bluuebunny/crossref_metadata_2025 huggingface dataset:
Ventricular arrhythmias after reperfusion: is there a correlation with infarct size?
Authors: Krejcy K. , Krumpl G. , Todt H. , Windisch A. , Mousavi M. , Raberger G.
Published: April 2011

The aim of this investigation was to examine whether any correlation exists between enzymatically estimated infarct size and arrhythmias arising in response to coronary reperfusion. Four hour occlusion of the left anterior coronary artery followed by reperfusion was carried out in conscious dogs. Serum creatine phosphokinase (CPK) analysis and planimetric determination of infarct size were performed. The Holter monitoring technique was used to analyze the arrhythmias. A good correlation was observed between the number of premature ventricular complexes (PVC) occurring during 4-h coronary artery occlusion and peak serum CPK values (CPKmax; r = 0.74). While PVC in the early 2-h reperfusion phase and on days 1 and 2 of the late reperfusion phase did not show a correlation with CPKmax nor with occlusion arrhythmias, arrhythmic activity on day 3 of the late reperfusion phase correlated well with CPKmax (r = 0.71) and occlusion arrhythmias (r = 0.75). Whereas it cannot be ruled out that arrhythmias on days 1 and 2 are related to coronary reperfusion as well as to the established infarction, we speculated that arrhythmias on day 3 are delayed arrhythmias in response to the occlusion procedure and not a consequence of reperfusion. Providing that arrhythmias occurring in the early reperfusion phase are almost exclusively induced by the arrhythmogenic phenomenon of reperfusion, we conclude that in contrast to occlusion arrhythmias, reperfusion arrhythmias are not markers of infarct size. Thus, a higher number of arrhythmias after reperfusion is not necessarily associated with a larger infarct size.Key words: Holter monitoring, coronary occlusion, reperfusion arrhythmias, infarct size, arrhythmia model in conscious dogs.
Basolateral glucose transport in distal segments of the dog nephron
Authors: Vinay P. , Sénécal J. , Noël J. , Chirinian C. , Vinay M. C. , Ammann H. , Boulanger Y. , Gougoux A. , Berteloot A.
Published: April 2011

The transport of glucose by canine thick ascending limbs (TAL) and inner medullary collecting ducts (IMCD) was studied using tubule suspensions and membrane vesicles. The uptake of D-[14C(U)]glucose by a suspension of intact TAL tubules was reduced largely by phloretin (Pt), moderately by phlorizin (Pz), and completely suppressed by a combination of both agents. A selective effect of Pz on the transport of [14C]α-methyl-D-glucoside, but not on 2-[3H]deoxyglucose, was also observed in TAL tubules. In contrast, glucose transport was unaffected by Pz but entirely suppressed by Pt alone in IMCD tubules. The metabolism of glucose was largely suppressed by Pt but unaffected by Pz in both types of tubules. Membrane vesicles were prepared from the red medulla and the white papilla or from TAL and IMCD tubules isolated from these tissues. Vesicle preparations from both tissues demonstrated a predominant carrier-mediated, sodium-independent, Pt- and cytochalasin B-sensitive glucose transport. Following purification of basolateral membrane on a Percoll gradient, the sodium-insensitive D-[14C(U)]glucose transport activity copurified with the activity of the basolateral marker Na+–K+ ATPase in both tissues. However, a small sodium-dependent and Pz-sensitive component of glucose transport was found in membrane vesicles prepared from the red medulla or from thick ascending limb tubules but not from the papilla nor collecting duct tubules. The kinetic analysis of the major sodium-independent processes showed that the affinity of the transporter for glucose was greater in collecting ducts (Km = 2.3 mM) than in thick ascending limbs (Km = 4.9 mM). We conclude that glucose gains access into the cells largely through a basolateral facilitated diffusion process in both segments. However a small sodium–glucose cotransport is also detected in membranes of TAL tubules. The transport of glucose presents an axial differentiation in the affinity of glucose transporters in the renal medulla, ensuring an adequate supply of glucose to the glycolytic inner medullary structures.Key words: basolateral membranes, tubules, medulla, thick ascending limbs, collecting ducts, glucose transport, phlorizin, phloretin, dog.
Arterial adaptations to altered blood flow
Authors: Lee Richard D. Brown , Langille B. Lowell
Published: April 2011

Arterial remodeling in response to altered blood flow is believed to be critical to vascular adaptations to developmental, physiological, pathological, and therapeutically induced changes in blood flow. To assess this remodeling, we used left-to-right carotid anastomosis to increase blood flow in the right common carotid arteries of adult rabbits by 60%. After 2 months, these vessels exhibited no compensatory enlargement. In contrast, the same procedure performed in 5- to 6-week-old weanling rabbits resulted in accelerated growth of the vessels: diameters exceeded those of control arteries by 19% after 2 months. Common carotid arteries in adult rabbits remodeled to produce a diameter reduced by 23% when blood flow was reduced by 63% by external carotid ligation. This adaptation restored shear stress exerted on the vessel wall to control levels. The reduced diameter was not reversed when the vessels were maximally dilated with nitroprusside, adenosine, and forskolin; however, normal diameters were restored within 1 week when normal blood flows were reestablished. Thus, the adult arteries did not respond to increased blood flow produced by the anastomosis, but this procedure did reverse adaptations to decreased flow. In contrast, immature arteries were responsive to this increase in blood flow, even in the absence of prior flow modulation.Key words: arterial remodeling, shear stress, rabbits, arterial development.
Contribution of erythrocytes to the control of the electrolyte changes of exercise
Authors: McKelvie R. S. , Lindinger M. I. , Heigenhauser G. J.F. , Jones N. L.
Published: April 2011

