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The purpose of the review is the analysis of clinical and experimental data on the etiology and pathogenesis of takotsubo syndrome (TS). TS is characterized by contractile dysfunction, which usually affects the apical region of the heart without obstruction of coronary artery, moderate increase in myocardial necrosis markers, prolonged QTc interval (in 50% of patients), sometimes elevation of ST segment (in 19% of patients), increase N-Terminal Pro-B-Type Natriuretic Peptide level, microvascular dysfunction, sometimes spasm of the epicardial coronary arteries (in 10% of patients), myocardial edema, and life-threatening ventricular arrhythmias (in 11% of patients). Stress cardiomyopathy is a rare disease, it is observed in 0.6 - 2.5% of patients with acute coronary syndrome. The occurrence of takotsubo syndrome is 9 times higher in women, who are aged 60-70 years old, than in men. The hospital mortality among patients with TS corresponds to 3.5% - 12%. Physical or emotional stress do not precede disease in all patients with TS. Most of patients with TS have neurological or mental illnesses. The level of catecholamines is increased in patients with TS, therefore, the occurrence of TS is associated with excessive activation of the adrenergic system. The negative inotropic effect of catecholamines is associated with the activation of β2 adrenergic receptors. An important role of the adrenergic system in the pathogenesis of TS is confirmed by studies which were performed using 125I-metaiodobenzylguanidine (125I -MIBG). TS causes edema and inflammation of the myocardium. The inflammatory response in TS is systemic. TS causes impaired coronary microcirculation and reduces coronary reserve. There is a reason to believe that an increase in blood viscosity may play an important role in the pathogenesis of microcirculatory dysfunction in patients with TS. Epicardial coronary artery spasm is not obligatory for the occurrence of TS. Cortisol, endothelin-1 and microRNAs are challengers for the role of TS triggers. A decrease in estrogen levels is a factor contributing to the onset of TS. The central nervous system appears to play an important role in the pathogenesis of TS.

Transient receptor potential vanilloid channel 2 (TRPV2) is required for normal cardiac contractility. The stimulation of TRPV1 in isolated cardiomyocytes can aggravate the effect of hypoxia/ reoxygenation (H/R) on H9C2 cells. The knockout of the TRPV1 gene promotes increased tolerance of the isolated perfused heart to the impact of ischemia/reperfusion (I/R). However, activation of TRPV1 increases the resistance of the heart to I/R due to calcitonin gene-related peptide (CGRP) release from afferent nerve endings. It has been established that TRPV1 and TRPV2 are involved in the pathogenesis of myocardial infarction and, in all likelihood, ensure the cardiac tolerance to the ischemia/reperfusion. It has also been documented that the activation of TRPV4 negatively affects the stability of cardiomyocytes to the H/R. The blockade of TRPV4 can be considered as a new approach to the prevention of I/R injury of the heart. Studies also indicate that TRPV1 is involved in the pathogenesis of cardiac hypertrophy and that TRPV2 channels participate in the pathogenesis of dilated cardiomyopathy. Excessive expression of TRPV2 leads to chronic Ca2+- overload of cardiomyocytes, which may contribute to the development of cardiomyopathy.

The hypothetical trigger of remote postconditioning (RPost) of the heart is the highmolecular weight hydrophobic peptide(s). Nitric oxide and adenosine serve as intermediaries between the peptide and intracellular structures. The role of the autonomic nervous system in RPost requires further study. In signaling mechanism RPost, kinases are involved: protein kinase C, PI3, Akt, JAK. The hypothetical end effector of RPost is aldehyde dehydrogenase-2, the transcription factors STAT, Nrf2, and also the BKCa channel.

Hypothalamic-pituitary-adrenal (HPA) axis function may change over the course of aging, and altered stress-induced secretion of cortisol could predispose older animals to negative health outcomes. The main questions arise about the HPA maturity and sensitivity/resilience to stressors as well as the role of endogenous opioid peptides in the modulation of HPA hormones responses. Thus, the aim of the study was twofold: 1. to determine the development of the pituitary-adrenocortical axis in growing sheep by examining responses to the isolation stress, and 2. to measure the effect of endogenous opioid peptide – Met-enkephalin on the HPA hormones. The experiment was carried on 3, 6 and 9 months old male and female sheep divided into control and isolated from the herd for 30 min. Blood was taken 10 min before and 10, 20, 30 and 60 min after the onset of isolation. This stress uniformly increased plasma concentrations of adrenocorticotrophic hormone (ACTH) and cortisol in sheep at each of 3, 6 and 9 months old. Peak plasma concentrations of ACTH were observed with isolation for 20 minutes. In contrast, the peak concentrations of cortisol were observed with 30 minutes of isolation stress. The ACTH response was greater in male than female lambs. Moreover, there was a large increase in the magnitude of the ACTH response between 3 and 6/9 months of age. There was a developmental increase in the response in both female and male lambs. Isolation stress also influenced plasma concentrations of Met-enkephalin with declining responses with the lambs aging. These results suggest modulating effect of endogenous opioid peptides on the HPA axis under stress responses which declines with lambs aging.

