bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Implications of a Newly Characterized Pathway of 11,12-Epoxyeicosatrienoic Acid Metabolism in Arterial Smooth Muscle
Authors: Fang Xiang , Kaduce Terry L. , Weintraub Neal L. , VanRollins Mike , Spector Arthur A.
Published: June 2012

Epoxyeicosatrienoic acids (EETs) are potent vasodilators derived from cytochrome P-450 metabolism of arachidonic acid. The rapid conversion of EETs to their corresponding dihydroxyeicosatrienoic acids (DHETs) has been proposed as a process whereby EETs are rendered biologically inactive. However, the vascular metabolism of EETs and the vasoactivities of EET metabolites have not been extensively studied. Accordingly, 11,12-EET metabolism was characterized in porcine aortic smooth muscle cells. The cells converted [
3
H]11,12-EET to 11,12-DHET and to a newly identified metabolite, 7,8-dihydroxy-hexadecadienoic acid (DHHD). 11,12-DHET accumulation in the medium reached a maximum in 2 to 4 hours and then declined, whereas 7,8-DHHD accumulation increased continuously and exceeded the amount of 11,12-DHET by 8 hours. [
3
H]11,12-EET conversion to radiolabeled 7,8-DHHD was reduced in the presence of unlabeled 11,12-DHET, indicating that 11,12-DHET is an intermediate in the conversion of 11,12-EET to 7,8-DHHD. This is consistent with a pathway whereby 11,12-EET is converted by an epoxide hydrolase to 11,12-DHET, which then undergoes two β-oxidations to form 7,8-DHHD. In porcine coronary artery rings contracted with a thromboxane mimetic, 11,12-DHET produced relaxation similar in magnitude to that produced by 11,12-EET (77% versus 64% relaxation at 5 μmol/L, respectively). 7,8-DHHD also produced vasorelaxation. Thus, the vasoactivity of 11,12-EET is not eliminated by conversion to 11,12-DHET and 7,8-DHHD. These results suggest that 11,12-DHET and its metabolite, 7,8-DHHD, may contribute to the regulation of vascular tone in the porcine coronary artery and possibly other vascular tissues.
Angiotensin II Stimulates MAP Kinase Kinase Kinase Activity in Vascular Smooth Muscle Cells
Authors: Liao Duan-Fang , Duff Jennifer L. , Daum Guenter , Pelech Steven L. , Berk Bradford C.
Published: June 2012

Both angiotensin II (Ang II) and platelet-derived growth factor (PDGF) rapidly increase intracellular Ca
2+
and activate protein kinase C (PKC) and MAP kinase in vascular smooth muscle cells (VSMCs). However, Ang II causes cell hypertrophy, whereas PDGF causes hyperplasia. These findings indicate that VSMCs are a good model for studying the relationship between cell growth and the MAP kinase pathway. In this study, we investigated the role of Raf in activation of 42- and 44-kD MAP kinases. Western blot analysis showed that c-Raf-1 was the predominant Raf isozyme in cultured rat aortic VSMCs. In response to Ang II, there was translocation of Raf to the membrane, which occurred significantly earlier than MAP kinase activation, suggesting that Raf activation precedes MAP kinase activation. Translocation of Raf to the membrane resulted in association with H-Ras as shown by c-Raf-1 coprecipitation with anti-Ras antibodies. Western blot analysis of H-Ras immunoprecipitates revealed c-Raf-1, but c-
mos
, MEK (MAP kinase/extracellular signal-regulated kinase) kinase-1 (MEKK-1), and Raf-B were not present. MAP kinase kinase kinase (MAPKKK) activity was assayed in c-Raf-1 and H-Ras immunoprecipitates by MAP kinase kinase–dependent phosphorylation of catalytically inactive 42-kD MAP kinase. In Ras immunoprecipitates, MAPKKK activity was stimulated approximately threefold by both Ang II and PDGF, with a peak at 5 minutes. Downregulation of PKC by 24-hour exposure to phorbol ester significantly inhibited Ang II–stimulated and PDGF-stimulated MAPKKK activity (≈80% decrease) and Raf translocation (≈90% decrease), suggesting that a phorbol-responsive PKC is upstream from MAPKKK and Raf. In contrast, Ang II (but not PDGF) stimulation of MAP kinase was unaffected by PKC downregulation or pharmacological PKC inhibition. These findings demonstrate for the first time that Ang II stimulation of MAP kinase may occur via a pathway independent of c-Raf-1 and of the phorbol-responsive PKC isozymes. The differing effects of Ang II and PDGF on VSMC growth may be a consequence of specific signal transduction events, as demonstrated here for activation of MAP kinase.
Gender Differences in Coronary Artery Diameter Involve Estrogen, Nitric Oxide, and Ca
2+
-Dependent K
+
Channels
Authors: Wellman George C. , Bonev Adrian D. , Nelson Mark T. , Brayden Joseph E.
Published: June 2012

