bluuebunny/crossref_metadata_2025 huggingface dataset:
Pressure and flow in epicardial coronary veins of the dog heart: responses to positive inotropism
Authors: Armour J. A. , Klassen G. A.
Published: April 2011

Peripheral coronary venous pressures and coronary sinus venous flow were measured in the canine heart as well as intramyocardial, intraventricular, aortic, and coronary artery pressures. Maximum coronary venous flow occurred after maximum intramyocardial and peripheral coronary artery pressures had been reached. Maximum venous flow occurred at or following the maximum peripheral coronary vein pressure. Positive inotropic changes induced by stimulation of the right or left stellate ganglia or infusing isoproterenol, norepinephrine, or dobutamine significantly increased intramyocardial pressure, systolic epicardial coronary venous pressure, and systolic coronary venous flow. Mean coronary sinus flow was augmented by all interventions except isoproterenol. The estimated systolic vein resistance was slightly increased following right stellate ganglion stimulation, but not following left stellate ganglion stimulation, isoproterenol, or dobutamine. Norepinephrine reduced this parameter minimally. These data indicate that coronary veins respond differently to a variety of different positive inotropic interventions.
The slowly exchanging pool of sodium in frog skeletal muscle is confined within a membranous organelle
Authors: Menard M. R.
Published: April 2011

In the sartorius of the frog (Rana pipiens), it was found that 10–15% of the tissue sodium was not lost in sodium-free lithium-substituted solution, and was not exchanged with radiosodium in normal frog Ringer's solution, after 4 h. This sodium is not detected by an intracellular sodium-selective glass microelectrode. Detergent or freezing and thawing, in sodium-free solution, cause the loss of all but about 2% of the tissue sodium. The ionophore monensin causes a similar loss but does not disrupt cellular membranes. It was concluded that the slowly exchanging sodium exists in solution inside an organelle whose membrane has a low sodium permeability relative to the sarcolemma, and that this organelle probably is the sarcoplasmic reticulum.
Release of prostaglandins by the mesenteric artery of the renovascular and spontaneously hypertensive rat
Authors: Desjardins-Giasson Suzanne , Gutkowska Jolanta , Garcia Raul , Genest Jacques
Published: April 2011

The release of prostaglandin E2 (PGE2) and 6-ketoprostaglandin F1α (6-keto-PGF1α), the stable metabolite of prostacyclin (PGI2), by the perfused mesenteric arteries of renal and spontaneously hypertensive rats (SHR) have been measured. Unstimulated mesenteric arteries from two-kidney one-clip hypertensive rats (2K-1C) released 1.6 times as much PGE2 and 2.7 times as much 6-keto-PGF1α as those of control rats. The release of PGE2 by mesenteric arteries from one-kidney one-clip hypertensive rats (1K-1C) was not significantly different from that of uninephrectomized normotensive rats, but the release of 6-keto-PGF1α was 3.5 times higher in the former than in the latter. Norepinephrine (NE) induced a dose-related increase in perfusion pressure, in PGE2, and 6-keto-PGF1α release in all four groups. However, its effect on the release of PGE2 was more pronounced in 2K-1C than in sham-operated rats. There was no difference between 1K-1C and the uninephrectomized group. The effect of NE on the release of 6-keto-PGF1α was significantly higher for both renal hypertensive groups. These results indicate that the release of PGE2 is more dependent on the loss of renal mass than on hypertension, while the reverse applies to the release of 6-keto-PGF1α. Unstimulated mesenteric arteries from SHR released less PGE2 and less 6-keto-PGF1α than those of Wistar–Kyoto normotensive rats (WKY), but the release was not significantly different from Wistar rats. Under NE stimulation, WKY mesenteric arteries showed almost no increase in release of PGs. Compared with those of Wistar rats, SHR mesenteric arteries showed a greater pressor response to NE, a lower PGE2 release, and the same release of 6-keto-PGF1α. These findings reveal the difficulty of selecting an appropriate control group in studies involving SHR. We concluded that in renal hypertensive rats the specific increase of PGI2 release by arterial tissue may represent an important adaptive mechanism to the elevated blood pressure. However, this mechanism seems not to be involved in SHR.
Ca2+dependence of positive inotropic responses of guinea pig isolated cardiac preparations to cAMP-generating and cAMP-independent agonists
Authors: Yao L. F. , MacLeod K. M. , McNeill J. H.
Published: April 2011

The effects of procedures which diminish Ca2+ influx into myocardial cells on responses of isolated cardiac preparations to cAMP-independent histamine H1 receptor stimulation and cAMP-generating β-receptor stimulation were measured. The histamine response of guinea pig left atria, which appears to be primarily mediated by H1 receptors, was depressed to a greater extent than was the response of this preparation to isoproterenol by decreasing the extracellular Ca2+ concentration, and by the Ca2+ influx blocker D-600. Similarly, while the H1 agonist 2-pyridylethylamine dihydrochloride (PEA) produced increases in tension of a similar magnitude as the partial β-agonist salbutamol in both left atria and in papillary muscles, responses of both preparations to PEA were depressed to a significantly greater extent by decreasing the extracellular Ca2+ concentration than were responses to salbutamol. Overall, both the basal developed force of papillary muscles and the responses of these preparations to H1 and β-receptor stimulation appeared to be less depressed by decreasing the extracellular Ca2+ concentration than were those of left atria. These results indicate that responses mediated via cAMP-independent H1 receptors, like those arising from α-receptor stimulation, are more sensitive to procedures which diminish Ca2+ influx than are responses arising from stimulation of cAMP-generating β-receptors. This may reflect differences in the mechanisms by which stimulation of H1, α-, and β-receptors give rise to positive inotropic responses. In addition, left atria may be more dependent than papillary muscles on extracellular Ca2+ for the support of contraction.
On the mechanism of myocardial sensitization to catecholamines by hydrocarbon anesthetics
Authors: Reynolds A. K.
Published: April 2011

