Clinical Outcomes and Return to Sport After Arthroscopic Anterior, Posterior, and Combined Shoulder Stabilization.

BACKGROUND: Glenohumeral instability is a common abnormality, especially among athletes. Previous studies have evaluated outcomes after arthroscopic stabilization in patients with anterior or posterior shoulder instability but have not compared outcomes between groups. PURPOSE: To compare return-to-sport and other patient-reported outcomes in patients after primary arthroscopic anterior, posterior, and combined anterior and posterior shoulder stabilization. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Patients who underwent primary arthroscopic anterior, posterior, or combined anterior and posterior shoulder stabilization were contacted at a minimum 2-year follow-up. Patients completed a survey that consisted of return-to-sport outcomes as well as the Western Ontario Shoulder Instability Index (WOSI), Single Assessment Numeric Evaluation (SANE), American Shoulder and Elbow Sur'geons (ASES) score, and Shoulder Activity Scale. RESULTS: A total of 151 patients were successfully contacted (anterior: n = 81; posterior: n = 22; combined: n = 48) at a mean follow-up of 3.6 years. No significant differences were found between the groups with regard to age at the time of surgery or time to follow-up. No significant differences were found between the groups in terms of WOSI (anterior: 76; posterior: 70; combined: 78; P = .28), SANE (anterior: 87; posterior: 85; combined: 87; P = .79), ASES (anterior: 88; posterior: 83; combined: 91; P = .083), or Shoulder Activity Scale (anterior: 12.0; posterior: 12.5; combined: 12.5; P = .74) scores. No significant difference was found between the groups in terms of the rate of return to sport (anterior: 73%; posterior: 68%; combined: 75%; P = .84). CONCLUSION: Athletes undergoing arthroscopic stabilization of anterior, posterior, or combined shoulder instability can be expected to share a similar prognosis. High patient-reported outcome scores and moderate to high rates of return to sport were achieved by all groups.

Total Synthesis of (-)-Spiroleucettadine.

One of a number of intriguing new alkaloids isolated from the Leucetta sp. sponge in 2004, spiroleucettadine displayed unique structural features on a restricted scaffold: a trans-fused 5,5-bicyclic ring system together with an amino hemiketal moiety. Attempts to synthesize the initially proposed structure failed, raising questions as to its veracity, and structure revision ensued in 2008; no successful synthetic approach has been reported to date. Herein, we describe the enantiospecific total synthesis of (-)-spiroleucettadine by a highly efficient biomimetic approach starting from l-tyrosine. One of two key hypervalent-iodine-mediated oxidation reactions forged the spirocyclic center, and the other enabled the installation of the methylamine side chain in the penultimate step. Our approach provides synthetic access to a new class of spiroannulated natural products and will enable future studies of the structure-biological-activity relationships of these antibacterial compounds.

Biomechanical comparison of traditional anchors to all-suture anchors in a double-row rotator cuff repair cadaver model.

BACKGROUND: To further reduce the invasiveness of arthroscopic rotator cuff repair surgery the all-suture anchor has been developed. The all-suture anchor requires less bone removal and reduces the potential of loose body complications. The all-suture anchor must also have adequate biomechanical strength for the repair to heal. The hypothesis is there is no significant difference in the biomechanical performance of supraspinatus repairs using an all-suture anchor when compared to traditional solid-body suture anchors. METHODS: Using nine shoulders per group, the supraspinatus tendon was dissected from the greater tuberosity. The four different double row repairs tested were (medial row/lateral row): A: ICONIX2/ICONIX2; B: ICONIX2/Stryker ReelX 3.9mm; C: ICONIX2/Stryker ReelX 4.5mm; D: Arthrex BioComposite CorkScrew FT 4.5mm/Arthrex BioComposite SwiveLock 4.75mm. The ICONIX2 was the only all-suture anchor tested. Tendons underwent cyclic loading from 10 to 100N for 500 cycles, followed by load-to-failure. Data was collected at cycles 5, 100, 200, 300, 400, and 500. One-way ANOVA analysis was used to assess significance (P≤0.05). FINDINGS: The anchor combinations tested did not differ significantly in anterior (P>0.4) or posterior (P>0.3) gap formation, construct stiffness (P>0.7), ultimate load (P=0.06), or load to 5mm gap formation (P=0.84). INTERPRETATION: The all-suture anchor demonstrated comparable biomechanical performance in multiple double-row anchor combinations to a combination of traditional solid-body anchors. Thus it may be an attractive option to further reduce the invasiveness of rotator cuff repairs.