During their reproductive years, women have a much lower incidence of coronary heart disease compared with men of similar age. Estrogen appears to be largely responsible for this decrease in cardiovascular mortality in women. In the present study, isolated pressurized coronary arteries from rats were used to assess the role of gender and circulating estrogen on coronary vascular function. Pressure-induced constrictions (“myogenic tone”) were greater (≈2-fold) in isolated coronary arteries from estrogen-deficient male or ovariectomized (OVX) rats compared with similar arteries obtained from female rats or OVX rats receiving physiological levels of estrogen replacement (OVX+E group). These differences in coronary artery diameter were abolished by removal of the vascular endothelium or chemical inhibition of NO synthase. The anti-estrogen, tamoxifen, increased pressure-induced constrictions of coronary arteries from female and OVX+E rats. Dilations of pressurized coronary arteries from female and OVX animals to sodium nitroprusside, a nitrovasodilator that generates NO, were reduced by >50% by iberiotoxin (IBTX), an inhibitor of Ca
2+
-dependent K
+
(K
Ca
) channels. Sodium nitroprusside (10 μmol/L) hyperpolarized coronary arteries by 13±2 mV, an effect that was greatly diminished (≈80%) by IBTX. Coronary arteries isolated from female rats produced greater constrictions in response to IBTX and KT 5823, an inhibitor of cGMP-dependent protein kinase, compared with coronary arteries from OVX rats. cGMP-dependent protein kinase increased the activity of K
Ca
channels 16.5±5-fold in excised membrane patches from smooth muscle cells enzymatically isolated from these small coronary arteries. We propose that physiological levels of circulating 17β-estradiol elevate basal NO release from the endothelial cells, which increases the diameter of pressurized coronary arteries. Further, our results suggest that part of the effect of this NO is through activation of K
Ca
channels in the smooth muscle cells of the coronary arteries.
Triggered Propagated Contractions in Rat Cardiac Trabeculae
Authors: Zhang Ying Ming , Miura Masahito , ter Keurs H.E.D.J.
Published: June 2012

We studied the role of Ca
2+
diffusion through gap junctions (GJs) in triggering and propagation of damage-induced contractions in cardiac muscle (TPCs) by evaluating effects of the GJ blockers octanol and heptanol (O&H) on TPCs. TPCs were elicited in trabeculae from rat right ventricle superfused with Krebs-Henseleit solution at 20°C and 0.7 to 1.75 mmol/L [Ca
2+
]
o
. Force was measured with a silicon strain gauge; sarcomere length, by laser diffraction techniques. O&H (3 to 300 μmol/L) decreased force, propagation velocity, and triggering rate of TPCs in a dose-dependent manner. At 300 μmol/L, O&H decreased TPC force to 21.3% and 25.7%, propagation velocity to 15.4% and 13.0%, and triggering rate to 26.5% and 25.7%. At 300 μmol/L, O&H decreased twitch force to 79.0% and 77.8% and reduced time to 90% relaxation by 10% to 15%. Above 1 mmol/L, O&H abolished twitch force and TPCs. Image analysis of spread of the fluorescence profile of microinjected fura 2 salt revealed an effective diffusion coefficient for fura 2 of 21.0±3.3 μm
2
/s, which decreased to 12.6±1.5 and 7.07±0.7 μm
2
/s after 1 and 3 hours of exposure, respectively, to 100 μmol/L octanol, with a time constant of decline of 1.5±0.5 hours. These results are consistent with the hypothesis that propagation of TPCs is due to Ca
2+
-induced Ca
2+
release mediated by Ca
2+
diffusion from cell to cell through GJs. Reduction of propagation velocity reduces the number of activated sarcomeres in the TPC, which reduces TPC force. O&H slow triggering of TPCs, presumably by blocking Ca
2+
diffusion from myocytes within damaged areas to adjacent normal cells.
Regulation of Cardiac Ca
2+
Release Channel (Ryanodine Receptor) by Ca
2+
, H
+
, Mg
2+
, and Adenine Nucleotides Under Normal and Simulated Ischemic Conditions
Authors: Xu Le , Mann Geoffrey , Meissner Gerhard
Published: June 2012

In myocardial ischemia, pH
i
and [ATP] fall, whereas the free [Ca
2+
] and [Mg
2+
] rise. The effects of these changes on cardiac Ca
2+
release channel (ryanodine receptor) activity were investigated in [
3
H]ryanodine binding and single-channel measurements, using isolated membrane and purified channel preparations. In the absence of the two channel ligands Mg
2+
and ATP, cardiac Ca
2+
release channels were half-maximally activated at pH 7.4 by ≈4 μmol/L cytosolic Ca
2+
and half-maximally inhibited by ≈9 mmol/L cytosolic Ca
2+
. Regulation of channel activity by Ca
2+
was modulated by Mg
2+
and ATP. Single-channel activities were more sensitive to a change of cytosolic pH than SR lumenal pH. Reduction in lumenal and/or cytosolic pH from 7.3 to 6.5 and 6.0 resulted in decreased single-channel activities without a change in single-channel conductance. [
3
H]Ryanodine binding measurements also indicated that acidosis impairs cardiac Ca
2+
release channel activity. Mg
2+
and adenine nucleotide concentrations regulated the extent of inhibition and the Ca
2+
dependence of binding. In the presence of 5 mmol/L Mg
2+
and 5 mmol/L β,γ-methyleneadenosine 5′-triphosphate (AMPPCP, a nonhydrolyzable ATP analogue), the free [Ca
2+
] for half-maximal [
3
H]ryanodine binding was increased from 1.9 μmol/L at pH 7.3 to 36 μmol/L at pH 6.5 and to 89 μmol/L at pH 6.2. These results suggest that ionic and metabolic changes that might be expected to affect sarcoplasmic reticulum Ca
2+
release channel activity in ischemic myocardium include an altered Ca
2+
sensitivity of the channel, a fall in pH, and a loss of the high-energy adenine nucleotide pool, leading to an increased inhibition by Mg
2+
.
Binding of the Novel Nonxanthine A
2A
Adenosine Receptor Antagonist [
3
H]SCH58261 to Coronary Artery Membranes
Authors: Belardinelli Luiz , Shryock John C. , Ruble Jackie , Monopoli Angela , Dionisotti Silvio , Ongini Ennio , Dennis Donn M. , Baker Stephen P.
Published: June 2012

