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Purified canine cardiac sarcolemmal membrane vesicles exhibit a sodium ion for proton exchange activity (Na+/H+ exchange). Na+/H+ exchange was demonstrated both by measuring rapid 22Na uptake into sarcolemmal vesicles in response to a transmembrane H+ gradient and by following H+ transport in response to a transmembrane Na+ gradient with use of the probe acridine orange. Maximal 22Na uptake into the sarcolemmal vesicles (with starting intravesicular pH = 6 and extravesicular pH = 8) was approximately 20 nmol/mg protein. The extravesicular Km of the Na+/H+ exchange activity for Na+ was determined to be between 2 and 4 mM (intravesicular pH = 5.9, extravesicular pH = 7.9), as assessed by measuring the concentration dependence of the 22Na uptake rate and the ability of extravesicular Na+ to collapse an imposed H+ gradient. All results suggested that Na+/H+ exchange was reversible and tightly coupled. The Na+/H+ exchange activity was assayed in membrane subfractions and found most concentrated in highly purified cardiac sarcolemmal vesicles and was absent from free and junctional sarcoplasmic reticulum vesicles. 22Na uptake into sarcolemmal vesicles mediated by Na+/H+ exchange was dependent on extravesicular pH, having an optimum around pH 9 (initial internal pH = 6). Although the Na+/H+ exchange activity was not inhibited by tetrodotoxin or digitoxin, it was inhibited by quinidine, quinacrine, amiloride, and several amiloride derivatives. The relative potencies of the various inhibitors tested were found to be: quinacrine greater than quinidine = ethylisopropylamiloride greater than methylisopropylamiloride greater than dimethylamiloride greater than amiloride. The Na+/H+ exchange activity identified in purified cardiac sarcolemmal vesicles appears to be qualitatively similar to Na+/H+ exchange activities recently described in intact cell systems. Isolated cardiac sarcolemmal vesicles should prove a useful model system for the study of Na+/H+ exchange regulation in myocardial tissue.
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PMID:Demonstration of a Na+/H+ exchange activity in purified canine cardiac sarcolemmal vesicles. 298 68

We examined the effect of histidine-specific reagents on the transport activity of the Na+-H+ exchanger in microvillus (brush-border) membrane vesicles isolated from the rabbit renal cortex. Rose bengal-catalyzed photo-oxidation caused irreversible inhibition of the rate of Na+-H+ exchange but also caused significant loss of vesicle integrity. Treatment of the membrane vesicles with diethylpyrocarbonate caused inactivation of Na+-H+ exchange that could not be attributed to vesicle disruption or collapse of transmembrane H+ gradients. Inactivation of Na+-H+ exchange by diethylpyrocarbonate followed pseudo-first order kinetics to below 10% residual activity, could be reversed by hydroxylamine, was reflected by a decreased Vmax with no change in the Km for Na+, was dependent on external pH but not internal pH, was blocked by amiloride, and was enhanced by Na+. These data are consistent with the hypothesis that a diethylpyrocarbonate-sensitive imidazolium residue is the titratable group found in kinetic studies to bind H+ at the external transport site of the Na+-H+ exchanger.
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PMID:Inactivation of the renal microvillus membrane Na+-H+ exchanger by histidine-specific reagents. 300 54

This paper summarizes the role of the renal pressure natriuresis and diuresis mechanisms in maintaining sodium and water balance in hypertension. In all forms of chronic hypertension studied to date, the renal pressure natriuresis and diuresis mechanisms are abnormal, since increased arterial pressure is required to maintain normal excretion of sodium and water, and therefore fluid balance. When renal perfusion pressure is prevented from increasing in various forms of experimental hypertension, caused by infusion of mineralocorticoids, angiotensin II, vasopressin, or norepinephrine and adrenocorticotrophic hormone (ACTH), sodium and water retention continues until ascites, pulmonary oedema and circulatory collapse occur within a few days. Thus, chronic hypertension appears to be an essential homeostatic response that permits sodium and water balance to be maintained despite various abnormalities which tend to decrease renal excretory capability. The intrarenal mechanisms by which increased renal perfusion pressure maintains sodium and water balance in hypertension have not been fully elucidated, but appear to involve small changes in glomerular filtration rate (GFR) and reductions in fractional sodium reabsorption, due either to the direct hydraulic effects of pressure or to various indirect effects, such as changes in angiotensin II formation.
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PMID:Mechanisms of sodium balance in hypertension: role of pressure natriuresis. 302 42

