Prostaglandin metabolism during circulatory shock

The rates of metabolic degradation and the patterns of metabolite formation of tritium-labeled prostaglandins E₂ and F_2α were assessed in vitro in tissues obtained from normal rabbits and from rabbits subjected to hemorrhagic or endotoxic shock. Normal rabbit tissues metabolized prostaglandin E₂ at the following rates: renal cortex 479 ± 34, liver 389 ± 95, and lung 881 ± 93 pmol of PGE₂ metabolized/mg soluble protein per min at 37°C (mean ± S.E.). Prostaglandin F_2α metabolism proceeded in normal animal tissues at rates of 477 ± 39, 324 ± 95, and 633 ± 69 pmol of PGF_2α metabolized/mg soluble protein per min for renal cortex, liver and lung, respectively. There were no significant differences between these rates of PGE₂ and PGF_2α metabolism when compared to rates in tissues obtained from animals subjected to either hemorrhagic or endotoxic shock. In addition, no significant differences were observed between the rate of PGE₂ metabolism and that of PGF_2α metabolism for any tissue. However, the lung was able to metabolize PGE₂ and PGF_2α significantly more rapidly than the liver, and to degrade PGE₂ at a significantly greater rate than the renal cortex. Although slightly different patterns of metabolite production were observed between lung and kidney homogenates, only the liver metabolized prostaglandins almost exclusively to more polar metabolites. While hemorrhagic or endotoxic shock induced slight changes in the patterns of PGE₂ metabolite formation in all three tissues studied, PGF_2α metabolite formation patterns were not significantly altered by circulatory shock. Thus, prostaglandin metabolism is not significantly impaired during the first 2 h of hemorrhagic or endotoxic shock in rabbit tissues. Therefore, impairment of prostaglandin metabolism is not the major factor responsible for the early increase in circulating prostaglandin concentrations in these forms of shock.     

The role of lysosomes in circulatory shock

Lysosomes are sensitive to the stressful stimuli which develop in the shock states (i.e., ischemia, hypoxia, acidosis). As a result, lysosomal membranes become leaky and tissue lysosomes swell. These conditions are favorable for the leakage of lysosomal contents, largely acid hydrolases, into the cytoplasm of splanchnic cells, particularly in the liver and pancreas. These acid hydrolases are then transported primarily via the lymphatic system to the systematic circulatin where they are free to exert a variety of deleterious actions particularly as the RES becomes impaired in shock. Some of these effects include damage to the microcirculation promoting hypotension and reduced nutritive blood flow to certain tissues. These enzymes also contribute to production of toxic factors and impairment of mitochondrial function in circulatory shock.     

Glucocorticoid-induced protection in circulatory shock: role of reticuloendotheilial system function.

Experiments with rats indicate that: (i) hydrocortisone sodium succinate (HC) and methylprednisolone sodium succine (MP) enhance survival after hemorrhage; (ii) MP is approximately 10-times more potent than HC; (iii) both HC and MP are more efficacious if administered prior to hemorrhage; (iv) efficacy of postshock therapy with both steroids is not only time- but dose-dependent; and (v) HC and MP can ameliorate or completely prevent the early RES phagocytic depression observed in circulatory shock. Overall, these data could be used to suggest that: (i) the RES may play a pivotal role in the beneficial actions of synthetic adrenocorticosteroids in circulatory shock, and (ii) numerical RES phagocytic indices may be diagnostic and prognostic parameters in circulatory shock therapy.     

Heat shock response and ageing: mechanisms and applications

Ageing is associated with a decrease in the ability of cells to cope with environmental challenges. This is due partly to the attenuation of a primordial stress response, the so-called heat shock (HS) response, which induces the expression of heat shock proteins (HSPs), composed of chaperones and proteases. The attenuation of the HS response during ageing may be responsible for the accumulation of damaged proteins as well as abnormal regulation of cell death. Maintenance of the HS response by repeated mild heat stress causes anti-ageing hormetic effects on cells and organisms. Here, we describe the molecular mechanism and the state of the HS response as well as the role of specific HSPs during ageing, and discuss the possibility of hormetic modulation of ageing and longevity by repeated mild stress.     