Five healthy males performed four 30-s bouts of maximal isokinetic cycling with 4 min rest between each bout. Arterial and femoral venous blood was sampled during and for 90 min following exercise. During exercise, arterial erythrocyte [K+] increased from 117.0 ± 6.6 mequiv./L at rest to 124.2 ± 5.9 mequiv./L after the second exercise bout. Arterial erythrocyte [K+] returned to the resting values during the first 5 min of recovery. No significant change was observed in femoral venous erythrocyte [K+]. Arterial erythrocyte lactate concentration ([Lac−]) increased during exercise from 0.2 ± 0.1 mequiv./L peaking at 9.5 ± 1.5 mequiv./L at 5 min of recovery, after which the values returned to control. Femoral venous erythrocyte [Lac−] changed in a similar fashion. Arterial erythrocyte [Cl−] rose during exercise to 76 ± 3 mequiv./L and returned to resting values (70 ± 2 mequiv./L) by 25 min recovery. During exercise there was a net flux of Cl− into the erythrocyte. We conclude that erythrocytes are a sink for K+ ions leaving working muscles. Furthermore, erythrocytes function to transport Lac− from working muscle and reduce plasma acidosis by uptake of Cl−. The erythrocyte uptake of K+, Lac−, and Cl− helps to maintain a concentration difference between plasma and muscle, facilitating diffusion of Lac− and K+ from the interstitial space into femoral venous plasma.Key words: isokinetic cycle ergometer, ion movement, hydrogen ion, cell volume, arterial blood.
GABA: history and perspectives
Authors: Florey Ernst
Published: April 2011

In 1957, factor I, a brain agent I had discovered earlier, was chemically identified as GABA in a collaboration between myself and Alva Bazemore at the Montréal Neurological Institute (MNI) in the Neurochemistry Laboratory then headed by K. A. C. Elliott. A personally biased excursion into the history of neurobiology illuminates the development of methods and concepts that led to this event, and recounts the early days at the MNI, when Hugh McLennan and I applied factor I to the exposed surface of the spinal cord and to sympathetic ganglia of cats and rabbits. It also tells of earlier studies at Graz, Naples, and elsewhere that prompted the experiments at the California Institute of Technology in which factor I was discovered as the agent in nerve extracts causing inhibition of isolated crayfish stretch receptor neurons, and in which it was found that this inhibition could be prevented by picrotoxin. There was justified doubt that GABA is indeed the transmitter substance of inhibitory neurones. Later studies, however, resolved the controversy. The functional role of GABA in brain and spinal cord and its mechanism of action are still far from being fully understood. Special problems are the extent and significance of spontaneous quantal and nonquantal release, the functional role and the mechanism of excitatory actions of GABA, its release from glial cells, and the energetics of its metabolic turnover.Key words: factor I, GABA, glia, convulsants, inhibition.
Some chemical highlights in the development of excitatory amino acid pharmacology
Authors: Watkins J. C.
Published: April 2011

Important findings in the excitatory amino acid (EAA) field that have stemmed directly from work initiated in chemical laboratories are discussed from a historical point of view, showing how each has contributed to our present knowledge of EAA receptors. The groups of compounds discussed include simple analogues and derivatives of short-chain excitatory amino acids, longer-chain analogues, analogues containing ring structures essential to the acidic nature of the ω-terminal, and conformationally restricted agonists and antagonists. Recent interest has centred on antagonists for the N-methyl-D-aspartate (NMDA) and α-methyl-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors typified by the long-chain ω-phosphono amino acids and the quinoxalinediones, respectively. Consideration of conformational aspects of both agonists and antagonists is currently providing considerable insight into the disposition of charged sites and general topological features in the various receptors, as well as the likely conformation adopted by L-glutamate in its physiological interaction with these receptors.Key words: excitatory amino acid receptors, historical development, structure–activity relations, NMDA receptors, AMPA receptors, kainate receptors.
Interactions between endothelin and atrial natriuretic factor in the rat aortic ring preparation
Authors: Bolger Gordon , Liard Francine , Krogsrud Richard , Welchner Ewald , Jaramillo Jorge
Published: April 2011

The potential interaction (s) between atrial natriuretic factor (ANF) and porcine–human endothelin (ET-1) was investigated in the endothelium-denuded rat aortic ring preparation. ET-1 produced a sustained contraction of aortic rings with an ED50 of 3.6 ± 0.49 × 10−9 M. Within the concentration range of 10−9 to 10−7 M, both rat ANF 103–126 and rat ANF 99–126 when preincubated with tissues reduced the contractile efficacy of ET-1 especially at low concentrations resulting in a small but significant rightward shift of the dose–response curve to ET-1. In contrast, at a concentration of 10−10 M, rANF 99–126 but not rANF 103–126 produced a significant leftward shift of the dose–response curve to ET-1 and an increase in the maximal developed tension for the dose–response curve to ET-1. For tissues incubated in the absence of extracellular calcium or in the presence of the calcium channel blocker nifedipine (5 × 10−7 M), both ANF derivatives produced a dose-dependent decrease in the maximum contraction, but no change in potency to ET-1. Addition of either rANF 103–126 or rANF 99–126 to tissues maximally contracted with ET-1 resulted in relaxation, reaching a maximum of 70%. The ED50 values for relaxation were 2.7 ± 0.51 × 10−8 and 3.5 ± 0.60 ± 10−8 M for rANF 103–126 and rANF 99–126, respectively. ET-1 did not interact with biologically responsive and clearance receptors for ANF. These results suggest that the major circulating form of ANF may act as a physiologic antagonist of endogenous ET-1 primarily affecting the intracellular calcium-dependent component of contraction to ET-1.Key words: endothelin, atrial natriuretic factor, rat aortic ring, contraction, relaxation.
Inhibitory effects of tetramethyl and tetraethyl derivatives of pyrazine on dog saphenous vein
Authors: Wang Z. L. , Kwan C. Y. , Ohta A. , Chen M. C.
Published: April 2011