We studied the effect of the carboxyl group-specific reagent N,N'-dicyclohexylcarbodiimide on the Na+/H+ exchanger present in microvillus membrane vesicles isolated from rabbit renal cortices. Pretreatment of membrane vesicles with dicyclohexylcarbodiimide resulted in irreversible inhibition of Na+/H+ exchange which was not due to vesicle disruption or collapse of imposed pH gradients. Inhibition by dicyclohexylcarbodiimide followed pseudo-first-order kinetics, resulted primarily from a decrease in binding affinity for substrate, was pH-dependent in a manner consistent with reaction with carboxyl groups, and was greater than inhibition by hydrophilic carbodiimides. Substrates Na+ and Li+ and the competitive inhibitor amiloride protected against inhibition by dicyclohexylcarbodiimide in a pH-dependent fashion. Finally, we demonstrated amiloride-sensitive covalent binding of radiolabeled dicyclohexylcarbodiimide to a 100-kDa protein. In conclusion, a catalytically important carboxyl group is located in a relatively hydrophobic microenvironment at or near the external transport site of the renal Na+/H+ exchanger; and the transporter itself, or a subunit thereof, may be a 100-kDa protein.
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PMID:Covalent modification of the renal Na+/H+ exchanger by N,N'-dicyclohexylcarbodiimide. 302 72

Bupivacaine and chloroprocaine have proven to be valuable local anesthetics for a variety of surgical and obstetrical situations. Bupivacaine is particularly useful as a long acting agent which provides excellent sensory analgesia particularly during labor with minimal blockade of motor fibers. The 0.75% solution is useful for epidural surgical anesthesia since it does result in a decrease in onset time and a more marked motor blockade. In recent years, this agent has been reported to cause rapid cardiovascular collapse in some patients. Cardiotoxicity associated with bupivacaine is related not to the concentration employed but to the total dosage administered as a rapid intravenous injection. The careful administration of this agents to avoid an accidental intravenous injection should not preclude the use of 0.75% bupivacaine for epidural anesthesia in surgical patients. This concentration is not recommended in obstetrical cases. Chloroprocaine is valuable as a rapid onset, short duration local anesthetic with a low potential for systemic toxicity. The 3% solution is particularly useful for providing a rapid onset of action. In recent years, localized neural irritation has occurred in some patients in whom large amounts of this agent were administered epidurally or intrathecally. The local neural toxicity of chloroprocaine solutions is referably to the low pH and the inclusion of sodium bisulfite in these particular solutions. The toxicity of chloroprocaine solutions is related to total dosage rather than the concentration of solution employed. Careful administration of chloroprocaine epidurally in order to avoid accidental subarachnoid injection should preclude the possibility of local neural toxicity.
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PMID:Is there a need for chloroprocaine 3% and bupivacaine 0.75%? 305 87

Critics of bicarbonate therapy for life-threatening lactic acidosis have argued that the treatment is not only ineffective but that it also worsens morbidity and mortality. We critically examine the six major arguments used to condemn alkali treatment. We highlight the shortcomings of frequently cited uncontrolled human studies, experiments in animals, and in-vitro chemical analyses not clearly related to the human condition. The damaging hemodynamic effects of acidemia, which centralizes blood volume while depressing myocardial contraction (thereby causing hemodynamic collapse), are discussed and offered in support of alkali therapy. We also emphasize the extreme sensitivity of patients with acidosis to further small decreases in serum bicarbonate concentration or increases in arterial PCO2. In short, we have found no basis by which to condemn the use of alkali and believe that those who have scorned its use have yet to demonstrate its danger clearly. Until that time, sodium bicarbonate should remain the standard of therapy for this life-threatening condition.
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PMID:Bicarbonate therapy for organic acidosis: the case for its continued use. 310 11