Role of neuropeptides in the mechanisms of chronic epileptization of the brain

We describe experimental studies of the anticonvulsive effects of neuropeptides from the kyotorphin family (kyotorphin, neokyotorphin, and 2-ser-neokyotorphin) and galanin tested in a model of picrotoxin-induced kindling in rats. Intraventricular injections of the above neuropeptides demonstrated their clear anticonvulsive efficacy: the latency of the first convulsive reactions increased, and the intensity of seizures decreased. A protective efficacy of these peptides observed under conditions of the kindling model (which is the most steady with respect to the effects of antiepileptic drugs, and whose phenomenology is the closest to clinical manifestations of epilepsy) allows us to believe that further studies of anticonvulsive action of the peptides is expedient.     

Systemic circulatory reaction in the initial period of Cannon's traumatic shock

In experiments on dogs it was shown that on the basis of the dynamics of circulatory parameters it is possible to divide the erectile phase of traumatic shock into two periods. The first period, similar to "defence reactions" in dangerous situations and under the action of potent non-specific stimuli, is characterized by an increased blood inflow to the myocardium, rise in the cardiac output and reduction of the tonus in peripheral vessels. The second period is characterized by the beginning of decompensation of the cardiovascular system. It is completed by the development of the torpid phase of shock.     

Lipid peroxidation in human diseases: evidence of red cell oxidative stress after circulatory shock

Erythrocytes obtained from human patients with circulatory shock of different aetiology consistently showed a strong increase in lipid peroxidation-derived aldehydes in comparison with red cells of normal adults. The highly toxic compound 4-hydroxynonenal has been recovered exclusively in the erythrocytes of the patients.     

Opioids and breathing

This review summarizes recent developments on the effects of opiate drugs and the various endogenous opioid peptides on breathing. These developments include demonstration of receptors and site-specific effects of application of opioids in the pons and medulla, demonstration of variable tolerance of respiratory responses in addicted individuals as well as their offspring, and demonstration of an endogenous opioid influence on breathing in early neonatal life and in certain physiological settings and disease states. The validity and limitations of using naloxone as a tool to uncover postulated endogenous opioid influences are also discussed as well as the potential problems imposed by the various settings in which this opiate antagonist drug is used. It is concluded that some parallelism exists between the role of endogenous opioids in pain modulation and their role in respiration especially in adults. Although more studies are needed especially with regard to defining specific effects of the various opioid receptors and ligands, it is felt that the effects of endogenous opioids on the control of breathing will probably be one of modulating the responses to drugs or nociceptive respiratory stimuli through inhibitory pathways.     

Clearance of prostaglandin F2ALPHA during circulatory shock.

The rate of disappearance of total circulating radioactivity following an intravenous bolus injection of 3HPGF_2α was determined during splanchnic artery occlusion (SAO) shock in the dog. In addition, the pattern of PGF_2α metabolite formation was assessed in both shocked and nonshocked animals. Although the clearance of circulating prostaglandin metabolites is significantly impaired during SAO shock as a result of decreased renal function, neither the pattern nor the time course of PGF_2α metabolite formation appears to be altered. Thus, increases in circulating prostaglandin concentrations during SAO shock reflect an increase in the rate of $\text{de novo}$ synthesis and release of these materials, and are not the result of decreased prostaglandin degradation.     

Heat shock proteins and DNA repair mechanisms: an updated overview

Heat shock proteins (HSPs), also known as molecular chaperones, participate in important cellular processes, such as protein aggregation, disaggregation, folding, and unfolding. HSPs have cytoprotective functions that are commonly explained by their antiapoptotic role. Their involvement in anticancer drug resistance has been the focus of intense research efforts, and the relationship between HSP induction and DNA repair mechanisms has been in the spotlight during the past decades. Because DNA is permanently subject to damage, many DNA repair pathways are involved in the recognition and removal of a diverse array of DNA lesions. Hence, DNA repair mechanisms are key to maintain genome stability. In addition, the interactome network of HSPs with DNA repair proteins has become an exciting research field and so their use as emerging targets for cancer therapy. This article provides a historical overview of the participation of HSPs in DNA repair mechanisms as part of their molecular chaperone capabilities.     

