Effect of Ethanol on Function of the Rat Heart and Skeletal Muscles

The present study was undertaken to evaluate the acute effects of ethanol on responses of the rat heart and skeletal muscles both in vivo and in vitro. In the anesthetized rat, intravenous infusion of ethanol at 0.1–0.5 g/kg body weight (33–167 m m ) decreased the breathing rate by 8–83%, heart rate by 4–52%, and QRS amplitude by 5–27%, and increased the P-R interval by 1–49%. In the anterior tibialis muscle subjected to repetitive nerve stimulation at 100 Hz for 0.5 sec, ethanol at 0.1 g/kg increased the amplitude of the muscle action potential (AP) by 7%, whereas at 0.5 g/kg it decreased the muscle AP by 32%. The nerve-evoked tetanic tension was reduced by 7–34% at 0.1–0.5 g/kg ethanol. In the isolated rat heart, perfusion of ethanol at 0.1–3.0% (22–651 m m ) decreased the heart rate by 8–48% and QRS amplitude by 10–39%, and increased the P-R interval by 5–61%. Left ventricular pressure was increased by 10% at 0.1 % ethanol, and decreased by 80% at 3.0% ethanol. In the isolated rat phrenic nerve-diaphragm muscle preparation subjected to repetitive nerve stimulation at 100 Hz for 0.5 sec, 0.1–3.0% ethanol decreased the amplitude of the nerve AP by 5–89%, nerve-evoked muscle AP by 2–96%, and peak tetanic tension by 1–87%. On repetitive direct muscle stimulation at 100 Hz for 0.5 sec, 0.1–3.0% ethanol decreased the amplitude of the muscle-evoked muscle AP by 8–65%, and muscle-evoked tetanic tension by 2–65%. These studies indicate that ethanol causes smaller reduction in responses of the heart and skeletal muscles at clinical concentrations, but marked reduction in these responses at higher concentrations due to direct action on excitability of these tissues. At higher concentrations, ethanol causes greater reduction in excitability of the skeletal muscle than of the heart.     

Effects of In Vitro Ethanol and Fetal Ethanol Exposure on Glutathione Stimulation of N-Methyl-D-Aspartate Receptor Function

The present studies investigated the effects of glutathione (GSH; γ-glutamylcysteinylglycine) and its oxidized form (GSSG) on neuronal N -methyl-D-aspartate (NMDA) receptor activation in both acute and chronic preparations of ethanol exposure. It was demonstrated using fura-2-loaded dissociated brain cells from newborn rat pups that both GSH and GSSG (0–4 mM) produced concentration-dependent increases in intracellular calcium similar to those produced by NMDA and other agonists of the NMDA receptor. GSH-stimulated calcium entry was not inhibited by low intoxicating concentrations of ethanol, which contrasts with ethanol's typical inhibitory effect on NMDA-stimulated receptor activation. Behavioral studies in adult rats demonstrated that ethanol-induced sleep times were significantly decreased when 10 μl of GSSG (20 mM) were administered intracere-broventricularly approximately 5 min before an intraperitoneal injection of 20% (w/v) ethanol (3 g/kg). These findings suggest that the less potent effect of ethanol on GSH-stimulated calcium entry as well as the reduction in ethanol-induced sleep times may be related to the presence of glycine in the peptide. The glycine found in GSH may activate the glycine site and block or reduce ethanol's action on this site. It appears that although GSH may play an important role in the activation of the NMDA receptor, this action does not involve a process that is sensitive to acute ethanol exposure. In contrast, when rat pups were chronically exposed to ethanol via prenatal exposure before the fura-2 preparation, increases in NMDA- and GSH-stimulated calcium entry were significantly decreased relative to those in pair-fed and ad libitum-fed controls. Thus, chronic in utero exposure to ethanol may alter the NMDA-receptor complex, such that calcium entry mediated by NMDA or GSH activation is significantly reduced.     

