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Resuscitation with lactated Ringer's solution after hemorrhage: lack of cardiac toxicity.

The toxicity of D-lactate has been recognized for almost 30 years. This compound is found in the racemic mixture of lactated Ringer's solutions routinely used for peritoneal dialysis and the resuscitation of trauma victims. The current study was designed to investigate whether toxicity occurred at the D-lactate concentrations achieved during hemorrhage resuscitation with racemic lactated Ringer's solution. Conscious unrestrained male Sprague-Dawley rats (n = 24) were monitored for electrocardiographic abnormalities while undergoing hemorrhage and subsequent resuscitation with either L-lactated, D-lactated, or racemic lactated Ringer's solution. The rats infused with D-lactate showed significant toxicity as evidenced by bradycardia, premature ventricular contractions, and ventricular fibrillation. No such alterations were observed in the animals resuscitated with L-lactate or racemic solutions. Resuscitation with the racemic lactate mixture increased the D-lactate concentrations in the blood, but was not associated with overt changes in cardiac rhythm. The infusion of the different resuscitation fluids produced few significant differences in acid-base status of hemorrhaged rats. These findings indicate that although toxicity may be achieved with a Ringer's solution containing only D-lactate, resuscitation using the racemic mixture does not achieve D-lactate concentrations high enough to be detrimental to the animal.

Animals↗

Ex vivo NMR study of lactate metabolism in rat brain under various depressed states.

Brain endogenous lactate metabolism was investigated by ex vivo nuclear magnetic resonance (NMR) spectroscopy study after the infusion of rats with a solution of glucose and lactate labeled as either [3-(13)C]lactate or [1-(13)C]glucose, when their cerebral activity was more or less depressed under the influence of either pentobarbital, alphachloralose, or morphine. We found that: (1) the ratio between the enrichment of alanine C3 and that of glutamate C4, gamma-aminobutyric acid (GABA) C2, glutamine C4, or aspartate C3 decreased from pentobarbital to alphachloralose and morphine whatever the labeled precursor, indicating a link between metabolic and cerebral activity; (2) under glucose + [3-(13)C]lactate infusion, alanine C3 and acetyl-CoA C2 enrichments were higher than that of lactate C3, revealing the occurrence of an isotopic dilution of the brain exogenous lactate (arising from the blood) by lactate from the brain (endogenous lactate), and that the latter was synthesized from glycolysis in a compartment other than neurons; and (3) the contribution of labeled glucose and lactate to acetyl-CoA and amino acid enrichment indicated that the involvement of blood glucose relative to that of blood lactate to brain metabolism was correlated with cerebral activity. The evolution of metabolite enrichments, however, indicated that the cerebral activity-dependent increase in the contribution of blood glucose relative to that of blood lactate to brain metabolism occurred partly via the increase in lactate metabolism generated from astrocytic glycolysis. These findings support the hypothesis for an astrocyte-neuron lactate shuttle component in the coupling mechanism between cerebral activity and energy metabolism.

Analysis of Variance↗

Transhepatic lactate gradient in relation to liver ischemia/reperfusion injury during major hepatectomies.