During the past decade, considerable progress has been made in our understanding of the mechanism underlying sensitization of the heart to the arrhythmogenic action of catecholamines by hydrocarbon anesthetics. This review includes the following: a brief discussion on the concepts of the mechanisms of induction of cardiac arrhythmias; recent studies on sensitization with special reference to the primary locus of this action and the principal mechanisms involved; and the contributions made by microelectrode studies on various types of cardiac tissue and the importance of cardiodynamic effects. In addition, atrioventricular conduction studies using bundle of His preparations are described. Drug interaction between anesthetic agents, muscle relaxants, and other drugs are discussed. Suggestions for future research and a section of summary and conclusions are included.
The effect of diet calcium on fluoride toxicity in growing rats
Authors: Harrison J. E. , Hitchman A. J. W. , Hasany S. A. , Hitchman A. , Tam C. S.
Published: April 2011

The effect of dietary Ca in response to fluoride (F) treatment was investigated in rats. Rats were maintained on either adequate (0.5%) or high (2.0%) dietary Ca and given for 5 weeks, NaF in drinking water. The minimum NaF levels that inhibited body growth and reduced survival were 300 mg/L with 0.5% diet Ca and 550 mg/L with 2.0% diet Ca. With these toxic F doses, bone histology showed increased formation surfaces and thickened osteoid seams (osteoid index 6–7%). Fluoride doses 30% below toxic levels (200 and 350 mg/L for 0.5 and 2.0% diet Ca, respectively) had no demonstrable effect on bone. Additional diet Ca reduced F absorption from 76 ± 3 to 47 ± 3% for 0.5 and 2.0% diet Ca, respectively. Comparable absorbed doses of F produced comparable effects on bone and body growth but, with additional dietary Ca, these effects were observed with 50% lower serum and bone F levels. Variable response to NaF therapy can be produced in rats by alterations in dietary Ca alone. Results indicate that for clinical treatment the NaF dose needs to be adjusted on an individual basis but neither serum nor bone F levels can be used reliably to establish optimal doses.
Cetamolol: a new cardioselective β-adrenoceptor blocking agent without membrane-stabilizing activity
Authors: Beaulieu Guy , Jaramillo Jorge , Cummings John R.
Published: April 2011

Cetamolol, a new β-adrenoceptor blocker with partial agonist activity and cardioselectivity, was studied in vivo to determine its membrane-stabilizing effects. Comparisons were carried out with atenolol, pindolol, practolol, propranolol, timolol, dexpropranolol, lidocaine, and procaine. The following results indicated that cetamolol lacked membrane-stabilizing activity: (i) failure to cause local anesthesia on the rabbit cornea and motor nerve of the rat tail; (ii) ineffectiveness in reversing ventricular arrhythmias induced by coronary artery ligation in dogs; (iii) failure to reduce cardiac automaticity in catecholamine-depleted dogs as determined by the rate of a subatrial rhythm during ventricular (vagal) escape; and (iv) lack of a significant increase in atrioventricular conduction time in vagotomized or atropinized dogs in contrast to the effect in normal dogs indicating a reflex effect of cetamolol. Other results include a restoration of sinus rhythm in dogs with ventricular tachycardia induced by ouabain, and a dose-related decline in the force of cardiac contraction in anesthetized dogs at doses from 3 to 15 mg/kg, which occurred after an initial increase in force owing to intrinsic sympathomimetic activity. Although the mechanisms for the latter two effects are not clear at this time, explanations other than membrane-stabilizing activity have been considered in view of the other findings. It is concluded that cetamolol lacks membrane-stabilizing activity even at inordinately high doses.
Alterations in aortic and tail artery reactivity to agonists after streptozotocin treatment
Authors: Ramanadham S. , Lyness W. H. , Tenner Jr. T. E.
Published: April 2011

In the present study, responses to various agonists in thoracic aorta and tail artery strips, obtained from 4-week streptozotocin (STZ)-treated rats and age-matched controls, were studied. Responses in aorta obtained from diabetic animals to the α-agonists, norepinephrine (NE), and methoxamine (MOX), to calcium (Ca2+) and potassium (K+) were found to be depressed relative to control tissue. Responses in tail artery however, were found to be different. While responses to K+ were decreased and to Ca2+ unchanged, tail artery strips obtained from diabetic animals were found to be supersensitive to both α-agonists relative to control tissue. Another observed difference between the two tissues was in their catecholamine content. While induction of diabetes did not alter catecholamine levels in the aorta, a significant decrease was produced in the tail artery, relative to control tissue levels. Our results indicate that inherent differences (such as the degree of innervation) may contribute to the differential responses observed in the two tissues studied. They further suggest the possible involvement of alterations in calcium utilization in aorta and the development of postjunctional supersensitivity in tail artery obtained from STZ-treated animals.
The effects of low-level lead exposure in developing rats: changes in circadian locomotor activity and hippocampal noradrenaline turnover
Authors: Collins M. F. , Hrdina P. D. , Whittle E. , Singhal R. L.
Published: April 2011