A concise total synthesis of naamidine A.

[reaction: see text]. A total synthesis of naamidine A is reported. Key benefits of the described pathway include its brevity, its synthetic ease, and its flexibility with respect to the preparation of analogues. Formation of the 2-aminoimidazole core is achieved by condensation of the appropriate alpha-aminoketone with cyanamide.

Inhibition of PI-3 kinase/Akt/mTOR, but not calcineurin signaling, reverses insulin-like growth factor I-induced protection against glucose toxicity in cardiomyocyte contractile function.

Insulin-like growth factor-I (IGF-1) ameliorates cardiac dysfunction in diabetes although the mechanism of action remains poorly understood. This study examined the role of PI-3 kinase/Akt/mammalian target of rapamycin (mTOR) and calcineurin pathways in cardiac effects of IGF-1 against glucose toxicity. Adult rat ventricular myocytes were cultured for 8 h with either normal (NG, 5.5 mM) or high (HG, 25.5 mM) glucose, in the presence or absence of IGF-1 (10-500 nM), the PI-3 kinase/Akt inhibitor LY294002 (10 microM), the mTOR inhibitor rapamycin (20 microM) or the calcineurin inhibitors cyclosporin A (5 microM) or FK506 (10 mg/l). Mechanical properties were evaluated using an IonOptix MyoCam system. HG depressed peak shortening (PS), reduced maximal velocity of shortening/relengthening (+/- dl/dt) and prolongs time-to-90% relengthening (TR90), which were abolished by IGF-1 (100 and 500 nM). Interestingly, the IGF-1-elicited protective effect against HG was nullified by either LY294002 or rapamycin, but not by cyclosporine A or FK506. None of the inhibitors affected cell mechanics. Western blot analysis indicated that HG and IGF-1 stimulated phosphorylation of Akt and mTOR. HG also activated p70s6k and suppressed GSK-3beta phosphorylation. However, the HG-induced alterations in phosphorylation of Akt, mTOR, p70s6k and GSK-3beta were significantly reversed by IGF-1. Protein expression of Akt, mTOR, p70s6k, GSK-3beta, SERCA2a and phospholamban was unaffected by HG, IGF-1 or rapamycin. Rapamycin significantly enhanced Akt phosphorylation whereas it inhibited mTOR phosphorylation. Collectively, our data suggest that IGF-1 may provide cardiac protection against glucose in part through a PI-3 kinase/Akt/mTOR/ p70s6k-dependent and calcineurin-independent pathway.

Doxorubicin induces cardiomyocyte dysfunction via a p38 MAP kinase-dependent oxidative stress mechanism.

Doxorubicin, an anthracycline used for cancer therapy, is known to elicit an irreversible cardiotoxicity. Several mechanisms were postulated for its cardiac toxicity including generation of reactive oxygen species (ROS). This study was designed to determine the acute effect of doxorubicin on cardiac mechanical and intracellular Ca(2+) properties in isolated ventricular myocytes. Contractile properties of male adult rat ventricular myocytes were analyzed including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR(90)) and maximal velocity of shortening/relengthening (+/-dL/dt). Intracellular Ca(2+) transients and generation of ROS were measured with fura-2 and fluoroprobe 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, respectively. Acute (5 min) incubation of myocytes with doxorubicin (10(-9)-10(-4)M) significantly prolonged TPS, TR(90) and intracellular Ca(2+) transient decay rate without affecting PS, +/-dL/dt, resting intracellular Ca(2+) levels and electrically triggered intracellular Ca(2+) rise. Interestingly, the doxorubicin-induced prolongation of TPS and TR(90) was ablated by treatment of the antioxidant Vitamin C (100 microM) or the p38 MAP kinase inhibitor SB203580 (10 microM). Both Vitamin C and SB203580 unmasked a doxorubicin-induced positive response in PS. Vitamin C itself enhanced basal +/-dL/dt, whereas, SB203580 unmasked a doxorubicin-induced positive response of +/-dL/dt. The doxorubicin-induced response of intracellular Ca(2+) transients was essentially unaffected by Vitamin C. The role of ROS in doxorubicin-induced cardiac contractile response was confirmed with the ability of doxorubicin to enhance ROS generation, which was prevented by Vitamin C and SB203580. These data provide evidence that doxorubicin impairs cardiac contractile property in single myocytes through an oxidative stress-mediated pathway.