Hepatectomies performed under selective hepatic vascular exclusion are associated with a series of events culminating in ischemia/reperfusion injury, a state that shares common characteristics with situations known to result in global or regional hyperlactatemia. Accordingly, we sought to determine whether lactate is released by the liver during hepatic resections performed under blood flow deprivation and what relation this has to a possible systemic hyperlactatemic state. After ethical approval, 14 consecutive patients with resectable liver tumors subjected to hepatectomy under inflow and outflow occlusion of the liver were studied. Lactate concentrations were assessed in simultaneously drawn arterial, portal venous, and hepatic venous blood before liver dissection and 50 minutes postreperfusion. Moreover, the transhepatic lactate gradient (hepatic vein - portal vein) was calculated to see if there was net production or consumption of lactate. Before hepatic dissection, the transhepatic lactate gradient was negative, suggesting consumption by the liver. Fifty minutes after reperfusion, this gradient became significantly positive, demonstrating release of lactate by the liver (0.12 +/- 0.31 vs. -0.38 +/- 0.30 mmol/L, P < 0.05). The magnitude of lactate release correlated with systemic arterial lactate levels at the same time point (r(2) = 0.63, P < 0.001). A weaker but significant correlation was demonstrated between the transhepatic lactate gradient postreperfusion and systemic arterial lactate levels 24 hours postoperatively (r(2) = 0.41, P = 0.013). A strong correlation between the transhepatic lactate gradient postreperfusion and peak postoperative aspartate aminotransferase values was also demonstrated (r(2) = 0.73, P < 0.001). The liver becomes a net producer of lactate in hepatectomies performed under blood flow deprivation. This lactate release can explain some of the systemic hyperlactatemia seen in this context and relates to the extent of ischemia/reperfusion injury.

Aged↗

Effect of cardiopulmonary bypass on lactate metabolism.

OBJECTIVE: We have investigated the role of cardiopulmonary bypass on lactate metabolism in patients undergoing uncomplicated surgery for elective coronary artery bypass grafting (CABG). DESIGN: Prospective non-randomized observational study. SETTINGS: National Cardiovascular Center. PATIENTS. Three independent groups were studied: preoperative ( n=20), postoperative with bypass (CPB, n=20) and postoperative without bypass (NO-CPB, n=20). INTERVENTIONS: Lactate metabolism was investigated with the use of an exogenous lactate challenge test (2.5 mmol Na-lactate/kg body weight in 15 min). Blood lactate was sequentially determined after the end of infusion. Lactate clearance and endogenous production were estimated from the area under the curve, and a bi-exponential fitting permitted modeling the lactate-decay into two compartments. MEASUREMENTS AND MAIN RESULTS: Lactate metabolism parameters (basal lactate, clearance, endogenous production and half-lives [HL] I and II) were not different between the NO-CPB and preoperative groups. In the CPB group, as compared to the other two groups, basal lactate and endogenous production were not significantly affected while lactate clearance (CPB: 6.02+/-0.97 versus preoperative: 9.41+/-0.93 and NO-CPB: 9.6+/-0.8 ml/kg per min) and HL-I (CPB: 10.6+/-1.4 versus preoperative: 17.2+/-2.3 and NO-CPB: 18.8+/-2.5 min) were decreased ( p<0.001) and HL-II was increased (CPB: 171+/-41 versus preoperative: 73+/-12 and NO-CPB: 48+/-2.9 min, p<0.01). CONCLUSION: While surgery and anesthesia per se do not seem to alter lactate metabolism, CPB significantly decreased lactate clearance, this effect being possibly related to a mild liver dysfunction even in uncomplicated elective surgery.

Adult↗

Lactate concentrations in incisions indicate ischemic-like conditions may contribute to postoperative pain.

UNLABELLED: The substances in wounds that cause incisional pain and hyperalgesia after surgery are poorly understood. We have developed and characterized rat models for incision-induced pain behaviors and measured increased tissue hydrogen ion concentration. Because lactate may facilitate nociceptor responses to low pH and contribute to ischemic pain mechanisms, we measured tissue lactate after incision of the plantar region of the hindpaw, gastrocnemius muscle, and paraspinal region in halothane anesthetized rats using in vivo microdialysis. Incisions were performed at 1 site (plantar, gastrocnemius, or paraspinal incision) in each rat. The corresponding contralateral side was used as the control. In anesthetized rats, a microdialysis fiber was passed into the incision and the control side. L-Lactate was measured using the lactate oxidase method. Tissue concentration was determined from postoperative day 0 to postoperative day 14 using the no net flux method. Lactate was increased on the day of hindpaw incision to 3.6 +/- 1.6 mmol/L compared with control (2.1 +/- .6 mmol/L) and remained increased through 7 days. In the gastrocnemius muscle, lactate was increased the day after incision (4.2 +/- 1.2 mmol/L vs 1.7 +/- .5 mmol/L) until postoperative day 7. On the day of the paraspinal incision, lactate was 3.4 +/- 1.1 mmol/L on the operated side and 2.2 +/- .6 mmol/L in the control side. Lactate remained increased through postoperative day 8 at the paraspinal incision. These experiments demonstrate that incision of the plantar hindpaw, the gastrocnemius muscle, and the paraspinal region increased tissue lactate concentration. The wound environment contains increased lactate at the same time that pH is decreased; lactate could potentially facilitate nociceptor activation by low pH and contribute to pain after surgery. PERSPECTIVE: This study demonstrates that lactate is increased in wounds when pain behaviors and acid are increased. Lactate and low pH are present in incisions and indicate an ischemic pain mechanism that may contribute to postsurgical pain.

