bluuebunny/crossref_metadata_2025 huggingface dataset:
Biochemical Correlates of Cardiac Hypertrophy: IV. OBSERVATIONS ON THE CELLULAR ORGANIZATION OF GROWTH DURING MYOCARDIAL HYPERTROPHY IN THE RAT
Authors: Grove D. , Zak R. , Nair K. G. , Aschenbrenner V.
Published: June 2012

The mechanisms by which the DNA content of the heart increases following acutely induced cardiac hypertrophy were investigated in mature Sprague-Dawley rats. Special attention was given to the cellular organization of the growth process. Autoradiographic studies provided conclusive evidence that the uptake of tritiated thymidine is completely limited to nonmuscular cellular elements, chiefly connective tissue cells. The frequency of labeled nuclei was increased by sixfold during hypertrophy. The thymidine pool was not appreciably different in the hypertrophied hearts. Connective tissue nuclei formed a larger proportion of the total nuclear population in hypertrophied hearts, and their distribution was less uniform than in the normal heart. Quantitative histologic studies also showed that the total number of left ventricular muscle cell nuclei did not increase during hypertrophy but rather may have decreased slightly. Both the concentration and the total amount of hydroxyproline increased in parallel with the proliferative changes in the connective tissue and provide further supportive evidence to the autoradiographic and histologic studies.
Effect of Methyldopa on Plasma Renin Activity in Man
Authors: MOHAMMED SHAKIL , FASOLA ALFRED F. , PRIVITERA PHILIP J. , LIPICKY RAYMOND J. , MARTZ B. L. , GAFFNEY THOMAS E.
Published: June 2012

The effect of methyldopa on plasma renin activity was studied in one hypertensive and four normotensive human volunteers. Peripheral venous blood for the estimation of plasma renin activity was obtained with the subjects supine and in a 70° head-up tilted position before, during and, in two subjects, after treatment with oral methyldopa. Despite a reduction in mean arterial pressure, the plasma renin activity was decreased by methyldopa in each subject. The increase in plasma renin activity associated with tilting, however, was not significantly suppressed by methyldopa. These results indicate that treatment with methyldopa can simultaneously decrease mean arterial pressure and plasma renin activity and it is possible that these effects may be causally related.
Rate of Calcium Binding and Uptake in Normal Animal and Failing Human Cardiac Muscle: MEMBRANE VESICLES (RELAXING SYSTEM) AND MITOCHONDRIA
Authors: Harigaya Shoichi , Schwartz Arnold
Published: June 2012

Cardiac relaxing system (CRS) and mitochondria were isolated by a modified rapid procedure from human, rabbit, and dog. Relaxing system (sarcoplasmic reticulum) was also isolated from white and red skeletal muscles for comparative purposes. Rapid kinetic measurements were made with a dual-beam spectrophotometric assay procedure. Maximum calcium binding (absence of oxalate), expressed as nmoles calcium/mg protein in 5 minutes at 25°C, for rabbit heart and red and white skeletal muscles were approximately 40, 58 and 170, respectively. The calcium binding constant for rabbit CRS was 2 x 10
6
M
-1
. The estimated initial binding rates (nmoles calcium/mg protein/minute) of cardiac, white and red skeletal muscle relaxing systems were 256, 1440 and 182, respectively. The rate constant (M
-1
sec
-1
) of CRS was about 2400, which falls between white and red skeletal muscle preparations. Human cardiac muscle from recipients obtained at the time of transplantation yielded CRS with slower rates of accumulation of calcium and very little calcium release, compared to normal animal heart preparations. ATP was the most effective of four nucleoside triphosphates in supporting calcium binding and uptake. Calcium binding and release and calcium uptake of CRS were temperature-sensitive. The energies of activation of binding and uptake were 10.5 kcal mole
-1
and 22.5 kcal mole
-1
, respectively. Under specific conditions, heart mitochondria accumulated calcium at a rate faster than CRS. Mitochondria could also release accumulated calcium.
Effects of Diphenylhydantoin on Excitability and Automaticity in the Canine Heart
Authors: BIGGER J. THOMAS , WEINBERG DANIEL I. , KOVALIK A. THOMAS W. , HARRIS PAUL D. , CRANEFIELD PAUL C. , HOFFMAN BRIAN F.
Published: June 2012

Studies were performed on the dog heart in situ to determine the effects of diphenylhydantoin (DPH) on excitability and automaticity. DPH decreased automaticity in the His-Purkinje system, evidenced by an increase in the ventricular escape time both during vagal stimulation in intact dogs and after ventricular overdrive in dogs with heart block. The spontaneous ventricular rate of dogs with heart block was unaffected by doses up to 20 mg/kg. DPH had no significant effect on either atrial or ventricular diastolic threshold when this variable was tested with bipolar stimuli or with stigmatic anodal or cathodal stimuli. The effective refractory period of atrial and particularly of ventricular muscle was shortened by DPH (10 mg/kg); a leftward shift in the strength-interval curve occurred consistently. Multiple response threshold and fibrillation thresholds were elevated by DPH in both the ventricle and atrium (20 of 24 experiments). In anesthetized dogs, intraventricular conduction velocity increased minimally after DPH administration. DPH increased transmembrane threshold voltage and reduced the current required to stimulate isolated Purkinje fibers. The commercial solvent used clinically as a diluent for DPH was found to increase diastolic threshold and prolong the effective refractory period.
Energy-Linked Calcium Transport in Subcellular Fractions of the Failing Rat Heart
Authors: MUIR JOHN R. , DHALLA NARANJAN S. , ORTEZA JOSEFINA M. , OLSON ROBERT E.
Published: June 2012