Bigendothelin-1 via p38-MAPK-dependent mechanism regulates adult rat ventricular myocyte contractility in sepsis.

We tested the hypothesis that exogenous administration of the ET-1 precursor, bigET-1, would regulate adult rat ventricular myocyte (ARVM) contractility in a p38-mitogen activated protein kinase (p38-MAPK)-dependent mechanism during sepsis. Ventricular myocytes from adult rat hearts (both sham and septic) were stimulated to contract at 0.5 Hz and mechanical properties were evaluated using an IonOptix Myocam system. Immunoblot analysis was used to determine the phosphorylation of p38-MAPK and extracellular signal-regulated kinase 1/2 (ERK1/2). ARVMs were treated with vehicle, bigET-1 and inhibitors for 24 h and then subjected to functional and biochemical estimations. Septic ARVM displayed a distorted cell membrane and irregular network within the cells along with increased cell contractility as evidenced by elevated peak shortening (PS), maximal velocity of shortening (+dL/dt) and relengthening (-dL/dt) in comparison to sham ARVM. BigET-1 treatment caused ARVM enlargement in both sham and sepsis groups. BigET-1 (100 nM) produced an increase in ARVM contractility in sham group as compared to vehicle treatment. However, septic ARVM treated with bigET-1 exhibited unaltered ARVM contractility, and upregulated ET(B) receptors as compared to respective sham group. BigET-1 increased the concentration of ET-1 and upregulated phosphorylation of p38-MAPK but not of ERK1/2 in sham and septic ARVM. Furthermore, inhibition of p38-MAPK by SB203580 (10 microM) increased ARVM contractility in sham but not in sepsis group. BigET-1 reversed SB203580-induced increase in PS in sham group but accentuated it in sepsis group. BigET-1 also reversed SB203580-induced inhibition of p38-MAPK phosphorylation in sham but not in septic ARVM. SB203580 pretreatment followed by bigET-1 administration significantly decreased p38-MAPK phosphorylation and downregulated ET(B) receptor expression as compared to bigET-1 treatment per se in sepsis group but not in sham. We concluded that a bigET-1-induced non-responsive effect on septic ARVM contractile function could be due to upregulation of p38-MAPK phosphorylation and ET(B) receptor expression.

Endothelin-converting enzyme-1-mediated signaling in adult rat ventricular myocyte contractility and apoptosis during sepsis.

We hypothesized that modulation of endothelin-converting enzyme-1 (ECE-1) activity would affect phosphorylation of p38-mitogen activated protein kinase (p38-MAPK) and potentiate apoptosis in adult rat ventricular myocytes (ARVMs) during sepsis. The activity of ECE-1 in ARVMs was altered by increasing the substrate availability for ECE-1 by exogenous administration of bigendothelin-1 (bigET-1, 100 nM) and by inhibiting ECE-1 using FR901533 (10 microM) for 24-h. FR901533 significantly decreased the concentration of ET-1 in both sham and sepsis groups. FR901533 decreased p38-MAPK phosphorylation in sepsis but not in sham group. BigET-1 upregulated p38-MAPK phosphorylation, produced hypertrophy, decreased cell viability and reversed FR901533-induced down-regulation of p38-MAPK phosphorylation in both groups. Although, FR901533 did not affect cell cross-sectional area, it significantly reduced the viability of ARVM in both groups. The peak shortening of sham ARVMs was elevated by bigET-1, FR901533 and pretreatment with FR901533 followed by bigET-1. However, the contractility of septic ARVMs was not altered by either bigET-1 or FR901533 treatments per se. Septic ARVM exhibited significantly increased caspase-3 activity at 12 and 24-h. Pretreatment with FR901533 significantly elevated caspase-3 activity in both sham and sepsis group. The data demonstrated that bigET-1-induced hypertrophy in septic ARVM correlates with an ECE-1 dependent-activation of p38-MAPK. The results suggest that non-responsiveness of ARVM to bigET-1 is due to ECE-1 dependent apoptosis. We concluded that ECE-1 may play a crucial role in ARVM dysfunction via increased caspase-3 activity and p38-MAPK phosphorylation during sepsis.