Anesthesia, Inhalation↗

Lactate in scalp and cord blood from fetuses with ominous fetal heart rate patterns.

OBJECTIVE: We investigated lactate concentrations in fetal scalp and cord blood to determine the sources of fetal lactacidosis in fetuses with ominous heart rate patterns. METHODS: Cord blood was collected from newly delivered infants who had been monitored by fetal scalp blood sampling during labor. In 250 cases umbilical arterial and venous cord blood lactate levels were measured. We assessed the umbilical arterial lactate concentrations in relation to the venous lactate levels, the arterial pH level, base excess, and arteriovenous lactate differences in cord blood. In 103 cases the levels of lactate in fetal scalp blood, sampled within 60 minutes of delivery, were compared with those in the umbilical artery and vein and the pH level and base excess immediately after birth. RESULTS: Lactate level in the umbilical artery showed a significant correlation to that in umbilical venous blood (r = .84, P < .001), to arteriovenous lactate differences (r = .52, P < .001), as well as to pH (r = -.55, P < .001) and base excess (r = -.63, P < .001) in arterial cord blood. Lactate concentrations in fetal scalp blood shortly before delivery showed a significant correlation to lactate levels in the umbilical arterial (r = .65, P < .001) and venous blood (r = .62, P < .001). CONCLUSION: The study indicates a close correlation between lactate levels in arterial and venous cord blood, as well as between the lactate levels and pH and base excess in cord arterial blood in patients with ominous fetal heart rate patterns. We also found an increased fetal contribution with increasing lactacidemia. Lactate concentrations in fetal scalp blood correlated well with those in cord arterial and venous blood.

Female↗

Effects of ammonia and lactate on growth, metabolism, and productivity of BHK cells.

The aim of the present work was to study the effect of ammonia and lactate on growth, metabolism, and productivity of BHK cells producing a recombinant fusion protein. Results show that cell growth was reduced with the increase in ammonia or lactate: k(1/2) of 1.1 mM and 3.5 mM for stirred and stationary cultures, respectively, for ammonia and of 28 mM for both stationary and stirred cultures for lactate, were obtained. The cell-specific consumption rates of both glucose (q(Glc)) and glutamine (q(Gln)) increased, whereas that of oxygen (q(O2)) decreased, with the increase in ammonia or lactate concentrations. The cell-specific production rates of lactate (q(Lac)) increased with an increase in ammonia concentration; similarly for the cell-specific production rates of ammonia (q(Amm)), which also increased with an increase in lactate concentration; on the other hand, both q(Lac) and q(Amm) markedly decreased when lactate or ammonia concentrations were increased, respectively; lactate was consumed at lactate concentrations above 30 mM and ammonia was consumed at ammonia concentrations above 5 mM. In vivo (31)P NMR experiments showed that ammonia and lactate affect the intracellular pH, leading to intracellular acidification, and decrease the content in phosphomonoesters, whereas the cell energy state was maintained. The effect of lactate on cell growth and q(Gln) is partially due to osmolarity, on q(Glc) and q(Amm) is entirely due to osmolarity, but on q(Lac) is mainly due to lactate effect per se. An increase in ammonia from 0 to 20 mM induced a 50% reduction in specific productivity, whereas an increase in lactate from 0 to 60 mM induced a 40% decrease.

