Molecular Mechanism Linking BRCA1 Dysfunction to High Grade Serous Epithelial Ovarian Cancers with Peritoneal Permeability and Ascites.

Ovarian cancer constitutes the second most common gynecological cancer with a five-year survival rate of 40%. Among the various histotypes associated with hereditary ovarian cancer, high-grade serous epithelial ovarian carcinoma (HGSEOC) is the most predominant and women with inherited mutations in BRCA1 have a lifetime risk of 40-60%. HGSEOC is a challenge for clinical oncologists, due to late presentation of patient, diagnosis and high rate of relapse. Ovarian tumors have a wide range of clinical presentations including development of ascites as a result of deregulated endothelial function thereby causing increased vascular permeability of peritoneal vessels. The molecular mechanisms remain elusive. Studies have shown that fallopian tube cancers develop in women with BRCA1 gene mutations more often than previously suspected. Recent studies suggest that many primary peritoneal cancers and some high-grade serous epithelial ovarian carcinomas actually start in the fallopian tubes. In this article we have addressed the molecular pathway of a recently identified potential biomarker Ubc9 whose deregulated expression due to BRCA1 dysfunction can result in HGSEOC with peritoneal permeability and formation of ascites. We also discuss the role of downstream targets Caveolin-1 and Vascular Endothelial Growth Factor (VEGF) in the pathogenesis of ascites in ovarian carcinomas. Finally we hypothesize a signaling axis between Ubc9 over expression, loss of Caveolin-1 and induction of VEGF in BRCA1 mutant HGSEOC cells. We suggest that Ubc9-mediated stimulation of VEGF as a novel mechanism underlying ovarian cancer aggressiveness and ascites formation. Agents that target Ubc9 and VEGF signaling may represent a novel therapeutic strategy to impede peritoneal growth and spread of HGSEOC.

Stereo-selective inhibition of transient receptor potential TRPC5 cation channels by neuroactive steroids.

BACKGROUND AND PURPOSE: Transient receptor potential canonical 5 (TRPC5) channels are widely expressed, including in the CNS, where they potentiate fear responses. They also contribute to other non-selective cation channels that are stimulated by G-protein-coupled receptor agonists and lipid and redox factors. Steroids are known to modulate fear and anxiety states, and we therefore investigated whether TRPC5 exhibited sensitivity to steroids. EXPERIMENTAL APPROACH: Human TRPC5 channels were conditionally expressed in HEK293 cells and studied using intracellular Ca2+ measurement, whole-cell voltage-clamp and excised patch techniques. For comparison, control experiments were performed with cells lacking TRPC5 channels or expressing another TRP channel, TRPM2. Native TRPC channel activity was recorded from vascular smooth muscle cells. KEY RESULTS: Extracellular application of pregnenolone sulphate, pregnanolone sulphate, pregnanolone, progesterone or dihydrotestosterone inhibited TRPC5 activity within 1-2min. Dehydroepiandrosterone sulphate or 17ß-oestradiol had weak inhibitory effects. Pregnenolone, and allopregnanolone, a progesterone metabolite and stereo-isomer of pregnanolone, all had no effects. Progesterone was the most potent of the steroids, especially against TRPC5 channel activity evoked by sphingosine-1-phosphate. In outside-out patch recordings, bath-applied progesterone and dihydrotestosterone had strong and reversible effects, suggesting relatively direct mechanisms of action. Progesterone inhibited native TRPC5-containing channel activity, evoked by oxidized phospholipid. CONCLUSIONS AND IMPLICATIONS: Our data suggest that TRPC5 channels are susceptible to relatively direct and rapid stereo-selective steroid modulation, leading to channel inhibition. The study adds to growing appreciation of TRP channels as non-genomic steroid sensors.

Upregulated TRPC1 channel in vascular injury in vivo and its role in human neointimal hyperplasia.