Ethanol and Cocaine Cause Additive Inhibitory Effects on the Calcium Transients and Contraction in Single Cardiomyocytes

The heart is a major locus for the toxic actions of cocaine and ethanol, each of which has been shown to interfere with excitation-contraction coupling in cardiac muscle cells. Because these drugs are frequently used in combination, the present study was designed to investigate how they interact to modify the Ca²⁺ transient and associated contraction in fura2-loaded cardiomyocytes. A high-speed imaging technique using a charge-coupled device as detector and short-term image store was used to measure cytosolic Ca²⁺ and contraction simultaneously from fluorescence images obtained during the contractile cycle. Ethanol (100 mM) and cocaine (50 μM) caused reversible reductions in Ca²⁺ transient amplitude of 24.3 ± 3.0% and 25.1 ± 3.6%, respectively. Neither agent modified basal Ca²⁺. Ethanol treatment decreased peak shortening by 44.3 ± 3.5%, whereas the contractile depression by cocaine was 31.4 ± 5.3%. The relatively greater effect of ethanol on contraction resulted from a Ca²⁺-independent component of ethanol action on contractility. When cardiomyocytes were exposed simultaneously to ethanol and cocaine, Ca²⁺ transient amplitude was reduced by 38.7 ± 3.0%, and peak contraction was decreased by 55.1 ± 3.5%. These values represent a significantly greater inhibition than observed with either drug alone (p < 0.02) and are compatible with additive effects of the two drugs acting at distinct loci within the excitation-contraction coupling pathway. Thus, simultaneous use of cocaine and ethanol leads to an enhanced depression of myocardial contractility, which is likely to contribute to the cardiotoxic actions of the combination of these two drugs.     

Differential Effects of Ethanol on Baroreceptor Heart Rate Responses of Conscious Spontaneously Hypertensive and Normotensive Rats

This study investigated the acute effects of ethanol (0.25, 0.5, or 1 g/kg, iv) on mean arterial pressure, heart rate, and gain of the baroreceptor reflex control of heart rate (BRS) in conscious spontaneously hypertensive rats (SHRs) and age-matched Wistar rats. BRS was substantially lower in the SHRs as compared with the Wistar rats when measured by phenylephrine (-0.95 ± 0.16 vs. -2.02 ± 0.22 beats/min/mm Hg) or nitroprusside (-1.90 ± 0.2 vs. -3.02 ± 0.32 beats/min/mm Hg). None of the doses of ethanol influenced BRS in the SHR. In contrast, ethanol attenuated BRS in Wistar rats, but this effect was dependent on the dose used and the type of response. The lower doses attenuated the reflex tachycardic response, but had no effect on the reflex bradycardic response. On the other hand, the 1 g/kg dose of ethanol attenuated the reflex bradycardic but not the tachycardic response. Ethanol produced a pressor effect (15-25 mm Hg; 5-min duration), which was neither dose- nor strain-dependent. However, only in the SHR mean arterial pressure remained elevated (10-15 mm Hg above control) for 20 min in response to the 0.5 g/kg dose of ethanol, and its recovery coincided with the occurrence of a slowly developing negative chronotropic response. Ethanol produced a dose-related negative chronotropic effect in both strains of rats that was of longer duration in the SHR, particularly with the 1 g/kg dose. It is possible that the bradycardic effect of ethanol influenced negatively its pressor effects. Data suggest that, in conscious rats, ethanol: (1) attenuates BRS in normotensive rats but not in the SHR; (2) causes a brief pressor effect that is not related to its dose, the level of arterial pressure, or its influence on the gain of the baroreceptor reflex; and (3) elicits dose-related bradycardic responses that are of longer duration in the SHR, particularly with the higher dose. This negative chronotropic effect of ethanol may limit its pressor effect in SHRs.     

Ethanol and Experimental Breast Cancer: A Review

There is considerable evidence from epidemiological studies to support a positive association between alcohol intake and risk for breast cancer. Yet, experimental evidence has provided less convincing evidence to support this relationship, although much less attention has been focused on elucidating the effect of ethanol on breast carcinogenesis in animal models. Although the number of reports are limited, information on the effect of ethanol on mammary carcinogenesis in spontaneous, chemically induced and metastatic models has been published. In addition, a small number of reports provide insights into an influence of ethanol on the physiological processes associated with the initiation, promotion, and progression stages of breast carcinogenesis in animals, as well as on the growth of human breast cancer cells. This information from the literature is summarized, and specific recommendations put forth so that greater progress can be made in this controversial and complex research area.     