The isolated rat heart perfused without substrate provides a good model in which to study biochemical changes in the failing myocardium. In this preparation, there is a decline in the ability of both the mitochondria and the sarcoplasmic reticulum to accumulate calcium in the absence of oxalate after 30 minutes of perfusion. Calcium binding by mitochondria fell from control levels of 47 ± 8 mµmoles/mg protein to 17.5 ± 4.9 mµmoles/mg protein and that by microsomes from 29.8 ± 5.1 mµmoles/mg protein to 15.2 ± 4.8 mµmoles/mg protein. This drop coincided with die start of the decline in myocardial contractility. The calcium uptake by the sarcoplasmic reticulum in the presence of oxalate decreased from control levels of 534.1 ± 32.0 to 160.5 ± 27.2 mµmoles/mg protein after 2 hours of perfusion, at which time the myocardial contractility had dropped to below 10% of control levels. This change in the calcium uptake by the sarcoplasmic reticulum is associated with an increase in its ATPase activity from 1.91 ± 0.21 to 3.00 ± 0.31 µmoles P
1
/mg protein/min over 2 hours of perfusion without substrate. This suggests that there is an uncoupling of the microsomal ATP-dependent calcium pump in these late stages of heart failure due to substrate lack. The change in calcium binding to reticulum occurred in association with the onset of contractile failure, whereas changes in calcium uptake in the presence of oxalate were delayed and probably represent irreversible disorganization of the intracellular membranes.
Depression of Myocardial Contractility in Rats by Free Fatty Acids during Hypoxia
Authors: HENDERSON ANDREW H. , MOST ALBERT S. , PARMLEY WILLIAM W. , GORLIN RICHARD , SONNENBLICK EDMUND H.
Published: June 2012

Rat papillary muscles were used to study the influence of glucose (5 m
M
), linoleate (1 to 1.75 m
M
), octanoate (0.5 to 1.75 m
M
) and pent-4-enoic acid (1 to 5 m
M
) on mechanical performance under oxygenated, hypoxic and anoxic conditions. The buffer solution contained 0.3 m
M
albumin. Free fatty acids (FFA) (1.0 to 1.75 m
M
) did not alter mechanical performance under oxygenated conditions. During hypoxia or anoxia, FFA (0.5 to 1.75 m
M
) depressed contractility and increased resting force; glucose improved mechanical performance and modified the depressant effects of FFA. The depressant effect of the nonmetabolized FFA, pentenoic acid, was similar to that of other FFA. This suggests that the effect was mediated directly by FFA or acyl CoA derivatives rather than their metabolic products, and that it might be due to a detergent effect or calcium binding by FFA present in excess of intracellular FFA binding capacity at low pH. Force development during anoxia could be augmented by calcium, implying that the reduced ability of the myofilaments to contract could not be attributed entirely to a reduction of high energy stores.
An Experimental Study of Propagated Electrical Activity in the Canine Heart
Authors: VANDER ARK CONDON R. , REYNOLDS ERNEST W.
Published: June 2012

The closest analog to propagated excitation of the heart is an electromotive surface. The width of the cardiac electromotive surface was 0.9 ± 0.1 mm and was remarkably constant. The mean epicardial surface component of voltage across the electromotive surface was 62.4 ± 7.2 mv with the chest closed and 74.1 ± 8.3 mv with the chest open. This 18.7% increase is significant (
P
< .001) and suggests a shunting effect of the lungs and thorax. Fortuitous measurement of voltage across the electromotive surface yielded nine values in excess of 80 mv and two above 90 mv, suggesting that the true voltage across the electromotive surface is of about the same magnitude as the transmembrane action potential. Cross-fiber activation resulted in a 29.5% reduction in voltage, a 51.8% reduction in conduction velocity and notched QRS complexes.

A closed electromotive surface has no external electrical field, suggesting that its voltage is uniform. The voltage between two electrodes, both in advance or toward the rear of a normally propagated open electromotive surface, is caused by an extracardiac current path, since removal of the lung from the epicardial surface greatly reduces this voltage and augments that across the electromotive surface.
Bulbar and Suprabulbar Control of the Cardiovascular Autonomic Effects during Arterial Hypoxia in the Rabbit
Authors: UTHER JOHN B. , HUNYOR STEPHEN N. , SHAW JOHN , KORNER PAUL I.
Published: June 2012

The autonomic effects on heart rate, portal, renal, cutaneous and muscle blood flows were studied during approximately constant severe arterial hypoxia in unanesthetized sham-operated, thalamic and pontine rabbits, 3 hours after operations conducted under halothane anesthesia. Neural and adrenal effects were estimated by comparing the responses of different groups of animals: (a) with all neural effectors intact, (b) after adrenalectomy, (c) after selective and (d) after complete pharmacological block of neural effector mechanisms. In pontine animals hypoxia greatly increased cardiac sympathetic activity and seemed to evoke a greater release of adrenal catecholamine (epinephrine) than in other preparations, but caused significant neural peripheral sympathetic constrictor effects in only the portal bed. In thalamic animals, hypoxia caused reflex bradycardia, striking neural constrictor effects in the portal, renal and muscle beds, and cutaneous dilatation. There was little evidence of an increase in epinephrine secretion. It is suggested that there is an inhibitory pathway between diencephalon and bulb that limits the release of epinephrine. Sham-operated animals exposed to hypoxia secreted epinephrine which played an important role in the total reflex response; this group had similar cardioinhibitory and cutaneous effects to thalamic animals, but a more rapid onset of portal and renal constriction and a marked increase in muscle blood flow. The sympathetic responses of the different preparations resulted in different rates of metabolic H
+
ion production.
Relationship between Fatty-Acid Composition of Platelets and Platelet Aggregation in Rat and Man
Authors: RENAUD S. , KUBA K. , GOULET C. , LEMIRE Y. , ALLARD C.
Published: June 2012