Regional differences in mechanisms of cerebral circulatory response to neuronal activation

Vibrissal stimulation raises cerebral blood flow (CBF) in the ipsilateral spinal and principal sensory trigeminal nuclei and contralateral ventroposteromedial (VPM) thalamic nucleus and barrel cortex. To investigate possible roles of adenosine and nitric oxide (NO) in these increases, local CBF was determined during unilateral vibrissal stimulation in unanesthetized rats after adenosine receptor blockade with caffeine or NO synthase inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) or 7-nitroindazole (7-NI). Caffeine lowered baseline CBF in all structures but reduced the percent increase during stimulation only in the two trigeminal nuclei. L-NAME and 7-NI lowered baseline CBF but reduced the percent increase during stimulation only in the higher stations of this sensory pathway, i.e., L-NAME in the VPM nucleus and 7-NI in both the VPM nucleus and barrel cortex. Combinations of caffeine with 7-NI or L-NAME did not have additive effects, and none alone or in combination completely eliminated functional activation of CBF. These results suggest that caffeine-sensitive and NO-dependent mechanisms are involved but with different regional distributions, and neither fully accounts for the functional activation of CBF.     

Opioids transiently prevent activation of apoptotic mechanisms following short periods of serum withdrawal

Opioids exert a proapoptotic effect on several normal and tumoral cells. The aim of the present article was to examine the effect of opioids on the PC12 rat pheochromocytoma cell line, a model for the study of chromaffin cell apoptosis. These cells produce delta- and kappa-opioid agonists and their receptors. Our results were as follows: The kappa- and delta2-opioid receptor agonists had a rapid but transient effect on apoptosis at 3 h, whereas mu opioids did not. The effect of opioids was reversible by the opioid antagonists naloxone and nor-binaltorphimine. The effect of opioids was protective, suppressing serum deprivation-induced apoptosis to approximately 50% of controls. The protective effect of opioids on PC12 apoptosis was measurable only under serum deprivation. The effect of opioids was remarkably reproducible and highly constant in timing, which did not appear to depend on the duration of the preceding serum deprivation. Finally, opioids prevented the elevation of the Bcl-2 and Bak proteins following serum deprivation to the levels attained by serum supplementation. Our combined data suggest that opioids protect PC12 cells from entering a state of induced apoptosis following serum deprivation.     

Sites and mechanisms of action of neuropeptides on canine gastric motility differ in vivo and in vitro

Motilin, pentagastrin and substance P (SP), injected intra-arterially into the canine gastric corpus in vivo increased the amplitude of contractions by an action dependent on activation of cholinergic nerves; i.e. atropine or tetrodotoxin (TTX) completely blocked the responses to motilin and pentagastrin and increased the ED50 of SP. TTX and atropine were not equally effective in increasing the ED50 for SP in vivo and the effect of combining them depended on the order of their addition. Both were much more effective than the SP analog D-Pro2, D-Trp7,9 SP (DSP) which appeared to be a weak antagonist of actions dependent on neural activity. In strips from the same region in vitro no receptors dependent on cholinergic nerve activation could be demonstrated for any peptide; i.e., all were atropine- and TTX-insensitive. Motilin, as expected in the absence of such receptors caused no contractile response in vitro. SP, also as predicted, caused contractions suggesting that a smooth muscle receptor, independent of nerve activation was present. However contrary to expectation pentagastrin induced an atropine and TTX-insensitive increase in the amplitude and frequency of contractions. These results show that 1) the most sensitive sites of action of a number of excitatory peptides depend on cholinergic nerve function in vivo; 2) such sites or the nerve activity on which they depend cannot be demonstrated in vitro; 3) SP has an additional site of action on smooth muscle demonstrable in vivo and in vitro, but motilin does not; 4) pentagastrin has only an action dependent on nerve function in vivo, but manifests an action independent of nerve function in vitro. We conclude that sites and mechanisms of action of peptides cannot be assumed to be identical in vivo and in vitro. Actions dependent on nerves are often lost in vitro and not all smooth muscle actions can be demonstrated in vivo.