Uterine sarcoma: twenty-seven years of experience.

PURPOSE: A correlation of treatment for uterine sarcoma with outcome, prognostic importance of pathology, and clinical parameters. PATIENTS AND METHODS: One hundred forty-one patients (median age: 56 years, range: 19-85 years) with a histologically verified uterine sarcoma were identified from a database compiled at the Royal Marsden Hospital and the University of Florence between 1974 and 2001. Seventy-two patients had leiomyosarcoma, 42 had mixed müllerian tumors, 22 had endometrial stromal sarcoma, 1 hemangiopericytoma, 1 rhabdomyosarcoma, and 3 patients had unspecified sarcoma. According to FIGO classification, Stage I, II, III, and IV tumors were identified in 71, 13, 31, and 26 patients, respectively. RESULTS: At the time of analysis, 73.7% of patients were dead, and 26.3% were alive with a median survival of 2 years from initial diagnosis. Univariate analysis for cause-specific survival demonstrated statistical significance for histology (p = 0.02), grade (p = 0.003), stage (p = 0.007), and age (p = 0.02). Multivariate analysis demonstrated significant prognostic values for stage (p = 0.02) and histology (p = 0.05) only. Postoperative radiotherapy with a total dose higher than 50 Gy seems to be significant (p = 0.001) in reducing local recurrence. CONCLUSIONS: Our data favor treatment for Stages I, II, and III of uterine sarcoma with radical surgery plus radical dose irradiation comprising both external beam radiotherapy and brachytherapy.

Design and synthesis of 4-substituted benzamides as potent, selective, and orally bioavailable I(Ks) blockers.

Multiple delayed rectifier potassium currents, including I(Ks), are responsible for the repolarization and termination of the cardiac action potential, and blockers of these currents may be useful as antiarrhythmic agents. Modification of compound 5 produced 19(S) that is the most potent I(Ks) blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced 24A with 23% oral bioavailability.

Pharmacologic characterization of BMS-191095, a mitochondrial K(ATP) opener with no peripheral vasodilator or cardiac action potential shortening activity.

Previous work described ATP-sensitive K(+) channel (K(ATP)) openers (e.g., BMS-180448), which retain the cardioprotective activity of agents such as cromakalim while being significantly less potent as vasodilators. In this study, we describe the pharmacologic profile of BMS-191095, which is devoid of peripheral vasodilating activity while retaining glyburide-reversible cardioprotective activity. In isolated rat hearts subjected to 25 min of global ischemia and 30 min of reperfusion, BMS-191095 increased the time to onset of ischemic contracture with an EC(25) of 1.5 microM, which is comparable to 4.7 microM and 3.0 microM for cromakalim and BMS-180448, respectively. Comparisons of cardioprotective and vasorelaxant potencies in vitro and in vivo showed BMS-191095 to be significantly more selective for cardioprotection with virtually no effect on peripheral smooth muscle, whereas cromakalim showed little selectivity. In addition to increasing the time to the onset of contracture, BMS-191095 improved postischemic recovery of function and reduced lactate dehydrogenase release in the isolated rat hearts. The cardioprotective effects of BMS-191095 were abolished by glyburide and sodium 5-hydroxydecanoate (5-HD). BMS-191095 did not shorten action potential duration in normal or hypoxic myocardium within its cardioprotective concentration range nor did it activate sarcolemmal K(ATP) current (< or =30 microM). BMS-191095 opened cardiac mitochondrial K(ATP) with a K(1/2) of 83 nM, and this was abolished by glyburide and 5-HD. These results show that the cardioprotective effects of BMS-191095 are dissociated from peripheral vasodilator and cardiac sarcolemmal K(ATP) activation. Agents like BMS-191095 may owe their cardioprotective selectivity to selective mitochondrial K(ATP) activation.

The identified needs of ethnic minority groups with cancer within the community: a review of the literature.