Male rats fed a diet rich in butter or stearic acid presented a marked predisposition to endotoxin-initiated thrombosis. This was preceded by hypercholesterolemia, hypercoagulability, and an increased susceptibility of platelets to thrombin-induced aggregation. In contrast to this, feeding of corn oil or linoleic or oleic acids did not result in such marked changes in the blood or in severe thrombosis.

Gas-liquid chromatographic analysis of total lipids of platelet and plasma indicated that the thrombogenic fat or fatty acid resulted in a highly significant increase, mostly in the platelets, of the ratio of saturated + monounsaturated to polyunsaturated fatty acids (S+M)/P.

In patients who had suffered a myocardial infarction as compared with men without risk factors for coronary heart disease, an increase in the (S+M)/P in plasma and platelets was also observed.

Among 17 active middle-aged businessmen, the five who presented signs of coronary heart disease also showed the highest susceptibility to thrombin-induced aggregation, but not to ADP or collagen. In these 17 subjects, the results of the thrombin aggregation could be correlated with the platelet (S+M)/P, but not with the plasma or platelet cholesterol.

In both the rat and man, a high thrombotic tendency may be associated with a platelet hypersusceptibility to thrombin which, in turn, is related to changes in fatty-acid composition.
In-Vivo and In-Vitro Conversion of Angiotensin I to Angiotensin II in Dog Blood
Authors: OPARIL SUZANNE , SANDERS CHARLES A. , HABER EDGAR
Published: June 2012

The conversion of angiotensin I to angiotensin II was studied in vivo in the intact anesthetized dog and in vitro in whole blood and plasma treated with various anticoagulants by fractionation of radioactively labeled peptides and by radioimmunoassay. After injection of angiotensin I into the pulmonary artery at 10,000 times the physiologic level, approximately 50% of the injected material was recovered in the aorta. Fifty three percent of the material recovered had been converted to angiotensin II, as measured both by peptide release and by radioimmunoassay. Following injection of 1000 to 10,000 times physiologic levels of angiotensin I into the renal artery, 7 to 10% of the immunoreactive material in the venous effluent after a single circulation time was angiotensin II. There was no evidence of conversion in the liver or hindlimb. Conversion in vitro was far slower than in vivo, the half-life in fresh blood being 3 minutes, with longer times observed in anticoagulated plasmas. The major metabolite of in-vivo conversion was leucine, of in-vitro conversion, histidyl leucine. These observations indicate that the major site of conversion of angiotensin I to angiotensin II is in the pulmonary capillary bed. The kidnev may participate as a secondary site. Conversion in plasma probably plays no important physiologic role. The mechanism of organ and plasma conversion may differ, as indicated by the different metabolites.
Estimation of Stroke Volume in the Dog by a Pulse Contour Method
Authors: KOUCHOUKOS NICHOLAS T. , SHEPPARD LOUIS C. , McDONALD DONALD A.
Published: June 2012

A method for estimating the stroke volume (SV) from the systolic area of a single-channel record of the central aortic pressure has been tested in 12 anesthetized open-chest dogs. The formula used was SV = K·Psa·(1 + Ts/Td), where Psa is the area under the systolic part of the curve above end-diastolic pressure, Ts and Td are the durations of systole and diastole, respectively, and K is an arbitrary constant derived from measurement of an initial SV by electromagnetic flowmeter in each dog and used thereafter without change, in that dog. In the 12 dogs, 541 simultaneous determinations of SV by the pressure contour and electromagnetic flowmeter methods were compared under normal and altered circulatory conditions employing 12 different interventions. The total range of SV was 2.4 to 28.1 ml, of heart rate 35 to 207/min, and of mean arterial pressure 24 to 166 mm Hg. The overall correlation coefficient (r) was 0.928 with a regression line y = 1.04x + 0.21 ml (SE) of estimate, ±17.4%. Except for three sympathomimetic drugs, the r values for all other interventions ranged from 0.93 to 0.99. These observations compare favorably with those of previously reported pulse contour methods. The windkessel origin of the formula is noted, and a new derivation from a modification of the "water-hammer" equation is given.
Electrophysiological and Beta-Receptor Blocking Effects of MJ 1999 on Dog and Rabbit Cardiac Tissue
Authors: STRAUSS HAROLD C. , BIGGER J. THOMAS , HOFFMAN BRIAN F.
Published: June 2012

