bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Drugs on the Pulmonary Circulation and Ventilation as Reflected by Changes in the Arterial Oxygen Saturation
Authors: NIDEN ALBERT H. , BURROWS BENJAMIN , BARCLAY WILLIAM R.
Published: June 2012

The effect of:
l
-epinephrine, acetylcholine, histamine, aminophylline, and serotonin on Ihe pulmonary circulation and ventilation was studied in anesthetized dogs. The following observations were noted: Serotonin produced an increase in arterial oxygen saturation, the other drugs a decrease. Although reduced, the effect was not eliminated by controlling the volume of ventilation or by the inhalation of 25 or 30 percent oxygen. The administration of 100 percent oxygen eliminated the response in all dogs studied. The effect was not abolished by controlling blood flow in addition to ventilation. Changes in the over-all ventilation/perfusion ratio appeared of major importance. In addition, these drugs apparently produced local changes in ventilation/perfusion ratios (physiologic shunting) and/or in the degree of anatomic intrapulmonary shunting of blood.

The effects of changes in pulmonary blood flow on peripheral arterial oxygen saturation were also investigated. With the volume of ventilation constant, the following was observed : Increasing pulmonary blood flow by whatever means decreased SaO
2
; decreasing blood flow resulted in an increase in SaO
2
.
Possible Reasons for Drop of Resting Potential of Mammalian Heart Preparations During Hypothermia
Authors: DÉLÉZE JEAN
Published: June 2012

Between 37 and 20 C., the resting potential of sheep ventricular and Purkinje fibers was found to be proportional to the absolute temperature. Prom 20 to 0 C., the potential drop was 3 times greater than that predicted from the theory of a concentration potential. Rapid heating by high-frequency current of previously cooled preparations, revealed no time lag between the rise of potential and the rise of temperature. Fibers kept in a Na-free solution still showed a large temperature sensitivity. With poisoned fibers, the resting potential was almost proportional to the absolute temperature. The results appear to contradict the hypothesis that extracellular K accumulation in the cold is the cause of the potential drop. They also exclude the hypothesis that a relative rise of the Na-inward current is the reason for depolarization. They support the idea that "active" extrusion of Na ions normally contributes to the resting potential, and that the pumping rate decreases considerably in the cold.
Adrenal Medullary Secretion of Epinephrine and Norepinephrine in Dogs Subjected to Hemorrhagic Hypotension
Authors: GLAVIANO VINCENT V. , BASS NOEL , NYKIEL FLORIAN
Published: June 2012

The response of the adrenal medulla in anesthetized dogs to hemorrhagic hypotension of a varied level and duration was observed to be primarily accompanied by a highly significant increase in adrenal plasma epinephrine. On the other hand, the secretion of norepinephrine had an unpredictable occurrence in adrenal blood samples collected in periods of hypotension. The essential determinant of adrenal blood flow was observed to be the level of mean blood pressure. While this relationship was not in strict proportion, changes in mean blood pressure were invariably followed by changes in adrenal blood flow in the same direction. The adrenal medulla of dogs in hemorrhagic irreversible shock was observed to continue to secrete epinephrine at very low levels of mean blood pressure, characteristic of terminal shock. Reports by other groups of investigators on elevated peripheral blood levels of epinephrine in hemorrhagic shock have been found to result mainly from an actively secreting adrenal medulla.
Characteristics of the Frequency Spectrum in the Normal Electrocardiogram and in Subjects Following Myocardial Infarction
Authors: LANGNER PAUL H. , GESELOWITZ DAVID B.
Published: June 2012

The results of a study of the sealar electrocardiogram, utilizing a wide-band recorder, expanded time scale and a low-pass filter, indicate that a recorder flat to at least 500 c.p.s. is required for faithful reproduction. With a high-pass filter, measurable residual signals are present at a cut-off frequency of 1,000 c.p.s., or higher. Therefore, to record these, an adequate response at 1,000 c.p.s. or more is reqnired. The high frequency energy of the electrocardiographic spectrum arises from the fast deflections contained in the original waveform. These may occur in a single fast deflection, notching, or both. Whereas, in the normal individual, high frequency energy usually arises from a relatively smooth, fast deflection, in abnormals the fast events may occur in conjunction with notching, and other deformities. Judging from the technic used in this experiment, a variable band-pass filter is valuable as an aid for studying the high frequency components of the electrocardiogram and establishing equipment requirements. Measurement of peak-to-peak voltage of residual signals gives partial but lot clear-cut separation of normal and abnormal subjects and would not seem to add to the value of high-fidelity electrocardiography per se in routine clinical diagnosis. It is possible that root mean square readings, reflecting the total energy content, might give a better separation between normal and abnormal subjects than peak-to-peak amplitude alone.
General and Pulmonary Hemodynamic Effects of Pure Decapeptide Angiotensin in Normotensive Man
Authors: SANCETTA SALVATORE M.
Published: June 2012