The effects of two structurally similar pyrazine derivatives, tetramethylpyrazine (TMP) and tetraethylpyrazine (TEP) on the contractile responses of dog saphenous vein to KCl (via membrane depolarization), phenylephrine (PHE, α1-adrenergic agonist), and B-HT 920 (α2-adrenergic agonist) were investigated. The relaxant or inhibitory effect of TMP and TEP was most potent on KCl-induced responses and least potent on PHE-induced responses. Their effect on KCl-induced responses was more prominent at 30 mM KCl than at 100 mM KCl. In Ca2+-free medium, PHE and B-HT 920 elicited transient responses, which were also markedly and reversibly inhibited by TMP and TEP. Similar results were also obtained when prostaglandin F2α was used as an agonist. In all four types of contractile responses involving different receptors, the inhibitory effect of TEP was consistently more potent than that of TMP. We conclude that both TMP and TEP behave as a nonselective smooth muscle relaxant having similar and multiple actions including their general interference with the processes involving both Ca2+ entry and intracellular Ca2+ release.Key words: vascular smooth muscle, calcium channels, tetramethylpyrazine, tetraethylpyrazine, α-adrenoceptors, saphenous vein.
Effects of the R(+)- and S(−)-isomers of β-adrenoceptor blockers with intrinsic sympathomimetic activity, befunolol and carteolol, on rabbit intraocular pressure
Authors: Takayanagi Issei , Hagiwara Hisashi , Koike Katsuo , Hosokawa Tomokazu , Kasuya Yutaka
Published: April 2011

Effects of the R(+)- and S(−)-isomers of befunolol and carteolol, β-adrenoceptors with intrinsic sympathomimetic activity, on the rabbit intraocular pressure were tested. The intraocular pressure was decreased by instillation of the R(+)- and S(−)-isomers of befunolol (0.1 and 0.3%) and of carteolol (1.0%) to the eye and attained the minimum level at 60 min. However, 0.3% of the R(+)- and S(−)-isomers of carteolol did not influence the pressure. The corresponding time courses for the intraocular pressure for the R(+)- and S(−)-isomers did not differ, suggesting that in the treatment of glaucoma, the therapeutic advantage of the R(+)-isomers of befunolol and carteolol may be similar to the S(−)-isomers.Key words: intraocular pressure, β-adrenoceptor blockade, R(+)-isomer, stereoselectivity.
Nitric oxide may be the final mediator of nonadrenergic, noncholinergic inhibitory junction potentials in the gut
Authors: Christinck Frank , Jury Jennifer , Cayabyab Francisco , Daniel E. E.
Published: April 2011

This study tested the hypothesis that the final mediator of nonadrenergic, noncholinergic (NANC) inhibitory junction potentials (ijps) and associated relaxation responses was nitric oxide (NO) or a related substance and not vasoactive intestinal polypeptide (VIP). We used opossum esophagus body circular muscle and canine intestine circular muscle. In both these tissues, ijps had reversal potentials near the potassium equilibrium potential, (EK); in esophagus the ijps were apamin insensitive, but in the intestine they were partially apamin sensitive. Nω-Nitro-L-arginine methyl ester (NAME) (10−5 to 5 × 10−4 M) abolished ijps in both tissues, an effect overcome by 10−3 M L-arginine but not D-arginine. NAME increased input resistance of esophagus tissues in the double sucrose gap but caused no significant depolarization in the sucrose gap or in studies with microelectrodes. Contractions and basal tension were increased in both tissues by NAME. The apamin sensitive and insensitive ijp components in canine muscle were both abolished by NAME, but the time course of this abolition was different for the two components. Methylene blue (10–50 μM) with variable rapidity and extent inhibited ijps in both tissues, but L-arginine could not overcome this effect. Methylene blue, like NAME, did not depolarize detectably but enhanced the contractile activity. VIP (10−6 M) had very small effects in both tissues, little or no hyperpolarization and increased input resistance in esophagus, these effects were not changed by NAME, and VIP did not affect ijps. We conclude that NO may be the final mediator of NANC-initiated inhibitory junction potentials in gastrointestinal circular smooth muscle.Key words: nitric oxide, nonadrenergic noncholinergic inhibitory mediator, vasoactive intestinal polypeptide, esophagus, intestine.
A decade of atrial natriuretic factor research
Authors: Bold Adolfo J. de , Bold Mercedes L. Kuroski-de , Boer Poppo H. , Dubé Gilles , Mangat Harman , Johnson Frank
Published: April 2011

