bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrophysiological effects of transient aortic occlusion in intact canine heart
Authors: Benditt D. G. , Kriett J. M. , Tobler H. G. , Gornick C. C. , Detloff B. L. , Anderson R. W.
Published: December 2017

This study utilized sonomicrometers transmural multipolar electrodes and cardiac electrical stimulation techniques to examine the effect on myocardial electrophysiological characteristics of altering ventricular systolic mechanical properties by transient aortic occlusion. Nine anesthetized open-chest dogs were atrially paced, and timed extrastimuli were inserted during alternate drive-train sequences at right or left ventricular (RV, LV) epicardial sites to measure ventricular effective refractory period (ERP). Sonomicrometer measurements of LV systolic mechanical parameters and both RV and LV electrophysiological findings were determined prior to and during periods of transient aortic occlusion. Aortic occlusion was applied just prior to the last beat of each eight-beat atrial drive train and released immediately following the programmed ventricular extrastimulus. Aortic occlusion increased LV systolic pressure (+42 +/- 26.6 mmHg, P less than 0.01) and diminished segmental stroke shortening (0.100 +/- 0.059 mm, P less than 0.02), shortening fraction (0.086 +/- 0.048, P less than 0.001), mean velocity of stroke shortening (0.444 +/- 0.186 mm/s, P less than 0.001), and stroke work (P less than 0.001). LV epicardial and endocardial ERP were prolonged as a result of aortic occlusion (5 +/- 7.2 and 6 +/- 6.5 ms, respectively, P less than 0.05), whereas RV ERP was unchanged. Latency of premature beats at equivalent coupling intervals was unaltered. ERP prolongation correlated most strongly with reductions of segmental stroke shortening (r = 0.928, P less than 0.001), shortening fraction (r = 0.901, P less than 0.001), and mean shortening velocity (r = 0.819, P less than 0.01). Thus transient aortic occlusion prolonged LV refractoriness, and electrophysiological changes closely paralleled the severity of systolic mechanical disturbance.
Lipolysis in isolated myocardial cells from diabetic rat hearts
Authors: Kenno K. A. , Severson D. L.
Published: December 2017

Diabetes in rats was induced with streptozotocin (100 mg/kg); myocardial cells (myocytes) were isolated from the hearts 3-4 days later. Diabetic myocytes were characterized as having the same viability and ATP content as control myocytes, but the yield was reduced. The triacylglycerol content of diabetic myocytes was elevated by 3.7-fold; this resulted in an increased rate of glycerol output during subsequent incubations. There was a stoichiometric relationship between the decline in the cellular triacylglycerol content and the release of glycerol into the incubation medium. Isoproterenol stimulated the output of glycerol from control myocytes by about twofold, but the stimulation of glycerol output from diabetic myocytes by isoproterenol was markedly less. The combination of 1-methyl-3-isobutylxanthine with isoproterenol or 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate also failed to produce the same lipolytic response in diabetic myocytes as in control myocytes. Triacylglycerol-loaded myocytes from control rats, prepared by including palmitate in the isolation buffers, were also characterized as having increased basal rates of glycerol output and a reduced lipolytic response to isoproterenol. The level of free fatty acids in diabetic myocytes was 2.8-fold greater than in myocytes from control hearts. The intracellular accumulation of free fatty acids in these quiescent populations of diabetic myocytes may limit the ability of catecholamines to produce a further stimulation of lipolysis.
Contrasting effects of vasopressin on baroreflex inhibition of lumbar sympathetic nerve activity
Authors: Sharabi F. M. , Guo G. B. , Abboud F. M. , Thames M. D. , Schmid P. G.
Published: December 2017

Baroreflex inhibition of lumbar sympathetic nerve activity (LSNA) during intravenous infusions of phenylephrine and vasopressin is contrasted in rats and rabbits. In rabbits, vasopressin caused smaller increases in arterial pressure and greater inhibition of LSNA than phenylephrine. In Sprague-Dawley rats, however, both vasopressin and phenylephrine caused equivalent increases in arterial pressure and reflex reductions in LSNA. The inhibition of LSNA was mediated through the arterial baroreceptors in both species because it was abolished by sinoaortic denervation. In rats, the possibility that a high level of endogenous vasopressin may have prevented the demonstration of a facilitated baroreflex with the infusion of exogenous vasopressin is unlikely since vasopressin also did not facilitate the reflex in Brattleboro rats, which lack circulating vasopressin. Further, Sprague-Dawley rats were responsive to exogenous vasopressin since infusion of increasing doses of vasopressin caused significant increases in urinary osmolality as well as progressive increments in arterial pressure. The results indicate that intravenous vasopressin given for a period of 6 min facilitates the reflex inhibition of LSNA mediated through arterial baroreceptors in rabbits, but not in rats. Vasopressin given for a period of up to 45 min to rats also fails to facilitate baroreflexes, emphasizing the difference from rabbits. In rabbits, this facilitation appears to involve a central mechanism.
Comparison of methods for measurement of interstitial fluid pressure in cat skin/subcutis and muscle
Authors: Wiig H.
Published: December 2017