Occlusive vascular disease is a widespread abnormality leading to lethal or debilitating outcomes such as myocardial infarction and stroke. It is part of atherosclerosis and is evoked by clinical procedures including angioplasty and grafting of saphenous vein in bypass surgery. A causative factor is the switch in smooth muscle cells to an invasive and proliferative mode, leading to neointimal hyperplasia. Here we reveal the importance to this process of TRPC1, a homolog of Drosophila transient receptor potential. Using 2 different in vivo models of vascular injury in rodents we show hyperplasic smooth muscle cells have upregulated TRPC1 associated with enhanced calcium entry and cell cycle activity. Neointimal smooth muscle cells after balloon angioplasty of pig coronary artery also express TRPC1. Furthermore, human vein samples obtained during coronary artery bypass graft surgery commonly exhibit an intimal structure containing smooth muscle cells that expressed more TRPC1 than the medial layer cells. Veins were organ cultured to allow growth of neointimal smooth muscle cells over a 2-week period. To explore the functional relevance of TRPC1, we used a specific E3-targeted antibody to TRPC1 and chemical blocker 2-aminoethoxydiphenyl borate. Both agents significantly reduced neointimal growth in human vein, as well as calcium entry and proliferation of smooth muscle cells in culture. The data suggest upregulated TRPC1 is a general feature of smooth muscle cells in occlusive vascular disease and that TRPC1 inhibitors have potential as protective agents against human vascular failure.

Quantitative unbiased estimates of endometrial gland surface area and volume in cycling cows and heifers.

Entire reproductive tracts were removed from seven normal healthy heifers and qualitative unbiased estimates made of endometrial gland volume density and glandular surface density. After examining approximately 55 microscopic fields of endometrium from each tract, a mean glandular surface density value of 10.2 mm(2)/mm(3) (CE 3.1%) was obtained. The stereological method was then employed in optimising the design of the main study. The endometrial height was measured for 17 healthy cycling heifers and 19 similar cows. Subsequently, unbiased estimates were made of intercaruncular endometrial gland volume per unit surface for all cattle were investigated; differences between heifers and cows generally, and the possible effect of the follicular and luteal phases of the oestrous cycle were compared. The mean surface area of glands per unit area of endometrium at the intercaruncular site in heifers and cows was approximately 18 mm(2)/mm(2) in the follicular phase and 26 mm(2)/mm(2) in the luteal phase, figures similar to the gland area found in women. The intercaruncular gland volume increased significantly, by about 30% during the luteal phase of the bovine oestrous cycle in heifers, from 0.01 to 0.13 per mm(3). The differences in endometrial anatomy between site of sampling and either follicular or luteal phases of the oestrous cycle were always more significant in heifers than cows. The endometrial thickness in cows was always greater than for heifers, irrespective of the site of sampling. It was concluded that the intercaruncular endometrium of cattle was far more active physiologically than recognised previously.

Prevention of a hypoxic Ca(2+)(i) response by SERCA inhibitors in cerebral arterioles.

1. The aim of the study was to investigate the mechanism of a novel effect of hypoxia on intracellular Ca(2+) signalling in rabbit cerebral arteriolar smooth muscle cells, an effect that was resistant to the L-type Ca(2+) channel antagonist methoxyverapamil (D600). 2.[Ca(2+)](i) of smooth muscle cells in intact arteriolar fragments was measured using the Ca(2+)-indicator dye fura-PE3. Hypoxia (PO(2) 10 - 20 mmHg) lowered basal [Ca(2+)](i) but did not inhibit Ca(2+) entry pathways measured by Mn(2+)-quenching of fura-PE3. 3. The effect of hypoxia was completely prevented by thapsigargin or cyclopiazonic acid, selective inhibitors of sarcoplasmic reticulum Ca(2+) ATPase (SERCA). Since these inhibitors do not block Ca(2+) extrusion or uptake via the plasma membrane, the data indicate that the effect of hypoxia depends on a functional sarcoplasmic reticulum. 4. Because actions of nitric oxide (NO) on vascular smooth muscle are also prevented by SERCA inhibitors it was explored whether the effect of hypoxia occurred via modulation of endogenous NO release. Residual NOS-I and NOS-III were detected by immunostaining, and there were NO-dependent effects of NOS inhibitors on Ca(2+)(i)-signalling. Nevertheless, inhibition of endogenous NO production did not prevent the effect of hypoxia on [Ca(2+)](i). 5. The experiments reveal a novel nitric oxide-independent effect of hypoxia that is prevented by SERCA inhibitors.