Ethanol interferes with the measurement of extracellular ionized calcium

BACKGROUND: Maintenance of extracellular calcium (Ca) concentration within narrow limits is critical for normal cell function and optimization of bone health. Ionized Ca (iCa), the form of Ca that is regulated, has been reported to vary inversely with blood alcohol concentration (BAC). The mechanism by which ethanol decreases blood iCa levels is unknown. However, one possible explanation is that it is, at least partially, a methodological artifact due to an effect of ethanol on the function of the ion selective electrode used to measure iCa. The purpose of this study was to determine if ethanol interferes with the measurement of iCa and if this interference can account for the typically observed in vivo effects of ethanol consumption on blood iCa levels. METHODS: Ethanol (0-5 microl/ml) was added to blood or iCa standards and the iCa concentration measured using the ICA2 iCa analyzer (Radiometer) or the I-Stat Clinical Analyzer (Abbott Laboratories). Both instruments use an ion selective electrode to measure iCa. The relationship between iCa and BAC determined from the ex vivo addition of ethanol to blood was compared with relationships obtained in vivo during chronic ethanol consumption. RESULTS: Addition of ethanol to blood or iCa standards resulted in a dose-dependent decrease in iCa concentration when iCa was measured using the ICA2 analyzer but had no effect on iCa concentration when measured with the I-Stat Clinical Analyzer. Ethanol's effect on iCa with the ICA2 analyzer did not differ between blood and standards, and ethanol had no effect on pH, suggesting that the ethanol-induced decrease in iCa was due to a methodological artifact. However, the magnitude of ethanol's effect was small and does not account entirely for the relationship between iCa and BAC observed in vivo with chronic ethanol consumption. CONCLUSION: Ethanol can interfere with the measurement of iCa using ion selective electrodes, but this interference depends on the analyzer used. This is a significant methodological issue that has largely been unrecognized in the field of alcohol research. Although this interference does not explain entirely the relationship between iCa and BAC observed in vivo in studies on chronic ethanol consumption, it complicates investigations designed to assess the effect of ethanol on Ca homeostasis.     

Effects of L-Type Voltage-Sensitive Calcium Channel Modulators on the Discriminative Stimulus Effects of Ethanol in Rats

The purpose of the present investigation was to determine whether administration of dihydropyridine-sensitive calcium channels plays a role in modulating the discriminative stimulus effects of ethanol. A food-reinforced operant methodology was used to train adult male Long-Evans rats to discriminate either 1.0 g/kg of ethanol from water or 2.0 g/kg of ethanol from water. After training, two sets of experiments were conducted. First, a time course procedure was implemented whereby a single intraperitoneal dose of either nimodipine (3, 10, 30 mg/kg), nifedipine (3, 10, 30 mg/kg), or isradipine (1, 3, 10, 17 mg/kg) was administered, and test sessions were conducted 10, 20, 30, 60, and 90 min postinjection. Complete substitution (80% or greater ethanol-appropriate responding) for ethanol by these dihydropyridine compounds varied among subjects with dose and pretreatment time. Overall, isradipine substituted for the discriminative stimulus effects of ethanol in the greatest percentage of animals in both training groups. However, substitution varied with dose. Nifedipine dose dependently substituted for ethanol in half of the animals trained with 1.0 g/kg of ethanol but was less effective in animals trained with 2.0 g/kg of ethanol. For the second set of experiments, a single dose of nimodipine, nifedipine, isradipine, or (-)-BAY k 8644 was administered before determination of the cumulative ethanol dose response. Nifedipine produced a significant leftward shift and (-)-BAY k 8644 produced a significant rightward shift in the ethanol dose-response curve in animals trained to discriminate 2.0 g/kg of ethanol from water. These results indicate that the administration of VGCC modulators plays an indirect role in the discriminative stimulus effects of ethanol.     