Acetaldehyde-induced cardiac contractile dysfunction may be alleviated by vitamin B1 but not by vitamins B6 or B12.

AIMS: Chronic alcohol exposure leads to a deficiency of group B vitamins and increased risk of alcoholic cardiomyopathy characterized by impaired ventricular contractility. This study was designed to examine the effect of group B vitamin supplementation on short-term exposure of the main alcohol metabolite acetaldehyde (ACA)-induced cardiac contractile dysfunction in rat ventricular myocytes. METHODS: Mechanical contractile properties were evaluated by an IonOptix SoftEdge system. Protein damage and apoptosis were determined by protein carbonyl and caspase-3 assays, respectively. RESULTS: Short-term (4-6 h) culture of myocytes with ACA (10 microM) depressed peak shortening amplitude, maximal velocity of shortening/relengthening, shortened duration of shortening but not the duration of relengthening. ACA exposure also enhanced protein carbonyl formation and apoptosis in ventricular myocytes. The toxin-induced mechanical defects, protein damage and apoptosis were ablated by vitamin B1 (10 microM), an essential vitamin required for DNA synthesis and repair. Vitamin B6 (10 microM) attenuated ACA-induced impairment of shortening duration. Vitamin B12 (1 mM) attenuated ACA-induced reduction in maximal velocity of shortening/relengthening. Unlike vitamin B1, none of the other ACA-elicited alterations in myocyte mechanical function were affected by vitamin B6 or vitamin B12. Vitamin B6 and vitamin B12 partially, but significantly, attenuated the ACA-induced carbonyl formation without affecting ACA-induced apoptosis. CONCLUSIONS: These data provide evidence that vitamin B1 supplementation may be protective for ACA-induced cytotoxicity through protection against protein damage and apoptotic cell death in ventricular myocytes.

Korean anti-inflammatory compound allergina enhances cardiac contractile function in isolated ventricular cardiomyocytes.

OBJECTIVES: The herbal compound Allergina has a long history in the clinical treatment of allergic inflammatory diseases in some countries including Korea. However, the direct effect of Allergina on ventricular contractile function has not been defined. DESIGN: This study was designed to investigate the impact of Allergina on ventricular contractile function. SETTINGS: Ventricular contractile function was examined in single isolated left ventricular cardiomyocytes. SUBJECTS/INTERVENTIONS: Isolated cardiomyocytes from adult male Sprague-Dawley rats were electrically stimulated to contract at 0.5 Hz. OUTCOME MEASURES: Mechanical and intracellular Ca2+ transients properties of cardiomyocytes were evaluated using an IonOptix Myocam (IonOptix Inc., Milton, MA) system and fura-2 fluorescent dye. Contractile properties analyzed included peak shortening (PS), time-to-peak shortening (TPS), time-to-90% relengthening (TR90), and maximal velocity of shortening/relengthening (+/- dL/dt). Intracellular Ca2+ transients were evaluated as the fura-fluorescence intensity change (DeltaFFI) and fluorescence decay time. RESULTS: Allergina (10(-7) - 10(-3) mg/mL) significantly augmented PS in a dose-dependent manner with a maximal response of 50.4%. Allergina did not elicit any effect on TPS, TR(90), and +/-dL/dt. Intracellular Ca2+ transients displayed consistent findings in that Allergina enhanced the electrically-stimulated increase in change of intracellular Ca2+ transients (DeltaFFI) and slowed intracellular Ca2+ fluorescence decay without affect the resting intracellular Ca2+ levels. CONCLUSIONS: Collectively, these data demonstrated a direct cardiac stimulatory property of Allergina on cardiac contraction and intracellular Ca2+ transients in isolated left ventricular cardiomyocytes.