The literature suggests that healthcare provision for ethnic minority groups is poorer than for the majority population. The intention of this paper is to review the literature available on healthcare provision for ethnic minority groups to see if this is the case for those with cancer. The introduction in the UK of monitoring of ethnic origins in the general population and healthcare service is recent and means that there are few data available. At present, cancer mortality is lower among ethnic minority groups than the majority population in the UK, which may partly be explained by a younger than average age within the ethnic minority groups and the fact that some members of ethnic groups retire to their country of origin. However, the mortality rates are expected to increase as the population ages. Breast and lung cancers are the most common cancers among ethnic minority groups in the UK. Traditional intervention strategies have been aimed at the majority white population and have not taken into account the needs identified by the ethnic communities themselves. Intervention strategies include advice on stopping smoking and chewing tobacco, increasing use of screening services by ethnic minority groups, targeted health promotion messages and education on cancer specifically for these groups. More data are required on cancer among ethnic minority groups in the UK. There are many similarities in the use of cancer services between ethnic minority groups and individuals with lower socioeconomic status in the UK.

An audit of outcome of adjuvant post-operative radiotherapy for 52 women with stage II carcinoma of the endometrium.

A retrospective review was undertaken of the medical records of 52 women with stage II carcinoma of the endometrium who received adjuvant radiotherapy following surgery. The information was obtained from medical notes and a hospital database. Actuarial disease-free survival was 68% at 5 years for those women with stage IIA disease, and 70% at 5 years for those women with stage IIB disease. 6 of the women (11.5%) had side effects from treatment. In contrast to the literature, the only statistically significant prognostic factor in this study was histological differentiation; patients with poorly differentiated tumours fared worse (p = 0.05). This may indicate that a greater number than 52 women is needed to demonstrate weaker prognostic factors such as substage. A larger review is being undertaken of the remaining women recorded on the database, with stage I, III and IV disease.

Stage IV endometrial carcinoma: a 10 year review of patients.

Stage IV endometrial cancer is uncommon, often occurs in elderly patients and has a poor prognosis, which makes the choice of treatment difficult. 18 patients with stage IV endometrial cancer presenting over a 10 year period, between 1987 and 1997, were reviewed with regard to mode of treatment and response. The mean age was 65 years. Five had disease confined to the pelvis and 13 had extra pelvic disease. 15 of 18 patients had a total abdominal hysterectomy (TAH). One patient received radiotherapy alone and five received post-operative radiotherapy. Overall freedom from pelvic symptoms was achieved in seven of 18 patients. All seven had undergone TAH and two had received post-operative radiotherapy. Progestogens were given to 13 patients. Six received progestogens alone, without radiotherapy or chemotherapy. Of these, two responded, one for 9 months and one with verified lung metastases, who had a complete response, is still alive at 6.5 years. Eight patients received chemotherapy, with single agent cisplatin or carboplatin AUC 6. Three patients responded, one for 4.5 years. The overall median survival was 12 months from diagnosis. Actuarial 5 year survival was 15% (CI 3-36). There was no significant survival difference for, hormone therapy or chemotherapy. Stage IV endometrial cancer has a poor prognosis but durable response can be achieved in some patients.

Palliative chemotherapy in recurrent carcinoma of the cervix: an audit of the use of ifosfamide and review of the literature.

A review was conducted on 34 patients treated with intravenous ifosfamide for relapsed, inoperable carcinoma of the cervix between 1988 and 1996. The median age of patients was 44 years. Thirty-two patients had squamous cell carcinoma and 2 had adenocarcinoma. Radiotherapy had been used in primary management in 33, neo-adjuvant platinum chemotherapy in 7, and previous palliative chemotherapy in 11. Symptomatic response was assessed with respect to the symptom requiring palliaton. 25 patients failed to complete 6 cycles of chemotherapy: due to progressive disease in 14, lack of symptom response in 2, and toxicity in 11 of whom 7 had encephalopathy sufficient to abandon treatment. 32 patients were evaluable for objective response. Pathologic complete response (CR) was achieved in 1 patient, and partial response (PR) was achieved in 3 patients. The objective response rate was 11.8%. Symptomatic response throughout treatment occurred in 8 patients (24%); objective response was seen in only 3 (1 CR, 2 PR) of them and progressive disease in the remaining 5. Response duration in the 4 objective responders was 25 months in the patient with CR and 4, 6 and 8 weeks in the 3 patients with PR. In conclusion, ifosfamide, as given, is associated with unacceptable toxicity and insufficient symptomatic efficacy for use as a palliative treatment in patients with relapsed carcinoma of the cervix.