Journal Article↗

Myocardial lactate metabolism in relation to preoperative regional wall motion and to early functional recovery after coronary revascularization.

OBJECTIVE: To evaluate myocardial lactate metabolism as a marker of functional status after surgical coronary revascularization. DESIGN: Single-center, prospective, cohort study. SETTING: Tertiary care teaching hospital. PARTICIPANTS: Fifty patients with stable angina, ejection fraction >0.40, undergoing coronary artery bypass surgery for multiple-vessel disease. MEASUREMENTS AND MAIN RESULTS: Before (T1) and 30 minutes (T2) after coronary artery bypass grafting, the authors simultaneously sampled blood from artery and coronary sinus to determine myocardial lactate dynamics and performed transesophageal echocardiography (TEE) to assess segmental wall motion. Wall motion score index (WMSI) was calculated with an online/offline comparison. At T2, WMSI improved from 1.40 +/- 0.31 to 1.17 +/- 0.23 (p = 0.0001). Preoperatively, 2 patterns of lactate balance were found: 39 patients were lactate extractors (17% +/- 10%) and 11 were lactate producers (-11% +/- 11%). At T2, lactate metabolism was shifted towards a pattern opposite to the baseline: delta lactate extraction was -8% +/- 16% in extractors at T1 versus 7% +/- 9% in producers at T1 (p = 0.003). Changes in WMSI were not correlated with changes in lactate utilization. No single preoperative variable predicted postoperative WMSI or its changes from baseline. Cardiopulmonary bypass (CPB) time was the only significant predictor of postoperative lactate extraction by multivariate regression (r = -0.46, p = 0.001): at T2, patients in the highest CPB time quartile showed frank lactate production (-6% +/- 13%) when compared with those in the lowest quartile (15% +/- 11%, p = 0.005). However, postoperative WMSI was similar in different CPB time groups. CONCLUSIONS: Myocardial lactate metabolism pattern is not associated with functional status before and early after successful coronary revascularization. CPB time was the only significant predictor of postoperative lactate extraction. Measurement of lactate does not appear to be a valuable tool to assess the coupling of myocardial regional function and metabolism in the setting of coronary artery surgery and mild-to-moderate functional impairment.

Aged↗

Compartmentation of lactate and glucose metabolism in C6 glioma cells. A 13c and 1H NMR study.

13C and 1H NMR spectroscopy was used to investigate the metabolism of L-lactate and D-glucose in C6 glioma cells. The changing of lactate and glucose concentration in the extracellular medium of C6 glioma cells incubated with 5.5 mM glucose and 11 mM lactate indicated a net production of lactate as the consequence of an active aerobic glycolysis. The 13C enrichments of various metabolites were determined after 4-h cell incubation in media containing both substrates, each of them being alternatively labeled in the form of either [3-13C]L-lactate or [1-13C]D-glucose. Using 11 mM [3-13C]L-lactate, the enrichment of glutamate C4, 69%, was found higher than that of alanine C3, 32%, when that of acetyl-CoA C2 was 78%. These results indicated that exogenous lactate was the major substrate for the oxidative metabolism of the cells. Nevertheless, an active glycolysis occurred, leading to a net lactate production. This lactate was, however, metabolically different from the exogenous lactate as both lactate species did not mix into a unique compartment. The results were actually consistent with the concept of the existence of two pools of both lactate and pyruvate, wherein one pool was closely connected with exogenous lactate and was the main fuel for the oxidative metabolism, and the other pool was closely related to aerobic glycolysis.

Aerobiosis↗

D- and L-lactate in rabbit and human bacterial meningitis.