This study demonstrates quantification of A
2A
adenosine receptors (A
2A
AdoRs) in membranes prepared from porcine coronary arteries, porcine striatum, and PC12 cells. Radioligand binding assays were performed using the new selective A
2A
AdoR antagonist radioligand [
3
H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-ε]-1,2,4-triazolo[1,5-
c
)pyrimidine ([
3
H]SCH58261). Binding of the radioligand to membranes was rapid, reversible, and saturable. The densities of A
2A
AdoRs in membranes prepared from porcine coronary arteries, porcine striatum, and PC12 cells were 900±61, 892±35, and 959±76 fmol/mg protein, respectively. Equilibrium dissociation constants (
K
d
values) calculated from results of saturation binding assays were 2.19, 1.20, and 0.81 nmol/L, and
K
d
values calculated from results of association and dissociation assays were 2.42, 1.01, and 0.40 nmol/L for [
3
H]SCH58261 binding to membranes prepared from porcine coronary arteries, porcine striatum, and PC12 cells, respectively. The specific binding of [
3
H]SCH58261 as a percentage of total binding at a radioligand concentration equal to the
K
d
value was 65% to 90% in the three membrane preparations. The order of ligand potencies determined by assay of competition binding to sites in porcine coronary membranes using [
3
H]SCH58261, unlabeled antagonists (
SCH58261
, 8-(3-chlorostyryl)caffeine [CSC], and xanthine amine congener [XAC]), and unlabeled agonists ([
3
H]2-
p
-(2-carboxyethyl)phenethylamino-5′-
N
-ethylcarboxamidoadenosine [CGS 21680], 2-hexynyl-5′-
N
-ethylcarboxamidoadenosine [HE-NECA], [
3
H]5′-
N
-ethylcarboxamidoadenosine [NECA], and
R
(−)
N
6
-(2-phenylisopropyl)adenosine [R-PIA]) was
SCH58261
>HE-NECA=CSC=CGS 21680=XAC>NECA=R-PIA. The Hill coefficients of displacement by A
2A
AdoR ligands of [
3
H]SCH58261 binding were not significantly different from unity, indicating that [
3
H]SCH58261 bound to a group of homogeneous noninteracting sites in all membrane preparations. The order of ligand potencies to compete for [
3
H]SCH58261 binding sites in porcine striatal and PC12 cell membranes was, in part, different from that for porcine coronary arterial membranes. The different rank orders of potencies for agonists and antagonists at A
2A
receptors of porcine coronary arteries, striatum, and PC12 cells and significant differences in absolute values of potency of ligands in the three preparations may indicate the existence of different subtypes of A
2A
AdoRs. The antagonist radioligand [
3
H]SCH58261 should be of value for pharmacological characterization of A
2A
adenosine receptors in other preparations.
Potential Changes Attending the Excitation Process in the Atrioventricular Conduction System of Bovine and Canine Hearts
Authors: PRUITT RAYMOND D. , ESSEX HIRAM E.
Published: June 2012

Potential changes attending excitation of the atrioventricular node, the common bundle, the bundle branches, and initial ramifications of the conducting tissue in the subendocardium of the bovine heart beating in situ have been recorded from unipolar exploring electrodes. Correlations between the form of nodal deflection and the location in the node of the electrode tip have been established. From right bundle branch and subendocardial action potentials, data were derived indicating a rate of transmission through the right branch of 2.02 M/sec. Certain observations on the effects of acute injury and severe hypoxia are recorded. The character of nodal deflections attending retrograde excitation is reviewed.

In studies on canine hearts beating
in situ
, electrograms have been made from the regions in which the atrioventricular node, the common bundle, and bundle branches are believed to lie. Deflections comparable to those recorded in bovine experiments were encountered and, by analogy with those bovine studies, certain morphologic correlations postulated. In general, canine nodal deflections are smaller than their bovine counterparts and lack the variety of form ascribed to potential changes in the several portions of the bovine node. In canine studies, deflections of atrial, atrionodal, and nodal type coexisted in recordings from a single needle electrode suggesting a degree of proximity between the sources of these potential changes not encountered in bovine experiments.
Left Ventricle as a Mixing Chamber
Authors: IRISAWA H. , WILSON M. F. , RUSHMER R. F.
Published: June 2012

It is generally assumed that blood is completely mixed while passing through a ventricular chamber. This assumption underlies use of indicator dilution technics for estimation of ventricular volume. In the left ventricle of the exposed canine heart, complete mixing of blood and injected saline during one cycle was rare, especially if the heart rate was in the normal range. Computations of absolute ventricular volume are subject to error if they are based on the assumption that indicator injected into the ventricular cavity becomes uniformly dispersed throughout the ventricular cavity before the end of diastole.
A Cineradiographic Study of the Snake Heart
Authors: JOHANSEN KJELL , HOL RAGNAR
Published: June 2012

Cineradiographic studies on the cardiovascular system in snakes form the basis of this report. The method provides anatomical informations at the functional level and differs greatly from classical anatomical studies. The physiological interpretations involve timing of the various heart phases and the active role of the right atrium during ventricular filling. The snake ventricle has an incomplete septum and the admixture problem is discussed, as are also some considerations regarding the pulmonary circulation and the reserve mechanism of the snake heart.
Effects of Experimental Regional Ischemia and Levarterenol on the RS-T Segment and Baseline of Ventricular Surface Electrocardiograms Obtained by Direct-Coupled Amplification
Authors: KATCHER A. H. , PEIRCE G. , SAYEN J. J.
Published: June 2012