The present study evaluated the effects of morphine or morphine together with corticotrophin releasing hormone (CRH) on Met-enkephalin synthesis, secretion, concentration and opioid receptors binding in the hypothalamus, anterior pituitary and adrenal cortex (HPA) in lambs. Lambs received a single i.v. injection of 0.9% NaCl (control) or morphine (MOR) or morphine in combination with CRH (MOR+CRH). Animals were decapitated after 60 min under anaesthesia and fragments of HPA tissues were dissected. Proenkephalin mRNA expression was measured byin situhybridization, Met-enkephalin concentrations by RIA method, opioid secretion byin vitroincubation. Specific radioligands were used for each type of receptors - 3H-DAGO for mu, 3H-DPDPE for delta and 3H-EKC for kappa binding sites. Acute injection of morphine affected the proenkephalin mRNA expression, native and cryptic Met-enkephalin concentrations as well as mu, delta and kappa receptors binding. There were multiple cases of the effects of morphine being reversed with CRH effects on the HPA axis level, however the most pronounced changes were observed in the hypothalamus. Interestingly, CRH reversed the effect of the morphine on the proenkephalin mRNA expression in all tested tissues. These results indicated an important role of CRH in the endogenous opioid peptides synthesis and opioid receptors binding.

The aim of the study was to evaluate changes in the opioid receptor binding (mu, delta and kappa) in the hypothalamus, anterior pituitary and adrenal cortex (HPA) of lambs treated in vivowith corticotrophin releasing hormone (CRH), naltrexone, an opioid receptor antagonist (NAL), and dexamethasone, a potent cortisol analog (DEX). Experiment was carried out on 3 months old female lambs of polish mountain strain. Lambs received a single i.v. injection of NaCl (control), CRH (alone or in combination with naltrexone), naltrexone or dexamethasone. One hour later animals were decapitated under anaesthesia, tissues were dissected out and receptor binding assays were performed with radioligands for each type of opioid receptors – 3H-DAGO, 3H-DPDPE and 3H-EKC for mu, delta and kappa receptor, respectively. Coexistence of specific binding sites for each type of opioid receptor was demonstrated in all levels of HPA axis of control lambs, however their distribution was uneven. Acute treatment with CRH, DEX and NAL caused downregulation or upregulation of mu, delta, kappa receptor binding in each level of HPA axis. CRH effects on mu, delta and kappa opioid receptor binding varied within the HPA axis and were modulated by naltrexone. Treatment with naltrexone increased in vitromu, delta and kappa receptor binding in most tested structures except delta receptor binding in adrenal (decrease by 52%) and kappa receptor binding in pituitary (decrease by 41%). Dexamethasone significantly decreased the mu, delta and kappa opioid receptor binding in adrenal cortex but differentially affected opioid receptor binding in hypothalamus and pituitary. It seems probable that endogenous opioid peptides acting through mu, delta and kappa receptors interact with the hormones released from the hypothalamic-pituitary-adrenal axis in physiological and pathophysiological situations.

Deltorphin E was investigated as a pharmaceutical intervention in the ischemic hemorrhagic model. To monitor the hemodynamic biomarkers mean arterial pressure (MAP) and heart rate (HR) and to facilitate i.v. injections, rats were surgically fitted with femoral artery and vein catheters under anesthesia. After removal of 48% of total blood volume (range, 12-15 mL), posthemorrhage i.v. injections of 5.5-mg/kg deltorphin E were found to significantly (P< 0.05) increase maximum MAP, pulse pressure, and survival after hemorrhage, whereas lactic acid concentration was decreased when compared with saline injections. The results for the 5.5-mg/kg deltorphin E-treated animals versussaline controls showed the following values (expressed as mean ± SEM) maximum MAP, 58 ± 7 vs. 35 ± 9 mmHg, respectively; lactic acid, 6.5 ± 1.25 vs. 8.9 ± 0.12 mmol/L, respectively; pulse pressure, 47.9 ± 0.55 vs. 38.3 ± 0.44 mmHg, respectively; and at least a fourfold increase in survival, 331 ± 18 vs. 50 ± 8 min, respectively. Heart rate in deltorphin E-treated groups was not significantly different from that in saline-treated groups (maximum HR, 396 ± 40 vs. 425 ± 94 bpm, respectively). Using logistic analysis, deltorphin E did not significantly alter the baroreflex sensitivity. However, a significant deltorphin E dose-dependent correlation was found between survival time and lactic acid production. Increased pulse pressure was also correlated with survival. Glibenclamide, a potassium-sensitive adenosine triphosphate-sensitive channel blocker, did not interfere with the positive effects of deltorphin E. Only the antagonists tested, known to affect 2-opioid receptors, interfered with the deltorphin E survival benefit after hemorrhage. As a conclusion, deltorphin E is an effective pharmaceutical intervention in severe hemorrhagic shock and, perhaps, in other ischemic shock scenarios when administered after the onset of stress. Therefore, deltorphin E may have clinical potential.