Effects of Prenatal Ethanol Exposure on Hypothalamic-Pituitary-Adrenal Function Across the Estrous Cycle

Background: Rats prenatally exposed to ethanol (E) typically show increased hypothalamic‐pituitary‐adrenal (HPA) responses to stressors in adulthood. Importantly, prenatal ethanol may differentially alter stress responsiveness in male and female offspring, suggesting a role for the gonadal hormones in mediating the effects of ethanol on HPA activity. We investigated the role of ethanol‐induced changes in hypothalamic‐pituitary‐gonadal (HPG) activity in the differential HPA regulation observed in E compared to control females across the estrous cycle. Methods: Peripheral hormones and changes in central neuropeptide mRNA levels were measured across the estrous cycle in adult female offspring from E, pair‐fed (PF) and ad libitum‐fed control (C) dams. Results: Ethanol females showed normal estrous cyclicity (vaginal smears) but delayed sexual maturation (vaginal opening). Both HPG and HPA activity were differentially altered in E (and in some cases, PF) compared to control females as a function of estrous cycle stage. In relation to HPG activity, E and PF females had higher basal and stress estradiol (E₂) levels in proestrus compared to other phases of the cycle, and decreased GnRH mRNA levels compared to C females in diestrus. Further, E females had greater variation in LH than PF and C females across the cycle, and in proestrus, only E females showed a significant LH increase following stress. In relation to HPA activity, both basal and stress CORT levels and overall ACTH levels were greater in E than in C females in proestrus. Furthermore, AVP mRNA levels were increased overall in E compared to PF and C females. Conclusions: These data demonstrate ethanol‐induced changes in both HPG and HPA activity that are estrous phase‐specific, and support the possibility that changes in HPA activity in E females may reflect differential sensitivity to ovarian steroids. E females appear to have an increased HPA sensitivity to E₂, and a possible shift toward AVP regulation of HPA activity. That PF were similar to E females on some measures suggests that nutritional effects of diet or food restriction played a role in mediating at least some of the changes observed.     

Altered hetero- and homeometric autoregulation in the terminally failing human heart

OBJECTIVE AND METHODS: To further investigate length-dependent force generation in human heart, nonfailing (donor hearts, NF) and terminally failing (heart transplants, dilated cardiomyopathy, DCM) left ventricular myocardium was studied under various preload (4-40 mN/mm2) or length conditions. In addition, morphological studies (van Giesson Trichrome staining, electron microscopy) were performed. RESULTS: In NF, a biphasic increase in force of contraction (FOC) was observed after elevating the preload (4-40 mN/mm2): there was an immediate fast increase (FOCf,), followed by a slow increase over several minutes (FOCs), which was paralleled by an increase in the systolic fura-2 transient. In DCM, FOCf, FOCs and the systolic fura-2 transient were blunted and diastolic tension was increased at increasing muscle length. Only in NF, a stretched induced increase in diastolic fura-2 ratio was observed. In DCM, no obvious interstitial fibrosis and no difference in basement membrane structure and attachment were observed. CONCLUSIONS: Since FOCf has been attributed to the Frank-Starling mechanism, whereas FOCs represents a length-dependent increase in the intracellular Ca2+-transient, the impaired length-dependent force generation in failing myocardium results from a dysregulation of both myofibrillar Ca2+-sensitivity as well as the intracellular Ca2+-homeostasis. Interstitial fibrosis may have only minor impact on force generation in human end-stage heart failure.     