Conventional electrocardiographie equipment (capacitance-coupled amplification) cannot distinguish between RS-T segment and baseline shifts of the ventricular complex. The so-called RS-T segment displacement is the net difference between the undetermined levels of those components. Using direct-coupled amplification, the absolute changes of baseline and RS-T segment on the surface of the exposed left ventricle during levarterenol administration and during regional ischemia, and release-recovery were studied in dogs. Ten significant patterns of displacement were observed. These permitted clear differentiation of the effects of levarterenol injection and hyperperfusion from those of ischemia. The centers and borders of an ischemic area could be distinguished and the change with prolonged ischemia described. The relationship of these observations to the literature and pertinent studies of intracellular action potentials are discussed.
Local Effects of Sodium, Calcium and Magnesium Upon Small and Large Blood Vessels of the Dog Forelimb
Authors: HADDY FRANCIS J.
Published: June 2012

Resistance to blood flow through the small vessels of the dog foreleg decreased following local elevation of serum sodium and magnesium concentrations. Small vessel resistance increased following elevation of calcium concentration. Associated with the former changes was decreased responsiveness to levarterenol and methacholine. These changes likely result from effects of the cations upon the smooth muscle cell of the arteriole.
Components of the "Central" Blood Volume in the Dog
Authors: MARSHALL ROBERT J. , WANG YANG , SHEPHERD JOHN T.
Published: June 2012

The indicator-dilution method was used in the dog in an attempt to define the proportion of the "central" blood volume contained in the lung vessels. When injections were made into the pulmonary artery with sampling from the femoral artery only half or even less of the calculated blood volume could be accounted for by the lungs. When a venous injection site was used, the proportion in the lungs was reduced to a third or less. Thus when peripheral sites are used for the inscription of indicator-dilution curves few deductions can be made about either the actual volume or even relative changes in the volume of blood in the lungs.
Pattern of Cholesterol Ester Fatty Acids in Serum in Normal Subjects and in Patients with Essential Hypercholesterolemia
Authors: BJOÖRNTORP PER , HOOD BERTIL
Published: June 2012

Sera from 10 patients with essential hypercholesterolemia on ad libitum diet have been analyzed for their content of polyunsaturated fatty acids in the cholesterol esters and the results compared with a matched group of normal subjects. Three cases were analyzed after corn oil substitution for other fats in the diet, and 2 of them were analyzed after addition of pyridoxine to the corn oil regimen. One patient was followed 18 months, and during that time he received a large dosage of corn oil.

Patients with essential hypercholesterolemia had an absolute increase in the amount, but generally a lower percentage content of dienes in their cholesterol esters than normals. After the change to corn oil, the content of polyunsaturated fatty acids increased to levels sometimes considerably above those in the normal subjects, although the total serum cholesterol in one of these cases was by no means normalized. The addition of 100 mg. of pyridoxine to the corn oil regimen did not produce any further decrease in the serum cholesterol level and did not produce any changes in the fatty acid fractions.

The absolute increase in the amount of polyunsaturated fatty acids in the cholesterol esters in essential hypercholesterolemia, particularly after an extremely high intake of unsaturated fat, speaks against factors causing an inhibition in esterification with polyenes as being of central importance.
Cardiopulmonary Effects of Pulmonary Venous Hypertension with Special Reference to Pulmonary Lymphatic Flow
Authors: RABIN ERWIN R. , MEYER EDWARD C.
Published: June 2012

Acute elevation of left atrial pressure could be precisely controlled at any desired level up to a mean of 60 mm. Hg in dogs with an intact thorax. The following observations were made in a series of 15 dogs. Right lymphatic duct flow did not increase at acutely elevated left atrial mean pressure below 25 mm. Hg, whereas flow increased 3- to 4-fold at mean pressure above 25 mm. Hg. The total amount of lymph at maximum flow, however, was only 0.3 ml./min. Lymph flow remained elevated for as long as 1 hour after left atrial pressure was restored to normal. Elevation of left atrial pressure did not affect lymph flow in the thoracic duct. Pulmonary edema did not occur readily at left atrial mean pressure elevated only slightly above plasma oncotic pressure. The production of pulmonary edema was observed only after a considerable elevation of left atrial pressure above plasma oncotic pressure was maintained for a period of one half hour or more in an otherwise normal dog. The hematocrit increased significantly after a 10-minute period of high left atrial pressure. Pulmonary vascular resistance decreased sharply as left atrial mean pressure was raised from 0 to 15 mm. Hg. The resistance gradually rose as left atrial pressure was raised to between 15 and 30 mm. Hg. Pulmonary arterial pressure uniformly rose and cardiac output uniformly declined with increasing left atrial pressure.

Chronic elevation of left atrial pressure was achieved in 15 dogs. Left atrial mean pressure varied from 10 to 23 mm. Hg. These dogs were followed up to 10 months and the following observations were made. Right lymphatic duct flow did not increase at chronically elevated left atrial mean pressure below 25 mm. Hg. Flow was not studied at higher pressures since we were unable to sustain left atrial mean pressure above 25 mm. Hg in any dog in our chronic group. The animals that were brought to left atrial mean pressure between 30 and 40 mm. Hg and in whom these high levels were presumably maintained were found dead in their cages with pulmonary edema 1 to 2 days after tightening the snare. Many of the usual functional and structural changes often found in lungs of patients with mitral stenosis, except for hemosiderosis, were not observed in our experimental animals although the extent of the supravalvular stenosis produced was marked. Pulmonary arterial pressure rose slightly and cardiac output declined slightly. No change was noted in pulmonary vascular resistance. Ascites and other signs of right sided failure were not encountered.
Relative Effect of Chronic Ischemia and a Myocardial Revascularization Procedure on the Ventricular Fibrillation Threshold
Authors: MACLEAN LLOYD D. , PHIBBS CLIFFORD M.
Published: June 2012

Since ventricular fibrillation is the predominate cause of death following experimental coronary occlusion, measurement of the ventricular fibrillation threshold is recommended to assess the value of cardiac revascularization procedures. This determination is quantitative, precise and permits measurement under controlled circumstances. It was dissatisfaction with measurement of mortality rate following coronary occlusion in control and experimental animals (bioassay technic) that led to the adoption of the present more exact method.