Effects of MJ 1999 (1 x 10
-9
M to 1 x10
-2
M) on rabbit right atrial and canine Purkinje fiber preparations were studied. MJ 1999 had a pA
2
of 6.1 against the chronotropic effect of isoproterenol on rabbit SA node. Significant slowing first occurred with MJ 1999 at 1 x 10
-4
M. The spontaneous firing rate of Purkinje fibers in vitro did not change significantly after exposure to MJ 1999 1 x 10
-4
M. Idioventricular rate was slowed and idioventricular escape time was prolonged in dogs with atrioventricular block after MJ 1999, 2.0 mg/kg. MJ 1999, 1 x 10
-7
M to 5 x 10
-4
M, had no effect on resting potential, overshoot and amplitude of phase 0 of transmembrane potentials (TMP) recorded from canine ventricular muscle, canine Purkinje fibers or rabbit atrial fibers nor did it affect phase 0 V
·
max
of TMP recorded from the Purkinje or atrial fibers. Similar concentrations of MJ 1999 had no effect on membrane responsiveness in Purkinje fibers. In Purkinje fibers, control action potential duration (APD) was 325 msec and the effective refractory period (ERP) 277 msec. MJ 1999, 1 x 10
-3
M, increased the APD to 470 msec and ERP to 404 msec. In ventricular muscle fibers, APD was 230 msec and the ERP was 223 msec, under control conditions. MJ 1999, 1 x 10
-3
M, increased the APD to 281 msec and ERP to 267 msec. Changes in APD and ERP induced by MJ 1999 were magnified at slower rates of stimulation. The effects of MJ 1999 on both APD and ERP were more marked in Purkinje fibers than in ventricular muscle fibers. The effects of MJ 1999 on phase 0 of the TMP and on repolarization and refractoriness of the TMP differ markedly from those seen with quinidine, procainamide, and lidocaine.
Morphology and Metabolism of Intact Muscle Cells Isolated from Adult Rat Heart
Authors: BERRY MICHAEL N. , FRIEND DANIEL S. , SCHEUER JAMES
Published: June 2012

Morphologically intact muscle cells were prepared by perfusing adult rat hearts with a balanced salt medium containing 0.1% collagenase and 0.2% hyaluronidase. Yields of intact cells representing up to 25% of the weight of the heart were obtained. The cells separated along the line of the intercalated discs, with cleavage of desmosomes but with tearing of the plasma membrane in the region of the gap junction, so that when two contiguous cells were parted, the gap junction was retained intact attached to one of the cells. The fine structure of undamaged cells was indistinguishable from that of normal myocardial cells in situ, whereas damaged cells characteristically revealed numerous cytoplasmic vacuoles, clumping of myofilaments, and blebbing of the cell membrane, but morphologically normal mitochondria. The earliest lesion detected was a dilatation of the T (transverse tubular) system.

Respiration in the intact cells was linear for 30 to 60 minutes and approximately two to three times the rate observed with heart muscle slices or the arrested isolated perfused heart. Oxygen uptake was stimulated by pyruvate but not by lactate. These observations demonstrate the feasibility of preparing intact isolated cells from adult rat heart and their potential value in histologic, pharmacologic, and metabolic studies.
Cytochemical and Physiological Effects of 6-Hydroxydopamine on Periarteriolar Nerves of Frogs
Authors: SIGGINS G. R. , BLOOM F. E.
Published: June 2012

The frog retrolingual membrane was used as a model microcirculatory system for evaluating the role of neural control. Terminal arterioles were studied before and 2 to 21 days after topical application of 6-hydroxydopamine (6-HDA). When arterioles were visualized microscopically in vivo and stimulated directly with a microelectrode, 6-HDA reduced the normal, longitudinally conducted vasoconstriction to a local response. Current intensities needed for threshold responses averaged more than fourfold those of control thresholds. Nerve induced vasoconstriction was abolished, whereas nerve-induced vasodilation persisted after 6-HDA. Ultrastructurally, 6-HDA produced extensive degeneration only in perivascular nerves containing large granular vesicles, although vasomotor nerves with clear vesicles, vascular smooth muscle, Schwann cells, endothelial cells, motor end plates, and striated muscle appeared normal after 6-HDA treatment. Autoradiography and fluorescence histochemistry revealed that the perivascular nerves were no longer capable of taking up or binding exogenous catecholamine. The results indicate that topically applied 6-HDA produces selective dysfunction of adrenergic nerves correlated with fine structural degeneration. The absence of conducted vasoconstrictor responses in this preparation indicates their dependence on an intact adrenergic nerve supply.
Effects of Hypothermia on Norepinephrine Release and Effector Response in Isolated Perfused Cat Spleen
Authors: WENNMALM ÅKE , HEDQVIST PER , STJÄRNE LENNART
Published: June 2012

The effects of hypothermia on the sympathetic neuroeffector junction were studied in the isolated perfused cat spleen. The experiments were aimed at determining the temperature dependence both of prejunctional events, i.e., efflux of norepinephrine from the sympathetic nerves in response to electrical stimulation or to indirectly acting sympathomimetic amines like tyramine or phenethylamine, and of postjunctional events, i.e., the contractile response of the smooth muscle to the norepinephrine liberated. Hypothermia was found to depress both the norepinephrine efflux in response to stimulation and the contractile response to the endogenous norepinephrine released, as well as to exogenous norepinephrine. However, these processes were found to respond differently to temperature change. Thus hypothermia depressed norepinephrine release as well as the pressor responses to tyramine and phenethylamine much more strongly than the corresponding responses to electrical nerve stimulation or the pressor response to exogenous norepinephrine. The results strongly support the concept that sympathomimetic amines release norepinephrine from sympathetic nerves by mechanisms which differ from those mediating norepinephrine release induced by depolarization.
Barium-Induced Automaticity in Relation to Calcium Ions and Norepinephrine in the Rabbit Left Atrium
Authors: TODA NOBORU
Published: June 2012