Effects of Ethanol and Temperature on NMDA Receptor Function in Different Mouse Genotypes

The present study investigated whether temperature-related changes in NMDA receptor sensitivity to ethanol might play a role in mediating the effects of body temperature on behavioral sensitivity to ethanol or in determining genotypic differences in sensitivity to ethanol. We accomplished this by determining the effects of ethanol on three different mouse genotypes (C57, LS, and SS) on two types of NMDA receptor-mediated responses at 30° and 35°C (i) extracellularly recorded synaptic potentials elicited in the CA1 region of the in vitro hippocampal slice preparation by stimulation of the Schaffer-commisural pathway in the presence of the cu-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor blocker, 6,7-dinitroqui-noxaline-2,3-dione, and low magnesium concentration; and (ii) increase in [³H]MK-801 binding elicited by glutamate in telencephalic membrane preparations. Ethanol significantly decreased NMDA receptor-mediated excitatory postsynaptic potential (EPSP) amplitude and area in the three genotypes. In C57, the effect of ethanol on NMDA receptor-mediated EPSP amplitude and area was more pronounced at 30°C, compared with that at 35°C. In most cases, there was a good correlation between the effects of ethanol on EPSP amplitude and area. The order of sensitivity between the three genotypes was C57 = LS > SS at 35°C and C57 > LS = SS at 30°C. Similarly, ethanol significantly decreased glutamate-stimulated [³H]MK-801 binding in membrane fractions. The effect of ethanol was temperature-dependent, because ethanol produced more inhibition at 30°C than at 35°C in all genotypes. The effect of ethanol on MK-801 binding was concentration-dependent, and the sensitivity to 100 mM ethanol of the genotypes at 35°C was LS > SS = C57, whereas it was SS > LS = C57 at 30°C. Collectively, the results demonstrate that temperature is an important variable that can influence NMDA receptor sensitivity to ethanol measured via electro-physiological and binding techniques, and that temperature can influence relative sensitivity of NMDA receptors to ethanol between mouse genotypes. Furthermore, the findings indicate that temperature-induced changes in sensitivity of NMDA receptors to ethanol may play a role in mediating the effects of body temperature on behavioral sensitivity to ethanol in LS, but not C57 and SS mice.     

Effects of Ethanol on Rat Sertoli Cell Function: Studies In Vitro and In Vivo

Chronic alcohol administration to male animals is associated with testicular atrophy and gonadal failure. The Sertoli cell seems to be the first testicular cell injured as a result of alcohol exposure. To investigate the adverse effects of ethanol on testicular and particularly Sertoli cell function, the consequences of in vivo and in vitro ethanol exposure on rat Sertoli cell mRNA and protein levels of transferrin and ornithine decarboxylase were investigated. In vivo, ethanol exposure enhanced the levels of both hepatic and testicular (Sertoli cell) transferrin protein and mRNA. Ethanol exposure also enhanced testicular, but not hepatic, levels of ornithine decarboxylase protein and mRNA. These in vivo findings were confirmed when isolated Sertoli cells were studied in vitro. Specifically, ethanol exposure increased Sertoli cell transferrin protein and mRNA levels. Ethanol exposure increased Sertoli cell ornithine decarboxylase mRNA and protein when cultured in serum-free media, but not when cultured in the presence of serum. These studies demonstrate that ethanol exposure of rat Sertoli cells is associated with alterations in the levels of mRNA and protein that are known to be important in the process of spermatogenesis. These findings add to the body of evidence that suggests that, within the testes, the Sertoli cell may be an important target for ethanol-induced gonadal injury.     

Effect of Ethanol on Platelet Function

Epidemiological studies have linked an inhibition of platelet function by ethanol, among other factors, to the cardioprotective effects of moderate ethanol consumption. Platelet defects have been noted in alcoholics and in human experimental studies. Importantly, in in vivo experimental settings, ethanol diminishes thrombus formation on damaged arterial walls. Ethanol inhibits platelet activation in vitro in response to diverse agonists. Phospholipase A2 is a major site for ethanol inhibition, corresponding to a reduction in the formation of stimulatory arachidonate metabolites. Additional signal transduction pathways are likely targets for ethanol including phosphoinositide-specific phospholipase C and cyclic AMP. The role of additional cofactors in the inhibition of platelet responses by ethanol is discussed.     