Interstitial fluid pressure (IFP) in cats was measured with four techniques, i.e., hollow perforated and porous polyethylene capsules, wick in needle (WIN), and micropipettes. During control conditions, skin IFP of -1.5 +/- 0.4 (SD) mmHg (n = 53) was obtained with micropipettes, whereas pressures recorded in subcutis with perforated and porous capsules were -1.6 +/- 0.9 (n = 26) and -1.6 +/- 0.8 mmHg (n = 13), respectively. These were all significantly different from the -1.2 +/- 0.5 mmHg (n = 50) obtained in subcutis with WIN. In skeletal muscle, control IFP of -0.5, -0.5, and -1.1 mmHg was measured with micropipettes, WIN, and porous capsules, respectively. During peritoneal dialysis skin and muscle IFP recorded with micropipettes and WIN was reduced by 3-3.5 mmHg, whereas pressure in porous and perforated capsules fell by 7 and 10 mmHg, respectively. Intravenous Ringer infusion caused a marked transient rise in capsular pressures, not reflected by micropipettes and WIN, but similar pressures were obtained 210 min after infusion. In conclusion, all techniques reflect true IFP under steady-state conditions. Both capsules apparently act like osmometers in acute overhydration or dehydration and are, in addition, sensitive to pressure changes in local veins and are therefore not suitable for measurement of changes in IFP that take place in less than a few hours.
Cooling and alpha 1- and alpha 2-adrenergic responses in cutaneous veins: role of receptor reserve
Authors: Flavahan N. A. , Lindblad L. E. , Verbeuren T. J. , Shepherd J. T. , Vanhoutte P. M.
Published: December 2017

Experiments were designed to determine the effects of cooling on alpha 1- and alpha 2-adrenergic responses in isolated canine cutaneous veins. Rings of saphenous veins were suspended for isometric tension recording in physiological salt solution. Cooling (from 37 to 24 degrees C) augmented contractions to norepinephrine under control conditions and after alpha 1-adrenergic blockade (prazosin) but not following alpha 2-adrenergic blockade (rauwolscine). Cooling augmented contractions evoked by the alpha 2-adrenergic agonists B-HT 920 and UK 14304 but did not affect responses to the full alpha 1-adrenergic agonist phenylephrine. These experiments suggest that cooling augments alpha 2-adrenergic responsiveness without affecting alpha 1-adrenergic responsiveness. However, the contractions evoked by the partial alpha 1-adrenergic agonist St 587 were virtually abolished by cooling. Moreover, following partial irreversible blockade of the alpha 1-adrenoceptors with phenoxybenzamine, cooling also reduced the contractions evoked by phenylephrine. Therefore, cooling reduces alpha 1-adrenergic responsiveness in canine cutaneous veins, but in the case of full alpha 1-adrenergic agonists such as norepinephrine and phenylephrine the inhibitory effect of cooling is buffered by an alpha 1-adrenoceptor reserve. With norepinephrine, this permits the potentiating effect of cooling on the alpha 2-adrenergic component of the response to predominate.
Contribution of myocardial diffuse double-layer calcium to contractile function
Authors: Fintel M. , Langer G. A. , Rohloff J. C. , Jung M. E.
Published: December 2017

The role of diffuse double-layer calcium in cardiac excitation-contraction coupling was examined using rabbit interventricular septa, cultured neonatal rat myocardial cells, and gas-dissected sarcolemmal membranes. The diffuse double layer refers to the space directly adjacent to the sarcolemma where the ionic composition of the media is a direct function of the membrane surface potential. The divalent cation dimethonium was used as a specific probe for the diffuse double layer. According to Gouy-Chapman theory, replacement of sodium with sucrose should increase the amount of calcium located in this compartment. Dimethonium (10 mM) was found to decrease calcium uptake and contractility during low-sodium (33 mM) perfusion when the perfusate contained sucrose but not LiCl. Dimethonium did not decrease calcium uptake or contractility during control perfusion. The results suggest that calcium present in the myocardial diffuse double layer can be augmented or reduced in accordance with Gouy-Chapman theory. Changes in diffuse double-layer calcium are accompanied by small (7.8%) but significant changes in contractility.
Effects of divalent cation ionophore A23187 on cardiac contractile parameters
Authors: Murray J. J. , Dobson J. G. , Reed P. W.
Published: December 2017

The divalent cation ionophore A23187, when added to guinea pig papillary muscle, produced contractile effects that were similar to those produced by isoproterenol or histamine, but the ionophore's effects did not appear to result from the release of endogenous transmitters or prostaglandin production. Optimally effective concentrations of A23187 (6 microM) and isoproterenol (1 microM) more than doubled the peak contractile force and the rates of force development and relaxation and caused a 25% decrease in the duration of the contraction. Both A23187 and isoproterenol decreased the resting tension by approximately 0.15 g and significantly diminished the magnitude of a potassium-induced contracture. The positive inotropic effect of A23187 was prevented by incubating the tissue in calcium-depleted medium and antagonized by D 600, a blocker of sarcolemmal calcium influx, and acetylcholine. The contractile effects of A23187 appear to be related, in part, to its ability to increase the movement of calcium across the sarcolemma electroneutrally, since no change of the action potential occurred. In addition, possible intracellular actions of this ionophore may produce contractile effects that resemble those produced by isoproterenol and that reflect an increased sequestration of calcium within the myocardial cell.
Biochemical changes accompanying enhanced cardiac contractility by ionophore A23187
Authors: Murray J. J. , Reed P. W. , Dobson J. G.
Published: December 2017