Membrane potentials were recorded from a region of the left atrium close to the interatrial septum and from an atrial appendage. Pacemaker activity was induced after exposure to Ba
2+
. The magnitude of the resting potential and of the overshoot decreased with increasing [Ba
2+
]o, whereas duration of the action potential and rise time increased with increasing [Ba
2+
]o. Electrical stimulation for 5 sec at 1/sec to left atria showing automaticity produced bradycardia followed by tachycardia. Bradycardia was abolished by atropine; tachycardia was suppressed by propranolol and previous treatment with reserpine. At zero [Ca
2+
]o, threshold concentrations of Ba
2+
for inducing automaticity were lower than those at normal [Ca
2+
]o. Ba
2+
markedly prolonged the action potential plateau in solutions deprived of Ca
2+
. The size of the overshoot was increased and the rise time was shortened despite a significant reduction in the resting potential. Ba
2+
partly restored atrial contractility abolished at zero [Ca
2+
]o. Each electrical discharge evoked an individual contraction, and a sufficiently fast discharge led to summation of the contractions. Pacemaker activity induced by Ba
2+
was suppressed by adding Ca
2+
and Mg
2+
. The threshold potential was raised by Ca
2+
and Mg
2+
. Threshold concentrations of Ba
2+
for inducing automaticity were not influenced by previous treatment with reserpine.

It is postulated that Ba
2+
antagonizes the movement of K
+
across the membrane, resulting in a decrease in the resting potential and a prolongation of the action potential duration, and that Ba
2+
serves as a current-carrying ion at zero [Ca
2+
]o. It seems unlikely that cardiac norepinephrine participates in pacemaker activity induced by Ba
2+
.
Depressed Myocardial Creatine Phosphokinase Activity Following Experimental Myocardial Infarction in Rabbit
Authors: KJEKSHUS JOHN K. , SOBEL BURTON E.
Published: June 2012

Since creatine phosphokinase (CPK) is found predominantly in myocardial and skeletal muscle cells, in contrast to cells participating in the inflammatory response, it was considered likely that measurement of activity of this enzyme in the heart would provide a sensitive and relatively specific index of the extent of ischemic injury following acute coronary artery occlusion. Accordingly, CPK activity was measured serially following coronary artery occlusion in extracts from rabbit myocardium with gross infarction and from normal rabbit left ventricle. In addition, myocardial CPK activity was assayed in extracts from various portions of dog hearts 24 hours after ligation of the coronary artery. CPK activity of rabbit myocardium with infarction was uniformly depressed within 6 hours following coronary occlusion. After 24 hours, activity declined from 15.5±0.9 (mean±SE) to 3.4±0.3. CPK activity in whole left ventricular extracts was depressed and in general, the extent of depression was proportional to the size of the gross infarct. CPK depression in various regions of the dog heart 24 hours after coronary occlusion correlated with the extent of reduction of blood flow determined with the use of radioactively labeled microspheres. Results suggest that depression of myocardial CPK activity may be useful in estimating the extent of tissue damage following experimental coronary artery occlusion and the effect of prophylactic and therapeutic measures on the survival of myocardium in this setting.
Mechanism of Synchronization in Isorhythmic Dissociation
Authors: LEVY MATTHEW N. , ZIESKE HARRISON
Published: June 2012

Third degree heart block was produced in anesthetized dogs by injecting 95% ethanol into the region of the A-V node. When the ventricles were paced artificially at a constant rate near the spontaneous rate of the S-A node, then the atria and ventricles became synchronized. During synchronization, the P wave oscillated rhythmically around the QRS. When the P preceded the QRS, the arterial blood pressure increased, whereas when the P wave followed the QRS, the blood pressure fell. Synchronization depended on such rhythmical fluctuations in blood pressure because (1) when the blood pressure changes were severely attenuated, synchronization ceased, and (2) simulation of the blood pressure changes by means of a servo-controlled pump also produced synchronization. A biological control system operates in such a way that (1) the P-R interval affects blood pressure by virtue of changes in the atrial contribution to ventricular filling; (2) the blood pressure has an inverse effect on atrial frequency through the baroreceptor reflex, and perhaps other mechanisms; and (3) changes in atrial frequency alter the P-R interval, to complete the control loop.
Strength-Duration Curves for Ventricular Defibrillation in Dogs
Authors: GEDDES L. A. , TACKER W. A. , MCFARLANE J. , BOURLAND J.
Published: June 2012

The threshold voltage and current necessary for ventricular defibrillation was measured in dogs using capacitor-discharge and half-sinusoidal pulses of current of various durations. From these quantities the electrical strength required for defibrillation was determined and expressed as energy, peak current, and charge per gram of heart. The optimum current duration depends on the criterion selected. It was found that with half-sinusoidal current, less energy, current, and charge were required; this type of waveform approximates that delivered by capacitor-inductor defibrillators. For minimum energy with this waveform, the optimum duration range is 1.25 to 8.3 msec and the energy required is approximately 7 mw-sec per gram of heart. For minimum current, the optimum duration is 8.3 msec; with this duration the peak half-sinusoidal current is about 30 mamp per gram of heart. There is no clearly defined duration for minimum charge for capacitor-discharge or half-sinusoidal current.
Effects of Calcium and Sodium on Cardiac Contractility and Heat Production in Rabbit Papillary Muscle
Authors: CHAPMAN J. B. , GIBBS C. L. , GIBSON W. R.
Published: June 2012