Acute ligation of the anterior descending branch of the left coronary artery causes an immediate drop in the fibrillation threshold to one-fifth of normal. This is not changed if one releases the artery and retests the animal with occlusion 5 to 6 months later. Implantation of the internal mammary artery into the myocardium of the left ventricle creates a greater resistance to ventricular fibrillation after coronary occlusion. In animals in which the internal mammary artery remained patent, the fibrillation threshold remained after coronary occlusion at 85 per cent (mean) of control without coronary occlusion. This was highly significant. If the internal mammary artery was thrombosed, as demonstrated by vinyl plastic injection technics, the fibrillation threshold dropped markedly after coronary occlusion and did not vary significantly from the controls. When the anterior descending branch of the left coronary artery was permanently ligated in 1 group of dogs, the expected decline of fibrillation threshold occurred. When the survivals from this group were retested 5 to 6 months later, the fibrillation threshold had increased slightly (not statistically significant) but remained below 50 per cent of control without coronary occlusion and significantly different from the threshold of animals with patent internal mammary artery implants.

The results of this investigation suggest that a greater resistance to ventricular fibrillation associated with coronary occlusion can be achieved by operative means than by either mild or severe ischemia alone.
Electrocardiographic Changes Produced by Potassium and Other Ions Injected into the Coronary Arteries of Intact Dogs
Authors: SOLOFF LOUIS A. , DE LOS SANTOS GUIDO ASCANIO , OPPENHEIMER M. J.
Published: June 2012

Ions injected into the circumflex branch of the left coronary artery of the intact dog produce sequential electrocardiographic changes different from those produced by exposure of the entire heart to these ions. Of all substances tested, the contour of the surface electrocardiogram is most sensitive to potassium. The electrocardiographic sequence of alterations produced by potassium so injected are characteristic and similar to those produced by subtotal and total occlusion of a coronary artery.
Regulation of Cardiac Output Through Stroke Volume
Authors: WARNER HOMER R. , TORONTO ALAN F.
Published: June 2012

Heart rate was controlled by direct stimulation of the right ventricle of a dog previously subjected to complete A-V block in order to study the effect of this variable on cardiac output. Measurements of cardiac output were made at various heart rates in unanesthetized dogs, both at rest and walking on a treadmill. Except at the extremes, cardiac output was independent of heart rate at rest and during mild exercise. This finding emphasizes the fact that cardiac output may be regulated to provide required flow through changes in stroke volume alone, even though adjustment of heart rate is the usual means for obtaining this end.
"Unidirectional" Atrioventricular Conduction Studied by Microelectrodes
Authors: SANO TOYOMI , OHTSUKA EHCHI , SHIMAMOTO TAKIO
Published: June 2012

By applying microelectrode technic in isolated dog hearts, the nature of the so-called unidirectional conduction of the atrioventricular conduction was investigated. Retrograde conduction, i.e., conduction from the ventricle, occurred frequently in the isolated whole heart from which the sinus node was removed, or in a preparation composed of the interatrial septum, right atrium, right ventricle, interventricular septum, and atrioventricular conduction system. Retrograde conduction was blocked just as frequently. In such cases, this unidirectional block was found not to be ascribed solely to the refractory period of the atrioventricular node or of the atrial muscle fibers. The site of unidirectional block was found to be located in the domain of the ventricle, i.e., in the region adjacent to the postero-inferior margin of the membranous portion of the interventricular septum. This site is of a very limited extension. This point responded to ventricular stimuli, frequently by localized depolarization only, or in the manner of decremental conduction, whereas following atrial stimuli, it responded with full-sized action potential. By histologic examination, it was found that this point is situated in the ventricular portion of the bundle of His, just above the bifurcating point to the right and left branches.
Pulmonary Vasomotor Responses to Epinephrine and Norepinephrine in the Cat
Authors: DUKE HELEN N. , STEDEFORD R. D.
Published: June 2012

Constant intravenous infusion of epinephrine has no effect on the pulmonary vascular resistance (P.V.R.) of the cat under chloralose anesthesia, either when the chest is opened and artificial ventilation is used, or when the animal is respiring naturally. The same dose of epinephrine given after removal of the stellate ganglia and upper 4 to 5 thoracic sympathetic ganglia, can cause an increase of P.V.R. Removal of such ganglia causes a decrease of P.V.R. Electrical stimulation of the cardiac branches from both stellate ganglia causes either an increase or a decrease of P.V.R. Increases of P.V.R. have been produced by intravenous infusion of norepinephrine.
Influence of Cholesterol Feeding on Phospholipid Metabolism of Connective Tissue
Authors: McCANDLESS ESTHER L. , BAILEY ROBERT E. , ZILVERSMIT D. B.
Published: June 2012

Subcutaneous injection of carrageenan, a sulfated polygalactose extracted from the red algae
Chondrus crispus
, stimulated the production of fibrous connective tissue in the rabbit. Animals fed cholesterol for 3 and 5 weeks had significantly higher phospholipid concentrations in this connective tissue than did control rabbits, but no alteration in phospholipid specific activity. These results are similar to those obtained in preliminary studies of connective tissue cultured by the sponge implantation technic.