Present views on the biological significance of atrial natriuretic factor (ANF) relate this polypeptide hormone to the regulation of blood pressure and volume through its modulating effects on renal function, on blood vessel tone and permeability, and on the renin–angiotensin–aldosterone system. Although very important advances in the understanding of ANF have been made over the decade since its discovery, some fundamental facts about ANF biosynthesis and release remain to be elucidated. Stretch-induced enhancement of ANF release appears as the most significant mechanism underlying the endocrine response of the atria to acute volume load. This response decays over a period of minutes, indicating that chronic stimulation of ANF release involves mechanisms different from, or in addition to, those acting during acute stretch-stimulated release. In neither acute nor chronic conditions are the cellular or molecular mechanisms underlying ANF release understood. To better understand long-term stimulation of ANF release, we have conducted extensive in vitro testing of several hormones and neurotransmitters to determine their ability to modify ANF release. From these studies, clear-cut evidence of ANF stimulation was obtained with the vasopressor peptide endothelin. Investigations on the cell and molecular biology of cardiac muscle development and hypertrophy have shown that ANF is involved in cardiac growth. The role played by ANF in these processes is now being determined, but this is one line of evidence that suggests that this hormone, together with other natriuretic peptides, may have autocrine or paracrine functions. Ten years after the discovery of ANF, much remains to be learned not only about ANF biosynthesis but also about details of the interaction of this hormone with its many targets. Nevertheless, the work accomplished to date has produced an astonishingly large amount of new knowledge ranging from new concepts in cell and molecular biology to the development of new therapeutic strategies for the treatment of hypertension and congestive heart failure.Key words: atrial natriuretic peptide, atrial stretch, peptide hormone, tissue culture.
Cellular signals regulating the release of ANF
Authors: Ruskoaho Heikki , Kinnunen Päivi , Mäntymaa Pentti , Uusimaa Paavo , Taskinen Tarja , Vuolteenaho Olli , Leppäluoto Juhani
Published: April 2011

Atrial natriuretic factor (ANF), a peptide hormone that regulates salt and water balance and blood pressure, is synthesized, stored, and secreted from mammalian myocytes. Stretching of atrial myocytes stimulates ANF secretion, but the cellular processes involved in linking mechanical distension to ANF release are unknown. We reported that phorbol esters, which mimic the action of diacylglycerol by acting directly on protein kinase C and the Ca2+ ionophore A23187, which introduces free Ca2+ into the cell, both increase basal ANF secretion in the isolated perfused rat heart. Phorbol ester also increased responsiveness to Ca2+ channel agonists, such as Bay k8644, and to agents that increase cAMP, such as forskolin and membrane-permeable cAMP analogs. In neonatal cultured rat atrial myocytes, protein kinase C activation by 12-O-tetradecanoylphorbol 13-acetate stimulated ANF secretion, whereas the release was unresponsive to changes in intracellular Ca2+. Endothelin, which stimulates phospholipase C mediated hydrolysis of phosphoinositides and activates protein kinase C, increased both basal and atrial stretch-induced ANF secretion from isolated perfused rat hearts. Similarly, phorbol ester enhanced atrial stretch-stimulated ANF secretion, while the increase in intracellular Ca2+ appeared to be negatively coupled to the stretch-induced ANF release. Finally, phorbol ester stimulated ANF release from the severely hypertrophied ventricles of hypertensive animals but not from normal rat myocardium. These results suggest that the protein kinase C activity may play an important role in the regulation of basal ANF secretion both from atria and ventricular cells, and that stretch of atrial myocytes appears to be positively modulated by phorbol esters.Key words: hormone secretion, atrial stretch, protein kinase C, phosphoinositide hydrolysis, cellular calcium.
Renal tubular actions of ANF
Authors: Knepper Mark A. , Lankford Scott P. , Terada Yoshio
Published: April 2011

Many of the earliest investigations of the renal effects of atrial natriuretic factor (ANF) pointed to the glomerulus as a major site of the peptide's action. More recently, there have been many reports showing various effects of ANF on renal tubular epithelia, including collecting ducts, thick ascending limbs of Henle's loop, thin limbs of Henle's loops, and proximal tubules. The purpose of this review is to summarize the evidence for renal tubular actions of ANF and analyze it from the perspective of the specialized functions of the individual nephron segments, addressing the question: can renal tubule effects of ANF play a significant role in the precise day-to-day regulation of renal NaCl and water excretion? Based on these considerations, we propose that long-term renal tubular action of ANF may be distinct from its short-term natriuretic effect. The short-term action of ANF to accelerate salt and water excretion may play a role in the overall response to acute volume overload. This action of ANF appears to be largely due to an ANF-mediated increase in glomerular filtration rate accompanied by a blunting of the tubuloglomerular feedback mechanism, perhaps with some contribution from ANF-mediated inhibition of fluid absorption in the proximal tubule. In contrast, contributions of ANF to the precise day-to-day regulation of salt and water excretion are likely to be chiefly due to ANF-mediated inhibition of NaCl and water absorption in collecting ducts, but may also involve actions of ANF on the loop of Henle.Key words: collecting duct, thick ascending limb, proximal tubule, NaCl transport, water transport.
Truncated atrial natriuretic factor analogs retain full agonist activity
Authors: Holleman W. H. , Budzik G. P. , Devine E. M. , Pollock D. M. , Opgenorth T. J. , Thomas A. M. , Geldern T. W. von , Rockway T. W.
Published: April 2011