The effects of altering the concentrations of sodium (Na
+
) and calcium (Ca
2+
) ions on the isometric energy output of rabbit papillary muscle at room temperature were examined by a myothermic technique. The well-known inotropic changes resulting from these alterations were not correlated with parallel changes in the magnitude of the tension-independent heat. Instead, the magnitude of the tension-independent heat was directly correlated with both increasing (Na
+
) concentration and with increasing (Ca
2+
) concentration, and these effects were additive. The energetics of ions pumping in cardiac muscle are discussed quantitatively and it is suggested that the combined enthalpy consumption of both the (Na
+
) and the (Ca
2+
) pumps constitutes the major determinant of cardiac tension-independent heat production.
Studies on the Pathogenesis of Hypertensive Vascular Disease
Authors: HILL GARY S.
Published: June 2012

Repeated high-pressure injection of saline into the arterial system via carotid cannula in normal, ether-anesthetized rats has been previously shown to produce acute necrotizing lesions in the renal vasculature. In this study administration of the vasodilator aminophylline prior to high-pressure injections led to similar lesions, produced in dilated, hyperdistended vessels, at far lower pressures than in control animals, demonstrating that neither vasoconstriction nor the absolute height of blood pressure is a critical determinant in production of lesions. In the second part of the study previous treatment with desoxycorticosterone (DOCA)-saline for 12 to 18 days rendered the renal vasculature abnormally prone to lesions after high-pressure injections, compared with normal rats so injected or those receiving a DOCA-saline regimen only. Glomerular lesions were more severe than can be explained on the basis of simple addition of the lesions resulting from high-pressure injections to those arising from DOCA administration. This increased susceptibility of the vasculature to elevated pressure is probably a function of focal alteration of vascular smooth muscle. These observations support the proposal that hypertensive vascular lesions occur in dilated, hyperdistended vessels and the glomeruli distal to them, the dilatation probably resulting from focal smooth muscle alteration with partial or complete loss of contractility.
Asynchrony of Conduction within the Canine Specialized Purkinje Fiber System
Authors: ANDERSON GARY J. , GREENSPAN KALMAN , BANDURA JACK P. , FISCH CHARLES
Published: June 2012

Asynchrony of conduction may prove to be an important mechanism for reentrant arrhythmias. The purpose of these experiments was to explore asynchronous conduction in the distal branches of the canine Purkinje system. Microelectrodes were placed in Purkinje bundle preparations resembling a T configuration, thereby permitting assessment of differential conduction times induced by premature beats (S
2
).

Equal conduction depression was observed in the post extrasystolic beat (S
1
at wide coupling intervals (S
2
-S
1
). Asynchrony of conduction was frequently observed in response to narrow coupling intervals. These differential conduction times induced disparities of activation times greater than 50 msec. In fibers exhibiting preferential depressed conduction, local block was observed with further decrease in the coupling interval. Disparities of activation times at very short S
2
-S
1
coupling times could be markedly increased by minimal decrease in coupling intervals (in the order of 1 to 5 msec). Conduction depression was not clearly dependent upon the level of "take-off" potential or action potential duration. Asynchronous conduction may thus be induced by narrow coupling of premature beats and could account for reentry.
Prostaglandin-Like Substances Appearing in Canine Renal Venous Blood During Renal Ischemia
Authors: McGIFF JOHN C. , CROWSHAW KEITH , TERRAGNO NORBERTO A. , LONIGRO ANDREW J. , STRAND JAMES C. , WILLIAMSON MARY ANNE , LEE JAMES B. , NG KEVIN K. F.
Published: June 2012

Renal prostaglandins (PC
s
) might mediate an antihypertensive function of the kidney. The blood-superfused organ technique possesses the sensitivity (threshold < 0.4 ng/ml blood) and specificity required for identification of PGs in blood. Induction of unilateral renal ischemia in 14 chloraloseanesthetized dogs reduced renal blood flows from a mean value of 257 to 109 ml/min on the ischemic side and from 250 to 209 ml/min on the contralateral side. Concomitantly, PG-like substances were detected by assay organs in the venous blood of ischemic (13 experiments) and contralateral (11 experiments) kidneys. In one experiment, in a spontaneously hypertensive dog, PGs were not detected during renal ischemia.

Renal venous blood and renal medullary tissue were extracted for acidic lipids and assayed for PG-like substances. Extracts of venous blood collected during renal ischemia and extracts of renal medulla yielded substances with biological activity indistinguishable from PG-like substances or PG standards. Chromatographic characterization of PG-like substances suggests that they are predominantly a mixture of PGE
2
and PGF
2α
.
Current and Potential Fields Generated by Two Dipoles
Authors: AMBROGGI LUIGI DE , TACCARDI BRUNO
Published: June 2012

The distribution of currents and potentials in a circular conducting medium surrounding two eccentric dipoles was studied to establish how much information on the number, location, and orientation of the dipoles could be deduced from measurements of potential in the medium at various distances from the generators. When a single, eccentric dipole was active, the curve illustrating the distribution of potentials along the boundary exhibited different kinds of asymmetry, which revealed that the dipole was eccentric and gave some information about its orientation. When both dipoles were active, two maxima and two minima, revealing the presence of two generators, appeared along the boundary when the angle between dipole moments was 150° or more. Along internal circumferences two maxima and two minima appeared at smaller angles between dipole moments and the location of the maxima was closely related to that of the dipole anodes. When the dipoles lay on the same diameter and had opposite polarity, the presence of two generators was clearly detectable from boundary measurements, whereas vector representation was zero. These data improve our understanding of electrical signals recorded from the body surface, whether in the form of electrocardiograms, vectorcardiograms, or equipotential contour maps.
Reversibility of Poststenotic Dilatation in the Femoral Arteries of Dogs
Authors: ROACH MARGOT R.
Published: June 2012