Significant increases occurred in cephalin, lecithin, and sphingomyelin concentrations in tissue proliferated after cearrageenan injection. The cholesterol content of connective tissue was increased 7- to 8-fold.

Histologically, the tissue taken after 3 weeks of cholesterol feeding could not be distinguished from that of control animals. At 5 weeks, connective tissue from cholesterol-fed rabbits contained mature fat cells and macrophages resembling foam cells, in addition to the fibroblasts and collagen present in control tissue. Development of collagenous fibers and alterations in lipids were not found to be directly related. It is suggested that the elaboration of collagen and the accumulation of phospholipid, both of which occur in experimental atheromatosis, represent independent processes of connective tissue cells.
Effect of Treatment with Radioactive Iodine and Iodine-Deficient Diet on Development and Maintenance of Renal Hypertension in Rats
Authors: FREGLY M. J. , GENNARO J. F. , OTIS A. B. , Baker M. I. , S. Jacobson, , M. Glichman
Published: June 2012

Treatment of kidney encapsulated rats with 850 µC. of radioactive iodine effectively prevented both the characteristic rise of blood pressure to hypertensive levels and cardiac hypertrophy. Iodine-deficient diet was ineffective under these conditions. Once hypertension was established, treatment with 850 µC. radioactive iodine lowered blood pressure toward normal levels although a significant decrease in heart weight was not observed. The iodine-deficient diet was also ineffective under these conditions. It is felt that hypothyroidism produced by administration of high doses of radioactive iodine is as effective in preventing blood pressure rise as that observed with propylthiouracil treatment. The antihypertensive effect of these antithyroid treatments appears to be the direct result of inhibition of secretion of thyroid hormone.
Inhibition of Experimental Hypercholesterolemia and Atherogenesis by 4-Amino Pteroylglutamic Acid (Aminopterin)
Authors: MUSCHENHEIM CARL , ADVOCATE SEYMOUR , HOSKINS DONALD W.
Published: June 2012

Rabbits pretreated with Aminopterin (4-amino pteroylglutamic acid) for 4 weeks were fed an atherogenic diet for 8 weeks, during which Aminopterin injections also were continued. The atherogenic diet consisted of a stock diet with 3/4 per cent cholesterol added. As a result of some manipulation of the Aminopterin dosage during the period before cholesterol feeding was begun, some of the Aminopterin-treated animals lost weight from overdosage, and 7 of the original 20 died. The surviving animals upon reduction of dosage made good weight gains, comparable to the controls, during the cholesterol feeding period. When sacrificed after 8 weeks of cholesterol feeding, the control animals, 21 in number, all had grossly demonstrable 1+ to 4+ atheromatosis of the aorta. Of the 13 surviving Aminopterin-treated animals, 9 had no atheromatosis or doubtful deposits of minimal extent. Only 4 had definite atheromatosis comparable in extent to the controls. Serum cholesterol levels were 30 to 50 per cent lower in the treated animals than in the controls.
Spread of Activity Through the Atrioventricular Node
Authors: DE CARVALHO ANTONIO PAES , DE ALMEIDA DARCY F.
Published: June 2012

Electrophysiologic mapping experiments on the excitation of the A-V node of isolated rabbit heart have been performed with intracellular microelectrodes. An area of tissue showing peculiar physiologic characteristics was shown to coincide, at least in part, with the histologic A-V node and His bundle. Three functional regions have been determined in the physiologic mapping of the A-V node. The middle layer (N) shows signs of decremental conduction and is the site of the slowest propagation velocity in the A-V node. The other layers are transitional regions between the N layer and atrium (AN) or the His bundle (NH). The AN layer shows a progressively slower propagation velocity as the N region is approached. The same holds for the NH region. A precise correlation between these findings and the 3 existent histologic layers remains to be determined. The existence of an area of peculiar tissue just above the A-V valves and encircling the A-V orifice has been confirmed. This area is continuous with the AN layer of the functional A-V node and has been named the atrioventricular ring (AVR) on the assumption that it is a remnant of the embryonic A-V ring. Wenckebach cycles and A-V block of nodal origin are tentatively explained as resulting from increased decrement in the middle nodal layer (N).
Effects of Epinephrine on Frog Ventricle
Authors: HENNACY RICHARD A.
Published: June 2012

Thirty-six isolated frog ventricles were attached to an inflow cannula with stopcocks that could permit direct systolic ejection back into the reservoir, return flow back to the reservoir by another route through a valve, or isochorie contractions. The heart, enclosed in a container with a "U" tube outlet, produced pressure changes (extra-cardiac) which could be used in determining the in-flow rate and transmural pressures. The rate of change of the transmural pressure was calculated for the frog ventricle during early diastole. This value was taken as a measurement of the rate of relaxation. The effects of epinephrine (.02 µg./ml.) were studied. At low filling pressures without valves (and therefore with outflow pressure equal to inflow pressure), epinephrine slows the rate of relaxation, although other inotropic effects, such as an increase in stroke volumes, are present. If, however, the heart contracts against a high outflow pressure or resistance the rate of relaxation is increased by epinephrine. The slowing of relaxation in the former case is a result of filling commencing before relaxation is complete. In the isochoric heart, epinephrine does not change the time of positive tension, but does accelerate the relaxation after contraction.
Ability of Serotonin and Norepinephrine to Mimic the Central Effects of Reserpine on Vasomotor Activity
Authors: McCUBBIN J. W. , KANEKO Y. , PAGE IRVINE H.
Published: June 2012