The circadian spontaneous locomotor activity of rats exposed to 0.1 mg lead/kg, po from 3 days until 4 and 6 weeks of age was similar to that of controls. However, hyperactivity during initial hours of recording was observed in rats that were treated with lead (Pb) until 8 weeks of age. When treatment was discontinued for 2 weeks, previously Pb-exposed rats had a tendency to be hypoactive. The elevated locomotor activity in 8-week-old lead-treated rats was not accompanied by any significant changes of noradrenaline levels in the cerebral cortex or hippocampus. Alterations in noradrenaline content of the hippocampus were, however, observed in rats that had been treated with Pb for 4 and 6 weeks. The turnover rate of noradrenaline in the hippocampus was also found to be significantly reduced following treatment for 6 weeks. Regional distribution of Pb in the brains of lead-exposed rats showed a large accumulation of the metal in the hippocampus. The alterations of the noradrenergic function in the hippocampus may be associated with the preferential storage of lead in this region.
Increased sensitivity to norepinephrine cardiac arrhythmias in the deoxycorticosterone acetate high salt rat before the onset of hypertension
Authors: Rabkin S. W. , Fung A. Y. M.
Published: April 2011

To determine whether salt loading increases the sensitivity of the myocardium to fatal arrhythmias induced by norepinephrine, four groups of Sprague–Dawley rats were studied. Group I received both saline (0.9%) as drinking water and deoxycorticosterone acetate (DOCA) (0.5 mg/kg, 3 times) for 14 days (DOCA high salt group); group II received only 0.9% saline as drinking water (high salt group); group III received DOCA in the same dose regime, but tap water to drink (DOCA group); and group IV received tap water (control). Under pentobarbital anesthesia, norepinephrine was infused and electrocardiogram and blood pressure were monitored. The DOCA high salt group developed arrhythmias significantly (p < 0.05) earlier than at lower norepinephrine doses. The dose at which 50% mortality occurred was 20 μg∙kg−1∙min−1 in DOCA high salt group, 37 μg∙kg−1∙min−1 in high salt group, 40 μg∙kg−1∙min−1 in the control, and 44 μg∙kg−1∙min−1 in the DOCA group. The cumulative dose of norepinephrine associated with 50% mortality was 160 μg/kg in the DOCA high salt group, 370 μg/kg in the high salt group, 530 μg/kg in the control group, and 600 μg/kg in the DOCA group. The blood pressure after sodium loading before norepinephrine infusion was similar in all three groups. The blood pressure response to norepinephrine was not significantly different between the four groups. Myocardial content of the electrolytes Na+, K+, Mg2+, and Ca2+, were not significantly different between three of the groups, namely those receiving DOCA plus high salt, high salt or neither DOCA nor high salt as ascertained in other animals who were treated according the the three protocols. These data suggest that excess dietary sodium enhances the sensitivity to norepinephrine-induced cardiac arrhythmias.
New agonist and antagonist analogues of bradykinin
Authors: Barabé J. , Caranikas S. , D'Orléans-Juste P. , Regoli D.
Published: April 2011

Three new analogues of bradykinin (BK) have been tested for their agonistic and antagonistic actions on the rabbit jugular vein and the guinea pig ileum (B2 receptors), and six were studied on rabbit aorta strips (B1 receptors). Substitution of Gly4, Phe5, and Phe8 in BK with D-Trp gives analogues with a relative affinity lower than 1.0% as compared with BK. These analogues have no antagonistic properties on the rabbit jugular vein and on guinea pig ileum (B2 receptors). Substitution of Pro7 in des-Arg9-BK by Gly and by D-Ala give compounds that antagonise the effects of kinins on the rabbit aorta strips (B1-receptor system). These new antagonists are fairly potent with a pA2 value of 6.03 to 7.29 and seem competitive because the pA2 – pA10 values approximate 0.95. These results suggest that the orientation of Phe8 is critical for the activation of B1 receptors by kinins.
Hepatic venoconstrictor effects of isoproterenol and nifedipine in anesthetized cats
Authors: Seaman K. L. , Greenway C. V.
Published: April 2011

In cats anesthetized with pentobarbital, isoproterenol infused into a peripheral vein causes a reduction in hepatic blood volume measured by plethysmography. As this response is accompanied by increases in portal and hepatic lobar venous pressures, the decrease in hepatic volume cannot be a passive emptying secondary to reduced intrahepatic pressure. We conclude that intravenous isoproterenol causes an active hepatic venoconstriction. Nifedipine produced similar responses. From this and our previous data, we conclude that in anesthetized cats, arteriolar vasodilators which increase cardiac output cause hepatic venoconstriction (hydralazine, adrenaline, dopamine, isoproterenol, and nifedipine), while those which do not increase cardiac output have no effect on the hepatic venous bed (nitroprusside and diazoxide) or cause venodilatation (nitroglycerine). The mechanism of the hepatic venoconstrictor effect of isoproterenol was investigated further. Because previous work has shown that this response does not occur when isoproterenol is infused locally into the hepatic artery or portal vein, the venoconstrictor effect of peripheral intravenous infusions must be indirectly mediated. The response was still present after hepatic denervation, adrenalectomy, nephrectomy, and after indomethacin administration indicating it is not mediated by the hepatic nerves, adrenal catecholamines, the renal renin-angiotensin system, or prostaglandins. The mechanism remains unknown.
Action of arachidonic acid in ureteral-ligated kidney of the anesthetized canine: possible lipoxygenase activity
Authors: Chapnick Barry M.
Published: April 2011