We have reported that the divalent cation ionophore A23187, like the beta-adrenergic agonist isoproterenol, increased the force of contraction and rate of relaxation and shortened the duration of contraction of papillary muscles isolated from guinea pigs. A23187 produced a fall in resting tension and decreased the contracture tension of K +/- depolarized muscles, as did isoproterenol. In the present studies, isoproterenol produced a concentration-dependent, rapid, and sustained increase in the cyclic AMP (cAMP) content of papillary muscle. In contrast, A23187 had no detectable effect on cAMP levels, even in the presence of the phosphodiesterase inhibitor, papaverine. Neither drug, at concentrations maximal for contractile effects, altered cyclic GMP (cGMP). Isoproterenol increased the cAMP-dependent protein kinase activity ratio, whereas A23187 did not change the activity of this enzyme. However, both A23187 and isoproterenol produced a concentration-dependent increase in phosphorylase activity. Concentrations of A23187 or isoproterenol that enhanced contractility maximally increased the alkali-labile phosphate (by ca. 35%) but were without effect on the acid-labile, alkali-stable phosphate in the total acid precipitable protein. Contractile effects of isoproterenol, which reflect activated Ca2+ uptake, and the increase in phosphorylase activity produced by this agent are believed to be due to an increase in cAMP with subsequent activation of cAMP-dependent protein kinases and phosphorylation of proteins. A23187 may produce similar contractile effects without an increase in cAMP or cAMP-dependent protein kinase activity by activating other protein kinases and/or inhibiting phosphoprotein phosphatases, most likely by its effects on intracellular calcium.
Low concentrations of A23187 increase calcium uptake by cardiac sarcoplasmic reticulum
Authors: Murray J. J. , Kuzmin A. V. , Reed P. W. , Levitsky D. O.
Published: December 2017

The divalent cation ionophore A23187 at a concentration of 1 nM produced an increased rate of oxalate-supported calcium uptake by isolated cardiac sarcoplasmic reticulum as determined by absorbance changes of the calcium-sensitive dye murexide. Addition of a higher concentration of A23187 (0.1 microM) produced a decreased rate of calcium uptake. Measurement of the time during which ATPase was activated by calcium addition also suggested an increased rate of calcium uptake in the presence of 1 nM A23187 and an inhibition of calcium uptake at a higher concentration of the ionophore (0.1 microM). Ca2+-stimulated ATPase activity and incorporation of 32Pi from [gamma-32P]ATP into sarcoplasmic reticular proteins were increased by A23187 at concentrations of 1 nM or greater. An increased coupling of calcium uptake to ATP hydrolysis was observed at 1 nM A23187, while concentrations of the ionophore greater than or equal to 10 nM produced a decreased coupling. Addition of an inhibitor of cyclic AMP-dependent protein kinase decreased the rate of calcium uptake, and this inhibition was reversed in a concentration-dependent manner by 0.01–1 nM A23187. These data suggest that A23187 can activate a mechanism involving the calcium-dependent phosphorylation of protein that may regulate the activity of the calcium uptake system of the sarcoplasmic reticulum. These observations appear to provide an explanation for some of the contractile effects of A23187 in intact cardiac muscle that suggest that treatment with the ionophore results in an increased sequestration of calcium from the cytoplasm.
Defining the mechanical border zone: a study in the pig heart
Authors: Sakai Kikuo , Watanabe Kozo , Millard Ronald W.
Published: December 2017

Page H88: Kikuo Sakai, Kozo Watanabe, and Ronald W. Millard. “Defining the mechanical border zone: a study in the pig heart.” Page H94: the acknowledgments were omitted and are as follows.

We are grateful to Dr. Arnold Schwartz, Dept. of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, and Dr. Mootomi Nakamura, Angiocardiology and Cardiovascular Clinic, Kyushu University, Fukuoka, Japan, for their support and encouragement. The expert technical assistance of Victoria Rapien and John Erickson was invaluable.

This study was supported in part by Grant P01-HL-22619 from the National Heart, Lung, and Blood Institute.

Preliminary findings of this study were first reported at the Annual Scientific Session of the American Heart Association held at Anaheim, CA, November 1983. An abstract of this work has appeared ( Circulation 68, Suppl. III: 194, 1983).
Compartmented pyruvate in perfused working heart
Authors: Bünger Rolf
Published: December 2017

Page H439: Rolf Bünger. “Compartmented pyruvate in perfused working heart.” Page H445: Figure 4 should be turned 90°, with Time as the abscissa.
Multiple tracer dilution estimates of D- and 2-deoxy-D-glucose uptake by the heart
Authors: Kuikka J. , Levin M. , Bassingthwaighte J. B.
Published: December 2017

Permeability-surface area products of the capillary wall, PSc, and the myocyte sarcolemma, PSpc, for D-glucose and 2-deoxy-D-glucose were estimated via the multiple indicator-dilution technique in isolated blood-perfused dog and Tyrode-perfused rabbit hearts. Aortic bolus injections contained 131I-albumin (intravascular reference), two of three glucoses: L-glucose (an extracellular reference solute), D-glucose, and 2-deoxy-D-glucose. Outflow dilution curves were sampled for 1-2.5 min without recirculation. The long duration sampling allowed accurate evaluation of PSpc by fitting the dilution curves with a multiregional axially distributed capillary-interstitial fluid-cell model accounting for the heterogeneity of regional flows (measured using microspheres and total heart sectioning). With average blood flow of 1.3 ml . g-1 . min-1, in the dog hearts the PSc for D-glucose was 0.72 +/- 0.17 ml . g-1 . min-1 (mean +/- SD; n = 11), and PSpc was 0.57 +/- 0.15 ml . g-1 . min-1. In the rabbit hearts with perfusate flow of 2.0 ml . g-1 . min-1 (n = 6), PSc was 1.2 +/- 0.1 and PSpc was 0.4 +/- 0.1 ml . g-1 . min-1. PSc for 2-deoxy-D-glucose was about 4% higher than for D-glucose and L-glucose in both preparations. Relative to L-glucose, there was no measurable transendothelial transport of either dextroglucose, indicating that transcapillary transport was by passive diffusion, presumably via the clefts between cells. The technique allows repeated measurements of D-glucose uptake at intervals of a few minutes; it may therefore be used to assess changes in transport rates occurring over intervals of several minutes.
Neurohumoral contributions to chronic angiotensin-induced hypertension
Authors: Bruner C. A. , Fink G. D.
Published: December 2017