Poststenotic dilatation (PSD) was produced in the femoral arteries of 14 adult dogs. After 9 days to 5 months, the band was removed. If the murmur disappeared, as it did immediately in all but four arteries, the PSD disappeared within 24 hours (studied radiologically by painting the arteries with radio-opaque thorium dioxide). In these four, the dilatation disappeared after the murmur did. Six arteries were studied at half-hour intervals for 16 hours after removal of band. In all of these, the dilatation increased during the first half hour, and then disappeared completely in 6 to 8 hours. Long term follow-up for 6 months showed no changes in diameter after the initial 24-hour period. The altered elastic properties of the distal segment previously described for the dilated segment returned to normal soon after the band was removed. The mechanism of this change is unknown, but may be produced by alterations of elastin crosslinks by vibration. We conclude that poststenotic dilatation is reversible, at least in the femoral arteries of dogs, if correction of the stenosis is associated with disappearance of the turbulence. The change is very rapid, and so does not appear related to synthesis of new connective tissue.
Myocardial Contraction Frequency and Onset of Cardiac Glycoside Action
Authors: KOCH-WESER JAN
Published: June 2012

Left atrial strips and right ventricular papillary muscles of kittens and left atrial strips of guinea pigs, rabbits, dogs, and chickens were exposed to ouabain, acetylstrophanthidin, or digoxin at 37°C during rest or while contracting at frequencies from 0.06 to 60/min. Both the positive inotropic effect and increases in resting tension developed fully in all preparations exposed to the three drugs during complete quiescence. Contraction frequency had some influence on the rate of development of these effects, but this influence was not the result of the number of beats during exposure. In ventricular myocardium, exposure times required for the attainment of the maximum positive inotropic effect and for the induction of contracture at different contraction frequencies were proportional to the increase in tension development. It is concluded that the development of the myocardial effects of digitalis-like compounds does not require cardiac activity. The limited influence of contraction frequency on the rate of development of these effects may be partly due to frequency-dependent changes in the functional state of the myocardium which affect the magnitude of the positive inotropic action of cardiac glycosides.
Effect of Oxygen on Growth of Cultured Myocardial Cells
Authors: HOLLENBERG MILTON
Published: June 2012

The present study was designed to explore the effects of environmental oxygen as a possible regulator of cardiac cell division and growth. Trypsindispersed heart cells from the ventricles of chick embryos 8 to 12 days old were grown in culture at 37°C in a nutrient medium (NCI) with 10% fetal calf serum. They were exposed to constant 5% CO
2
gas environments in which the percent of O
2
was varied. Net protein synthesis increased progressively as O
2
was reduced from 80% to 2 to 5%. After the first 24 hours, little further protein synthesis occurred in plates grown in 80% O
2
. The rates of cellular incorporation of
14
C-amino acids and uridine-2-
14
C increased progressively as the fraction of O
2
was reduced. In cells grown at 80% O
2
, incorporation of uridine-2-
14
C into RNA was impaired before that of
14
C-amino acid into protein. After actinomycin-D (5 µg/ml) (which quickly halted uridine incorporation into the rapidly labeled fraction of RNA), the rate of incorporation of
14
C-amino acid into protein declined exponentially. This allowed for calculation of the half-life of messenger RNA (mRNA), which was the same for cells grown at 80% O
2
as for cells grown at 20% O
2
; increased degradation of mRNA at higher P
o
2
is thus ruled out. Decreased O
2
tension results in increased rates of cell division and protein synthesis in vitro. The molecular site of action appears to be at or before RNA readout from DNA.
New Technique for Determining Instantaneous Myocardial Force-Velocity Relations in the Intact Heart
Authors: GROSSMAN WILLIAM , BROOKS HAROLD , MEISTER STEVEN , SHERMAN HERBERT , DEXTER LEWIS
Published: June 2012

A new technique is described for the instantaneous determination of myocardial force-velocity relationships. The method employs electronic differentiation of the logarithm of intraventricular pressure, which yields a continuous on-line record of (dP/dt)P
-1
(the ratio of the rate of rise of ventricular pressure [dP/dt] to the simultaneous ventricular pressure [P]). A further technique is described for the automatic projection of force-velocity vector loops, displaying (dP/dt)P
-1
on the ordinate against ventricular pressure on the abscissa in a beat-to-beat fashion. An excellent correlation (
r
=0.982) was demonstrated between (dP/dt)P
-1
determined by conventional methods and that derived electronically by use of the logarithmic amplifier circuit. Experimental studies are described which document the responsiveness of (dP/dt)P
-1
determined by the present method to interventions known to affect myocardial contractility. An increase in (dP/dt)P
-1
was observed following infusions of CaCl
2
, norepinephrine, and glucagon, and a decrease following pentobarbital. Insofar as (dP/dt)P
-1
is a valid index of myocardial contractility, the present method permits on-line, beat-to-beat evaluation of changes in ventricular function under a variety of circumstances.
Serum Dopamine-Beta-Hydroxylase Activity
Authors: WEINSHILBOUM RICHARD , AXELROD JULIUS
Published: June 2012