The toxicity of local anesthetic agents can be divided into two categories: (1) systemic toxic reactions due usually to an accidental intravascular injection and (2) local tissue toxicity. The systemic toxicity of local anesthetic agents is primarily characterized by CNS excitation and convulsive activity. The cardiovascular system is more resistant to the toxic actions of local anesthetics. However, local anesthetics can exert a negative chronotropic and inotropic action and cause profound peripheral vasodilation. The combination of cardiac depression and peripheral vascular dilation results in irreversible circulatory collapse. The more potent agents such as bupivacaine appear to be more cardiotoxic and may precipitate ventricular arrhythmias and ventricular fibrillation. Local tissue toxicity is rare following the administration of local anesthetics. However, large doses of chloroprocaine solutions administered intrathecally have been associated with prolonged sensory-motor deficits in a few patients due probably to the low pH and presence of sodium bisulfite in the chloroprocaine solutions. In general, local anesthetic agents are relatively safe if administered properly. However, as with any pharmacological agents, local anesthetics may cause severe toxic reactions due to the improper use of these drugs.
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PMID:Toxicity of local anesthetic agents. 317 46

A number of metabolic inhibitors including the mRNA transcription inhibitor actinomycin D; the protein synthesis inhibitors emetine, cycloheximide, and puromycin; the energy metabolism inhibitors sodium azide and oligomycin; the amino acid analog L-azetidine-2-carboxylic acid; sodium fluoride; and acrylamide each cause the collapse of vimentin filament organization while leaving microtubule organization apparently unaffected in the human fibroblastic cell line MCH23. The protein kinase inhibitor N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H8) caused a partial collapse of vimentin organization but its effect was more difficult to discern, since it also induced a dramatic change in cellular morphology. Each of these drugs produced a significant inhibition of protein synthesis at concentrations that affected vimentin organization. The mechanisms by which these drugs affect intermediate filament organization are unclear, but our results demonstrate that intermediate filament organization in MCH23 cells is affected by a wide range of drugs and that such drugs cannot be used without great caution as reagents for the study of intermediate filament organization and function.
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PMID:Metabolic inhibitors and intermediate filament organization in human fibroblasts. 327 45

Shock describes a group of circulatory syndromes, all of which result in generalized cellular hypoxia. This leads to the depletion of adenosine triphosphate, the failure of the sodium-potassium pump, mitochondrial dysfunction, and ultimately, the release of a variety of toxic substances. Eventually these given rise to irreversible cardiovascular collapse because of their effects on the microcirculation. Shock may arise due to a failure of preload (hypovolaemic shock), myocardial contractility (cardiogenic shock), afterload (septic shock) or combinations of these (for example, anaphylactic shock, traumatic shock and neurogenic shock). During shock, important physiological changes occur in the nervous, respiratory, renal and gastrointestinal systems, as well as in intermediary metabolism. Hypotension is not synonymous with shock, and emphasis should be placed on the detection of more subtle, early signs. Management requires a systematic approach in which diagnostic and therapeutic processes take place in parallel. Particular attention must be paid to ventilation, oxygenation, fluid and electrolyte therapy, haemodynamic monitoring and, where appropriate, inotropic drugs. Corticosteroid and opioid antagonist agents probably do not have a role, but other agents, such as thyroid hormones, are under investigation.
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PMID:The pathophysiology of shock. 328 10

We report here the detection of a high molecular weight (greater than 400,000) cytoskeletal protein in the myogenic and neural tube derived structures of the chick embryo using a monoclonal antibody, F51H2. Immunohistological analysis reveals that this protein is concentrated in the myotome part of the somites, in the heart primordium, and in the neural tube at the end of the 2nd day of incubation. In cultured fibroblasts, the antibody appeared to decorate a filamentous network, although immunoreactivity was not detected on mesenchymal cells in situ. This network was also observed in cultured myoblasts where it has been demonstrated to be coincident to that of desmin. In colchicine-treated cells the immunoreactivity coincided with the perinuclear cap formed by the collapse of intermediate filaments (IFs). Immunoblot experiments confirmed the early distribution of F51H2 antigen in muscle and nerve tissues and its concentration in a salt-resistant IF-rich fraction of muscle tissues. In addition, there is a progressive loss of immunoreactivity during development. The immunoreactive band on sodium dodecyl sulfate gels was faint in tissues from newly hatched chickens and absent in adult tissues. It is suggested that the monoclonal antibody observed herein reacts with an embryo specific high molecular weight protein that is associated with IFs.
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PMID:Identification of a developmentally modulated, intermediate filament associated protein in the chick embryo. 328 85


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