In anesthetized dogs 48 h after unilateral ureteral ligation, intra-arterial injection of arachidonic acid produced a transient increase followed by a prolonged decrease of resistance in the ureterai-ligated kidney; whereas, in the control kidney, only the prolonged decrease in resistance was observed in response to arachidonate. Indomethacin blocked not only the arachidonate-induced renal efflux of both immunoreactive 6-keto-prostaglandin F1α and thromboxane B2 but also vasodilation in both kidneys, in contrast, the initial vasoconstriction in the obstructed kidney was not affected by pretreatment with the cyclo-oxygenase inhibitor. Infusion of 5,8,11,14-eicosatetraynoie acid, an inhibitor of lipoxygenase activity, into the ureteral-ligated kidney after indomethacin markedly reduced the initial vasoconstrictor response to arachidonate. These data demonstrate that vascular reactivity to arachidonic acid is altered in the ureteral-obstructed kidney and are consistent with the hypothesis that formation of lipoxygenase as well as cyclooxygenase derivatives may participate in the hemodynamic responses to arachidonic acid in this pathophysiologic model.
Effects of the oral hypoglycemic agent methyl palmoxirate on exercise capacity of rats
Authors: Young J. C. , Bryan J. E. , Constable S. H. , Tutwiler G. F. , Holloszy J. O.
Published: April 2011

The effect of the oral hypoglycemic agent methyl palmoxirate (methyl 2-tetradecylglycidate, McN-3716), a selective inhibitor of long chain fatty acid oxidation, on the exercise capacity of normal rats was evaluated. Daily administration of 2.5 mg/kg for 7 days, or of a single dose of 10 mg/kg, of methyl palmoxirate did not affect the ability of rats to perform strenuous exercise of an intensity that caused exhaustion in less than 30 min. The ability to perform prolonged, moderately strenuous exercise of an intensity that could be maintained for more than 60 min was decreased slightly (17%) in the methyl palmoxirate treated rats. This effect appeared to be mediated by a significant reduction in initial liver glycogen content in the methyl palmoxirate treated rats. As a consequence, the methyl palmoxirate treated rats became hypoglycemic during prolonged exercise. Inhibition of fatty acid oxidation in skeletal muscle was minimal. Treatment with methyl palmoxirate protected against the development of exercise-induced ketosis. It appears that the liver is the major site of action of methyl palmoxirate when given in low dosage.
The destruction of halogenated organic chemicals by plasma pyrolysis
Authors: Barton T. G. , Mordy J. A.
Published: April 2011

Very high destruction efficiencies for halogenated chemicals have been achieved by plasma pyrolysis. Destruction efficiencies exceeded 99.9999999% for tests with polychlorinated biphenyls (PCBs). Preliminary tests with tetrachloromethane have obtained destruction efficiencies exceeding 99.99%. The plasma pyrolysis process involved the creation of a 250-kW plasma with a temperature in excess of 25 000 °C. The toxic material was injected into the plasma zone at a rate between 1 and 2 L/min. Thermochemical and photochemical dissociation of the toxic materials produced atoms and ions which recombined to form primarily H2, CO, HCl, and particulate carbon. The HCl was neutralized by NaOH. The flaring of the H2 and CO should destroy to a high degree any trace residuals. The application of plasma pyrolysis for the ultimate disposal of toxicological waste was also investigated. Rat carcasses containing mean lethal dosage of PCB were pyrolyzed.
Immobilization and geological disposal of nuclear fuel waste
Authors: Tait J. C.
Published: April 2011

The Canadian Nuclear Fuel Waste Management Program is developing methods for the safe disposal of both used nuclear fuel and fuel recycle waste. The disposal strategy is based on interim storage of the used fuel, immobilization of either used fuel or recycle waste, and disposal, deep in a stable geological formation in the Canadian Shield. The disposal concept proposes a multibarrier system to inhibit the release of the radioactive waste from the disposal vault. The principal components of the multibarrier system are (i) the waste form in whch the radionuclides are immobilized, (ii) engineered barriers including high integrity containers, buffers and backfills designed to retard the movement of groundwaters in the disposal vault, and (iii) the natural barrier provided by the massive geological formation itself. The research programs to investigate this concept are discussed briefly. Several different waste forms are being developed for the immobilization of high-level fuel recycle waste, including glass, glass-ceramics and crystalline materials. Dissolution of these materials in groundwater is the only likely scenario that could lead to radionuclide release. The factors that influence the aqueous dissolution behaviour of these materials are reviewed.
Renal metabolism and ammoniagenesis during acute respiratory alkalosis in the dog
Authors: Gougoux André , Vinay Patrick , Cardoso Manuel , Duplain Marcelle
Published: April 2011