A central pressor effect of angiotensin II (ANG II) has been implicated in the pathogenesis of several forms of experimental hypertension. Therefore, the present studies were designed to investigate mechanisms that contribute to hypertension resulting from selective stimulation of brain ANG II receptors by chronic intracerebroventricular (ICV) infusion of ANG II. Specifically, the role of the sympathetic nervous system, the pressor actions of vasopressin, and the direct vasoconstrictor effect of blood-borne ANG II were investigated in rats made hypertensive by 5- to 7-day ICV ANG II infusions (6 micrograms/h). Rats were chronically instrumented with indwelling arterial and venous catheters and a lateral cerebral ventricular cannula. Acute intravenous infusion of the competitive ANG II receptor antagonist [Sar1-Ala8]ANG II during the period of ICV ANG II infusion resulted in a moderate decrease in arterial pressure, indicating that an increase in blood-borne ANG II may account for a small component of the hypertensive response to ICV ANG II. Activation of the sympathetic nervous system appeared to be the major contributor to the elevated arterial pressure, since acute ganglionic blockade and combined alpha- and beta-adrenergic blockade produced greater depressor responses in rats made hypertensive with chronic ICV ANG II infusion than in normotensive rats. Furthermore, peripheral sympathectomy delayed hypertension development. Intravenous administration of a specific antagonist of the vascular vasopressin receptor did not cause a depressor response in rats made hypertensive with chronic ICV ANG II infusions. These studies demonstrate that a major mechanism involved in the pressor response to acute ICV ANG II injections, namely vasopressin release, does not appear to contribute to hypertension produced by chronic ICV infusions of ANG II. Rather, this form of hypertension is characterized predominantly by an increase in sympathetic vasoconstrictor tone and possibly by a mechanism activated by a small increase in circulating levels of ANG II.
Augmented catecholamine uptake by the heart during hemorrhage in the conscious dog
Authors: Woodman O. L. , Amano J. , Hintze T. H. , Vatner S. F.
Published: December 2017

Changes in arterial and coronary sinus concentrations of norepinephrine (NE) and epinephrine (E) in response to hemorrhage were examined in conscious dogs. Hemorrhage (45 +/- 3.2 ml/kg) decreased mean arterial pressure by 47 +/- 6%, left ventricular (LV) dP/dt by 38 +/- 6%, and mean left circumflex coronary blood flow by 47 +/- 6%, while heart rate increased by 44 +/- 13%. Increases in concentrations of arterial NE (5,050 +/- 1,080 from 190 +/- 20 pg/ml) and E (12,700 +/- 3,280 from 110 +/- 20 pg/ml) were far greater than increases in coronary sinus NE (1,700 +/- 780 from 270 +/- 50 pg/ml) and E (4,300 +/- 2,590 from 90 +/- 10 pg/ml). Net release of NE from the heart at rest was converted to a fractional extraction of 66 +/- 9% after hemorrhage. Fractional extraction of E increased from 16 +/- 6% at rest to 73 +/- 8% after hemorrhage. In cardiac-denervated dogs, hemorrhage (46 +/- 2.8 ml/kg) decreased mean arterial pressure by 39 +/- 15%, LV dP/dt by 36 +/- 10%, and mean left circumflex coronary blood flow by 36 +/- 13%, while heart rate increased by 24 +/- 10%. Hemorrhage increased arterial NE (1,740 +/- 150 from 210 +/- 30 pg/ml) and E (3,050 +/- 880 from 140 +/- 20 pg/ml) more than it increased coronary sinus NE (460 +/- 50 from 150 +/- 30 pg/ml) and E (660 +/- 160 from 90 +/- 20 pg/ml) but significantly less (P less than 0.05) than observed in intact dogs. These experiments indicate that hemorrhage, unlike exercise and sympathetic nerve stimulation, does not induce net overflow of NE from the heart.(ABSTRACT TRUNCATED AT 250 WORDS)
Stretch-dependent (myogenic) tone in rabbit ear resistance arteries
Authors: Hwa J. J. , Bevan J. A.
Published: December 2017

Rabbit ear resistance arteries are vessels with three to six layers of smooth muscle cells and an unstretched lumen diameter of 75-150 micron. Ring segments of these arteries, in response to mechanical stretch in vitro, developed a maintained tonic contraction. The stretch-dependent contraction achieved a plateau within 10-30 min. Smooth muscle relaxants, such as NaNO2 and papaverine, substitution of extracellular Ca2+ by subthreshold Ca2+ (25 microM), or exposure to the Ca2+ influx antagonist Mn2+ abolished the stretch-dependent tone. The extent of the tone was dependent on the level of the applied stretch and the extracellular Ca2+ concentration ( [Ca2+]o). The maximal tone developed at optimal stretch, and [Ca2+]o in the bath solution was 18.1 +/- 4.6% of the maximal contraction of the vessel to histamine. This level of tone is comparable to neurogenic tone developed in response to nerve stimulation within the physiological frequency range. The stretch-dependent tone is considered probably myogenic in origin, since it was present in arterial segments that had been chronically denervated by surgical sympathectomy, mechanically deprived of the endothelium, and multireceptor blocked (phenoxybenzamine, 10(-6) M). Our findings suggest first that the stretch-dependent tone is myogenic and may be similar to basal vascular tone arising from the stretch of arterial pressure and its changes in vivo. Second, the magnitude of myogenic tone is a function of the applied stretch and the [Ca2+]o. Finally, myogenic tone is important in the physiological regulation of arterial tone in the rabbit ear resistance arteries.
Acute aortic stenosis in the conscious dog: effects of inotropic state on heart rate
Authors: Zucker I. H. , Niebauer M. J. , Cornish K. G.
Published: December 2017