The synthesis, receptor binding, and agonist activity of a series of truncated atrial natriuretic analogs (ANF) are described. These analogs incorporate two portions of the native 28 amino peptide, the eight amino acids C-terminal to Cys7, and two amino acids from the C-terminus (phenylalanine and arginine), into disulfide-bonded cyclic peptides. The inclusion of the C-terminal amino acids converted the ANF analogs from receptor ligands to full agonists, as measured by several methods, including the stimulation of cGMP biosynthesis in endothelial cells, inhibition of aldosterone biosynthesis in rat adrenal cells, and natriuretic–hypotensive activity in vivo. The most potent analogs have cyclohexylalanine (Cha) at position 8. The lead compound (Arg6,Cha8 ANF 6–15 Phe-Arg-Cys-NH2) is a tridecapeptide that integrates the C-terminal amino acids inside the disulfide ring. This peptide, designated as A-68828, has a binding affinity of IC50 = 120 nM, approximately 1/400 of ANF 1–28. However, this analog, in vivo, is only slightly less natriuretic (1/20–1/50) than ANF 1–28. Unlike the native peptide, A-68828 is only mildly hypotensive and at the highest concentration tested reduced blood pressure less than 15 mmHg (1 mmHg = 133.322 Pa). A-68828 inhibited ACTH-induced aldosterone release to a greater extent than ANF 1–28: 100 vs. 50%. The selective natriuretic activity of A-66828, relative to ANF, suggests clinical utility for the treatment of acute renal failure.Key words: atrial natriuretic factor, renal failure, dopamine, peptide analogs, cGMP.
The 1990 Borden Award Lecture Dietary regulation of fatty acid and triglyceride metabolism
Authors: Herzberg Gene R.
Published: April 2011

The level of circulating triacylglycerols is determined by the balance between their delivery into the plasma and their removal from it. Plasma triacylglycerols are derived either from dietary fat as chylomicrons or from endogenous hepatic synthesis as very low density lipoproteins. Their removal occurs through the action of lipoprotein lipase after which the fatty acids are either stored in adipose tissue or oxidized, primarily in skeletal muscle and heart. The composition of the diet has been shown to influence many of these processes. Hepatic fatty acid synthesis and triacylglycerol secretion are affected by the quantity and composition of dietary fat, carbohydrate, and protein. Polyunsaturated but not saturated fats reduce hepatic fatty acid synthesis by decreasing the amount of the lipogenic enzymes needed for de novo fatty acid synthesis. Dietary fish oils are particularly effective at reducing both fatty acid synthesis and triacylglycerol secretion and as a result are hypotriacylglycerolemic, particularly in hypertriacylglycerolemic individuals. In addition, dietary fish oils can increase the oxidation of fatty acids and lead to increased activity of lipoprotein lipase in skeletal muscle and heart. It appears that the hypotriacylglycerolemic effect of dietary fish oils is mediated by effects on both synthesis and removal of circulating triacylglycerols.Key words: lipid, fish oil, fructose, liver, adipose tissue, oxidation.
The effect of partial denervation of tibialis anterior (TA) muscle on the number and sizes of motorneurons in TA motornucleus of normal and dystrophic (C57BL dy2j/dy2j) mice
Authors: Tissenbaum H. A. , Parry D. J.
Published: April 2011

The tibialis anterior (TA) muscle in one leg of normal (C57BL) and dystrophic (dy2j) mice was partially denervated by resection of a part of the lateral popliteal nerve. Two months later the muscle was injected with horseradish peroxidase to permit visualization of the motorneurons that survived. Partial denervation in both C57 and dy2j mice resulted in reduction of the number of motorneurons that supplied the muscle to approximately one-half the normal complement. The surviving motorneurons were found to be significantly larger (about 25%) than their contralateral counterparts. This condition persisted up to 18 months and is not considered to be a transient response to the trauma associated with the partial denervation. When the size of the target tissue was also reduced by extirpation of one-half of TA together with partial denervation, motorneuron size was not found to increase. It is suggested that the increase in size is a response to the metabolic demands placed upon the motorneuron by an increase in the size of the motor unit.Key words: mouse, tibialis anterior muscle, partial denervation, motorneuron size.
Changes in the myocardial area at risk, infarct size, and collateral flow following nicardipine infusion in dogs
Authors: Sandhu Reena , Biro George P.
Published: April 2011

The area at risk of infarction after an acute occlusion of the left anterior descending coronary artery was defined in anesthetized dogs using the distribution of 99mTc-labelled albumin microaggregates and Monastral blue dye. In thirteen dogs, it was determined that these two particulate labels identified identical areas of unperfused myocardium. In a second group of dogs (n = 12), the risk areas determined at 10 (99mTc-labelled macroaggregates) and at 180 min (Monastral blue dye) were found to be identical, with no change in collateral blood flow, indicating the absence of a spontaneous change in underperfused myocardium over this time. In a third group of dogs (n = 17) nicardipine was infused (10 μg∙kg−1∙min−1 for 5 min, followed by 8 μg∙kg−1∙min−1 for 165 min). This resulted in a significant and sustained fall (32 ± 4 mmHg; 1 mmHg = 133.32 Pa) in mean arterial blood pressure but no significant change in collateral blood flow was found, except for a marginal increase in the center of the ischemic zone. Area at risk and infarct sizes were also not significantly different between the latter two groups (18.2 ± 4.1 vs. 21.6 ± 4.0% of left ventricle). In this model, the magnitude of the area at risk appears to be determined early after a coronary occlusion and appears to be unmodified by treatment with nicardipine begun after the occlusion.Key words: area at risk, nicardipine, collateral flow, risk region, risk zone, infarct size limitation.
Pharmacology of the leukotriene antagonist verlukast: The (R)-enantiomer of MK-571
Authors: Jones T. R. , Zamboni R. , Belley M. , Champion E. , Charette L. , Ford-Hutchinson A. W. , Gauthier J.-Y. , Leger S. , Lord A. , Masson P. , McFarlane C. S. , Metters K. M. , Pickett C. , Piechuta H. , Young R. N.
Published: April 2011