Acute respiratory alkalosis (blood pH, 7.60; arterial [Formula: see text], 15 mmHg (1 mmHg = 133.322 Pa); plasma bicarbonate, 14 mM) was induced in nine anesthetized dogs by increasing their respiratory rate and depth. Renal glutamine extraction and ammonia production expressed per 100 mL of glomerular filtration rate did not change during acute hypocapnia, whereas arterial glutamine concentration decreased significantly from 0.47 to 0.36 mM. Hypocapnia did not change plasma potassium concentration and its urinary excretion. Acute hypocapnia increased lactate extraction and pyruvate production, whereas citrate extraction and glutamate and alanine production did not change. Citraturia remained minimal. Renal cortical glutamine concentration fell from 0.64 to 0.38 mM during hypocapnia while α-ketoglutarate, glutamate, malate, oxaloacetate, and citrate did not change. Lactate concentration rose from 1.1 to 2.0 mM. Glutamine concentration in the liver and muscle decreased following acute hypocapnia. Our data are compatible with the hypothesis that an acute respiratory alkalosis might not result in any change in the hydrogen ion concentration and (or) gradient between the mitochondrial matrix and the cytosol. Consequently, renal glutamine extraction and ammonia production are not reduced, renal cortical concentrations of relevant metabolites in the ammoniagenic pathway are not changed, and renal handling of citrate remains unaffected.
Low extracellular Ca2+ and enzyme release in the perfused rabbit heart
Authors: Fortier Pierre A. , Bedford Gary K. , Chiong Miguel A.
Published: April 2011

Previous studies have shown that the well-oxygenated perfused rabbit heart releases creatine kinase when treated with the calcium antagonist drug verapamil (VER) in a dose-related manner. It is possible that this effect is related to Ca2+ ion deprivation of the sarcolemma. This possibility was explored by perfusing hearts with low Ca2+ (0.5, 0.23, 0.15, and 0 mM) versus a control group (1.27 mM Ca2+) for 60 min. Low Ca2+ perfusion was associated with (i) reduction in the heart rate – left ventricular systolic pressure product and O2 consumption, (ii) tendency for the coronary sinus flow to increase, (iii) electromechanical dissociation, prolongation of atrioventricular conduction and QT interval, and (iv) decrease in myocardial glycogen. Lower total adenosine nucleotides were found only in the 0 mM Ca2+ group. As the Ca2+ concentration was reduced, the hearts lost increasing amounts of creatine kinase, aspartate aminotransferase, and lactate dehydrogenase. These results confirm the importance of Ca2+ ions in contractile and electrical cardiac functions and show that decreased availability of this cation leads to increasing enzyme leakage resembling that seen in VER-treated hearts.
Physiological studies of small mediastinal ganglia in the cardiopulmonary nerves of dogs
Authors: Armour J. A.
Published: April 2011

Stimulation of the cranial end of a decentralized canine cardiopulmonary nerve results in the generation of a compound action potential which can be recorded at the caudal end. A region has been identified which, on stimulation, produces a compound action potential with complex configuration which is different from simpler wave forms obtained by stimulating 1 mm or more in either the rostral or caudal direction. Histological examination reveals that clusters of neuronal cell bodies are localized to this region of the nerve, whereas none is found to either side. Characteristics of the different wave forms evoked by changing the site of stimulation and reversing the stimulation and recording electrodes provide evidence for the existence of both afferent and efferent synaptic pathways. The compound action potential evoked by the most rostral stimulations and presumed to contain synaptic components was not altered by intravenously administered cholinergic and adrenergic pharmacological blocking agents (hexamethonium, atropine, phentolamine, or propranolol). It was, however, depressed by local injections of chymotrypsin or manganese into the functionally identified transitional region. It is concluded that synapses, which can be activated at relatively high frequencies (1–10 Hz) and may be important for rapidly changing local neural regulation of the heart and lungs, appear to exist within the course of cardiopulmonary nerves.
The disposition and the liver and thymus gland toxicity of 3,3′,4,4′-tetrachlorobiphenyl in the female rat
Authors: Clarke D. W. , Brien J. F. , Racz W. J. , Nakatsu K. , Marks G. S.
Published: April 2011

3,3′,4,4′-Tetrachlorobiphenyl (TCBP) was administered orally to adult female Sprague–Dawley rats in the oral dosage regimen, 5 mg∙kg−1∙day−1 for 21 days, followed by a 22-day postdosing period. Control animals received either the corn-oil vehicle (1 mL∙kg−1∙day−1) or no treatment. 3,3′,4,4′-TCBP distributed preferentially into the adipose tissue and liver, and apparent steady-state xenobiotic concentrations were attained in the adipose tissue (8 μg/g) and liver (300 ng/g) prior to the cessation of dosing. The 3,3′,4,4′-TCBP concentrations in the serum, brain, kidneys, and thymus gland were lower and more variable than those in the adipose tissue and liver. During the postdosing period, 3,3′,4,4′-TCBP was eliminated from the adipose tissue and liver by apparent first-order kinetics with elimination half-life values of 2.5 days and 0.8 day, respectively. The major route of excretion of unmetabolized 3,3′,4,4′-TCBP was via the feces, and the amount excreted over 24 h did not exceed 8% of the dose administered on any given day. Throughout the experiment, there were no differences in the body weight or food and water intake for the 3,3′,4,4′-TCBP-treated animals compared with the corn-oil-treated and nontreated rats. There was a significant increase in liver weight and a significant decrease in thymus gland weight for the 3,3′,4,4′-TCBP-treated rats compared with the corn-oil-treated rats at the cessation of dosing and at 11 days thereafter, but there were no observable histological changes in these organs as assessed by light microscopy. By the end of the postdosing period, there were no significant differences in the liver and thymus gland weights among the 3,3′,4,4′-TCBP-treated, corn-oil-treated, and non-treated rats. Hepatic microsomal cytochrome P-450 content was significantly greater for the 3,3′,4,4′-TCBP-treated rats compared with the corn-oil-treated animals at the end of the dosing period and during the subsequent postdosing period.
A comparison of the effects of cationic, anionic, and neutral amphipathic agents on the contractile behaviour of frog skeletal muscle. II. Amplitude of depolarization and repolarization-induced contractures
Authors: Foulks James G. , Morishita Lillian
Published: April 2011