Comparison of cardiac contractile and intracellular Ca2+ response between estrogen and phytoestrogen alpha-zearalanol in ventricular myocytes.

While the benefit and risk of estrogen replacement therapy for cardiovascular disease remains controversial, women frequently choose alternatives to estrogen such as phytoestrogen for treatment of menopause even though medical indications for estrogens may exist. Phytoestrogens also possess distinct advantages over mammalian estrogens because their usage in men without feminizing side effects. Nevertheless, the cardiac contractile function of estrogen or phytoestrogen has not been clearly elucidated. The aim of the present study was to compare the effect of 17beta estradiol (E2) and phytoestrogen alpha-zearalanol (ZAL) on cardiac mechanical function and intracellular Ca2+ transients at cellular levels. Isolated ventricular myocytes from adult female rats were stimulated to contract at 0.5 Hz. Contractile properties were evaluated using an IonOptix MyoCam system including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), and maximal velocity of shortening/relengthening (+/- dL/dt). Intracellular Ca2+ properties were evaluated as fura-2 fluorescent intensity change (DeltaFFI) and intracellular Ca2+ decay rate. Acute administration of E2 (10(-9) - 10(-5) M) elicited a concentration-dependent increase in PS and DeltaFFI, with maximal augmentation of approx 35% and 25%, respectively. TPS, TR90, +/- dL/dt, resting intracellular Ca2+ level, and intracellular Ca2+ decay were unaffected by E2. None of the mechanical or intracellular Ca2+ indices tested was affected by phytoestrogen ZAL (10(-9) - 10(-5) M). Our results revealed a direct cardiac stimulatory action from E2 but not from phytoestrogen ZAL on ventricular contraction, likely mediated through enhanced intracellular Ca2+ release.

Inhibition of cardiac myocyte contraction by 4-hydroxy-trans-2-nonenal.

Lipid peroxidation, initiated by hydroxyl radicals, results in production of 4-Hydroxy-trans-2-nonenal (HNE) and leads to cardiac injury. However, impact of HNE on ventricular function has not been clearly defined. This study was to examine the direct effect of HNE on cardiac contractile function at cardiac myocyte level. Adult male rat ventricular myocytes were isolated and electrically stimulated to contract at 0.5 Hz. Mechanical and intracellular Ca2+ properties were evaluated using an Ionoptix Myocam system. Contractile properties analyzed included peak shortening (PS), time-PS, time-to-90% relengthening, maximal velocities of shortening and relengthening (+/-dL/dt), change of electrically stimulated intracellular Ca2+ fura-2 fluorescent intensity, and intracellular Ca2+ decay. Our results indicated that short-term incubation of HNE (10(-6) to 10(-4) M) with myocytes depressed PS, +/-dL/dt, and fura-2 fluorescent intensity; shortened time-PS; and elevated resting intracellular Ca2+ levels without affecting time-to-90% relengthening and intracellular Ca2+ decay. Interestingly, the HNE-induced cardiac mechanical effects (with the exception of shortened time-PS) were abolished by either the aldehyde dehydrogenase inhibitor cyanamide or the p38 mitogen-activated protein kinase inhibitor SB203580. These findings reveal a possible role of HNE in the lipid peroxidation-associated cardiac contractile dysfunction that is likely mediated through HNE metabolism and mitogen-activated protein kinase activation.

Depressed contractile function and adrenergic responsiveness of cardiac myocytes in an experimental model of Parkinson disease, the MPTP-treated mouse.