Increased total CSF lactate is an important indicator differentiating bacterial from aseptic meningitis. Bacteria can produce D- and L-lactate; mammalian cells produce only L-lactate. We measured D- and L-lactate production of Streptococcus pneumoniae, Staphylococcus aureus, Neisseria meningitidis and Escherichia coli in vitro, of S. pneumoniae and E. coli in rabbit experimental meningitis and of various common pathogens in CSF from patients with bacterial meningitis. Despite marked in vitro production of D-lactate by S. aureus (maximum: 4.59 mmol/l; i.e. 34.9% of total lactate), N. meningitidis (4.62 mmol/l; i.e. 98.1%) and E. coli (3.14 mmol/l; i.e. 97.2%), minimal amounts were measured in human S. aureus (0.38 mmol/l; i.e. 1.3% of total lactate) or N. meningitidis (0.28 mmol/l; i.e. 3.9%) and experimental E. coli meningitis (0.75 mmol/l; i.e. 4.4%). In only 9 of 54 human CSF samples did D-lactate exceed 0.15 mmol/l. S. pneumoniae did not produce significant amounts of D-lactate in vitro (maximum: 0.55 mmol/l; i.e. 2.7% of total lactate), in experimental meningitis (0.18 mmol/l; i.e. 3%) or in human cases of meningitis (0.28 mmol/l; i.e. 1.9%). In conclusion, increased total CSF lactate in meningitis consists mainly of L-lactate and originates predominantly from host cells. CSF D-lactate is of limited diagnostic value.

Animals↗

The relationship between nucleoside analogue treatment duration, insulin resistance, and fasting arterialized lactate level in patients with HIV infection.

BACKGROUND: Treatment with nucleoside reverse-transcriptase inhibitors (NRTIs) is associated with hyperlactatemia, presumably as a result of NRTI-induced mitochondrial toxicity. We examined the association of NRTI treatment duration and lactate level in human immunodeficiency virus (HIV)-infected patients and assessed the relationship of treatment duration and lactate level with insulin resistance. METHODS: Fasting arterialized venous lactate levels, routine blood chemistry findings, insulin resistance (determined by homeostasis model assessment [HOMA-IR]), percentage of body fat (determined by dual-energy radiographic absorptiometry), and detailed histories of antiretroviral therapy were obtained for 95 HIV-infected individuals. The independent association of NRTI treatment duration and lactate level was examined using multivariable linear regression. RESULTS: Among 95 subjects with a mean age (+/- standard deviation [SD]) of 44 +/- 8 years), 95% had NRTI exposure, with current NRTI use in 83%. The mean (+/- SD) lactate level was 1.24 +/- 0.46 mmol/L (6% had a lactate level > 2 mmol/L). Longer duration of NRTI use was positively associated with lactate level (beta = 0.047; P < .01), as were age, duration of protease inhibitor treatment, and HOMA-IR. Female sex and percentage of body fat were negatively associated with lactate level. After adjustment for age, sex, diabetes, percentage of body fat, and duration of protease inhibitor therapy, an increased duration of NRTI therapy remained significantly associated with lactate level (beta = 0.035; P = .04). However, the addition of HOMA-IR to the adjusted model attenuated the relation between duration of NRTI therapy and lactate level (beta = 0.024; P = .14), whereas HOMA-IR was significantly associated with lactate level (beta = 0.206; P < .01). Furthermore, HOMA-IR was also associated with NRTI treatment duration in adjusted analyses. CONCLUSION: NRTI treatment duration was independently associated with higher lactate level, but this relationship was attenuated after adjusting for HOMA-IR. These data raise the possibility that insulin resistance may be an additional mechanism through which NRTI therapy is related to lactate level.

Adult↗

Factors affecting accumulation of lactate in red blood cells.