Effects of acute distension of the left ventricle on heart rate were studied in conscious, instrumented dogs. In intact dogs, increasing left ventricular (LV) systolic pressure by a maximum of 77.6 +/- 3.6 mmHg from a control of 123.1 +/- 3.6 and LV end-diastolic pressure by a maximum of 24.1 +/- 2.0 mmHg from a control of 8.5 +/- 1.3 did not result in any consistent change in heart rate. Reduction of arterial pressure with sodium nitroprusside caused an increase in heart rate to 143.9 +/- 13.8 beats/min. With baroreceptors unloaded, increasing LV pressure by a similar degree as in the control group now resulted in consistent and significant bradycardia. Removal of arterial baroreceptors in a final group of dogs abolished the baroreflex. Increasing LV pressure by aortic stenosis now resulted in a stimulus-dependent decrease in heart rate that was significantly greater than that in the nitroprusside group. Both administration of atropine and bilateral cervical vagotomy abolished bradycardia. The second part of this study was concerned with effects of increases in LV inotropic state on heart rate change evoked by aortic stenosis. Each group was infused with intracoronary epinephrine. Infusion of epinephrine (12.5-50.0 ng . kg-1 . min-1) significantly increased LV dP/dt without any significant change in heart rate or mean arterial blood pressure. Aortic stenosis during epinephrine infusion did not result in any significant difference in heart rate responses in any group studied. It is concluded that LV distension can cause a reduction in heart rate that is opposed by the presence of arterial baroreceptors and that increases in LV myocardial contractility do not have any effect on the magnitude of this response.
Metabolic response of skeletal muscle to ischemia
Authors: Harris K. , Walker P. M. , Mickle D. A. , Harding R. , Gatley R. , Wilson G. J. , Kuzon B. , McKee N. , Romaschin A. D.
Published: December 2017

To evaluate the temporal relationship and potential correlation between intramuscular phosphagen levels, lipid oxidation, and extent of muscle injury, a canine gracilis muscle model was used to study the consequences of a global ischemic episode for up to 7 h duration with reperfusion for 4 h. In this model the contralateral gracilis muscle was prepared identically to the test side but was not subjected to ischemia and thus served as a control. Blood flow, oxygen consumption, and lactate and glycerol release were measured before and after 2- and 7-h ischemic stress periods. The intramuscular metabolites, glycogen, lactate, phosphocreatine, and ATP, as well as free fatty acid conjugated dienes, were measured before, during, and after the ischemic insult. A 2-h ischemic insult resulted in minimal ultrastructural damage and complete regeneration of intramuscular phosphagens and glycogen on reperfusion with complete normalization of lipid oxidation products. In contrast, a 7-h ischemic insult resulted in profound injury at the ultrastructural level with an inability to restore intramuscular phosphagens and glycogen on reperfusion. This severe muscle injury correlated with a 2.5-fold increase in lipid oxidation products (free fatty acid conjugated dienes) and a decline in ATP levels below 5 mumol/g dry wt on reperfusion. Our results emphasize the prolonged glycolytic activity of skeletal muscle during global ischemia and document the increased production of oxygen free radical-mediated lipid oxidation products in irreversibly injured muscle.
Na+-H+ exchange is present in sarcolemmal vesicles from dog superior mesenteric artery
Authors: Kahn A. M. , Shelat H. , Allen J. C.
Published: December 2017

The Na+ concentration inside vascular smooth muscle cells is an important regulator of vascular smooth muscle function, but the mechanisms that mediate Na+ influx are not known. We studied Na+ transport in a newly described vesicle preparation preferentially enriched in sarcolemma and obtained by Mg2+ aggregation and differential centrifugation of homogenized dog superior mesenteric artery. In the presence of an outwardly directed proton gradient (pHout = 7.5, pHin = 5.0), 1 mM 22Na+ uptake was stimulated over twofold relative to the absence of a pH gradient (pHin = 7.5 or 5.0). pH gradient-stimulated Na+ uptake was inhibited by 1 mM amiloride. 22Na efflux was stimulated by an inwardly directed proton gradient (pHin = 7.5, pHout = 5.7 vs. 7.5). The rate of proton efflux from acid-loaded vesicles was measured by acridine orange fluorescence and was stimulated by 100 mM Naout but not by Nain = Naout = 100 mM. H+ gradient-stimulated Na+ transport and Na+ gradient-stimulated H+ transport were not due to electrical coupling between the two cations. The pH gradient-stimulated component of Na+ transport in the final vesicles, an intermediate fraction, and microsomes were proportional to the respective enzyme marker activities for sarcolemma but not for sarcoplasmic reticulum or mitochondrial membranes. We conclude that Mg2+ aggregation and differential centrifugation of homogenized vascular smooth muscle yield a vesicle preparation preferentially enriched in sarcolemma. Furthermore, the sarcolemma of vascular smooth muscle contains an amiloride-sensitive Na+-H+ proton countertransport system.
Improved technique for monitoring electrocardiograms during exposure to radio-frequency radiation
Authors: Watkinson W. P. , Gordon C. J.
Published: December 2017