Sufficiently high concentrations of cationic (n-alkyl trimethylammonium) or neutral (n-alkanols) amphipathic agents reduced the amplitude of maximum K contractures of frog toe muscles, an effect which was antagonized by reduced temperature, by the presence of perchlorate anions, or (to a lesser extent) by an increased concentration of divalent cations. Enhancement of the similar effect of tetracaine was prominent only with alkyl trimethylammonium compounds. Enhancement of the depressant effect of acidity (pH 5.0) was observed with octyl trimethylammonium and octanol but not with octanesulfonate or butanol. Partial restoration of potassium contractures in media lacking divalent cations was produced by octane- or nonane-sulfonate and by propanol but not by octyl trimethylammonium or octanol. The alkyl sulfonates differed from the other agents studied in producing tonic contractures at concentration which did not reduce maximum K-contracture tension. The alkyl sulfonates also differed from other amphipaths of similar size in their ability to elicit small repolarization-induced contractures in the absence of perchlorate, although this property also was shared by small alkanols. Sufficient concentrations of all amphipaths reduced the amplitude of repolarization-induced contractures in the presence of perchlorate. The intensity of the effects of these agents on contractile function usually was proportional to the size of their apolar group, and with ionic apmphipaths such effects were apparent only with compounds having hydrocarbon chains containing eight or more carbon atoms. These experiments indicate that hydrophobic interactions in the external lamina of the sarcolemma can influence the potential-dependent control of contractile function in skeletal muscle, presumably by effects on the conformational transitions of integral membrane proteins. The similarity between many of the effects of alkyl sulfonate and small n-alkanols as well as those of small concentrations of perchlorate suggest that chaotropic actions can contribute to these effects. The difference between the effects of anionic and cationic agents, as well as between the effects of n-alkanols of different size may be attributable to the different intensity of similar effects at different membrane sites.
Insulin binding and 2-deoxy-D-glucose uptake in fast- and slow-twitch mouse skeletal muscle at 18 and 37 °C
Authors: Watson-Wright Wendy M. , Tan Meng H. , Bonen Arend
Published: April 2011

Insulin binding, insulin degradation, and 2-deoxyglucose uptake were examined at 18 and 37 °C in soleus and extensor digitorum longus muscles of mice. Insulin binding and degradation were greater in the soleus than in the extensor digitorum longus at both temperatures (p < 0.05). At 37 °C, binding was decreased in both muscles while percentage degradation was increased in comparison with 18 °C (p < 0.05). Dose–response curves (percentage of binding at 4 nM of insulin) remained the same for both muscles at the two temperatures. Basal (no insulin) 2-deoxyglucose uptake was increased at 37 °C in the extensor digitorum longus but not the soleus. Insulin responsiveness in terms of the amount of 2-deoxyglucose taken up per femtomole of insulin bound was almost identical for the two muscles at 18 °C, whereas at 37 °C it was increased more in the soleus than in the extensor digitorum longus. The results indicate that in the presence of physiological concentrations of insulin (0.2–4 nM), insulin binding trends are minimally affected by increased temperature. In contrast, the ability of insulin to stimulate 2-deoxyglucose uptake varies between the two temperatures, and at the higher temperature between fast- and slow-twitch muscle.
The "intermediate component" of the radiosodium efflux from frog skeletal muscle
Authors: Menard M. R.
Published: April 2011

The influence of diversity in the size of the cells of the frog's sartorius on the radiosodium efflux from the muscle was investigated. Morphometric analyses of light micrographs of complete cross sections of the muscle were done in the proximal and distal regions. The results were used to predict the shape of the radiosodium washout curve under the following assumptions: the cells differ in size and shape, but each has a single internal pool of exchangeable sodium; the sodium exchange properties of the limiting membranes are the same for all cells; and the diversity of the true areas of the limiting membranes is reflected by the diversity of the apparent areas measured at the light microscopic level. Radiosodium efflux measurements were performed on similar muscles. The model correctly predicted the occurrence of a continuous decline of the fractional loss of radiosodium, which was not due to diffusional delay and which would be interpreted as a second internal compartment in a compartmental analysis, and an effect of short versus long isotope loading intervals on the efflux. It was concluded that the existence of cell size diversity satisfactorily explains the flux data. No "special region" must be postulated.
Prostaglandin E1 increases myocardial contractility in the conscious dog
Authors: Roux S. , Latour J. G. , Théroux P. , Clozel J. P. , Bourassa M. G.
Published: April 2011

The systemic and inotropic properties of prostaglandin E1 (PGE1) were investigated in 20 unanesthetized dogs. Pairs of ultrasonic dimension gauges and a micromanometer were implanted in the subendocardium and the apex of the left ventricle (LV), respectively. Seven to ten days later, increasing doses of PGE1 were infused into the left atrium. To appreciate the inotropic effects of the agent, the heart rate was maintained constant at 150 beats/min in a subgroup of dogs while preload was modified by bleeding or saline infusion over matched ranges of end-diastolic segmental length (EDL) during placebo and PGE1 infusions (0.25 μg∙kg−1∙min−1). LV function curves (ΔL: systolic segmental shortening versus EDL) were plotted. Increasing doses of PGE1 above 0.031 μg∙kg−1∙min−1 brought a progressive decrease of left ventricular end-diastolic pressure, EDL, ΔL, and peak left ventricular systolic pressure. The heart rate increased significantly at dosages from 0.063 to 0.125 μg∙kg−1∙min−1, and peak positive dP/dt after an initial increase fell at the dose of 0.5 μg∙kg−1∙min−1. The LV function curves invariably showed a shift to the left when PGE1 was administered; as the basal EDL was restored during PGE, infusion, ΔL reached a 33% increase (p < 0.001). Thus, in addition to its potent vasodilating properties that are more prominent on preload than afterload, PGE1 increases myocardial contractility in the conscious dog.
Vagal effects on sinoatrial and atrial conduction studied with epicardial mapping in dogs: the influence of pacemaker shifts on the measurement of sinoatrial conduction time
Authors: Watanabe Hidehiko , Perry Jean-Benoît , Pagé Pierre , Savard Pierre , Nadeau Réginald
Published: April 2011