Ethanol and Polyamine Metabolism: Physiologic and Pathologic Implications: A Review

This review summarizes the effects of ethanol on the metabolism of polyamines (putrescine, spermidine, and spermine), which are endogenous polycations required for cell physiology, growth, and differentiation. Polyamines regulate DNA, RNA, and protein syntheses; stabilize ribosomes, membranes, and nucleic acids; and protect the cell against lipid peroxidation. Polyamine biosynthesis and catabolism may change after acute and chronic ethanol treatment, thereby playing a negative or positive role in the ethanol-induced injury on liver, extrahepatic tissues, embryo, and fetus.     

螺内酯对慢性心力衰竭患者醛固酮水平及心功能的影响

目的 :观察慢性心力衰竭 (心衰 )患者应用血管紧张素转化酶抑制剂 (ACEI)治疗中加用醛固酮受体拮抗剂螺内酯对血浆醛固酮和心功能的影响。方法 :选择心衰患者 6 9例 ,心功能 (NYHA)分级为Ⅱ～Ⅳ级 ,左心室射血分数 (LVEF)≤ 0 45 ,均接受利尿剂、洋地黄、ACEI类药物治疗。随机分为 :治疗组 ( 34例 )每日给予螺内酯 40mg ,并行上述治疗 ;对照组 ( 35例 )除不给予螺内酯外 ,余处理与治疗组相同。所有患者于治疗前 (基线 )、治疗后 1、3、6个月化验血清钾、血浆醛固酮浓度 ,同时测定LVEF值和心功能分级。结果 :①血浆醛固酮水平的变化 :1个月时治疗组和对照组血浆醛固酮水平均有所降低 ,两组血浆醛固酮水平与基线比较有显著性差异 (P <0 0 5 ) ,但两组间无统计学差异。 3个月时治疗组和对照组血浆醛固酮水平均有所回升 ,两组比较有显著性差异 (P <0 .0 5～ 0 0 1)。 6个月时血浆醛固酮水平回升至基线水平 ,对照组较治疗组组间无明显差异 (P>0 0 5 )。②观察 6个月时心功能明显改善 ,较基线时及治疗组与对照组组间比较均有显著性差异 (P <0 0 5 )。③血清钾水平治疗组呈上升趋势 ,6个月时已明显高于对照组 ,有显著性差异 (P <0 0 5 )。结论 :①慢性心衰患者在应用ACEI治疗中 ,早期血浆醛固酮水平降低     

Ethanol Effects on Cultured Embryonic Hippocampal Neuronal Calcium Homeostasis Are Altered by Nerve Growth Factor

The neurotoxic effect of acute ethanol treatment (AET) may lead to an alteration in the regulation of calcium (Ca²⁺) homeostasis in hippocampal neurons. Ca²⁺ homeostasis could be affected by AET when neurons are at rest or after depolarizing activity during synaptic transmission. It has been shown that nerve growth factor (NGF) can ameloriate some types of neurotoxicity by stabilizing Ca²⁺ homeostasis. Previously, we observed that ethanol (EtOH) changed unstimulated (basal) and potassium (K⁺)-stimulated intracellular calcium ([Ca²⁺]ⁱ) in embryonic septohippocampal neurons (Webb et al., Brain Res. 729:176-189,1996). The purpose of the present study is to determine the effects of NGF and EtOH on neuronal Ca²⁺ homeostasis in cultured embryonic hippocampal neurons. The hypotheses tested were the following: EtOH alters Ca²⁺ homeostasis in hippocampal neurons; NGF modulates Ca²⁺ homeostasis in hippocampal neurons; and NGF treatment alters the effect of EtOH on [Ca²⁺]¹, in hippocampal neurons. Our results indicated that hippocampal neuronal cultures treated with EtOH had lower basal [Ca²⁺]¹ than untreated neurons. EtOH decreased K⁺-stimulated (30 mM KCl) changes in [Ca²⁺]¹ in a dose-dependent manner. During K⁺ stimulation, 20 ng/ml of NGF slowed and reduced the increase in [Ca²⁺]¹. Hippocampal neurons treated with NGF increased or did not change basal [Ca²⁺]¹ and did not change or increase K⁺-stimulated [Ca²⁺], in response to EtOH. These responses were dose-related and indicated that NGF could alter the response of hippocampal neurons to EtOH. In conclusion, AET results in the alteration of Ca²⁺ homeostasis in unstimulated and depolarized cultured embryonic hippocampal neurons. NGF and EtOH independently and collectively affected the regulation of Ca²⁺ homeostasis in this neuronal population. Changes in [Ca²⁺]¹ can disrupt normal cellular function and contribute to cell death. Therefore, alteration of Ca²⁺ homeostasis may be an underlying mechanism involved in EtOH toxicity. NGF may ameliorate the toxic effects of EtOH by regulating Ca²⁺ homeostasis.     