Studies were conducted utilizing improved methodology that examined the effects of radio-frequency (RF) radiation on heart rate (HR), deep body temperature (Tco), and electrocardiographic (ECG) waveform parameters in anesthetized rats. One group of animals was exposed to two power levels of continuous-wave RF radiation averaging 1.0 and 7.4 W/kg at a frequency of 600 MHz. A second group of animals, treated identically but not exposed to RF radiation, served as a control. The electrodes used for monitoring the ECG during RF exposure were fabricated from carbon-loaded Teflon wire, a semiconductor material that does not perturb the RF field. Analyses of the ECG were conducted by use of a recently developed computer-assisted procedure that quantitates HR and waveform intervals over 25-40 individual ECG complexes. There were no artifacts or arrhythmias in the ECGs of the animals exposed to RF radiation. There was a significant linear correlation between HR and Tco in the RF-exposed group that was not present in the control group.
Fatty acid metabolism in hearts containing elevated levels of CoA
Authors: Lopaschuk G. D. , Hansen C. A. , Neely J. R.
Published: December 2017

Palmitate metabolism was determined in isolated perfused hearts containing elevated levels of coenzyme A (CoA). CoA levels were elevated by perfusing hearts with Krebs-Henseleit buffer containing 0.1 mM cysteine, 0.2 mM dithiothreitol, 15 microM pantothenic acid, and no energy substrate. After 45 min, CoA levels had increased from 537 +/- 14 to 818 +/- 44 nmol/g dry wt. When these hearts containing high CoA were subsequently perfused as working hearts with buffer containing 11 mM glucose and 1.2 mM palmitate, long chain acyl CoA levels increased (94 +/- 5-305 +/- 6 nmol/g dry wt). Oxidation of exogenous palmitate (as measured by 14CO2 production from [U-14C]palmitate) was significantly depressed in hearts containing elevated CoA levels. This apparent reduction in fatty acid oxidation was not due to increased glucose or glycogen utilization. When the concentration of palmitate was decreased to 0.4 mM, acyl CoA levels increased much less, and the apparent rate of [14C]palmitate oxidation was unaffected by elevated CoA. Hearts containing high CoA also incorporated [14C]palmitate into triacylglycerols to a greater extent than did control hearts. To determine whether the apparent decrease in exogenous palmitate oxidation resulted from an increased utilization of unlabeled endogenous triacylglycerol fatty acid, [14C]palmitate specific activity was measured in myocardial acylcarnitine. The specific activity of this pool of fatty acid was similar in both control hearts and hearts containing elevated CoA. Thus dilution of the total cellular [14C]acyl carnitine by triacylglycerol hydrolysis was not sufficient to account for the decrease in [U-14C]palmitate oxidation. The possibility that a small pool of rapidly turning over acyl carnitine becomes dilated is discussed.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of verapamil and diltiazem on human platelet function
Authors: Addonizio V. P. , Fisher C. A. , Strauss J. F. , Wachtfogel Y. T. , Colman R. W. , Josephson M. E.
Published: December 2017

In this study the antiplatelet properties of two calcium channel blockers, verapamil and diltiazem, were evaluated. In 20 random aspirin-abstaining donors, both diltiazem and verapamil (0.01-10 microM) reduced epinephrine-induced aggregation [46 +/- 6% (SE) inhibition] and demonstrated a dose-dependent inhibition of epinephrine-induced [14C]serotonin release (43 +/- 3% reduction). However, at equimolar concentrations, verapamil was twice as effective. Neither drug altered ADP, collagen, thrombin, or calcium ionophore-induced platelet aggregation or platelet granule secretion. Neither drug prevented formation of thromboxane B2 during secondary aggregation. Verapamil, but not diltiazem, increased the Kd of [3H]yohimbine binding from 2.03 to 46.99 nM without altering the calculated number of binding sites per platelet (124 sites/platelet). Supplemental calcium added to citrated platelet-rich plasma reversed both verapamil and diltiazem-induced inhibition of platelet aggregation. We conclude that, at the concentrations tested, both verapamil and diltiazem are specific inhibitors of epinephrine-induced platelet activation. Clearly, both agents may be acting by preventing epinephrine-induced increases in plasma membrane permeability to calcium. However, the greater potency of verapamil compared with diltiazem with only verapamil binding to alpha2-adrenergic receptors suggests that alpha-blockade represents a significant component of verapamil-induced platelet inhibition.
Reactive hyperemia following one-beat coronary occlusions in the awake dog
Authors: Bache R. J. , Hess D. S.
Published: December 2017

This study was performed to examine the effect of alterations of cardiac activity during brief coronary artery occlusions on the subsequent reactive hyperemic response. Reactive hyperemia following coronary occlusions equal in duration to one cardiac cycle were examined in 12 chronically instrumented awake dogs while heart rate was maintained constant by cardiac pacing. During continuous pacing, one-beat coronary occlusions resulted in reactive hyperemia with excess flow equal to 220 +/- 23% blood flow debt repayment. When coronary occlusions of identical duration were performed while a single cycle of pacing was omitted during the interval of occlusion, the subsequent reactive hyperemia was decreased. Conversely, when coronary occlusion was produced during the first potentiated beat following a single cycle of paired ventricular stimulation, the reactive hyperemia was increased. Since, in the absence of coronary occlusion, omitting a single paced beat caused a transient decrease in coronary flow, while a single cycle of paired ventricular stimulation caused a brief increase in coronary flow, the reactive hyperemic responses were corrected for these perturbations in flow. Despite these corrections, the influence of alterations of myocardial activity during the interval of occlusion persisted, with the decreased reactive hyperemia when occlusion occurred during an omitted beat and increased hyperemia when occlusion was performed during a potentiated beat. These data indicate substantial coupling between myocardial activity during coronary occlusions as brief as one cardiac cycle in duration and the subsequent reactive hyperemic response.
Endothelial cell uptake of adenosine in canine skeletal muscle
Authors: Gorman M. W. , Bassingthwaighte J. B. , Olsson R. A. , Sparks H. V.
Published: December 2017