Purified natural decapeptide angiotensin was infused intravenously at a constant rate for 32 minutes in 5 normotensive subjects. There was no significant change in the cardiac output. There were significant increases in the pulmonary artery, the pulmonary wedge, and the brachial artery pressures. There were significant increases in the systemic vascular and the total pulmonary resistances. There was no significant change in the pulmonary arteriolar resistance. The data indicate that angiotensin I produces peripheral arteriolar constriction and fail to demonstrate a concomitant pulmonary arteriolar constriction. Thus, they are consistent with an hypothesis implicating angiotensin as a causative agent in human essential hypertension.
Special Issue: Significance of Tissue Chromaffin Cells and Mast Cells in Man
Authors: PHILLIPS JOHN H. , BURCH GEORGE E. , HIBBS RICHARD G.
Published: June 2012

Tissue mast cells have been a source of great curiosity since their conclusive description by Ehrlich over 80 years ago. They have been implicated in a vast majority of connective tissue reactions both of physiologic and pathologic nature. In some species at least, mast cells have been implicated in the production, storage and release of potent cardiovascular substances including heparin, serotonin and histamine.

The present report is directed particularly toward man. Evidence is presented suggesting that human tissue cells previously lumped into one large group on the basis of granular metachromasia and termed tissue mast cells, represent at least two morphologically distinct cellular types. Difference in function of these cells may be great. There is evidence that one type may be a local tissue source for epinephrine, norepinephrine, or both. It is suggested that mast cells as a whole may represent a spectrum of cell types having numerous differences in ultrastructure and function. It is believed that their continued study in various physiologic and pathologic states should prove fruitful.
Effect of Acute Myocardial Infarction on Electrical Recovery and Transmural Temperature Gradient in Left Ventricular Wall of Dogs
Authors: REYNOLDS ERNEST W. , ARK CONDON R. VANDER , JOHNSTON FRANKLIN D.
Published: June 2012

Accelerated recovery, as manifested by shortening of the effective refractory period after coronary artery ligation, occurred at either the epicardial or endocardial surface or both in 11 of 13 animals tested with a mean shortening of 15.7 per cent at the epicardial and 13 per cent at the endocardial levels. These changes are attributed to severe anoxia and are believed to be limited to the ischemic area, since studies in the periphery of an infarcted zone show no significant changes in the first 3 hours. In one instance a minor acceleration of recovery was found after 3 hours at the endocardium. All studies showed a final period of delayed recovery. It is felt that this probably reflects a prolonged duration of the membrane action potential during the later stages of myocardial infarction. This is supported by both experimental and human electrocardiographic data which show prolongation of the Q-T interval in association with deeply inverted T waves following the period of acute injury. Transmural temperature studies after coronary artery ligation showed a prompt fall in 2 studies out of 7 and no acute change in the others. Irrigating the pericardial sac with warm Ringer's solution reversed the pre-existing transmural temperature gradient, caused the T waves in epicardial leads to change from negative to positive, and reduced the duration of the effective refractory period at both the endocardial and epicardial surfaces, especially the latter. During the time that the T waves were upright, recovery was completed earlier at the epicardial than at the endocardial surface.
Nitrogen-Free Plasmalogen Observed in Infarcted Myocardium of the Dog
Authors: HACK M. H. , FERRANS V. J.
Published: June 2012

Heart tissue from dogs in which myocardial infarction was induced experimentally was analyzed histochemically and chromatographically for plasmalogens. A new, nitrogen-free plasmalogen was observed that was confined to the infarcted area; marked histochemical alterations in the pattern of distribution of the plasmalogens occurred. The new plasmalogen is believed to be a polymer of phosphatidic acid plasmalogen.
Metabolism of Cholesterol-4-C
14
in Bile Duct Cannulated Chicks and Rats
Authors: NISHIDA TOSHIRO , UENO AKIRA , KUMMEROW FRED A.
Published: June 2012