Radiotracer and biochemical studies have shown that patients with Parkinson disease lack functional sympathetic innervation to the heart. The same observation was made in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an experimental model of Parkinson disease. This study examined the mechanical properties, adrenergic receptor level and intracellular Ca2+ handling in cardiac myocytes isolated from C57/BL6 mice that received either MPTP (30 mg/kg, i.p., twice in 24 h) or vehicle. Mechanical properties were evaluated using an IonOptix MyoCam system. Myocytes were electrically stimulated at 0.5 Hz. The contractile properties analyzed included peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), and maximal velocities of shortening and relengthen (+/-dL/dt). Intracellular Ca2+ handling was evaluated with fura 2. Myocytes from MPTP-treated mice exhibited a depressed PS (85% of normal), normal TPS, prolonged TR90 (147% of normal), and reduced +/-dL/dt (both 79% of normal). These results were correlated with a 67% reduction of beta-adrenergic receptor expression in myocardial membranes from MPTP-treated mice when compared to normal. Myocytes from MPTP-treated mice also exhibited a reduced peak of intracellular Ca2+ sequestration and sarcoplasmic reticulum (SR) Ca2+ load (55 and 38% of normal, respectively). The resting intracellular Ca2+ and Ca2+-transient decay were comparable to the values seen in myocytes from untreated mice. Myocytes from MPTP-treated and untreated mice were equally responsive over a range of stimulation frequencies (0.1, 0.5, 1, 3 and 5 z). Response to norepinephrine (1 microM) and isoproterenol (1 microM) was reduced in myocytes from MPTP-treated mice. These results demonstrate substantial cardiac dysfunctions in this model of experimental Parkinson disease, probably due to reduced adrenergic responsiveness and SR Ca2+ load.

Combined acetaldehyde and nicotine exposure depresses cardiac contraction in ventricular myocytes: prevention by folic acid.

Chronic alcoholism can progress to alcoholic cardiomyopathy characterized by ventricular dilation and impaired ventricular contractility. Nicotine abuse continues to remain a serious risk factor for cardiovascular diseases. However, little is know regarding the combined effects. This study was designed to examine the role of short-term combined exposure of the main alcohol metabolite acetaldehyde (ACA) and nicotine on cardiac contractile function in adult rat ventricular myocytes, and if folate exposure attenuates the effect of ACA/nicotine. Mechanical and intracellular Ca2+ properties were evaluated by an IonOptix SoftEdge system. Short-term (4-6 h) culture of myocytes with ACA (10 microM), nicotine (100 microM), or combination of the two in sealed vials with silicone septa depressed maximal velocity of shortening/relengthening, without affecting duration of shortening/relengthening and intracellular Ca2+ handling. Interestingly, the toxin-induced defects on myocyte mechanical properties were ablated with cotreatment of folate (100 microM), an essential vitamin required for DNA synthesis and repair. Collectively, these data provided evidence that ACA and nicotine, either alone or in combination, directly depressed cardiomyocyte mechanical function possibly through mechanisms related to DNA damage.

Short-term acetaldehyde exposure depresses ventricular myocyte contraction: role of cytochrome P450 oxidase, xanthine oxidase, and lipid peroxidation.

BACKGROUND: Chronic alcoholism leads to the development of alcoholic cardiomyopathy, manifested as ventricular dilation and impaired ventricular contractility. However, the specific toxic mechanism responsible for alcoholic cardiomyopathy remains unclear. One major candidate toxin is the first metabolic product of ethanol, acetaldehyde (ACA). This study was designed to examine the role of cytochrome P450 oxidase 2E1 (CYP 2E1), xanthine oxidase, and lipid peroxidation in the short-term ACA exposure-induced mechanical defects in adult rat ventricular myocytes. METHODS: Mechanical and intracellular Ca2+ properties were evaluated by an IonOptix SoftEdge system. Lipid peroxidation was assessed with malondialdehyde levels by using high-performance liquid chromatography. RESULTS: Short-term (4- to 6-hr) culture of myocytes with ACA (1-100 microM) in sealed containers with silicone septum depressed cell-shortening amplitude, maximal velocity of shortening/relengthening, and prolonged duration of relengthening, as well as intracellular Ca2+ clearing without any effect on the duration of shortening and electrically stimulated an intracellular Ca2+ increase. It is interesting to note that the ACA-induced effects on myocyte mechanical properties were abolished with co-treatment of the lipid peroxidation inhibitor butylated hydroxytoluene (20 microM), the CYP 2E1 inhibitor diallyl sulfide (100 microM), and the xanthine oxidase inhibitor allopurinol (100 microM). Short-term incubation of ACA with the myocytes also produced a significant increase of the lipid peroxidation end product malondialdehyde, which may be prevented by butylated hydroxytoluene. CONCLUSIONS: Collectively, these data provided evidence that ACA depressed cardiomyocyte mechanical function at micromolar levels, possibly through mechanisms related to CYP oxidase, xanthine oxidase, and lipid peroxidation.