Objectives:δopioids have been shown to confer ischemic preconditioning and pharmacologic ischemic preconditioning to the myocardium. However, their role in providing extended pharmacologic ischemic preconditioning in hemorrhagic shock has not been explored. The authors examined the effects of 24‐hour preinfusions of a selective δopioid receptor agonist, Deltorphin‐Dvariant(Delt‐Dvar), on hemodynamic stability and duration of survival in a rat model of severe hemorrhagic shock.

δ opioid receptor agonists exert potent hemodynamic effects under ischemic conditions. This study was designed to assess the cardiovascular effects of Deltorphin-Dvariant(Delt-Dvar), a selective δ2opioid receptor agonist, in conscious, freely moving male rats during the posthemorrhage, recompensatory phase of a hemorrhagic trauma. Rats were fitted with femoral arterial and venous catheters for measurements of mean arterial pressure (MAP), heart rate (HR), and intravenous (i.v.) injections of isotonic saline, 1 mg/kg Delt-Dvar, or 2 mg/kg Delt-Dvar. During hemorrhaging, 30% (∼5 mL) of total blood volume was collected from the arterial catheter. MAP-HR was fitted to a logistic equation to determine baroreceptor reflex properties. Hemorrhaged rats progressed through three distinct phases: compensation, decompensation, and recompensation. Saline and 1 mg/kg Delt-Dvarrats treated posthemorrhage had similar MAP and HR after hemorrhage. In contrast, 2 mg/kg Delt-Dvaradministered after hemorrhaging led to a faster and more complete recovery of MAP than compared with the other groups. In hemorrhaged rats, the average HR gain (bpm/mmHg) after 2 mg/kg Delt-Dvartreatment was greater and the BP50(BP at one-half the HR range) was significantly lower than after saline treatment. The results show that after hemorrhage, during the recompensatory period, stimulation of δ2opioid receptors leads to improved MAP, and this recovery may involve a change in baroreflex sensitivity.

Objective:δ-Opioid receptors are involved in the cardioprotective effect of ischemic preconditioning. This study was designed (1) to assess the protective capacities of ischemic preconditioning and the synthetic δ-opioid receptor agonist D-Ala2-D-Leu5enkephalin (DADLE) in a functionally oriented experimental model of ischemia and reperfusion and (2) to assess whether the effects of both protective measures are similarly blocked by naloxone, a nonspecific δ-opioid receptor antagonist. Methods:Sixty-four isolated working rat hearts were subjected to 45 minutes of hypothermic ischemia at 30°C followed by 25 minutes of normothermic reperfusion. Rats were pretreated with DADLE (1 mg/kg body weight intravenously), naloxone (3 mg/kg body weight intravenously), or a combination thereof within 60 minutes before onset of isolated heart perfusion. During the preischemic perfusion period, 8 hearts per group were preconditioned by one cycle of 5 minutes of normothermic global ischemia and subsequent reperfusion whereas another 8 served as nonpreconditioned controls. The postischemic functional recovery of hearts and their creatine kinase leakage were determined. Results:Pretreatment with DADLE and ischemic preconditioning improved the postischemic recovery of aortic flow when compared with nonpreconditioning (57.7% ± 4.0% and 60.8% ± 4.3% vs 40.0% ± 4.2% of preischemic baseline value, P||.001). Combined pretreatment with DADLE before ischemic preconditioning afforded additional aortic flow recovery compared with pretreatment with DADLE alone (68.6% ± 3.3% vs 57.7% ± 4.0% of preischemic baseline value; P=.038). With combined pretreatment, early postischemic creatine kinase release was lower than control in hearts without pretreatment (0.48 ± 0.11 vs 0.80 ± 0.12 IU/5 minutes per heart; P=.001). Naloxone abolished the beneficial functional effects of pretreatment with DADLE and ischemic preconditioning. Conclusions:Pharmacologic activation of δ-opioid receptors affords improvement of functional protection in isolated working rat hearts similar to that conferred by classic ischemic preconditioning. The combination of both pretreatments reduces ischemic cellular damage and further adds to postischemic functional recovery. These changes are reversed by naloxone, an observation providing evidence that ischemic preconditioning involves signaling through opioid receptors.