In horses, both the post exercise distribution of lactate between plasma and red blood cells (RBC) and the activity of lactate transporters on the RBC membrane vary widely between individuals. In this study, we investigated the effects of pH, time and temperature on lactate distribution in vitro, and compared the in vitro activity of lactate transporters with the accumulation of lactate into RBC in vivo. To accomplish this, we took venous blood samples at rest and after trotting races. The post exercise accumulation of lactate into RBC was shown to depend on the activity of lactate transporters. The results, in vitro, also indicate that pH, incubation time and temperature influence the activity of lactate transporters and the accumulation of lactate into RBC, underscoring the fact that in practice it is important to standardise the measurement conditions of lactate. These results support the view that whole blood lactate concentrations should be measured in estimating the accumulation of lactate from exercising muscles into the blood, because the effect of blood pH, temperature, time to centrifugation of the sample and also interindividual variation in lactate transport into RBC are therefore minimised.

Animals↗

Differential depression of myocardial function and metabolism by lactate and H+.

The effects of both high blood H+ concentration ([H+]) and high blood lactate concentration ([lactate]) under ischemia-reperfusion conditions are receiving attention, but little is known about their effects in nonischemic hearts. Isolated rat hearts were Langendorff perfused at constant flow with media at two pH values (7.4 and 7.0) and two [lactate] (0 and 20 mM) in various sequences (n = 6/group). Coronary flow and arterial O2 content were kept constant at levels that allowed hearts to function without O2 supply limitation. We measured contractility, O2 uptake, diastolic pressure, and at the end of the protocol, tissue [lactate] and pH. Perfusion with high [lactate] raised tissue [lactate] from 5.5 +/- 0.1 to 17.5 +/- 2.6 micromol/heart (P < 0.0001), whereas decreasing the pH of the medium decreased tissue pH from 6.94 +/- 0.02 to 6.81 +/- 0.06 (P = 0.002). Heart rate was not affected by high [lactate] but was reversibly depressed by high [H+] (P = 0.004). Developed pressure declined by 20% in response to high [lactate], high [H+], and high [lactate] + high [H+] (P = 0.002). After the high-[lactate] challenge was withdrawn, pressure continued to decline. In contrast, withdrawing the high [H+] challenge allowed partial recovery. The behavior of diastolic pressure mirrored that of developed pressure. Although unaffected by high [lactate], the O2 uptake was reversibly depressed by high [H+]. This suggests higher O2 cost per contraction in the presence of high [lactate]. We conclude that for similar acute contractility depression, high [lactate] induces irreversible damage, likely at some point in the pathway of O2 utilization. In contrast, the effect of high [H+] appears reversible. These differential behaviors may have implications for heart function during heavy exercise and ischemia-reperfusion events.

Animals↗

Lactate measurement interference by hemoglobin-based oxygen carriers (Oxyglobin, Hemopure, and Hemolink).

We sought to determine whether hemoglobin-based oxygen carriers (HBOCs), hemoglobin glutamer-200 [bovine] (HBOC-200, Oxyglobin), hemoglobin glutamer-250 [bovine] (HBOC-201, Hemopure), and hemoglobin raffimer (Hemolink) interfere with the accuracy of lactate measurements. Combinations of concentrated L-lactate solution, HBOC, and blood or plasma with added PlasmaLyte-A were added to sample tubes to make a linear and constant increase in lactate concentration in consecutive samples. Sample lactate concentrations ranged from 5-110 mg/dL (0.6-12 mm) (physiological reference range: 5-20 mg/dL [0.56-2.2 mm]). Comparisons were made between machine measured lactate concentrations and calculated lactate concentrations. For Hb glutamer-250, the average difference between measured and calculated lactate concentrations was -5.1 mg/dL (-0.57 mm) (LX-20), with greater underestimation at larger lactate concentrations. For Hb raffimer, the average difference was -2.2 mg/dL (-0.24 mm) (LX-20). The veterinary product, Hb glutamer-200, was tested on 3 analyzers (LX-20(R), YSI 1500, and YSI 2300). The YSI 1500 was the most accurate instrument with the mean difference between measured minus calculated lactate being +1.3 mg/dL versus -2.6 mg/dL (YSI 2300) and -8.4 mg/dL (LX-20). The clinical implications of this study are that with increasing levels of an HBOC in plasma, lactate interpretation may become inaccurate, especially at larger lactate concentrations, causing underestimation of measured lactate values and possible under-treatment of the patient. Therefore, caution must be exercised when interpreting lactate results when a HBOC is present in plasma.