The influence of pacemaker shifts on sinoatrial conduction time (SACT) was studied by investigating the effects of vagal stimulation on SACT and atrial conduction in anesthetized open-chest dogs. Isochronal maps were drawn from unipolar electrograms simultaneously recorded at 60 epicardial sites on the right atrial free wall and the inferior and superior vena cava. Vagal stimulation caused atrial conduction velocity to increase from 0.99 ± 0.10 m/s (mean ± SD) to 1.23 ± 0.23 m/s (p < 0.01), and the pacemaker to shift to lower positions along the superior vena cava – right atrial junction. As a result of the changes, the distances and the atrial conduction times from the stimulating and recording electrodes to the pacemaker site varied, and hence, the SACT values obtained indirectly by premature atrial stimulation varied. The isochronal maps were used to measure the atrial conduction times from stimulating to recording electrodes (a), from stimulating electrode to pacemaker site (b), and from pacemaker site to recording electrode (c). Indirect SACT was lengthened by vagal stimulation from 43 ± 16 to 64 ± 22 ms (p < 0.02). After correcting by subtracting the atrial conduction time (b + c − a), these values became 26 ± 6 ms (control) and 40 ± 11 ms (vagal stimulation) (p < 0.01). SACT values measured directly from the electrograms were 27 ± 7 ms (control) and 42 ± 10 ms (vagal stimulation) (p < 0.01). Corrected indirect SACTs were closer to direct SACTs than were the uncorrected indirect SACTs. It was concluded that (i) vagal stimulation induced pacemaker shift, increased atrial conduction velocity, and prolonged SACT; (ii) constant atrial pacing induced a pacemaker shift toward the stimulating electrode; and (iii) atrial conduction time must be taken into account to correctly estimate SACT.
Renal responses to atrial natriuretic factor during converting enzyme inhibition
Authors: Wang Sue-Lin , Gilmore Joseph P.
Published: April 2011

The effect of converting enzyme inhibitor (CEI) on the renal response to atrial natriuretic factor (ANF) was determined in the rat. In the absence of CEI, ANF produced rapid and significant increases in sodium, potassium, calcium, and urine excretions while blood pressure declined transiently. In the presence of CEI, ANF enhanced the excretion of sodium and potassium but not of calcium and urine. The activity of CEI was documented by observing that, in the presence of CEI, the elevation of blood pressure produced by angiotensin I was significantly attenuated. The potentiating effect of CEI on the natriuretic response to ANF supports the hypothesis that converting enzyme may be involved in the metabolism of ANF.
Modifications evoked by piretanide in the mechanical activity of cardiovascular tissues
Authors: Lacuara J. L. , Ruiz R. D. , Cuneo M. Fiol de
Published: April 2011

The effects of piretanide upon mechanical activity and pharmacological reactivity of vascular and myocardial tissues from normotensive rats were investigated. Magnitude of phasic contractions of isolated rat portal vein was diminished by the drug in a dose-related manner; contractile depression induced by piretanide (10−4 M) was less in the presence of insulin (0.1 U/mL), glucose (22 mM) or pyruvate (5 mM). Responses to KCl (90 mM), or norepinephrine (2.5 × 10−5 M) were also reduced. Contractile activity of atria and ventricle strips was diminished only when piretanide reached 10−4 M. Results support direct actions of piretanide upon cardiac and vascular tissues. Possible mechanisms of action are discussed.
Ketamine: evidence of tissue specific inhibition of neuronal and extraneuronal catecholamine uptake processes
Authors: Lundy Paul M. , Gverzdys Sharunas , Frew Robert
Published: April 2011

Ketamine (1.1 × 10−5 to 3.7 × 10−4 M) potentiated catecholamine responses of rat anococcygeus muscle and rabbit aorta in vitro. In the anococcygeus, potentiation was abolished by cocaine (2.9 × 10−5 M) pretreatment or by chemical sympathectomy using 6-hydroxydopamine (6-OHDA), but was unaffected by pretreatment with the extraneuronal uptake inhibitor cortisol (8.3 × 10−5 M), or the catechol-O-methyltransferase inhibitor tropolone (2.4 × 10−4 M). The action of ketamine mimicked the potentiating effect of cocaine on tyramine responses. In contrast, the potentiation by ketamine in rabbit aorta was unaffected by cocaine or 6-OHDA but was abolished by cortisol or tropolone; and ketamine potentiated tyramine responses, whereas cocaine inhibited them. Thus the mechanism of action by which ketamine produces potentiation of catecholamines in these two tissues is completely different. These results suggest that ketamine has the unusual ability to block neuronal and extraneuronal uptake and that the predominating mechanism will depend on the type of tissue examined and the morphology of its adrenergic innervation.
Effect of alkylation of tryptophan residues on the enzymatic and pharmacological properties of snake venom phospholipase A2
Authors: Condrea Eleonora , Soons Karen R. , Barrington Peggy L. , Yang Chen-Chung , Rosenberg Philip
Published: April 2011