The level of dietary protein influenced the rate of cholesterol-4-C
14
catabolism in bile duct cannulated chicks and rats. Animals which had been kept on a high protein diet for 5 weeks excreted cholesterol-4-C
14
as bile acids at a faster rate than those on a low protein diet. The presence of dietary cholesterol did not change the rate of cholesterol-4-C
14
catabolism at either high or low dietary protein levels. A species difference in the rate of cholesterol catabolism was also noted. Bile duct cannulated chicks excreted an average of only 8 per cent, while bile duct cannulated rats excreted as much as 46 per cent of injected cholesterol-4-C
14
in a 72 hour period. It was shown that cannulation of the bile ducts caused a significant decrease in the serum cholesterol and serum β-lipoprotein levels in chicks. Furthermore, the liver cholesterol level did not seem to influence the rate of cholesterol catabolism. Serum cholesterol, especially in the form of low Sf β-lipoproteins, appeared to be used rapidly for the conversion of cholesterol to bile acids.
Regional Uptake of Radioactive Oxygen, Carbon Monoxide and Carbon Dioxide in the Lungs of Patients with Mitral Stenosis
Authors: DOLLERY C. T. , WEST J. B.
Published: June 2012

Using radioactive oxygen (O
15
), carbon monoxide and carbon dioxide with external counting over the chest, it is possible to measure perfusion and diffusion per unit of lung volume. Patients with mitral stenosis, particularly those with high pulmonary artery pressures, may show a higher blood flow through the upper zone of the lung than the lower. This distribution of blood flow is the reverse of that found in normal subjects. The observed changes in blood flow are consistent with the radiological and pathological changes in the pulmonary vascular tree in mitral stenosis.
Increased Sensitivity to Corticosterone as a Possible Factor in the Development of Adrenal Regeneration Hypertension
Authors: SKELTON FLOYD R.
Published: June 2012

The suggestion that the pathogenesis of adrenal-regeneration hypertension might involve sensitization to the hypertensive properties of corticosterone by the period of cortical insufficiency which follows adrenal enucleation has been investigated. Nonhypertensive doses of corticosterone were given to uninephrectomized, salt-treated and adrenalectomized rats after periods of insufficiency of variable length and to similar rats bearing regenerating adrenals, beginning such treatment at intervals after enucleation. The following conclusions have been drawn from the data obtained: (1) Adrenal cortical insufficiency for as long as 2 weeks did not sensitize to the hypertension-inducing property of corticosterone; (2) Corticosterone administration to rats bearing regenerating adrenals, beginning treatment up to 3 weeks after operation, did not enhance the development of hypertension or increase the severity of vascular lesions.
Dye Dilution in Canine Heart-Lung Preparations
Authors: SHEPPARD C. W. , COUCH BILLY L. , CROWDER BENNETT L.
Published: June 2012

In a large series of canine heart-lung preparations, system volumes were determined by the T 1824 dye bolus teehnic of Hamilton. Results were compared with volumes independently determined by equilibration of label in a recirculating system. The mean differences of values in the largest group of experiments was 3.9 ml., and was not significantly different from zero. A small but significant mean difference in a second smaller group is discussed relative to the basic postulates of the method.
Cofibrins and Fibrin-Intermediates as Indicators of Thrombin Activity in Vivo
Authors: SHAINOFF JOHN R. , PAGE IRVINE H. , Andrasi Miss Dolores
Published: June 2012

A cold-precipitable, thrombin-coagulable protein, tentatively designated "cryoprofibrin," was separated from plasma of rabbits treated with
E. coli
endotoxin. It was shown to contain fibrin-intermediates, consisting of fibrinogen that has lost only a portion of the peptides liberated during the conversion of rabbit fibrinogen to fibrin. These peptides have been called cofibrins. On reaction with thrombin, fibrinogen and cryoprofibrin yielded the same amount of cofibrin B (0.9 moles per 220,000 Gm. of fibrin clot); however, cryoprofibrin yielded 30 per cent less cofibrin A than did fibrinogen. Cryoprofibrin and fibrinogen yielded 0.7 and 1.0 moles of cofibrin A per 220,000 Gm. of fibrin, respectively. The deficit of cofibrin A in preference to cofibrin B provides evidence that, cryoprofibrin consists of fibrinogen that had lost cofibrin A by limited action of thrombin, because cofibrin A is liberated from fibrinogen by thrombin more rapidly than is cofibrin B.

Only a small portion of the cryoprofibrin could have been produced by action of thrombin subsequent to exsanguination, because the plasma contained only about one-third of the cofibrin A that had been liberated from fibrin-ogen during its conversion to cryoprofibrin. Accordingly, cryoprofibrin provides a valid measure of thrombin activity in vivo, at least in the endotoxin-treated rabbits.

An alternative approach to measurement of thrombin activity involving recovery of cofibrin A from urine proved inapplicable, because no confibrin A was found to be excreted in urine.