Objective:This study compared susceptibility to oxidation of low-density lipoproteins (LDL) of non-diabetic and diabetic (Type 2) men and examined the response of diabetic men to antioxidant supplementation (α-tocopherol, β-carotene and ascorbate).Research Design and Methods:Twenty adult non-diabetic and 20 diabetic men were recruited. Oxidation of LDL was assessed by four different assay systems, and the extent of oxidation was assessed by four different measurements. Diabetic men received eight weeks of placebo (“baseline”), twelve weeks of antioxidant supplements (“treated”) and eight weeks of placebo (“post-treatment”). Supplements provided 24 mg of β-carotene, 1000 mg of ascorbate and 800 IU of α-tocopherol daily.Results:With Cu oxidation at 37°C, thiobarbituric reactive substances (TBARS) formation was significantly higher (p=0.032) and loss of free amine groups was significantly greater (p=0.013) in the LDL from diabetic subjects than controls. Antioxidant supplementation of diabetic subjects significantly decreased all parameters of LDL oxidation with Cu at 30°C and 37°C. At 30°C the lag phase increased from 55 to 129 minutes (p<0.0001); conjugated diene formation decreased from 1.23 to 0.62 OD units (p<0.0001); TBARS formation decreased from 78 to 33 nmoles MDA/mg LDL protein (p<0.0001); and free amine loss decreased from 41 to 12% (p<0.0001). With Cu oxidation at 37°C, similar changes occurred.Conclusions:These studies indicate that the LDL from diabetic subjects are more susceptible to oxidation than LDL from non-diabetic subjects. Supplementation of diabetic subjects with antioxidant vitamins significantly decreases susceptibility of LDL to oxidation by Cu. These studies are consistent with epidemiological and intervention studies suggesting that antioxidant vitamin use significantly decreases risk for coronary heart disease.

A new autoperfusion multiorgan preparation was studied in which the heart and lungs were removed with the liver, pancreas, duodenum, and both kidneys en bloc while being perfused by the heart and oxygenated by the lungs. A respirator with 50% oxygen was used for ventilation. Fresh blood, glucose, electrolytes, mannitol, and antibiotics were given through the portal vein. Fifteen mongrel dogs were used. In the study group (seven dogs), 10 ml of plasma containing hibernation induction trigger, obtained from deeply hibernating woodchucks, was given intravenously 2 hours before the operation, and 4 ml was given every 4 hours during the preservation period. In the control group (eight dogs), no hibernation induction trigger was used. Survival time in the study group ranged from 33 to 56 hours (mean 43.4 ± 4.1 hours), longer than that of the control group, which was 9 to 31 hours (mean 16.2 ± 2.6 hours, p < 0.001). In the study group aortic systolic pressure ranged from 64 ± 5 to 92 ± 7 mm Hg, arterial oxygen tension from 180 ± 35 to 285 ± 66 mm Hg. Urine output ranged from 15 to 70 ml/hour. Blood urea nitrogen declined from 15.6 ± 2.5 to 6.6 ± 1.3 mg/dl (p < 0.01); creatinine declined from 0.8 ± 0.03 to 0.3 ± 0.01 mg/dl (p < 0.01). Severe liver congestion and premature renal failure occurred in the control group but did not occur in the study group. In the study group one lung was transplanted after 33 hours of preservation with simultaneous contralateral pulmonary artery ligation. Good lung function was maintained after transplantation. Although the exact mechanism by which hibernation induction trigger extends tissue survival time is still not clear, its effect on organ preservation is profound. This study also produced one of the longest average survival times for organ preservation.