Animals↗

Lactate efflux from sarcolemmal vesicles isolated from rainbow trout Oncorhynchus mykiss white muscle is via simple diffusion.

Lactic acid is produced as an end product of glycolysis in rainbow trout white muscle following exhaustive exercise. The metabolically produced lactic acid causes an intramuscular acidosis that must be cleared, either via net transport out of the muscle or by conversion to glycogen, thereby replenishing the muscle energy store. Trout muscle has been shown to retain lactate and utilise it as a substrate for in situ glycogen resynthesis. The giant sarcolemmal vesicle preparation was used to characterise the potential for lactate loss from white muscle of rainbow trout. Minimal lactate loss was expected due to the requirement within the intramuscular compartment of lactate for glycogen resynthesis. The sarcolemma was found to be highly resistant to lactate loss, with efflux rates approximately 500-fold lower than influx rates [0.049+/-0.006 nmol mg(-1) min(-1) (N=21) versus 26.4+/-6.3 nmol mg(-1) min(-1) (N=5), respectively, at 25 mmol l(-1) lactate concentration]. Lactate efflux was linear over the range 10-250 mmol l(-1) lactate, and greatest under conditions when intravesicular pH was lower than extravesicular pH, but was unaffected by alpha-cyano-4-hydroxycinnamate, a known inhibitor of lactate transport. These results suggest that lactate is relatively impermeant to the trout white muscle membrane and any lactate loss occurs via passive diffusion. This resistance to lactate diffusion can explain why trout muscle retains lactate post-exercise, despite transmembrane gradients that should favour net efflux.

Animals↗

Hyperthyroidism and production of precocious involution in the mammary glands of lactating rats.

This study investigated the influence of chronic hyperthyroidism on mammary function in lactating rats and the effects on their pups. Thyroxine-treated (10 microg per 100 g body weight per day; hyperthyroid (HT)) or vehicle-treated rats were mated 2 weeks after the start of treatment and killed with their litters on days 7, 14 and 21 of lactation. Serum concentrations of triiodothyronine (T(3)) and tetraiodothyronine (T(4)) increased in thyroxine-treated rats. In HT mothers, serum prolactin decreased on day 7 and day 14 of lactation, whereas insulin-like growth factor I (IGF-I) and progesterone concentrations decreased, and corticosterone increased on day 7 of lactation. In HT pups, T(4) concentration increased on day 7 and day 14 of lactation, whereas T(3) increased only on day 14 of lactation, and growth hormone increased on day 7 of lactation. Mammary prolactin binding sites did not vary, but there was an increase in the binding sites in the liver on day 14 of lactation in thyroxine-treated rats. In an acute suckling experiment, thyroxine-treated rats released less oxytocin, growth hormone and prolactin and excreted less milk than did control rats. Mammary casein, lactose and total lipid concentrations in thyroxine-treated rats were similar to those of control rats on day 14 of lactation. Histological studies of the mammary glands showed an increased proportion of alveoli showing reduced or no lumina and cells with condensed nuclei on day 14 and day 21 of lactation; the TdT-mediated dUTP nick-end labelling (TUNEL) test revealed an increase in apoptosis in alveolar cells on day 21 of lactation in thyroxine-treated rats. Expression of SGP-2, a gene expressed during mammary involution, increased in thyroxine-treated rats on day 14 and day 21 of lactation, whereas expression of insulin-like growth factor binding protein 5, a proapoptotic signal, was unchanged. Bcl-2, which promotes survival of mammary gland epithelial cells was unchanged, whereas expression of IGF-I, which also promotes survival of mammary gland epithelial cells, increased on day 21 of lactation in thyroxine-treated rats. These results indicate that thyroxine treatment produces some milk stasis as a result of impairments in suckling induced release of oxytocin that may initiate the first stage of mammary involution, increasing apoptosis in a gland that is otherwise actively producing and secreting milk.