An average of 0.264 ± 0.038 mg. cryoprofibrin per ml. was obtained from plasma of treated rabbits, as compared with 0.044 ± 0.016 mg. of cold-precipitable fibrinogen per ml. of normal plasma. The demonstration of increased thrombin activity after endotoxin treatment, as evidenced by the cryoprofibrin, implicates thrombin in the mechanism of fibrinoid deposition. The demonstration that cryoprofibrin consists of fibrin-intermediates supports Thomas' hypothesis that fibrinoid consists of fibrin-intermediates.
Distribution and Transcapillary Exchange of Albumin in Congestive Heart Failure
Authors: ROSS RICHARD S. , WALKER W. GORDON , HAMMOND JOHN D. S.
Published: June 2012

The distribution and transcapillary exchange of albumin have been studied in patients with congestive heart failure and the results compared with a group of control subjects who did not have heart failure.

The normal relation between vascular albumin mass and plasma volume on the one hand and transcapillary albumin exchange on the other does not exist in patients with congestive failure. The transcapillary albumin exchange rate, which presumably reflects capillary permeability, is decreased relative to the plasma volume and vascular albumin mass. It appears that decreased permeability of capillaries to albumin is associated with congestive failure and may be responsible for the increased plasma volume characteristic of this disease.

The appearance of labeled protein in edema fluid has been studied in 7 patients and compared with the simultaneously determined serum disappearance curves. The albumin contained in the edema fluid constitutes a small fraction of the total extravascular albumin pool. The vascular albumin mass equilibrates less rapidly with the local edema albumin mass than with the total extravasenlar albumin mass.
Role of the Veins in Venous Return
Authors: BARTELSTONE HERBERT J.
Published: June 2012

The major vessel occlusion method applied to the supine, anesthetized dog with an open chest has proven useful in elucidating the role of the venous system in the complex phenomenon of venous return. This method momentarily isolates a large part of the venous system from the arterial system and from the action of the heart and the respiratory and muscle pumps. Simultaneous occlusion of the thoracic inferior vena cava and the descending aorta (MVO) divides the dog's circulation into a cephalad zone and a caudad zone. Experimentally induced changes in the status of the cephalad circulation during MVO can affect the caudad zone only through neuronal pathways. Therefore, MVO makes it possible to investigate the responses of the venous system to vascular reflex activity as well as direct and indirect actions of drugs. During the "resting" state, blood returns to the heart because of the existence of a venous pressure gradient of 3 to 4 mm. Hg, operant between the reactive venous reservoir and the central venous conduit ("intra-venous" gradient). Augmentation of sympathetic tone produces an increase in venous return, of venous origin, due to an increase in the effective "intra-venous" pressure gradient from 3 to 4 mm. Hg to 5 to 10 mm. Hg. The ability of the venous system to increase venous return independently, has been shown to be a significant factor in the
arterial
hypertensive response to carotid occlusion. The venous system can serve as a buffer against the effects of sudden, momentary changes in arterial flow by maintaining, reducing, or augmenting venous return.
Relation Between Left Ventricular Diastolic Pressure and Myocardial Segment Length and Observations on the Contribution of Atrial Systole
Authors: LINDEN R. J. , MITCHELL J. H.
Published: June 2012

A method is described for the continuous recording of changes in the length of a segment of left ventricular myocardium, and its advantages and limitations are discussed. The curve depicting the relation between ventricular diastolic pressure and simultaneous changes in the length of a myocardial segment is presented. For a given increment in pressure, the myocardial segment length increases more at low ventricular diastolic pressure than at high pressure. Atrial systole causes a substantial increase in myocardial segment length when the ventricle is on the sensitive part of its pressure-length curve.
Regulation of Ventricular Contraction by the Carotid Sinus
Authors: SARNOFF S. J. , GILMORE J. P. , BROCKMAN S. K. , MITCHELL J. H. , LINDEN R. J.
Published: June 2012

A lowering of pressure in the carotid sinus reflexly increases the force of atrial systole by (a) increasing sympathetic activity to the heart (carotido-sympatho-atrial reflex) and(b) decreasing efferent vagal activity to the heart (carotido-vago-atrial reflex); an elevation of carotid pressure has the reverse effect. The carotid sinus can thereby vary ventricular end-diastolic pressure and fiber length. A change of pressure in the carotid sinus reflexly modifies the ventricle's contractility such that from a given end-diastolic pressure or fiber length, with a low carotid pressure the ventricle's contraction will be substantially augmented and from a high carotid pressure it will be diminished. The role of the carotid sinus in circulatory regulation has been likened to a voltage regulating element in an electronic system; i.e., it causes an appropriate variation of input into the system so as to maintain a constant voltage when the current requirements of the system it is supplying are changed.
Reflex Circulatory Effects Elicited by Hypertonic and Hypotonic Solutions Injected into Femoral and Brachial Arteries of Dogs
Authors: LASSER RICHARD P. , SCHOENFELD MYRON R. , ALLEN DOUGLAS F. , FRIEDBERG CHARLES K. , Lalosi Dimitri
Published: June 2012