Melanoma in African-Americans: trends in biological behavior and clinical characteristics over two decades.

BACKGROUND: The incidence of melanoma in the United States is increasing. Data on this disease in African-Americans is sparse. METHODS: Chart review of patients diagnozed with melanoma from 1975 to 1997 at Charity Hospital New Orleans (CHNO). Age, gender, anatomic distribution, histology, presenting stage, survival, and race were evaluated. RESULTS: Forty-four of 198 patients were African-American, of whom the majority developed cutaneous melanoma on the acral surface of the foot. African-American males were four times more likely to present with a cutaneous lesion than were African-American females. The median survival time for African-American with cutaneous lesions was 45 months, compared to 135 months for caucasians who were 3.6 times more likely to present with early disease (P < 0.05). TNM stage at presentation, and ulceration were significant, independent factors associated with a worse outcome in African-Americans. CONCLUSION: Overall survival time for African-Americans with cutaneous melanoma is significantly shorter than for caucasians with this disease. This trend may be attributable to the fact that African-Americans present with advanced disease. An increased level of awareness among both patients and health-care providers is necessary to identify African-Americans with melanoma at earlier stages of disease and to improve survival.

Nonfunctional parathyroid carcinoma.

Parathyroid carcinoma is a rare entity accounting for 0.5% to 5% of parathyroid neoplasia. Most of these malignancies present as functional hormone-producing masses with elevated serum levels of parathormone and calcium. These tumors may also be nonfunctional. Clinical detection of nonfunctioning parathyroid malignancies preoperatively is primarily based on symptoms of an expanding neck mass. This ominous complaint is typically accompanied with an advanced stage of the disease at initial diagnosis. Because there is a paucity of data in the literature regarding nonfunctioning parathyroid carcinoma, prognosis can not be readily assessed. In both functional and nonfunctional parathyroid carcinoma, early surgery has proven to be the only curative treatment approach whereas both chemotherapy and radiation therapy fail to produce systemic or regional benefit when used alone. Hence, parathyroid cancer should be considered in every patient evaluated for a neck mass regardless of the blood calcium and blood parathormone level.

Magnification views of mammography decrease biopsy rates.

Mammography is a valuable tool for screening and has increased early detection of breast cancer. Magnification views are commonly used to further elucidate suspicious changes seen on routine mammograms. The effect of magnification views and their utility have not been studied regarding the influence on treatment strategies. All patients who had magnification views performed along with their mammogram at Tulane University Medical Center over a one-year period were included. Patient charts were reviewed for mammogram readings, recommendations, and any biopsy results. The original mammograms without the magnification views were given to a physician who was blinded to the final results of the magnification views for a recommendation of whether or not to biopsy the lesion. These recommendations were compared with the results with actual recommendations. Magnification views were performed on 127 patients. After the additional magnification views were taken 27 per cent (34 of 127) of patients had biopsies performed. Biopsy results revealed benign findings in 71 per cent and nonbenign findings (lobular carcinoma in situ, ductal carcinoma in situ, or carcinoma) in 29 per cent. On the basis of the recommendations without magnification views 64 per cent of patients would have had biopsies performed. Magnification views decreased the biopsy rates by 58 per cent (P < 0.001; chi2 tests). Magnification views can help decrease the number of biopsies performed for suspicious small areas on mammograms. Their judicious use can help decrease unnecessary procedures, patient anxiety, and cost. Magnification views are useful to help surgeons and radiologists best screen for breast cancer.