Animals↗

Repeated, transient lactate exposure does not "precondition" rat myocardium.

The precise mechanism of the cardioprotective effect of ischemic preconditioning (IPC) is still unclear, although various mechanisms have been suggested, including activation of ATP-dependent potassium (KATP) channels by adenosine and protein kinase C as well as increased expression of heat shock protein (HSP). Increasing evidence suggests that lactate, which accumulates during IPC periods, can activate several of these "triggers" of preconditioning. We tested whether repeated exposure to lactate, producing tissue lactate concentrations similar to those during brief ischemic periods, could contribute to IPC benefits. Five isolated rat hearts were subjected to a previously reported IPC protocol composed of two 5-min ischemia-reperfusion cycles; another five hearts served as controls; and six hearts underwent a "lactate-preconditioning" protocol, consisting of two 5-min exposures to 15 mM lactate and two 5-min periods of reflow with a lactate-free buffer. Subsequently all hearts underwent 30 min of normothermic, total ischemia followed by 30 min of reflow at a constant perfusion pressure of 80 mmHg (1 mmHg = 133.3 Pa). Lactate exposure resulted in tissue lactate levels similar to those during ischemia in ischemia-preconditioned hearts (10.5 +/- 0.6 versus 10.5 +/- 1.2 mumol/g wet weight, mean +/- SEM). However, the recovery of left ventricular developed pressure (DevP) following 30 min of total ischemia was significantly higher in the IPC hearts than in either the control or lactate-exposed hearts, reaching 56.8 +/- 3.4, 14.2 +/- 6.8, and 9.5 +/- 3.6%, respectively, of the baseline values. There was no significant difference between lactate-preconditioned and control hearts. End-diastolic pressure (EDP) was significantly lower during reperfusion in IPC hearts than in lactate-exposed and control hearts, with no significant differences between the latter two groups (36.2 +/- 3.5, 82.0 +/- 2.9, and 81.2 +/- 8.5 mmHg, respectively). In contrast with the proposed hypothesis, repeated, transient lactate exposure resulting in tissue lactate levels similar to ischemic preconditioning did not improve contractile recovery after a prolonged ischemic period in this model.

Animals↗

Identification of risk factors for delayed onset of lactation.

OBJECTIVE: To identify infant feeding, socioeconomic, demographic, and delivery-related factors that affect women's self-reported timing of the onset of lactation. DESIGN: Longitudinal survey of women from day 1 postpartum until self-reported onset of lactation. Subjects were interviewed in person on day 1 postpartum, then surveyed daily by telephone regarding infant feeding method, breast symptoms, and perception of whether the onset of lactation had occurred. Medical records were reviewed. SUBJECTS/SETTING: Data were collected from 192 women after they gave birth to a healthy, term singleton. STATISTICAL ANALYSES PERFORMED: chi 2 Analyses were used to identify variables associated with delayed onset of lactation (onset of lactation > or = 72 hours postpartum). Multivariate logistic regression was used to identify the independent association of each significant variable with delayed onset of lactation. RESULTS: Risk factors for delayed onset of lactation included white/Hispanic ethnicity, heavy/obese body build, delivery of offspring by unscheduled cesarean delivery, vaginal delivery with prolonged stage 2 labor, infant birth weight less than 8 lb, and exclusive formula-feeding before the onset of lactation. APPLICATIONS/CONCLUSIONS: Women who are at risk for delayed onset of lactation need additional breast-feeding support during the first week postpartum. During their hospitalization, these women should be instructed about the normal lactation process and the possibility that onset of lactation may occur later than 72 hours postpartum. Frequent nursing should be recommended, as delayed onset of lactation was associated with the lack of infant suckling.

Adult↗