Ethanol Sensitivity of Brain NMDA Receptors in Mice Selectively Bred for Differences in Response to the Low-Dose Locomotor Stimulant Effects of Ethanol

Brain NMDA receptor responses and their sensitivity to ethanol in vitro were determined in replicate lines of FAST and SLOW mice, selectively bred for differences in sensitivity to the locomotor stimulant effects of a low dose of ethanol. L-Glutamate-stimulated increases in the intracellular free calcium concentration (Ca₁) were determined in microsacs, a cell-free brain membrane preparation, isolated from hippocampus or cerebral cortex. Previous work showed that l -glutamate-stimulated increases in Ca₁ in microsacs are mediated by activation of NMDA receptors. The concentration response for l -glutamate-stimulated increases in Ca, did not differ between the lines in either hippocampal or cerebrocortical microsacs. Ethanol produced a concentration-dependent decrease in l- glutamate-stimulated increase in Ca₁ in hippocampal and cerebrocortical microsacs from SLOW mice, but this effect of ethanol was reduced or absent in microsacs isolated from FAST mice. Resting Ca₁ and the ability of a high ethanol concentration to increase resting Ca₁ did not differ between the lines. These results suggest that differences in the sensitivity of brain NMDA receptors to the effects of ethanol determine, at least in part, differences in the locomotor stimulant effects of low doses of ethanol in FAST and SLOW mice. These differences are not due to ethanol effects on resting Ca₁.     

Ethanol Inhibits Nonadrenergic, Noncholinergic Neurotransmission in the Anococcygeus Muscle of the Rat

The anococcygeus muscle of the rat is innervated by both excitatory adrenergic and inhibitory nonadrenergic, noncholinergic (NANC) neurons. The transmitter released from NANC neurons appears to be nitric oxide or a related molecule. In vitro, acute administration of ethanol inhibited, in a dose-dependent manner, NANC-induced relaxation of anococcygeus muscle obtained from ethanol-naive animals. Two days of in vivo ethanol administration resulted in an increase in the maximal relaxation induced by stimulation of NANC neurons and in a significant shift to the right of the acute ethanol dose-response curve for inhibition of NANC relaxation. The sensitivity of the anococcygeus muscle to relaxation induced by the nitric oxide donors, acidified sodium nitrite or sodium nitroprusside, was not altered significantly by acute in vitro or chronic ethanol treatment 2 days in vivo. These data suggest that acutely administered in vitro ethanol inhibits the production of nitric oxide induced by stimulation of NANC neurons. Data further suggest that 2 days of ethanol administration in vivo produce an enhanced responsiveness of the NANC neurons to transmural stimulation and that this enhanced responsiveness accounts for the tolerance to the inhibition induced by the acutely administered ethanol in vitro.     