Identification of [3H]P1075 binding sites and P1075-activated K+ currents in ovine choroid plexus cells.

This study examined the pharmacological characteristics of binding sites for the potent K+ channel opener [3H]P1075, as well as the functional effects of P1075 on ionic currents and membrane potential, in ovine choroid plexus (OCP) cells. [3H]P1075 bound to OCP cells with a Kd of 26 +/- 4 nM and a Bmax of 10400 +/- 480 sites/cell. Labelled sites were stereoselective and inhibited by potassium channel openers with a rank order of potency: P1075 > BMS-182264, ((4-[[9cyanoimino)[(1,2,2-trimethylpropyl)amino]-methyl]amino]benz onitrile) > pinacidil >> nicorandil > diazoxide. The K(ATP) channel antagonist glyburide inhibited [3H]P1075 binding with a Ki of 2 microM. The presence of K(ATP) channels on OCP cells was examined by patch clamp and fluorescent (membrane-potential sensitive dye) techniques. In some cells, P1075 activated an outward potassium current which was blocked by glyburide. P1075 produced a glyburide-sensitive, concentration-dependent, hyperpolarization of OCP cells. Levcromakalim hyperpolarized more strongly than its 3R,4S enantiomer, BRL 38226 ((3R-trans)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)- 2H-1-benzopyran-6-carbonitrile) indicating a stereoselective interaction. These data indicate that epithelial OCP cells contain glyburide-sensitive K(ATP) channels.

Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection.

Previous studies showed a poor correlation between sarcolemmal K+ currents and cardioprotection for ATP-sensitive K+ channel (KATP) openers. Diazoxide is a weak cardiac sarcolemmal KATP opener, but it is a potent opener of mitochondrial KATP, making it a useful tool for determining the importance of this mitochondrial site. In reconstituted bovine heart KATP, diazoxide opened mitochondrial KATP with a K1/2 of 0.8 mumol/L while being 1000-fold less potent at opening sarcolemmal KATP. To compare cardioprotective potency, diazoxide or cromakalim was given to isolated rat hearts subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. Diazoxide and cromakalim increased the time to onset of contracture with a similar potency (EC25, 11.0 and 8.8 mumol/L, respectively) and improved postischemic functional recovery in a glibenclamide (glyburide)-reversible manner. In addition, sodium 5-hydroxydecanoic acid completely abolished the protective effect of diazoxide. While-myocyte studies showed that diazoxide was significantly less potent than cromakalim in increasing sarcolemmal K+ currents. Diazoxide shortened ischemic action potential duration significantly less than cromakalim at equicardioprotective concentrations. We also determined the effects of cromakalim and diazoxide on reconstituted rat mitochondrial cardiac KATP activity. Cromakalim and diazoxide were both potent activators of K+ flux in this preparation (K1/2 values, 1.1 +/- 0.1 and 0.49 +/- 0.05 mumol/L, respectively). Both glibenclamide and sodium 5-hydroxydecanoic acid inhibited K+ flux through the diazoxide-opened mitochondrial KATP. The profile of activity of diazoxide (and perhaps KATP openers in general) suggests that they protect ischemic hearts in a manner that is consistent with an interaction with mitochondrial KATP.

A study to ascertain gynaecological patients' perceived levels of embarrassment with physical and psychological care given by female and male nurses.

The Sex Discrimination Act lifted the barriers which prevented men from training and practising as midwives. However, cultural attitudes perceive nursing to be a female profession, and whilst care from a male doctor is considered to be acceptable, care from a male nurse is said to be embarrassing. The purpose of the study was to identify if there was any relationship between the intimacy of a nursing interaction and the patient's level of embarrassment. Data collection was by questionnaires with rating scales. Demographic data was obtained from nursing and medical notes. Statistical analysis was performed by non-parametric methods using Mini-tab. Ninety-one questionnaires were returned from a convenience sample of patients on a gynaecological oncology ward. Analysis of the data indicates that in a population of patients who have no prior experience of hospital admission, or of being cared for by a male nurse, there is a preference for care by a female nurse. However, this preference is not demonstrated in patients who have undergone previous hospital admission within the last five years or who have been cared for by a male nurse. These findings would indicate a cultural preference for care by a female nurse in patients with gynaecological cancer that is changed by experience during hospital admission.