Lung development: number of terminal bronchiolar duct endings and gas exchange surface area in victims of sudden infant death syndrome.

Previous research has demonstrated impaired renal development, particularly with respect to glomerular number, in victims of sudden infant death syndrome (SIDS). The present study used stereological principles to estimate the volume of the upper lobe of the right lung, total number of terminal bronchiolar duct endings (TBDE), and gas exchange surface area of this lobe within a group of human infants. The infants were classified according to cause of death (SIDS or non-SIDS), and further subdivided according to birth-weight: normal birth-weight (NBW) or low birth-weight (LBW). The results demonstrated that TBDE density was significantly reduced in SIDS compared to non-SIDS (P = 0.014), but only reduced from non-SIDS NBW values in the SIDS NBW group (P = 0.044). Total TBDE number was significantly reduced in SIDS from non-SIDS (P = 0.001), and was significantly reduced from non-SIDS NBW values in SIDS NBW (P = 0.023). Mean gas exchange surface area per TBDE was significantly increased in SIDS compared to non-SIDS cases (P = 0.049). The results of the present study indicate developmental delay of the lung in SIDS NBW infants who had previously not been considered growth retarded based on their normal body parameters.

Ageism in medical students' treatment recommendations: the example of breast-conserving procedures.

PURPOSE: Age bias may play a role in physicians' discussions of equivalent therapeutic options with patients, especially in respect to breast-conservation therapy. This study investigated bias based on age (ageism) among physicians-in-training in their treatment recommendations for breast-conserving procedures. METHOD: Second-year medical students responded to a questionnaire concerning recommendations they would make for breast conservation or mastectomies with or without breast reconstruction for eight patients with similar-stage breast cancer. The patients differed by age (older were > or =59 years, younger < or =31 years), race, and marital status. A total of 116 students made 1,146 recommendations. Percentages of the students' recommendations for breast-conservation therapy (BCT) were calculated for the two patient age groups and for the recommendations for breast reconstruction after the patient had already chosen modified radical mastectomy (MRM). Chi-square tests were used for statistical analysis. RESULTS: The students recommended BCT for a significantly higher percentage of younger patients than older patients (86% versus 66%; p<.001). They recommended MRM to 34% of older patients versus 14% of younger patients (p<.001). Furthermore, the students recommended breast reconstruction after MRM to a significantly higher percentage of younger patients than older patients (95% versus 65%; p<.001). CONCLUSIONS: Medical students' recommendations of breast conservation and breast reconstruction showed age bias. Educational efforts should be instituted during the medical school to decrease ageism in students' treatment recommendations.

Age bias: a cause of underutilization of breast conservation treatment.

BACKGROUND: Breast conservation therapy (BCT) has been shown to result i about the same disease control and survival as modified radical mastectomy (MRM) for stage I and II breast cancers. Barriers to using BCT in patients with invasive breast cancer include "physician preference." This study was undertaken to investigate the bias of residents with respect to breast-conserving procedures. METHODS: Internal medicine and surgery residents were instructed about the efficacy of BCT. Subsequently, their opinions were assessed using a questionnaire concerning recommendations for BCT versus MRM as well as breast reconstruction after MRM in similar patients. Chi square tests were used for statistical analysis. RESULTS: Seventy-nine residents (54 medical, 25 surgical) participated. MRM was recommended for 38% of older (> 59 years old) versus 11% of younger patients (< 31 years old), p < 0.01. Furthermore, breast reconstruction was recommended for 96% of younger versus only 70% of older patients (p < 0.01). CONCLUSIONS: Residents are biased against older women in their recommendations for breast conservation and breast reconstruction. Educational efforts to decrease this age bias should be instituted during residency.

Drugs, guns, and kids: the association between substance use and injury caused by interpersonal violence.