Snake venom phospholipases A2 show a remarkable degree of amino acid sequence homology yet differ markedly in enzymatic and pharmacological activities. The basic phospholipase A2 from Naja nigricollis venom has much greater lethal potency, cardiotoxicity, hemolytic and anticoagulant activity than the acidic or neutral enzymes from Naja naja atra or Hemachatus haemachatus venoms, respectively, even though it has lower enzymatic activity than the latter two enzymes. Previous studies in which we selectively modified lysine and free carboxyl groups suggested that the pharmacological and enzymatic active sites are not identical. Tryptophan residues have been suggested as being involved in substrate binding although some phospholipases have no tryptophan. We investigated the effect of alkylating the tryptophans in N. nigricollis, N. n. atra, and H. haemachatus phospholipases A2 with 2-hydroxy-5-nitrobenzyl bromide. Chemical modification caused decreases in enzymatic activity, although the extent of inactivation varied with the enzyme and with the substrate (lecithin micelles, egg yolk, heart homogenates). The specificity of the enzymes for individual phospholipid substrates was not affected. Alkylation of the tryptophans also caused decreases in lethal, hemolytic, anticoagulant, and cardiotoxic potencies, which were similar to the extents of decrease in enzymatic activity. Our results suggest that tryptophans are not specifically associated with either the enzymatic or the pharmacological active site nor are essential for either activity.
Timolol plus acetazolamide: effect on formation of cerebrospinal fluid in cats and rats
Authors: Vogh Betty P. , Godman David R.
Published: April 2011

Administration iv of 50 mg∙kg−1 acetazolamide (A) and 3 mg∙kg−1 timolol (T) causes the formation of cerebrospinal fluid (f-CSF) to be reduced to 43.7% of the control rate compared with a reduction to 82.5% of control by T alone and to 52.6% of control by A alone. The effect of combined drugs is the same when A is combined with T initially, when A is added to T after studying T alone, or when T is added to A after studying A alone. In contrast, in rats f-CSF is not influenced by T, either alone or when in combination with A. The rate in rats is reduced to 55% of control by treatments with A or A and T. Decrease in formation of cerebrospinal fluid by A occurs through inhibition of carbonic anhydrase, but the means whereby T (a known blocker of beta-adrenergic receptors) causes a reduction in f-CSF is not established; it is known that it does not inhibit carbonic anhydrase. Control of f-CSF by the sympathetic nervous system is discussed.
Dysfunction of calcium handling by smooth muscle in hypertension
Authors: Kwan C. Y.
Published: April 2011

Dysfunction of ion handling, including binding and fluxes (passive and active transport) of physiologically important ions such as potassium, sodium, calcium, and magnesium, by vascular smooth muscle cell membranes has repeatedly been reported to be associated with the pathophysiology of hypertension. The specific purpose of this review is to summarize and evaluate the evidence for alterations of calcium ion (Ca2+) handling by vascular smooth muscle in various forms of hypertension in the animal model on the basis that regulation of cytoplasmic Ca2+ concentration is a complex and yet vitally important process for a normal function of vascular smooth muscle and that derangement of such a regulation may result in excessive retention of cytoplasmic Ca2+, contribute toward increase of total peripheral resistance, and ultimately lead to elevation of blood pressure. Emphasis is placed upon the consideration of the usefulness of the subcellular membrane fractionation technique in studies of binding and transport of Ca2+ by vascular and nonvascular smooth muscle membranes from genetic as well as experimental hypertensive rats. The limitations of the interpretation of data using such an approach are also considered. Decreased active transport of Ca2+ across isolated plasma membrane vesicles from large and small arteries occurs in several but not all forms of hypertension. This membrane abnormality also occurs in nonvascular smooth muscles and other tissues or cells not confined to the cardiovascular system in genetic hypertension, but not in experimental hypertension. A hypothesis of general membrane defects in spontaneous hypertension is proposed. Since the long-term regulation of blood pressure at the sites of resistant blood vessels is under finely integrated and interacting control systems, namely, the myogenic, neurogenic, and humoral controls, involving many tissues or cells not necessarily confined to cardiovascular system, membrane abnormalities in Ca2+ handling by tissues in each or a combination of these control systems can conceivably lead to hypertension.
The conditioning effect of large doses of ascorbic acid in guinea pigs
Authors: Basu Tapan K.
Published: April 2011

The influence of prolonged exposure of guinea pigs to excessive ascorbic acid (AA) on the outcome of pregnancy, as well as the adaptive effect of the vitamin either during preweanling life or following weaning, were examined. Continuous exposure to AA (1 mg/mL drinking water) from the time they were first mated up to the time of second pregnancy, had no significant effect on the number of offspring and on their weights at birth, when compared with that of the animals receiving 0.1 mg AA/mL drinking water. However, change in AA intake from 1 to 0.1 mg/mL drinking water, at the age of 21 days, resulted in a significant loss in body weight and reductions in the plasma, leucocyte, and adrenal concentrations of AA, as compared with those of the pair-fed animals receiving 0.1 mg/mL drinking water throughout. The present study also indicated that the conditioning effect is less pronounced in guinea pigs when exposed to the high AA following weanling age than in utero.