Reserpine, serotonin, norepinephrine, 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine had qualitatively the same cardiovascular effects when they were injected into a lateral ventricle or into the cisterna magna. All lowered arterial pressure, usually caused bradycardia despite prior section of the vagus nerves, and caused marked inhibition of the pressor response to occlusion of the common carotid arteries. Essentially the same results were obtained in unanesthetized as in anesthetized dogs. On a weight basis, norepinephrine was the more active amine tested and 5-hydroxytryptophan was more active than serotonin and 3,4 dihydroxyphenylalanine. Reserpine injected centrally had an effect equivalent to that of 20 or more times larger dosage given intravenously. All drugs were more active against the response to carotid occlusion than against the reflex pressor response to stimulation of a cut central end of a sciatic or vagus nerve. Decreased afferent electric activity of the carotid sinus nerve accompanied lowering of arterial pressure following central injection of small dosage, or intravenous injection of large dosage, of 5-hydroxytryptophan, indicating that the cardiovascular effects are not due to a direct action of 5-hydroxytryptophan on carotid sinus baroceptors.

Central injection of an amine oxidase inhibitor, beta-phenylisopropylhydrazine, markedly augmented and prolonged the cardiovascular effects of the amines and of reserpine as well.

These results are all consistent with, though they do not validate, the premise that the acute cardiovascular effects of reserpine are mediated centrally by serotonin and/or norepinephrine, either released from a bound and inactive to a free and active form, or formed by decarboxylation of their respective amino acids.
Hemodynamic Effects of Methoxamine in Mitral Valve Disease
Authors: STANFILED C. ALPHEUS , YU PAUL N.
Published: June 2012

The hemodynamic changes following elevation of systemic arterial pressure and total systemic resistance by methoxamine were studied by right heart catheterization in 18 patients with mitral valve disease and 4 patients with no significant cardiovascular abnormality. This is the first detailed report of the circulatory effects of this drug in man. Changes in oxygen consumption, arterial oxygen saturation, stroke index and pulmonary artery to pulmonary "capillary" mean pressure gradient were insignificant. Forward cardiac index and heart rate decreased significantly while arteriovenous oxygen difference increased markedly in all groups of patients. The hemodynamic mechanisms involved in the changes observed during methoxamine infusion are discussed. Characteristic of patients with mitral insufficiency were significant increments of pulmonary arterial mean, pulmonary "capillary" mean, and pulmonary "capillary" V peak pressures. These subjects also had significantly greater increments in "left heart" resistance than patients without mitral insufficiency. An elevation of pulmonary "capillary" V peak pressure of 35 per cent or more of the elevation of systemic arterial systolic pressure was found to be a useful index of the presence of mitral insufficiency. Study of the pulmonary "capillary" pressure records during methoxamine infusion may obviate the necessity of left heart catheterization in the detection of significant mitral insufficiency.
Persistent Hypertension in the Dog Following Disruption of the Carotid Sinus Nerves and Subsequent Unilateral Renal Artery Constriction
Authors: KEZDI PAUL
Published: June 2012

Constriction of 1 renal artery in combination with disruption of the carotid sinus nerves resulted in moderate chronic hypertension in dogs. Hypertension persisted at the same level in some of the animals after removal of the kidney 1 year later, while in others blood pressure decreased somewhat though not to the prehypertensive control level. Narrowing of 1 renal artery without carotid nerve disruption did not lead to significant chronic hypertension. Disruption of the carotid sinus nerves alone, on the other hand, produced mild to moderate hypertension. Constriction of 1 renal artery, if performed several months after carotid nerve disruption, further increased the blood pressure in these animals. Tests of the carotid sinus nerves function by the occlusion reflex of the common carotids indicated a return of function several months after disruption in animals in which the carotid sinus nerves were only crushed. Hypertension persisted in these animals despite the return of the carotid sinus function. Tetraethylammonium choride given intravenously to combined carotid sinus-unilateral renal hypertensive dogs resulted in blood pressure decrease similar to that produced in normal animals. Glomerular filtration rate and renal plasma flow decreased, and filtration fraction increased in 3 dogs following production of the combined type of hypertension.
Longitudinal Waves in the Walls of Fluid-Filled Elastic Tubes
Authors: VAN CITTERS ROBERT L.
Published: June 2012

Experiments with a rubber tube model of the aorta have demonstrated the presence of longitudinal waves in the wall of the tubing. This mode of vibration was predicted by Lamb from the theoretical considerations, but has not previously been described. The characteristics of "impact waves" in arteries and of the longitudinal mural waves in the model appear to be similar. Longitudinal waves undoubtedly influence the arterial pulse contour. Theoretically, the damping coefficient for them is the same as that for radial waves.
Direct Measurement of Bronchial Arterial Flow
Authors: HORISBERGER BRUNO , RODBARD SIMON
Published: June 2012

A method is described for the measurement of the collateral pulmonary blood flow in the thoracotomized dog by utilization of a flow-meter which measures flow into an aortic sac from which the bronchial arteries arise. This preparation maintains the normal perfusing pressures and diminishes phase changes in the arterial pulse waves. The bronchial vascular resistance is increased by an increase in the insufflation air pressure, by bilateral vagotomy, or by the administration of
l
-epinephrine into the bronchial arterial circulation. The bronchial vascular resistance was decreased after a transitory interruption of the bronchial arterial blood flow (reactive hyperemia). After administration of serotonin in the bronchial artery, a transient increase in resistance was followed by a marked decrease. Intrapulmonary vascular injections produced only a decrease in resistance. The present data demonstrate the sensitivity of the preparation described.
Cardiac Malformations in Rats Induced by Exposure of the Mother to Carbon Dioxide During Pregnancy
Authors: HARING OLGA M.
Published: June 2012