BACKGROUND: Drug and alcohol uses have been linked to the frequency of injury events, recurrent hospital admission for injury, and interpersonal violence. Data regarding the association of recent substance use and injury type and frequency in children and young adults are not available. Such data probably would be valuable in planning interventions to prevent substance use and reduce the risks of injuries. METHODS: Evidence of substance use was assessed in trauma patients presenting to the authors' level 1 trauma center over a 6-month interval. Demographic data, mechanisms of injury, revised trauma scores (RTS), injury severity scores (ISS), hospital days, and mortality rate were evaluated. Chi square analysis and 2-tailed, paired t tests were used for statistical analysis. Multivariate logistic regression was utilized to determine the influence of individual variables. RESULTS: From a total group of 743 patients with life-threatening injuries, trauma registry records of 186 patients less than 21 years old were eligible for evaluation, and 126 of these had complete blood and urine drug assessments completed on admission to the trauma center. Forty-two percent (53 of 126) patients tested positive for alcohol or drugs. No patients less than 14 years of age (n = 61) had positive drug screen results. However, in the cohort of patients aged 14 and 15 (n = 17), 71% tested positive. Also, 72% of adolescents (age < 18) who were victims of injuries from gunshot wounds had evidence of substance use. Multivariate analysis showed gunshot wounds (P <.003) to be associated independently with positive drug screens. No statistical differences were observed in ethnic distribution, ISS, RTS, hospital days, or mortality rate when patients with positive screen results were compared with those without evidence of substance use. CONCLUSIONS: Trauma victims had evidence of substance use in early teen age years especially in the 14 and 15-year-old age groups. Toxicology screening disclosed that substance use is associated strongly with gunshot wounds. Substance use, along with poverty, inadequate family support, and peer pressure are factors that influence injury risk. Interventions to prevent substance use in young children may reduce the risk of injury.

Insulin-like growth factor-I receptor antagonism results in increased cytotoxicity of breast cancer cells to doxorubicin and taxol.

Therapeutic strategies for patients with advanced-stage adenocarcinoma of the breast frequently include the use of cytotoxic chemotherapy. Insulin-like growth factor I (IGF-I) receptor, a key factor in cell-cycle regulation, is frequently overexpressed in high-grade breast cancers. IGF-I receptor overexpression in these tumors may provide a target for novel molecular therapy against this disease. Early passage samples of estrogen-responsive (ER+) MCF 7 and estrogen receptor-negative (ER-) MDA-231 cells were cultured in semi-confluent conditions. Dose-titrations were performed for doxorubicin and taxol with receptor modulation using IGF-I or a competitive receptor inhibitor, alphaIR3. The addition of 100 ng/ml IGF-I resulted in a >2-fold mitogenic response in both ER+ and ER- cells. Receptor activation prior to the treatment with cytotoxic chemotherapeutic agents altered the pattern of response with a 26.3% increase in IC50. Doxorubicin and taxol both produced dose-related toxicity with IC50 of 0.05 microg/ml and 0.00 microg/ml respectively. The addition of alphaIR3 resulted in increased cytotoxicity in IGF-I stimulated cells compared with the use of doxorubicin or taxol alone. These results suggest that IGF-I receptor modulation alters the response to cytotoxic chemotherapeutic agents in breast cancer cells.

Axillary lymph node status of T1 primary breast cancer in a diverse population.

The utility of level I and II axillary lymph node dissection in women with primary tumors less than 1 cm in diameter has recently received extensive evaluation. Numerous patients undergo axillary lymph node dissection ultimately to discover no pathological involvement. This study investigates the lymph node status in T1 primary breast adenocarcinoma in our diverse patient population. A retrospective evaluation of patients treated at the Medical Center of Louisiana at New Orleans and the Tulane University Medical Center with breast adenocarcinoma less than or equal to 2 cm was performed. Demographic data and pathological reports were reviewed to obtain breast lesion size and lymph node status. One hundred sixteen patients were found to have T1 lesions. Ethnic distribution was African American 66 per cent; Caucasians 30 per cent; Hispanic 2 per cent; and Asian 3 per cent. Whereas no patients with T1a lesions had positive lymph nodes, 11 per cent of patients with T1b lesions and 36 per cent of patients with T1c lesions had positive lymph nodes. However, in our patient population no patients with tumors less than 1.0 cm. in diameter had positive lymph nodes. Although this may be due to our relatively small sample size axillary lymph node dissection may be unnecessary in this select patient population. For patients with lesions 1.0 cm and greater an axillary lymph node dissection seems to add necessary information for correct treatment in a small percentage of patients. The use of lymphatic mapping with sentinel axillary lymph node biopsy may reduce the number of unnecessary axillary dissections in early breast cancer.