Dopamine-β-hydroxylase, the enzyme which converts dopamine to norepinephrine, is released into the perfusate upon stimulation of the isolated perfused adrenal gland and after stimulation of the nerves to the isolated perfused spleen. This study was undertaken to determine whether dopamine-β-hydroxylase activity could be detected circulating in blood. By using a sensitive new enzymatic assay, a dopamine-β-hydroxylase activity was found in the blood of both man and the rat. It is located in the serum and is not associated with the formed elements of blood. The serum activity is similar to that of purified bovine adrenal dopamine-β-hydroxylase in that it requires the presence of ascorbic acid, catalase, fumarate and oxygen for full activity. Furthermore, as is also the case with the adrenal enzyme, serum activity is increased in the presence of cupric ions. The Km values for substrate in human and rat sera are similar, and both are close to values determined in rat adrenal glands and stellate ganglia. The mean activity ±
SE
in the serum of six rats was 2.27±.04 nmoles/ml serum/20 min, and that of four normal humans ranged from 96.2 to 284 nmoles/ml/20 min.
Atrial Transmural Pressures during Experimental Pericardial Tamponade
Authors: BRECHER GERHARD A. , GILBERT CHARLES A.
Published: June 2012

To elucidate the mechanism responsible for the occurrence of negative transmural atrial pressures in pericardial tamponade, saline or air was progressively injected into the pericardial sac. In 14 anesthetized, open-chest dogs, left atrial (LA), left ventricular (LV), and pericardial pressures (PP) were measured with catheter tip manometers. In beating and fibrillated hearts, measurements were carried out at normovolemia, hypovolemia and hypervolemia. Transmural atrial pressure (TAP = LA - PP) became negative when the PP reached 130 mm H
2
O whether the heart was beating or not. In normovolemia the relation between TAP and PP was: TAP (mm H
2
O) = 38.1--0.237PP--0.00042PP
2
. In anesthetized, closed-chest dogs, air inflation of pleural space produced pressures around the heart similar to those obtained in pericardial tamponade. With such pneumothorax, no negative TAP occurred either with beating or quiescent hearts. It is hypothesized that pericardial filling stiffens the pliable structures surrounding the heart and thereby diminishes the collapsibility of the atrial walls which form the inner part of the pericardial sac. Veins entering the atria through the filled pericardial sac are held open like the hole in an inflated inner tube. Through these mechanisms some cardiac filling is assured even with marked pericardial tamponade.
Blood Hyperosmolality and Pulmonary Vascular Resistance in the Cat
Authors: HAUGE ANTON , Bφ GUNNAR
Published: June 2012

Blood osmolality rises during general muscle exercise. The purpose of this work was to investigate the effect of similar slow, graded rises of blood osmolality on pulmonary vascular resistance. Hyperosmolar solutions of sodium chloride, mannitol, urea, glucose, thiourea and ethylene glycol were infused into the left lower lobe pulmonary arterial branch in the cat. Lobe blood flow, pulmonary arterial, left atrial and systemic arterial pressures were recorded. With the exception of ethylene glycol, all the test solutions caused dose-dependent, reversible reductions in lobe vascular resistance (LVR). Maximal reduction in LVR was 30% of initial value. A rise of blood osmolality of 25 milliosmols/liter, comparable with levels found during exercise, caused a 10% reduction in LVR. Hyperosmolar solutions of ethylene glycol, which has the highest rate of cell wall penetration of the test substances, caused no change in LVR. Bolus injections of 1M solutions of sodium chloride caused rapid transient rises in LVR. It appears that the resistance vessels of the lungs react to graded rises of blood osmolality in a way qualitatively similar to that seen in the resistance vessels of skeletal muscle.
Effects of Prostaglandin A
1
on the Systemic and Coronary Circulations in the Conscious Dog
Authors: HIGGINS CHARLES B. , VATNER STEPHEN F. , FRANKLIN DEAN , PATRICK THOMAS , BRAUNWALD EUGENE , MCKOWN DANIEL P. , HENDRICK DAVID
Published: June 2012

The effects of intravenous prostaglandin A
1
(PGA
1
) on systemic and coronary hemodynamics were studied in 13 intact, conscious dogs after recovery from operation for implantation of Doppler ultrasonic flow probes on the ascending aorta and left circumflex coronary artery. Graded doses of PGA
1
(0.01 to 1.0 µg/kg) caused arterial pressure and total systemic resistance to decrease progressively and heart rate and cardiac output to increase progressively. At the maximum dose administered (1.0 µg/kg), arterial pressure and systemic resistance decreased by averages of 30% and 51% below control, respectively, and heart rate and cardiac output rose 64% and 47%, respectively. After beta-receptor blockade with propranolol, PGA
1
still caused a similar increase in cardiac output. In spite of arterial hypotension, PGA
1
produced a progressive increase in coronary flow, with a peak increase of 74% above control with 1.0 µg/kg and a corresponding graded decrease in coronary resistance, with a decrease of 61% below control with 1.0 µg/kg. Marked increases occurred in systolic as well as diastolic coronary flow. The coronary vasodilation was not abolished by preventing the PGA
1
-induced tachycardia with electrical pacing, by beta-receptor blockade, or by combined blockade of beta receptors and cholinergic nerve fibers. While arterial Po
2
remained constant, coronary sinus Po
2
rose when coronary flow was increased by PGA
1
. Thus PGA
1
is both a primary and secondary coronary vasodilator which increases cardiac output and decreases total systemic resistance.