A Review: Acute and Chronic Effects of Ethanol and Alcoholic Beverages on the Pancreatic Exocrine Secretion In Vivo and In Vitro

Whereas oral or intraduodenal ethanol causes a moderate stimulation of pancreatic bicahonate and enzyme output, intravenous ethanol inhibits basal and hormonally stimulated pancreatic exocrine secretion in humans, dogs, cats, pigs, rabbits, and rats. This inhibition could be mediated by inhibitory cholinergic mechanisms or be the result of a direct cellular effect of ethanol. In vitro investigations have specified several signaling molecules that may be involved in the action of ethanol on stimulus-secretion coupling in the exocrine pancreas, including cyclic adenosine monophosphate, intracellular calcium, and cholecystokinin and somatostatin receptors. In difference to pure ethanol solutions and distilled spirits, beer strongly stimulates pancreatic enzyme output, probably by nonalcoholic fermentation products. During chronic alcoholism, the ethanol-induced inhibition is replaced by an enhanced enzyme output that causes intraductal protein precipitation. In vitro investigations suggest that this increase is reversible after alcohol withdrawal. The occurrence of protein precipitates is considered to be a crucial step in the development of chronic alcoholic pancreatitis in humans. Other ethanol-induced secretory alterations that may contribute to the development of alcoholic pancreatitis are a decreased secretion of trypsin inhibitor, an increased cholinergic tone, and changes in the concentration of lithostathine.     

Role of the GTP-Binding Protein Go in the Suppressant Effect of Ethanol on Voltage-Activated Calcium Channels of Murine Sensory Neurons

Whole-cell and single-channel recording techniques were used to investigate the acute, in vitro effects of ethanol on the function of voltage-activated Ca²⁺ channels in cultured neurons derived from dorsal root ganglia (DRG) of embryonic mice. Although 5.4 MM ethanol produced a sustained increase of the amplitude of the whole-cell Ca²⁺ current (I_Ca), 43.2 mM ethanol had a time-dependent biphasic effect. That is, within 0.5 min of exposure to 43.2 MM ethanol, the maximal amplitude of I_Ca initially increased before declining to a new steady-state value. As anticipated, the facilitatory and inhibitory effects of ethanol on I_Ca were associated with an increase and decrease, respectively, in the probability of single-channel open events. Pretreatment of DRG with 200 ng/ml of pertussis toxin abolished the inhibitory, but not the facilitatory, effect of 43.2 mM ethanol on I_Ca Pretreatment with pertussis toxin also prevented the reduction of the probability of single-channel opening caused by 43.2 mM ethanol. Similarly, dialysis of neurons with polyclonal antibodies against the a-subunit of Go but not G., abolished the inhibitory effect of 43.2 mM ethanol on I_Ca These data demonstrate concentration- and time-dependent biphasic effects of ethanol on the activity of Ca²⁺ channels. The inhibitory effect of ethanol requires activation of the a-subunit of Go, which then decreases the probability of Ca²⁺ channel opening.     

Testicular Function in Asymptomatic Chronic Alcoholics: Relation to Ethanol Intake

To evaluate the effect of ethanol on testicular function in chronic alcoholics without chronic liver disease, we studied 38 asymptomatic chronic alcoholics and 19 age-matched controls. Detailed clinical history, nutritional status, hormonal analysis, and seminal studies were conducted in each case and control. Alcoholic patients had an average of 39 2 2 years old (range: 26 to 60) and reported a daily ethanol consumption from 100 to 350 g (mean: 198 ± 15) over a period of 18.0 ± 1.2 years. Alcoholics exhibited a significant increase of the luteinizing hormone ( p < 0.001) and a decrease of the Free Androgen Index, compared with controls ( p < 0.05) that related significantly with the total lifetime dose of ethanol ( p < 0.01, both). Seminal studies indicate that 39.4% of alcoholics had significantly reduced their spermatozoa count ( p < 0.01), whereas significant morphological abnormalities were observed in 44.7% of the alcoholics ( p < 0.01). Spermatozoa motility from alcoholics was also found to be altered in half of the patients ( p < 0.01). A significant increase of serum luteinizing hormone, follicle-stimulating hormone, and sex hormone binding globulin levels, and a decrease of Free Androgen Index were observed in alcoholics with morphology and motility abnormalities ( p < 0.05, all). In multivariate analysis, the only independent factor that determined the alterations in sperm (count, morphology abnormalities, and motility alterations) was the total lifetime of ethanol intake ( p < 0.001, all). We conclude that alcoholics frequently develop a situation of primary hypogonadism related to a lifetime of ethanol consumption.