Seventy-one pregnant rats of a Sprague-Dawley strain were exposed for a single 24-hour period to a gas mixture of 6 per cent carbon dioxide, 20 per cent oxygen and 74 per cent nitrogen on different days during gestation. There were 530 offspring and these were compared with 159 newborn rats from 21 control dams. The incidence of cardiac malformations was 23.4 per cent in the test group and 6.8 per cent in the control group with the highest incidence in the test group occurring when the exposure was on the tenth day of gestation. Isolated ventricular septal defects, situated in the lower and posterior part of the muscle septum, were found in 8 cases, ventricular septal defects with overriding aorta in 24 cases and ventricular septal defects with partial transposition in 20 cases. Forty-seven of the abnormal hearts had a myocardial thickening accompanied by narrowing of the pulmonic or aortic outflow channel with or without other abnormalities, such as atresia of the mitral or tricuspid valves and hypoplasia of the aorta or pulmonary artery. There was a slight increase in perinatal mortality in the test group, and a lower frequency of male offspring. The average body weight was 18.9 per cent higher in the test group.
Effects of Hypertensin on Arterial Pressure, Heart Work and Cardiac Oxygen Utilization
Authors: FORTE IVAN E. , POTGIETER LOUIS , SCHMITTHENNER JERRY E. , WILLIAM A. JANE , WILLIAM A. JANE , NEAL HUNTER , TOUSSEF SHAKASHIR , RICHARD ROBERT , Hafkenschiel J. H.
Published: June 2012

Pharmacodynamically induced changes in left ventricular work, using an intravenous infusion of Hypertensin, were studied in intact anesthetized dogs. Coronary and systemic hemodynamics and cardiac metabolism under a combined morphine- "Dial" -urethane-pentobarbital-sodium (MDUP) anesthesia were measured during the action of the drug. The significant hemodynamic changes induced were increased mean arterial pressure and increased left ventricular work. A greater cardiac lactate utilization during the Hypertensin infusion was the only change in cardiac metabolism. The oxygen tension in left ventricular venous blood was not reduced during the action of the drug.
Involvement of Phosphorylation in Doxorubicin-Mediated Myofibril Degeneration
Authors: Sussman Mark A. , Hamm-Alvarez Sarah F. , Vilalta Patricia M. , Welch Sara , Kedes Larry
Published: June 2012

Loss of myofilaments has been observed in both adaptive cardiac responses (ie, hypertrophy) as well as in chemotheraputic use of antineoplastic drugs with cardiotoxic side effects (ie, doxorubicin). An understanding of the degenerative process is a prerequisite for determining approaches to limit the cardiomyopathic changes associated with chronic heart disease or long-term chemotheraputic treatments. However, little is known about the specific events and molecular changes that initiate the degenerative process. To study this process, neonatal rat cardiomyocytes were treated with doxorubicin, which induced rapid and widespread thin-filament degeneration as observed by fluorescence confocal microscopy. which demonstrated deterioration of sarcomeric thin-filament structure. Changes in the spontaneous beating of cardiomyocytes corresponding with myofibrillar degeneration were apparent using differential interference contrast video microscopy. After finding induction of kinase activity by doxorubicin in cultured cardiomyocytes, the protective effects of specific inhibitors of kinase activity were assessed for their ability to inhibit doxorubicin-induced myofibrillar breakdown. Doxorubicin-induced changes appeared similar to the degeneration observed after treatment with a protein kinase activator (phorbol 12-myristate 13-acetate) or a serine-threonine protein phosphatase inhibitor (okadaic acid). Collectively, these results indicate that activation of protein kinase is an important event in the initiation of myofibrillar degeneration by doxorubicin. Further analyses of myofibrillar proteins with respect to biochemical modifications will be necessary to determine if phosphorylation events transmit signal(s) to initiate degeneration.
Termination of Reentry by Lidocaine in the Tricuspid Ring In Vitro
Authors: Fei Hailing , Yazmajian Dina , Hanna Michael S. , Frame Lawrence H.
Published: June 2012

We hypothesized that drugs with rapid recovery kinetics from use-dependent sodium channel block could promote oscillatory termination of reentry by enhancing interval-dependent conduction. Mechanisms of termination were related to properties of the reentrant circuit. Nine adjustable reentrant preparations were used in which the canine atrial tricuspid ring was cut and then reconnected electronically by sensing activation on one side of the cut and pacing the other after an adjustable delay. The cycle length and diastolic interval during reentry were manipulated by changing this delay. Lidocaine (1.28×10
−5
mol/L) significantly increased refractoriness (94±39 ms) and the slope of the conduction curve (−0.12±0.07) at the site of block during pacing. Lidocaine terminated sustained reentry by two mechanisms. Early termination resulted from increased cycle length oscillation and refractoriness (reproducible in each experiment) but only at short delays with short initial diastolic intervals. The range of delays showing this mechanism of termination was 100±48 ms. Increased cycle-length oscillation resulted from an increased slope of the conduction curve. In eight experiments, lidocaine terminated reentry by causing fixed block after 50 minutes of drug superfusion, which prevented reentry at all delays. Fixed block occurred at one of two vulnerable sites and was transiently reversed by acetylcholine. Termination due to refractory block occurred only when the initial diastolic interval was short, and termination due to fixed block developed when there was a susceptible region with a low safety factor for propagation. Fast recovery from sodium channel block promotes oscillatory termination by increasing the slope of the conduction curve.