Alterations in Ito1, IKr and Ik1 density in the BIO TO-2 strain of syrian myopathic hamsters.

The BIO TO-2 strain of cardiomyopathic hamster provides a model of dilated low output heart failure. The goal of the study was to determine whether changes in potassium currents occur in this model of heart failure. The densities of Ito1, IKr and IK1 in 8-month-old myopathic hamsters were not significantly different from their age-matched controls. The half-maximum activation voltage (V1/2) of IKr and Ito1, as well as the voltage-dependence of Ito1 inactivation were also similar in both groups at 8 months. Ito1 inactivation exhibited a double exponential time-course; the slow component (tau2), but not the rapid component (tau1), was larger in the myopathic animals. The densities of Ito1, IKr and IK1 were not significantly different in the 8- and 10-month-old control animals. However, the densities of Ito1, IKr and IK1 were all significantly lower in the 10-month-old myopathic hamsters relative to the 10-month-old controls. The V1/2 for IKr and Ito1 activation was the same in myopathic and control animals. tau2, but not tau1, of Ito1 inactivation was again larger in the myopathic animals. The voltage-dependence of Ito1 inactivation was shifted slightly, but significantly, positive in the myopathic animals. Lastly, a sustained outwardly rectifying current that activated upon depolarization was found to be larger in the myopathic animals at both 8 and 10 months of age. In conclusion, many of the alterations in potassium current densities in the 10-month-old cardiomyopathic hamsters are qualitatively similar to the changes observed in the failing human heart.

The novel cardioprotective agent BMS-180448 activates a potassium conductance in cardiac and vascular smooth muscle.

The goal of the present study was to further characterize the effects of the novel cardioprotective agent BMS-180448 on potassium fluxes in cardiac and vascular smooth muscle. Exposure of voltage-clamped guinea pig ventricular myocytes to BMS-180448 (300 microM) produced an inhibition of IK followed by the delayed (5.5 +/- 0.5 min) activation of a large time-independent potassium current. At 100 microM, BMS-180448 produced only inhibition of IK. The BMS-180448 activated current was refractory to block by 30 microM glyburide but was largely inhibited by 100 microM alinidine (84 +/- 6% inhibition at +40 mV). Cromakalim (100 microM)-activated currents were fully inhibited by 3 microM glyburide and 79 +/- 4% blocked by 100 microM alinidine. The current responses to BMS-180448 were unaffected by the inclusion of 10 mM UDP (100 microM ATP) in the pipette. BMS-180448 also produced a concentration-dependent increase in 86Rb efflux from aortic strips; efflux responses were increased in low calcium medium and fully antagonized by 3 microM glyburide. Thus, BMS-180448 activates a potassium conductance in both cardiac and smooth muscle. The glyburide sensitivity of the BMS-180448-induced increase in 86Rb efflux from the aortic preparations suggests that this drug activates IKATP in vascular smooth muscle. Moreover, the observation that BMS-180448 (100 microM) partially inhibits the effects of cromakalim in ventricular muscle cells suggests that these drugs interact, directly or indirectly, with a common site in cardiac muscle.

Pharmacological characterization of the isolated canine prostate.

PURPOSE: The goal of the present study was to characterize the responses of the isolated normal canine prostate to various contracting and relaxing stimuli to determine which pharmacological agents may have utility against the dynamic component of benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Isometric force development was measured in isolated strips of prostate tissue. RESULTS: The alpha-adrenergic agonists were the most efficacious stimulants tested (phenylephrine EC50=2.1 microM.). Endothelin-1, acting primarily via ETA receptors, was more potent (EC50=27nM.) but less efficacious. Histamine (EC50=14.7 microM.), serotonin (EC50=0.12 microM.), carbachol (EC50=5.9 microM.) and KC1 (EC50=48.8 mM.) were also less efficacious than phenylephrine. Nifedipine was a potent (IC50=28 nM.) and efficacious (74% inhibition) inhibitor of phenylephrine-induced force. Potassium channel activator drugs were also efficacious relaxants, producing approximately 80% inhibition of force; rank order of potency was P1075 > cromakalim > diazoxide. Sodium nitroprusside was a weak relaxant, producing only approximately 40% relaxation at a concentration of 100 micronM. Both isoproterenol and forskolin were effective relaxants (75 to 90% relaxation). CONCLUSIONS: We conclude that potassium channel activators, adenylate cyclase stimulators, or endothelin antagonists may have utility against the dynamic component of outflow obstruction secondary to BPH.