Influence of gender on ethanol-induced ventricular myocyte contractile depression in transgenic mice with cardiac overexpression of alcohol dehydrogenase.

Acute ethanol exposure depresses ventricular contractility and contributes to alcoholic cardiomyopathy in both men and women chronically consuming ethanol. However, a gender-related difference in the severity of myopathy exists with female being more sensitive to ethanol-induced tissue damage. Acetaldehyde (ACA), the major oxidized product of ethanol, has been implicated to play a role in the pathogenesis and gender-related difference of alcoholic cardiomyopathy, possibly due to its direct cardiac effect and interaction with estrogen. This study was designed to compare the effects of cardiac overexpression of alcohol dehydrogenase (ADH), which converts ethanol into ACA, on the cardiac contractile response to ethanol in ventricular myocytes isolated from age-matched adult male and female transgenic (ADH) and wild-type (FVB) mice. Mechanical properties were measured with an IonOptix SoftEdge system. ACA production was assessed by gas chromatography. The ADH myocytes from both genders exhibited similar mechanical properties but a higher efficacy to produce ACA compared to FVB myocytes. Exposure to ethanol (80-640 mg/dl) for 60 min elicited concentration-dependent decrease of cell shortening in both FVB and ADH groups. The ethanol-induced depression on cell shortening was significantly augmented in female but not male ADH group. ADH transgene did not exacerbate the ethanol-induced inhibition of maximal velocity of shortening/relengthening in either gender. In addition, neither ethanol nor ADH transgene affect the duration of shortening and relengthening in male or female mice. These data suggest that females may be more sensitive to ACA-induced cardiac contractile depression than male, which may attribute to the gender-related difference of alcoholic cardiomyopathy.

Influence of prenatal ethanol exposure on vascular contractile response in rat thoracic aorta.

Fetal alcohol syndrome is associated with cardiovascular malformation. However, the impact of prenatal ethanol exposure on vascular function is not clear. The purpose of this study was to examine the influence of prenatal ethanol exposure on vascular response in adulthood. Timed-pregnancy, female rats were fed an ethanol-containing liquid diet (36% calorically or 6.36% [vol./vol.]) or control diet from gestation day 2 until labor. The pups continued to receive a standard rat chow through adulthood, and the force-generating capacity of aortic ring segments was examined. Prenatal ethanol exposure did not significantly affect postnatal growth, but it did lead to elevated blood pressure in adulthood. The contractile response to potassium chloride was similar in vessels with intact endothelium, although the median effective concentration (EC(50)) was significantly reduced by prenatal ethanol exposure in rings with denuded endothelium. The response to norepinephrine was attenuated by prenatal ethanol exposure in rings with either intact or denuded endothelium. The endothelium-dependent relaxation to carbamylcholine chloride was significantly attenuated by prenatal ethanol exposure. Vasorelaxant response to the nitric oxide donor sodium nitroprusside or beta-adrenergic agonist isoproterenol was similar between control and prenatal-ethanol-exposed groups with either intact or denuded endothelium. Ethanol elicited a dose-dependent endothelium-dependent vasorelaxation, which was comparable between the two animal groups. The ethanol-induced endothelium-dependent vasorelaxation was attenuated by the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester. These findings seem to indicate that prenatal ethanol exposure contributes to alterations of both endothelium-dependent and endothelium-independent vascular contractile responses.