Verlukast (MK-679) (3-(((3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl)((3-(dimethylamino)-3-oxopropyl)thio)methyl)-thio)propionic acid) is a potent and selective inhibitor of [3H]leukotriene D4 binding in guinea-pig (IC50 = 3.1 ± 0.5 nM) and human (IC50 = 8.0 ± 3.0 nM) lung homogenates and dimethyl sulfoxide differentiated U937 cell membrane preparations (IC50 = 10.7 ± 1.6 nM) but is essentially inactive versus [3H]leukotriene C4 binding in guinea-pig lung homogenates (IC50 values of 19 and 33 μM). Functionally, when tested at 60 nM, it antagonized contractions of guinea-pig trachea (GPT) induced by leukotriene C4, leukotriene D4, and leukotriene E4 (respective −log KB values of 8.6, 8.8, and 8.9) and contractions of human trachea (HT) induced by leukotriene D4 (−log KB value 8.3 ± 0.2). In contrast, verlukast (20–200 nM) failed to antagonize contractions of GPT induced by leukotriene C4 in the presence of 45 mM L-serine borate. Intravenous (i.v.) and aerosol verlukast antagonized bronchoconstriction (BC) induced in anaesthetized guinea pigs by i.v. leukotriene D4 but did not block BC to arachidonic acid or histamine. Intraduodenal verlukast (0.25 mg/kg) antagonized leukotriene D4 (0.2 μg/kg) induced BC in guinea pigs. Oral and aerosol administration blocked leukotriene D4-induced BC in conscious squirrel monkeys. Orally administered compound also blocked ovalbumin-induced BC in conscious sensitized rats treated with methysergide (3 μg/kg). The pharmacological profile for verlukast is similar to that of the racemic compound, MK-571. Verlukast is currently in clinical development for the treatment of asthma and related diseases.Key words: verlukast, MK-679, leukotriene D4 antagonist, airway smooth muscle.
Inhibition of glucose metabolism by progesterone in adipocytes: role of protein synthesis
Authors: Cordoba P. , Kaaya A. , Richard O. , Sutter-Dub M.-Th.
Published: April 2011

Progesterone decreases [1-14C]glucose oxidation in isolated female rat adipocytes within 20 min of incubation. Because steroids regulate transcription mechanisms, the relationship between protein synthesis and glucose metabolism was studied in the presence of progesterone. Actinomycin D does not affect basal glucose oxidation or the progesterone effects on it; cycloheximide and puromycin decrease basal glucose oxidation, but only puromycin decreases the inhibitory progesterone effect. Although puromycin inhibits glucose transport, the common site of action of puromycin and progesterone does not seem to be glucose transport, which, as we showed previously, is not modified by the steroid. Incorporation of [3H]leucine into acid-precipitable proteins is decreased by puromycin and cycloheximide but not by actinomycin D or progesterone; moreover, the action of these inhibitors does not change in the presence of the steroid. As shown by electrophoresis (SDS–PAGE) and autoradiography, L-leucine is incorporated into adipocyte proteins as early as 20 min and progesterone increases this incorporation into five proteins. Leucine is a ketogenic amino acid that is also incorporated into lipids; progesterone depresses L-leucine incorporation into fatty acids by a glucose-dependent mechanism. These results suggest that the inhibitory effect of progesterone on glucose metabolism is related to an enhanced protein synthesis counterbalanced by decreased fatty acid synthesis.Key words: adipocytes, glucose metabolism, progesterone, protein synthesis, gel autoradiography.
Time-dependent potentiation of contractile response to norepinephrine in canine isolated cerebral arteries
Authors: Kawai Yasuaki , Yokoyama Shin , Ohhashi Toshio
Published: April 2011

The time course of contractile responses to α-adrenoceptor agonists was investigated using various arteries isolated from dogs and monkeys. The contractile response to norepinephrine was increased during the time course of the experiment in canine basilar and internal carotid arteries, whereas the response of isolated canine external carotid arteries and monkey internal carotid arteries did not change significantly. Treatment with 10−7 M propranolol, 5 × 10−6 M cocaine plus 10−5 M hydrocortisone, or 5 × 10−5 M acetylsalicylic acid did not significantly affect the time-dependent potentiation of the norepinephrine-induced contraction in canine internal carotid arteries. The time-dependent enhancement in the response to norepinephrine was also observed in the arterial preparations from which the endothelial cells were removed. The contractile response of canine internal carotid arteries to phenylephrine did not alter significantly throughout the experiments. On the other hand, the responses to clonidine and xylazine were markedly enhanced with time. Significant potentiation of the norepinephrine-induced contraction was observed in canine internal carotid arteries treated with 10−8 M prazosin, whereas 10−8 M yohimbine attenuated the time-dependent potentiation. These results suggest that the contractile responses of isolated canine basilar and internal carotid arteries to norepinephrine are potentiated during the course of the experiment, which is likely to be related, in part, to an enhancement in α2-adrenoceptor mediated contraction.Key words: α2-adrenoceptor, dog, cerebral artery, enhancement of contraction, vascular smooth muscle.
Vasodilative and anti-adrenergic effects of adenosine in diabetic rat hearts
Authors: Warner Eve L. , Galasso Franco , Thompson Carl I. , Belloni Francis L.
Published: April 2011