The vascularly isolated muscles in the hindlimbs of five dogs were perfused with an oxygenated physiological salt solution. The extractions of adenosine and of a nontransported analogue of adenosine, 9-beta-D-arabinofuranosyl hypoxanthine (AraH), were determined by the single-pass indicator-dilution technique. A bolus containing [125I]albumin (reference tracer), [14C]adenosine, and [3H]AraH was injected into the artery while samples of venous effluent were collected over the next minute. This injection was repeated with dipyridamole (10(-5) M) in the perfusate. Early extractions of AraH (EAra) and adenosine (EAdo) under control conditions were 48 +/- 4 and 80 +/- 4%, respectively. In the presence of dipyridamole, EAra was unchanged (47 +/- 5) while EAdo decreased to 45 +/- 7%. Since early extraction reflects primarily the barrier posed by endothelial cells, these results demonstrate significant endothelial uptake of adenosine. Analysis of these data using a mathematical model of blood-tissue exchange indicates that, under the conditions of these experiments, at least 78% of the adenosine taken up by skeletal muscle entered endothelial cells.
Proteolysis of the platelet surface: dissociation of shape change from aggregation
Authors: Kornecki E. , Ehrlich Y. H. , Hardwick D. H. , Lenox R. H.
Published: December 2017

Stimulation of intact platelets by ADP results in a shape change followed by aggregation in the presence of fibrinogen. ADP was found to induce a shape change in chymotrypsin-treated platelets that was similar in extent and initial velocity to that of intact (untreated) platelets. Scanning-electron microscopy verified an ADP-induced shape change in chymotrypsin-treated platelets. This shape change could be completely blocked by stimulators of platelet adenylate cyclase (forskolin, prostaglandin E1, and prostacyclin). On the other hand, the aggregation of chymotrypsin-treated platelets by fibrinogen was not dependent on the presence of ADP and could not be blocked by forskolin, prostaglandin E1, or prostacyclin, even though the levels of cyclic AMP (cAMP) formed in chymotrypsin-treated platelets were comparable to levels that completely inhibited the ADP-induced aggregation of intact platelets. This lack of inhibition of platelet aggregation was not due to degradation of the adenylate cyclase or prostaglandin receptors, since chymotrypsin-treated platelets were found to have a functional adenylate cyclase system that could be stimulated by forskolin, prostaglandin E1, and prostacyclin and inhibited by ADP and epinephrine, similar to that of intact platelets. These results provide direct evidence that cAMP does not interact with fibrinogen binding sites once they have become permanently exposed on the surface of platelets. Pretreatment of platelets with chymotrypsin therefore appears to be a useful tool that allows for the dissociation of platelet shape change from aggregation, without inhibiting either response.
End-systolic pressure-diameter relationships during pulsus alternans in intact pig hearts
Authors: Miller W. P. , Liedtke A. J. , Nellis S. H.
Published: December 2017

Pulsus alternans has previously been ascribed to variations in end-diastolic fiber length and/or an alternating contractile state. In six paced, whole blood-perfused, intact, working pig hearts, left ventricular internal diameters were measured with ultrasonic crystals, and left ventricular pressures were measured with a micromanometer-tipped catheter. Pulsus alternans was induced with propranolol (24-51 micrograms X kg-1 X min-1). End-systolic pressure-diameter relationships were determined during pulsus alternans from a series of consecutive, variably volume-loaded beats using a previously described technique. Beats analyzed prior to any change in loading conditions revealed a left ventricular pressure of 62.7 +/- 8.7 mmHg for the strong beats and 55.2 +/- 7.0 for the weak beats (P less than 0.050). The end-diastolic diameter prior to the stronger beats was larger than that prior to the weaker beats (24.80 +/- 2.73 vs. 23.82 +/- 2.82 mm, P less than 0.025), but there was no significant difference in the corresponding end-diastolic pressures. The maximum dP/dt of the strong beats was 1,275 +/- 249 mmHg/s compared with 1,038 +/- 222 for the weak beats (P less than 0.025). The slope of the end-systolic pressure-diameter relationship, which provides an index of contractility independent of end-diastolic diameter, averaged 42.3 +/- 6.4 mmHg/mm for the strong beats and 24.4 +/- 6.8 for the weak beats (P less than 0.025). These data support an alternating contractile state as an independent mechanism for pulsus alternans in the intact animal.
Comparison of effects of ryanodine and caffeine on rat ventricular myocardium
Authors: Sutko J. L. , Thompson L. J. , Kort A. A. , Lakatta E. G.
Published: December 2017

Ryanodine and caffeine have the ability to diminish sarcoplasmic reticulum (SR) calcium release in cardiac muscle cells. To determine whether these agents also share a common mechanism of action, we compared their effects on rat papillary muscles using two different experimental approaches. First, using the protocol of Jundt et al. (19), in which quiescent rat papillary muscles were exposed to sodium-free solutions, we found that 1 microM ryanodine decreased resting force, phosphorylase alpha activity, and the scattered light intensity fluctuations (SLIF) due to calcium-dependent myofilament interactions. In contrast, 10-20 mM caffeine increased both resting force and phosphorylase alpha levels and initially increased then decreased SLIF to below detectable levels. In a second series of experiments, contractures were elicited by exposing rat papillary muscles to 125 mM KCl. Pretreatment with ryanodine (1 microM) or caffeine (10 mM) abolished the initial phasic component of this response, while increasing the subsequent tonic component. These effects were different from those of isoproterenol, which decreased tonic contracture force. The depression of twitch force produced by ryanodine developed more rapidly in the presence of 125 mM KCl than in normal buffer, suggesting that the negative inotropic effects of this agent may, in part, depend on membrane depolarization. The results of these experiments suggest that ryanodine and caffeine affect SR calcium release through different mechanisms of action. Ryanodine appears to decrease, while caffeine initially increases, cytoplasmic calcium. Once these effects have occurred, the alterations of SR function produced by both agents can similarly alter other inotropic responses.
Microvascular pressure in venules of skeletal muscle during arterial pressure reduction
Authors: House S. D. , Johnson P. C.
Published: December 2017