A comparison between the effects of BMS-180448, a novel K+ channel opener, and cromakalim in rat and dog.

BMS-180448 [(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-(6-cyano-3, 4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) guanidine] is a structural analog of cromakalim, which was found to similarly decrease ischemic injury, but was 18- to 100-fold less potent as a vasodilator. In the present study, the vascular and cardiac effects of cromakalim and BMS-180448 were evaluated in both in vitro and in vivo preparations. Cromakalim evoked a concentration-dependent relaxation to a K(+)-induced contracture in rat aorta. BMS-180448 behaved in a similar fashion but was 18-fold less potent than cromakalim. Measurements of ischemic damage made in isolated perfused rat hearts demonstrated that cromakalim and BMS-180448 were equipotent as cardioprotective agents; time to contracture was increased with an EC25 value of 4.8 and 4.7 microM, respectively, and lactate dehydrogenase levels were significantly reduced compared to those in the presence of vehicle. In vivo electrophysiologic studies in anesthetized dogs were conducted at basic cycle lengths of 400, 333, and 286 ms, and showed that BMS-180448 caused no significant effect on electrophysiologic parameters with the exception of decreasing atrial effective refractory periods by 12 +/- 3% and 17 +/- 4% at 3 and 10 mg/kg, respectively. There was also a significant drop in mean blood pressure of 18 +/- 5% and 33 +/- 4% at these doses. In contrast, cromakalim was shown to produce shortening of atrial to His conduction time (20 +/- 7%; basic cycle length = 286 ms), atrial effective refractory period (34 +/- 3%; basic cycle length = 400 ms), ventricular effective refractory period (14 +/- 2%; basic cycle length = 400 ms), wavelength (13 +/- 3%; basic cycle length = 400 ms), PR-interval (14 +/- 3%; basic cycle length = 333 ms) and mean blood pressure (65 +/- 3%; basic cycle length = 400 ms) at a dose of 0.3 mg/kg. No supraventricular or ventricular arrhythmias were observed for either compound tested. Based on the reduced cardiac electrophysiologic and vascular effects of BMS-180448, we suggest that BMS-180448 should provide cardioprotective efficacy similar to cromakalim with reduced risk of hypotension or arrhythmias.

Functional role of endothelin ETA and ETB receptors in venous and arterial smooth muscle.

The functional importance of endothelin ETA and ETB receptors in selected arterial and venous smooth muscle preparations was characterized. Endothelin-1 induced force in the saphenous and jugular veins is normally mediated by endothelin ETB-like receptors. However, desensitization or pharmacological block of these receptors reveals an endothelin ETA receptor population that is of sufficient size to mediate full endothelin-1-evoked force. Block of either endothelin ETA or endothelin ETB receptors alone is insufficient to antagonize endothelin-1-evoked force in saphenous vein. Endothelin-1-induced force in hamster aorta may also be mediated by activation of both endothelin ETA and ETB receptors. However, activation of endothelin ETB-like receptors alone is insufficient to generate a full endothelin-1 response. Sarafotoxin S6c treatment, to desensitize endothelin ETB receptors, failed to affect the responses of rat aorta and rabbit carotid artery to endothelin-1 or endothelin ETA receptor antagonists. These findings indicate that selective endothelin receptor antagonists will vary enormously in their efficacy against endothelin-induced force in different vascular beds.

A randomized cross-over study of the efficacy of codeine phosphate versus Ispaghulahusk in patients with gynaecological cancer experiencing diarrhoea during pelvic radiotherapy.