To determine the vasodilative and negative inotropic effects of adenosine in hearts of diabetic rats, isolated hearts, perfused at constant perfusion pressure (Langendorff technique), were prepared from age-matched control Wistar rats and rats made diabetic 10 weeks prior to study by a single injection of streptozotocin (65 mg∙kg−1, i.p.). Adenosine and nitroprusside each increased coronary inflow when administered either as bolus injections or as infusions. Coronary flow responses to nitroprusside were unchanged in diabetic hearts. Coronary flow responses of diabetic hearts to adenosine injections were unchanged, but responses to adenosine infusions tended to be larger than in normal hearts. Diabetes had no significant effect on the EC50 for either vasodilator. Adenosine inhibited the inotropic effect of isoproterenol (enhanced left ventricular (LV) pressure (P) and LV dP/dtmax) in normal hearts, independently of its vasodilative action. This negative inotropic action of adenosine appeared equally strong in diabetic hearts. We conclude that adenosine's coronary vasodilative and anti-β-adrenergic, negative inotropic effects in the rat heart were not diminished after 10 weeks of streptozotocin-induced diabetes mellitus. Thus, earlier reports of diminished adenosine dilative efficacy in experimental diabetes may have been unique to those particular models.Key words: experimental diabetes mellitus, coronary, adenosine, isoproterenol, myocardial contraction.
Cysteamine in combination with N-acetylcysteine prevents acetaminophen-induced hepatotoxicity
Authors: Peterson Theresa C. , Brown Ian R.
Published: April 2011

N-Acetylcysteine (NAC) is protective against acetaminophen-induced hepatotoxicity primarily by providing precursor for the glutathione synthetase pathway, while cysteamine has been demonstrated to alter the cytochrome P-450 dependent formation of toxic acetaminophen metabolite. Mice administered acetaminophen (500 mg/kg) had elevations of serum alanine aminotransferase (ALT) to 273.0 ± 37.5 and 555.8 ± 193.4 U/mL at 12 and 24 h, respectively, after injection. Administration of cysteamine (100 mg/kg) or NAC (500 mg/kg) significantly reduced serum ALT activity (p < 0.001). Reducing the dose of NAC or cysteamine by 50% greatly reduced their hepatoprotective effect while the co-administration of the reduced doses of NAC (250 mg/kg) and cysteamine (50 mg/kg) following acetaminophen overdose prevented elevation of serum ALT activity (39.2 ± 1.17 and 32.5 ± 5.63 U/mL at 12 and 24 h post-injection, p < 0.001) and preserved normal mouse hepatic histology. Neither NAC (500 mg/kg), cysteamine (100 mg/kg), or the lower doses in combination of both agents were found to alter the half-life or peak levels of acetaminophen. Liver microsomal aryl hydrocarbon hydroxylase activity measured 24 h after drug administration was not significantly different between treatment groups and controls receiving only saline. These results indicate a possible role for the concomitant use of NAC and cysteamine in the prevention of hepatic necrosis following toxic doses of acetaminophen. Neither decrease in plasma acetaminophen levels nor depression of cytochrome P-450 enzyme activity appears to be the mechanism of protection when these doses of NAC, cysteamine, or both drugs together are administered with a toxic dose of acetaminophen in mice.Key words: cysteamine, N-acetylcysteine, acetaminophen, hepatotoxicity, hepatoprotection.
Prostaglandin E2 receptors in the heart are coupled to inhibition of adenylyl cyclase via a pertussis toxin sensitive G protein
Authors: Lerner Richard W. , Lopaschuk Gary D. , Olley Peter M.
Published: April 2011

In previous studies we have identified and isolated a prostaglandin E2 (PGE2) receptor from cardiac sarcolemmal (SL) membranes. Binding of PGE2 to this receptor in permeabilized SL vesicles inhibits adenylyl cyclase activity. The purpose of this study was to determine if the cardiac PGE2 receptor is coupled to adenylyl cyclase via a pertussis toxin sensitive guanine nucleotide binding inhibitory (Gi) protein. Incubation of permeabilized SL vesicles in the presence of 100 μM 5′-guanylamidiophosphate, Gpp(NH)p, a nonhydrolyzable analogue of GTP, resulted in a shift in [3H]PGE2 binding from two sites, one of high affinity (KD = 0.018 ± 0.003 nM) comprising 7.7% of the total available binding sites and one of lower affinity (KD = 1.9 ± 0.7 nM) to one site of intermediate affinity (KD = 0.52 ± 0.01 nM) without a significant change in the total number of PGE2 binding sites. A shift from two binding sites to one binding site in the presence of Gpp(NH)p was also observed for [3H]dihydroalprenolol binding to permeabilized cardiac SL. When permeabilized SL vesicles were pretreated with activated pertussis toxin, ADP-ribosylation of a 40- to 41-kDa protein corresponding to Gi was observed. ADP-ribosylation of SL resulted in a shift in [3H]PGE2 binding to one site of intermediate affinity without significantly changing the number of binding sites. In alamethicin permeabilized SL vesicles, 1 nM PGE2 significantly decreased (30%) adenylyl cyclase activity. Pretreatment with activated pertussis toxin overcame the inhibitory effects of PGE2. These results demonstrate that the cardiac PGE2 receptor is coupled to adenylyl cyclase via a pertussis toxin sensitive Gi protein. They also demonstrate that the interaction of this Gi protein with the PGE2 receptor is important in the regulation of PGE2 binding to its receptor.Key words: prostaglandin E2, sarcolemma, heart, adenylyl cyclase, G protein.
The 1991 Borden Award Lecture. Selected aspects of intraluminal and intracellular phases of intestinal fat absorption
Authors: Levy Emile
Published: April 2011