Rho-kinase inhibitors prevent agonist-induced vasospasm in human internal mammary artery.

1. Vasospasm of arterial conduits used for coronary artery surgery is an important cause of graft failure and is likely to result partly from raised levels of vasoconstrictor substances such as thromboxane A(2) and endothelin-1. Our aim was to find pharmacological agents that could prevent agonist-induced vasospasm. 2. Isometric tension was recorded from discarded segments of human left internal mammary artery (LIMA). Submaximal contraction evoked by the thromboxane A(2) mimetic U46619 (10 nM) was not inhibited by a blocker of store- and receptor-operated Ca(2+) channels (30 microM SKF96365) in the presence of diltiazem. Furthermore, contractions to < or =1 nM U46619 were preserved when extracellular Ca(2+) was reduced from 2.5 mM to 60 nM. Thus, sustained U46619-evoked contraction occurred without Ca(2+) influx. 3., We hypothesized that contraction might occur via Rho-kinase-mediated Ca(2+)-sensitization of myofilaments. Inhibitors of Rho-kinase (Y27632 and HA1077) were profound relaxants. If contraction was pre-evoked by 10 nM U46619, Y27632 and HA1077 caused full relaxation with EC(50)s of 1.67+/-0.22 microM and 3.58+/-0.35 microM respectively. Y27632 was also effective if applied before U46619, but was less potent. 4. Y27632 abolished contraction evoked by endothelin-1 and significantly reduced resting tone in the absence of a vasoconstrictor. 5. Rho-kinase-mediated Ca(2+)-sensitization appears to be a major mechanism of vasoconstriction in human LIMA. Rho-kinase inhibitors may have an important role in preventing vasospasm in arterial grafts used for coronary artery surgery.

Insulin-like growth factor I receptor antagonism augments response to chemoradiation therapy in colon cancer cells.

BACKGROUND: Colorectal cancer remains one of the most prevalent malignancies in the United States. Improvement in local disease control is seen when 5-fluorouracil (5-FU) is used in combination with pelvic irradiation for rectal adenocarcinoma. The frequent overexpression of insulin-like growth factor I receptor (IGF-I-R) in rectal adenocarcinoma suggests that inhibition of the signal transduction pathway may be a novel approach to enhance tumor response. This investigation seeks to define the role of IGF-I-R antagonism, using monoclonal antibody alpha-IR3, in augmenting cytotoxicity to adjuvant chemoradiation therapy for adenocarcinoma of the rectum. MATERIALS AND METHODS: SW 480 colon cancer cells were cultured to semiconfluent conditions with dose titrations performed for 5-FU to determine that the IC(50) (inhibitory concentration of 50% of the cells) was 0.5 microg/ml. The IC(50) for 5-FU was reassessed in the presence of IGF-I. Experimental groups included colon cancer cells combined with 5-FU; 6-MeV external beam radiation (100-500 cGy); and alpha-IR-3. RESULTS: The addition of 100 ng/ml IGF-I 1 h prior to 5-FU or radiation significantly blunted the expected cytotoxicity, resulting in a 10-fold increase in the IC(50) (from 0.5 to 5 microg/ml). Receptor antagonism using the monoclonal antibody alpha-IR-3 (100-400 ng/ml) produced a dose-dependent increase in cytotoxicity compared with 5-FU alone. The addition of radiation produced synergistic amplification of this response. CONCLUSIONS: IGF-I-R activation blocks the expected cytotoxic effects of 5-FU and external beam radiation. Receptor antagonism increased the cytotoxic response of chemoradiation therapy. These data suggest the utility of inhibiting IGF-I-R signal transduction in the treatment of rectal adenocarcinoma.