• The effect of psyllium hydrophilic mucilloid on serum cholesterol levels was investigated in 26 men with mild to moderate hypercholesterolemia (range of cholesterol level, 4.86 to 8.12 mmol/L [188 to 314 mg/dL]) in a double-blind, placebo-controlled parallel study. Following a two-week baseline period, subjects were treated for eight weeks with 3.4 g of psyllium or cellulose placebo at mealtimes (three doses per day). All subjects maintained their usual diets, which provided less than 300 mg of cholesterol per day and approximately 20% of energy from protein, 40% from carbohydrate, and 40% from fat. Eight weeks of treatment with psyllium reduced serum total cholesterol levels by 14.8%, low-density lipoprotein (LDL) cholesterol by 20.2%, and the ratio of LDL cholesterol to high-density lipoprotein cholesterol by 14.8% relative to baseline values. The reductions in total cholesterol and LDL cholesterol became progressively larger with time, and this trend appeared to be continuing at the eighth week. Psyllium treatment did not affect body weight, blood pressure, or serum levels of high-density lipoprotein cholesterol, triglycerides, glucose, iron, or zinc. No significant changes in serum lipid levels, body weight, blood pressure, or other serum parameters were observed with placebo treatment. Subject adherence to psyllium treatment was excellent, and no adverse effects were observed. Results of this study show that psyllium is an effective and well-tolerated therapy for mild to moderate hypercholesterolemia.(Arch Intern Med 1988;148:292-296)

The Abbott TDx fluorescence polarization immunoassay (FPIA) system was evaluated and compared with well-established enzyme multiplied immunoassay technique (EMIT) and radioimmunoassay (RIA) methods utilizing five high-volume drug assays including theophylline, gentamicin, phenytoin, phenobarbital, and digoxin. These drug assays were evaluated for precision, calibration stability, specificity, and accuracy. Within-run precision studies utilizing control samples (n = 20) in the subtherapeutic, therapeutic, and toxic ranges resulted in coefficients of variation (CV) of > 4.0 for the theophylline, gentamicin, phenytoin, and phenobarbital assays and of > 9.5 for the digoxin assay. Between-run precision studies based on an initial TDx calibration curve over a 2–3 week period yielded CVs of less than 8 for all five drug assays. Cross-reactivity of the FPIA gentamicin assay with concurrently used aminoglycosides such as tobramycin and amikacin was > 0.1, and interference due to hemolysis and lipemia was negligible. Highly icteric specimens resulted in clinically significant decreases in theophylline and phenytoin concentrations, but this problem can be corrected by subtraction of blank intensity values. Comparison of the FPIA method with the EMIT and RIA methods indicated an extremely good analytical correlation (r < 0.97) for all five comparisons. The Abbott TDx FPIA system offers significant advantages in calibration and reagent stability, and greater sensitivity in the low drug concentration ranges while maintaining accuracy and precision comparable with those of established EMIT and RIA procedures.

Accurate determination of postmortem interval (PMI) is a problem for the forensic thanatologist, especially in unwitnessed deaths. A number of objective chemical methods for determining PMI have been developed, the most widely used being accumulation of potassium in the vitreous humor. The authors previously have reported a chemical method for determining PMI from the predictable accumulation or clearance of the dopaminergic metabolite 3-methoxytyramine (3-MT) in the putamen of the brain.They have extended their previous study to compare directly the accuracy of determining PMI from the level of 3-MT in putamen with the level of potassium in vitreous humor. The data indicate that 3-MT is at least as accurate as, if not more accurate than, potassium accumulation in vitreous humor, although 3-MT levels can be affected by the cause of death and drugs present at the time of death. Nevertheless, determination of both the 3-MT and potassium levels can afford the most accurate method of determining PMI; preliminary nomograms for determining PMI from both variables are presented.

Cardiac transplant is hindered by donor shortage and preservation time. Extended extracorporeal preservation could increase the number and distribution of hearts for transplantation. Interestingly, mammalian hibernation biology closely parallels the altered cardiac cellular physiology noted with hypothermic organ storage. The present study undertook to test whether treatment with hibernation induction triggers could improve myocardial functional recovery following prolonged ischemic storage in a nonhibernating mammalian model. To study this hypothesis, isolated rabbit hearts had baseline functional and metabolic parameters recorded and then received either hypothermic storage only or standard cardioplegia, or cardioplegia containing 1 mg/kg D-Ala2-Leu5-enkaphalin (DADLE), which mimics natural hibernation, or preperfusion with DADLE, administered for 15 min at 2 mmol, 25 min prior to cardioplegic ischemia. Hearts were then subjected to 18 hr of global ischemic storage at 4°C. Isovolumic developed pressure, coronary flows, and myocardial oxygen consumption were significantly improved with DADLE pretreatment vs. all groups after storage and reflow. Furthermore, DADLE hearts demonstrated better histological ultrastructure preservation following prolonged storage ischemia. This study demonstrates that hibernation protection with DADLE is beneficial for prolonged cardiac storage. The use of hibernation induction triggers is promising for organ preservation and deserve further mechanistic study.