The recognition of chylomicrons as dietary lipid transporters dates back to more than 70 years and marks a milestone in lipoprotein history. Conventionally, three phases constitute the process of absorption of exogenous fat: intraluminal, intestinal, and delivery. The intraluminal phase includes chemical hydrolysis by lipolytic enzymes and the micellar solubilization of lipolytic products by bile acids. The intestinal phase comprises the diffusion of micelles through the unstirred water layer, passive diffusion across the microvillous membrane of the enterocyte, and the formation of lipid-carrying lipoproteins. The delivery phase involves the exocytosis of chylomicrons from the absorptive cells and their subsequent removal by lymphatic structures and the systemic circulation. The precise steps and factors involved in all phases of chylomicron synthesis are not yet known, but both experimental and clinical studies have been helpful. Of the inborn metabolic disorders, the prerequisite function of apolipoprotein (apo B) for the assembly and release of lipoprotein particles stood out. Moreover, evidence emerged that the enterocyte produces apo B-100 in addition to apo B-48. Calcium and essential fatty acid status originates as determinants for triglyceride-rich particle synthesis. Furthermore, the developmental changes and regulatory factors of lipoprotein elaboration represent excellent tools in the study of the intracellular mechanisms of lipid transport.Key words: intestinal fat absorption, chylomicron, lipoproteins and apoproteins, ontogeny, essential fatty acid deficiency, calcium.
Glycogen consumption in hypoxic rat cardiomyocytes
Authors: Myrmel Truls , Larsen Terje S.
Published: April 2011

Glycogen consumption was investigated in isolated adult rat myocytes incubated for 2 h (37 °C) in substrate-free, hypoxic Krebs–Henseleit bicarbonate buffer. No consumption of glycogen occurred after 1 h of incubation, and the residual glycogen after 2 h was 23% despite an 89% reduction of the initial ATP content (from 27.1 ± 1.8 to 3.1 ± 0.5 nmol/mg dry weight, n = 12). The residual glycogen was not due to lactate inhibition of glycolytic enzymes, since myocytes incubated in the presence of 5 mM glucose maintained high energy phosphates throughout the incubation period despite a considerable lactate accumulation (1740 ± 43 nmol/mg dry weight in glucose-supplemented vs. 138 ± 14 nmol/mg dry weight in substrate-free incubations, n = 12). We have previously shown that the content of cyclic AMP in myocytes is not altered in response to hypoxia, thereby excluding activation of glycogen phosphorylase a. In the present study, the fall in myocyte ATP content was not followed by a rise in AMP, possibly preventing allosteric activation of glycogen phosphorylase b. However, addition of cyanide to the hypoxic incubations increased cellular AMP (initial level 2.1 ± 0.4 nmol/mg dry weight vs. 9.8 ± 0.7 after 30 min, n = 12) without increasing the amount of glycogen consumed, also ruling out the lack of glycogen phosphorylase b activation in the myocytes. Therefore, the glycogen rest was probably confined to the 17% of myocytes hypercontracted at the start of incubations.Key words: isolated adult rat cardiomyocytes, hypoxia, high energy phosphates, glycogen, lactate.
Daily variations in the sensitivity of proestrous LH surge in the inhibitory effect of intraventricular injection of 5-HT or GABA in rats
Authors: Morello H. , Caligaris L. , Haymal B. , Taleisnik S.
Published: April 2011

Intraventricular injection of 5-hydroxytryptamine (5-HT) into female rats at 11:00 h on the day of proestrus inhibited the preovulatory surge of luteinizing hormone (LH) and ovulation. A similar response was observed after the activation of the serotonergic system by stimulation of the median raphe nucleus. A diurnal rhythm of these responses was observed. In rats acclimated to a 14-h:10-h light: dark cycle the potency of 5-HT to inhibit the LH surge and ovulation was 2.06 and 2.3 times greater, respectively, when injected at 11:00 h than at 13:00 h. Also stimulation of the median raphe nucleus at 11:00 h was significantly more effective in inhibiting these parameters than stimulation at 13:00 h. Similarly, the ability of γ-aminobutyric acid (GABA) to inhibit the preovulatory LH surge and ovulation was greater in rats injected in the morning than in the afternoon. The results of this study indicate that during proestrus the sensitivity of 5-HT and GABA to induce inhibition of preovulatory LH release and ovulation shows daily variations with maximal effect before the critical period.Key words: serotonin, GABA, proestrous LH surge, ovulation, median raphe nucleus, daily rhythms.
Hypertensive structural changes in blood vessels: Do endothelial cells hold the key?
Authors: Todd Mary E.
Published: April 2011

In recent decades, the complexity of the endothelium and its major role in maintaining or altering blood vessel architecture are being revealed. In contrast, the vascular smooth muscle cell previously received the most attention. I suggest support of the hypothesis that the endothelium is the key to vascular disease. An altered endothelium in diabetes mellitus likewise is likely to be pivotal in vascular complications that develop. We have demonstrated that adherent monocytes, indicators of altered endothelium, occur in deoxycorticosterone acetate induced hypertension in male Wistar rats. The coronary artery and thoracic aorta were investigated using transmission electron microscopy. Details of hypertensive changes were revealed as well as early atherogenic pathology in the absence of dietary modifications. Scanning electron microscopy of thoracic aorta showed details of the luminal endothelial surface and adherent monocyte–macrophages in hypertensive animals. There were two cell types: numerous typical monocytes with upstream tails, and larger cells that may have been free grazing macrophages or macrophages that had returned to the circulation. Debris and amorphous material were particularly evident in vessels from hypertensive animals. Monocytes squeezed between intact endothelial plasma membranes (as seen in section), and were found as subendothelial foam cells and phagocytosing macrophages. The endothelial adherence of monocytes to the aortas from diabetic animals was significantly (p < 0.05) elevated over that found in controls (but not different from control–hypertensive or diabetic–hypertensive animals) supporting the concept of altered endothelium in diabetes.Key words: arteries, morphology, electron microscopy, hypertension, diabetes.