Diarrhoea is the commonest acute complication during radiotherapy treatment to the pelvis. Codeine phosphate and a low residue diet is the standard therapy for radiation-induced diarrhoea at The Royal Marsden NHS Trust. The hypothesis put forward was that Ispaghulahusk and codeine phosphate were equally effective in the treatment of diarrhoea during radiotherapy. Participants in the study were female patients who had experienced change of bowel habit whilst receiving radiotherapy for their gynaecological cancer. Quantitative data was collected from patient diaries and treatment flow-sheets. Ten patients were randomized into the trial, five to codeine phosphate, and five to Ispaghulahusk. Continuing the trial was questioned after 10 patients had been treated. All five patients in the codeine phosphate arm received adequate control, while the five patients allocated to the Ispaghulahusk arm were all crossed-over to codeine phosphate with resolution of their diarrhoea. The results show that Ispaghulahusk, whilst not totally ineffective at controlling diarrhoea, was significantly less effective than codeine phosphate. Our conclusion is that there is insufficient reason to change to a less effective and less palatable preparation for the control of radiation-induced diarrhoea.

Direct vasoconstrictor effects of sandimmune (cyclosporine A) are mediated by its vehicle cremophor EL: inhibition by the thromboxane A2/prostaglandin endoperoxide receptor antagonist ifetroban.

The use of cyclosporine A (CsA), a cyclic polypeptidic immunosuppressive agent, is associated with a number of cardiovascular problems. This study assessed the effects of CsA and its vehicle, cremophor EL (cremophor), on force development in isolated vascular tissue. CsA evoked a concentration-dependent increase in force (EC50 = 2.5 +/- 0.8 micrograms/ml) in the rabbit jugular vein. Cremophor alone also produced a concentration-dependent increase in force (EC50 = 39.5 +/- 10.9 micrograms/ml) that matched the CsA/cremophor response at equivalent cremophor concentrations. The cremophor-induced vasoconstriction was inhibited by the structurally distinct thromboxane A2 receptor antagonists ifetroban and glyburide, but not by indomethacin (10 microM). Ricinoleic acid also produced vasoconstriction (EC50 = 0.24 +/- 0.04 microgram/ml) that was sensitive to inhibition by ifetroban but not by indomethacin. CsA dissolved directly in ethanol produced a small increase in force that was indistinguishable from that evoked by ethanol alone. Cremophor (EC50 = 1.5 +/- 0.5 mg/ml) and ricinoleic acid (EC50 = 4.7 +/- 0.7 microgram/ml) also evoked force development in the rabbit aorta, responses that were antagonized by ifetroban. Thus, force development evoked by CsA in the rabbit jugular vein appears to be mediated primarily by its vehicle, cremophor. It is hypothesized that cremophor, by virtue of its ricinoleic acid component, evoked force development by acting as a weak thromboxane A2 agonist.

8-(Diethylamino)-octyl-3,4,5-trimethoxybenzoate inhibits cromakalim-induced 86Rb efflux from the rat aorta.

The effects of 8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) on cromakalim-induced 86Rb efflux and vasorelaxation in the rat aorta have been assessed. TMB-8 inhibited cromakalim (10 microM)-induced 86Rb efflux with an IC50 of 0.50 +/- 0.15 microM (n = 4; IC50 for glyburide 0.17 +/- 0.05 microM, n = 4), but it produced minimal antagonism of the cromakalim-induced vasorelaxation (rings precontracted with 30 mM KCl-PSS) at TMB-8 concentrations < or = 3 microM. TMB-8 at 10 microM produced significant inhibition of the cromakalim-induced vasodilation. Inhibition of cromakalim-induced 86Rb efflux produced by TMB-8 was little affected by raising the KCl concentration to 30 mM (inhibition by 0.5 microM TMB-8: 62.9 +/- 6.9 and 52.5 +/- 10.9% in 4.6 and 30 mM KCl, respectively; n = 4 for both). Similarly, the inhibitory effects of glyburide on the cromakalim-induced 86Rb efflux were minimally affected by this maneuver. TMB-8 was approximately equipotent against the increase in 86Rb efflux generated by either 1 or 10 microM cromakalim (IC50: 0.73 +/- 0.11 and 0.65 +/- 0.33 microM, respectively; n = 4 of both). In contrast, the glyburide IC50 was reduced approximately 10-fold by reducing the concentration of cromakalim used from 10 to 1 microM (IC50: 182.5 +/- 4.8 and 19.5 +/- 2.6 nM, respectively; n = 4 for both). We hypothesize that TMB-8 inhibits the potassium channel that is opened by cromakalim.(ABSTRACT TRUNCATED AT 250 WORDS)