Sodium-potassium-ATPase electrogenicity in cerebral precapillary arterioles.

Electrogenicity of the Na(+)/K(+) pump has the capability to generate a large negative membrane potential independently of ion-channel current. The high background membrane resistance of arterioles may make them susceptible to such an effect. Pump current was detected by patch-clamp recording from smooth muscle cells in fragments of arterioles (diameter 24-58 microm) isolated from pial membrane of rabbit cerebral cortex. The current was 20 pA at -60 mV, and the extrapolated zero current potential was -160 mV. Two methods of estimating the effect of pump electrogenicity on resting potential indicated an average contribution of -35 mV. In 20% of the recordings, block of inward rectifier K(+) channels by 10-100 microM Ba(2+) led to a small depolarization, but hyperpolarization was a more common response. Ba(2+) also inhibited depolarization evoked by 20 mM K(+). In arterioles within intact pial membrane, Ba(2+) failed to evoke constriction but inhibited K(+)-induced constriction. The data suggest that cerebral arterioles are vulnerable to the hyperpolarizing effect of the Na(+)/K(+) pump, excessive effects of which are prevented by depolarizing inward rectifier K(+) current

Atypical presentation of hepatocellular carcinoma.

Hepatocellular carcinoma is relatively rare in the United States, and the patterns of extrahepatic manifestations are diverse. Disease dissemination occurs through hematogenous routes to frequently involve the lungs, bone, adrenal glands, and pancreas. Soft tissue metastasis is extremely rare and mandates systematic pathologic analysis, which may include the use of immunohistochemical staining for tumor-specific markers. Relevant tumor markers that can assist in localizing the site of origin for adenocarcinoma include carcinoembryonic antigen, alpha-fetoprotein, vimentin, and anticytokeratins. We detail the utility of immunohistochemistry in evaluating tumors of unknown origin.

Vasorelaxant properties of nicorandil on human radial artery.

OBJECTIVE: The radial artery is becoming popular as a conduit for coronary artery surgery but there is concern about its tendency to vasospasm. Diltiazem is used clinically in an effort to prevent vasospasm but there are suggestions that it is relatively ineffective. The first aim of the study was to test the effectiveness of Ca(2+) antagonists against vasospasm evoked by vasoconstrictor agonists. Because a large component of vasospasm was resistant to Ca(2+) antagonists, the second aim was to test if a different class of vasodilator, nicorandil, might relax the residual tone. METHODS: Isometric tension was recorded in human radial artery segments harvested from patients undergoing myocardial revascularization surgery. RESULTS: Diltiazem at 10 microM, which strongly inhibits L-type voltage-gated Ca(2+) channels, induced partial relaxation (mean+/-SEM, 44.6+/-3.5%, n=31) of phenylephrine-evoked contraction, but only 14.0+/-4.1% (n=10) and 12. 2+/-4.2% (n=10) relaxation of U46619- (a thromboxane A(2) analogue) or endothelin-1-evoked contraction. Strikingly, nicorandil relaxed agonist-evoked contractions that were resistant to diltiazem or nicardipine. In the absence of a Ca(2+) antagonist, nicorandil (30 microM) evoked 74.1+/-5.6% (n=24), 36.8+/-9.3% (n=10) and 64.5+/-7. 9% (n=14) relaxation of phenylephrine-, U46619- and endothelin-1-evoked contractions. CONCLUSIONS: Nicorandil has a marked relaxant effect on contractions evoked by three different vasoconstrictor agonists, and relaxes vasospasm that is resistant to conventional Ca(2+) antagonists. These in vitro data suggest that nicorandil might be a useful drug for the inhibition of radial artery vasospasm in myocardial revascularization surgery.