It has been suggested from whole organ studies that the viscosity of blood in skeletal muscle venules varies inversely with flow over physiological flow ranges. If this is the case, the hydrostatic pressure gradient in venules should change less than flow as flow is altered. To test this hypothesis, pressure in venules of cat sartorius muscle was measured during stepwise arterial pressure reduction to 20 mmHg. Large vein pressure remained constant at about 5 mmHg. Average pressures in the large venules (40–185 microns) ranged from 13.6 to 10.0 mmHg. The difference between pressure in these venules and large vein pressure fell in proportion to the reduction in blood pressure and blood flow. Pressures in the smallest venules studied (25 microns) averaged 19.7 +/- 6.2 (SD) mmHg. The pressure difference between the smallest venules and the large vein fell less than the arteriovenous pressure difference or blood flow when arterial pressure was reduced. During reactive hyperemia the pressure gradient between the smallest venules and the large vein rose proportionately less than blood flow. The stability of pressure in the smallest venules is consistent with the hypothesis that blood viscosity varies inversely with flow rate.
Alterations in ventricular excitability in conscious dogs during development of chronic heart failure
Authors: White C. W. , Mirro M. J. , Lund D. D. , Skorton D. J. , Pandian N. G. , Kerber R. E.
Published: December 2017

Arrhythmias in patients with heart failure may result from altered electrophysiological properties of the myocardium. To examine changes in ventricular excitability during cardiac failure and to relate these changes to ventricular structural and neurochemical abnormalities, right ventricular failure was produced in dogs by pulmonary artery banding and by creating tricuspid regurgitation. Right and left ventricular excitability thresholds were tested biweekly in heart failure (HF) and sham-operated conscious dogs by means of strength-duration curves (1-40 ms) at basic cycle lengths (BCL) of 300-500 ms until time of death (21-188 days). Marked increases in the excitability threshold of the right ventricle occurred in HF (mean maximum % increase, 205 +/- 42 at BCL 500 ms). Smaller, though significant increases in the left ventricular excitability threshold in HF were also seen (mean maximum % increase 103 +/- 36 at BCL 500 ms). Increases in the excitability threshold of the left as well as the right ventricles occurred, even though ventricular dilation (2-D Echo) was confined to the right ventricle. The time course of changes in the excitability threshold was variable (maximum occurrence at 21 +/- 3 days right ventricle, 23 +/- 11 days left ventricle). Tyrosine hydroxylase activity and norepinephrine content of the right ventricle were markedly depleted at death, when the excitability threshold was high. Similar though nonsignificant trends in reductions of these sympathetic neurochemicals were seen in the left ventricle. Levels of choline acetyltransferase and QNB binding in both ventricles were unaffected.
Fetal O2 consumption in sheep during controlled long-term reductions in umbilical blood flow
Authors: Anderson D. F. , Parks C. M. , Faber J. J.
Published: December 2017

Electromagnetic flow sensors and inflatable occluders were placed on the distal aortas of nine fetal lambs of 111-124 days gestation; indwelling vascular catheters were placed in a lower body artery and vein and the common umbilical vein. After a control period of 7.6 +/- 2.1 (SD) days, distal aortic flow was reduced to about 60% of control flow; placental flow fractions of distal aortic flow were 77 +/- 5%, control; 69 +/- 11% during flow reduction. Duration of the flow reductions was 9.6 +/- 6.5 days. Fetal O2 consumption fell from 6.4 +/- 1.5 to 5.3 +/- 1.1 ml X min-1 X kg-1 (P less than 0.02) as umbilical blood flow was reduced from 202 +/- 47 to 116 +/- 36 ml X min-1 X kg-1 (P less than 0.001). Least-squares polynomial regression analysis showed that O2 consumption was a linear function of umbilical blood flow (P less than 0.01). With regard to long-term fetal O2 consumption, there was no evidence for a margin of safety in fetal umbilical blood flow.
Vascular reactivity of contralateral kidney in awake Goldblatt hypertensive dog
Authors: Zimmerman B. G.
Published: December 2017

Sixteen dogs were instrumented for recording mean arterial blood pressure (MAP) and blood flow from the left renal artery (RBF) and for intra-arterial infusions of norepinephrine (NE) and angiotensin II (ANG II). Nine dogs (group 1) were studied while normotensive and also when hypertensive. Seven control dogs (group 2) were studied only when normotensive. In a control session conducted in group 1 and at weekly intervals for up to 6-12 wk after the right renal artery was clipped, infusions of NE and ANG II were given intra-arterially to produce graded decreases in RBF. Group 2 was studied similarly in a control session and 4-7 wk later. Regressions of the values of percent change RBF (arc sin transformation) on the concentrations of NE and ANG II in renal arterial blood estimated the renal vascular reactivity of the hypertensives' contralateral kidney and the normotensives' kidney. In group 1, during the postclipping intervals when MAP and plasma renin activity were increased, the renal vascular reactivity to NE, but not to ANG II was increased. This was based on the significant elevation above the X axis in the postclipping regressions. In group 2, MAP, plasma renin activity, and renal vascular reactivity to NE and ANG II were unchanged over the 4- to 7-wk interval of study. These results indicate that the contralateral kidney develops an increased vascular reactivity to NE but not to ANG II in Goldblatt hypertension.