were investigated in the isolated perfused rat kidney (IPRK) model. Cyclosporine delivered by nontoxic liposomes had no effect on IPRK resistance, perfusate flow, inulin clearance, or fractional reabsorption of sodium, despite marked tissue accumulation of CsA (55.1 +/- 7.2 micrograms/g kidney tissue). In contrast, a 63% decrease in inulin clearance was observed following the administration of intravenous cyclosporine (0.1 ml). However, similar changes in IPRK function were seen after the administration of 0.1 ml of the intravenous cyclosporine vehicle, cremophor, suggesting that the alterations in function were secondary to the vehicle. All together, these findings suggest that cyclosporine nephrotoxicity may be secondary to renal innervation, toxic metabolites, or other systemic effects of cyclosporine not present in the IPRK.     

Effect of timing of cyclosporine administration on recovery from renal ischemia in rats

The effect of timing of cyclosporine administration on functional recovery from renal ischemia was studied in Sprague-Dawley rats. Animals were given cyclosporine and subjected to renal ischemia by temporarily occluding both the renal artery and vein. Our data demonstrate no significant difference in serum creatinine among rats subjected to renal ischemia, cyclosporine, or cyclosporine-vehicle cremophor EL administration, or the control group. On the other hand, renal ischemia in combination with cyclosporine resulted in rapid and marked deterioration in renal function with serum creatinine peaking on Day 2. The most significant rise was in rats that received cyclosporine 4 hr prior to induction of renal ischemia (4.7 +/- 0.5 mg/dl), followed by those that received cyclosporine 4 and 24 hr postischemia (2.8 +/- 0.5 and 3.2 +/- 0.7 mg/dl, respectively). Cyclosporine administration 24 hr prior to renal ischemia resulted in the least elevation of the serum creatinine (2.1 +/- 0.5 mg/dl) and the earliest return to the baseline value. Our data suggest that the timing of cyclosporine administration in rats subjected to renal ischemia influences the extent of renal injury and the subsequent recovery of renal function.     

The influence of the cyclosporine vehicle, cremophor EL, on renal microvascular blood flow in the rat.

Cyclosporine nephrotoxicity may be due to glomerular hypoperfusion. Previous experimental and clinical studies have demonstrated a decrease in renal blood flow and an increase in renal vascular resistance. Cremophor EL, which is the vehicle in which CsA is dissolved, is thought to be a factor involved in intrarenal arteriolar vasoconstriction. To determine the relative contributions of the vehicle and CsA to intrarenal arteriolar vasoconstriction, we used in vivo videomicroscopy and Doppler velocimetry to measure changes in renal microvascular blood flow in the rat. A 5-min intravenous infusion of 20 mg/kg of CsA resulted in a 17% mean reduction (P less than 0.05) in the diameter of preglomerular interlobular arterioles and an associated 60% reduction (P less than 0.05) in microvascular blood flow by 15 min. Cremophor EL/ethanol equivalent caused less vasoconstriction (up to 10%) but resulted in a 42% mean decrease (P less than 0.05) in microvascular blood flow, probably secondary to a 38% mean decrease (P less than 0.05) in cardiac output and 13% decrease in arterial pressure. We conclude that cremophor EL does contribute to in vivo reduction of preglomerular microvascular blood flow in the rat. This may be particularly important when using this intravenous preparation in the study of CsA nephrotoxicity.     

Cyclosporine-induced coronary artery constriction--dissociation between thromboxane release and coronary vasospasm.

Cyclosporine influences vascular tone, including that of coronary arteries. But its effect on myocardial prostanoid release, which may contribute to a drug-induced coronary and/or myocardial dysfunction, remains unknown. We used the isolated perfused rat heart to study the effect of cyclosporine on both the mechanical function parameters and myocardial prostanoid release into the effluent by ELISA. Cyclosporine (5 microM) induced an increase of perfusion pressure from 40 +/- 3 to 73 +/- 4 mm Hg within 60 minutes (p < 0.001), reflecting an increase of coronary tone. Cyclosporine did not affect heart rate but contractility (+dp/dtmax) tended to decrease, although not significantly. The drug's effect on coronary tone was rapidly reversible upon withdrawal. Cyclosporine perfusion resulted in an increase of thromboxane B2 liberation from 236 +/- 150 to 1321 +/- 354 pg/ml effluent (p < 0.001), whereas the 6-keto-prostaglandin F1 alpha release was unaffected. The vehicle cremophor did not change any of these parameters. Neither inhibition of myocardial prostanoid formation with acetylsalicylic acid nor thromboxane receptor blockade prevented the cyclosporine-induced increase of perfusion pressure. However, perfusion with nitroglycerin or the voltage-sensitive calcium channel antagonist nifedipine in addition to cyclosporine were able to prevent the increase of perfusion pressure. This is the first time it has been demonstrated that cyclosporine induces an acute release of the prostanoid thromboxane within the myocardium. Despite the resulting imbalance in favor of the vasoconstrictive prostanoid, a dependency of the cyclosporine-induced increase of coronary tone on this imbalance was excluded. Conversely, nitric oxide donation or calcium channel blockade were able to prevent the negative effect of the drug on coronary tone, supporting the concept of endothelium-dependent and/or myogenic mechanism of cyclosporine toxicity on the coronary vascular bed.