Rapid injection of 40 ml. of 5 per cent saline into the femoral or brachial arteries of 24 dogs resulted in an average elevation of arterial blood pressure of +42/+20 mm. Hg, an increase in the heart rate of +20 beats/min., and an acceleration of the respiratory rate of +140 per cent. The response began 6 to 10 seconds after the onset of injection and lasted for 5 to 30 minutes. It occurred with the injection of hypertonic solution of saline, dextrose, and urea. The magnitude of the response was related to the degree of hypertonicity. Responses could be provoked by 10 ml. of 1.25 per cent saline. Rapid intra-arterial injection of isotonic saline, dextrose, and urea solutions, and of whole blood in volumes up to 80 ml. had no circulatory effect. Rapid injection of distilled water, 0.225 per cent and 0.45 per cent saline into the femoral or brachial arteries resulted in a slight degree of hypotension and a rise in the respiratory rate. The appearance of circulating catechol amines following the response to intra-arterial injection of hypertonic solutions was suggested by the demonstration of hypotensive response to intravenous injection of phentolamine. These responses to injection of hypertonic and hypotonic solutions in the femoral artery were abolished by section of the sciatic nerve in animals with an ipsilateral partially-transected hind limb, a preparation which left intact only the femoral artery, femoral vein, and femur. Sciatic section in the intact limb reduced but did not abolish the response. Removal of the sympathetic chain from the eleventh thoracic through the third lumbar ganglia had no apparent effect. It is concluded that the response to femoral aud brachial intra-arterial injection of hypertonic and hypotonic solutions is initiated by peripherally located "osmoreceptors" in the distribution of these arteries and is mediated via a reflex whose afferent fibers travel in the peripheral somatic nerves and enter the spinal cord without passing through the sympathetic chain. The efferent are is the sympathetic nervous system.
Effect of Ischemia and Reoxygenation on Glycolytic Reactions and Adenosinetriphosphate in Heart Muscle
Authors: DANFORTH WILLIAM H. , NAEGLE SIEGFRIED , BING R. J.
Published: June 2012

During a 15-minute period of myocardial ischemia, glycogen concentration fell. This decrease was roughly accounted for by increases in hexosemonophosphate and lactic acid. Fructose 1,6-diphosphate, dihydroxyace-tone-phosphate and pyruvate did not accumulate. The myocardial concentration of adenosinetriphosphate declined. Reperfusion of the ischemie heart with oxygenated blood was accompanied by inconstant changes in myocardial glycogen and by rapid lowering of hexosemonophosphate. The hexosemonophosphate decrease occurred even when the ischemie myocardium was perfused with a deoxygenated buffered salt solution and is attributed in part at least to lactic acid washout. Adeno-sinetriphosphate rose steadily when the heart was perfused with oxygenated blood containing 15 mmoles KCl to prevent cardiac activity. When KCl was not added, fibrillation and irregular contractions occurred within 1 to 2 minutes. In these instances, the rise in adenosinetriphosphate was irregular and inconstant.
Ventricular Nonmixing as a Source of Error in the Estimation of Ventricular Volume by the Indicator-Dilution Technic
Authors: SWAN H. J. C. , BECK WALTER
Published: June 2012

1. In the anesthetized dog, end-diastolic, end-systolic and stroke volumes for the left ventricle have been calculated according to the method of Holt from dilution curves recorded at the aortic root. For heart rates of less than 120 beats per minute, the catheterdensitometer systems used gave 90 to 95 per cent of the true concentration in the aortic root at the end of diastole.

2. Average volumes of 2.96, 1.63 and 1.33 ml./Kg. of body weight were calculated for each of these parameters. The interindividual and intraindividual variations about these means amounted to ± 30 to 50 per cent.

3. In approximately 15 per cent of the dilution curves the concentration of dye in the aortic root during early systole (phase of maximal ejection) showed a transient, markedly low value compared with that of the end of diastole. This can be explained only on the basis of the preferential ejection from the heart in early systole of the undyed, newly entering blood from the left atrium, which had mixed poorly with the residual volume of the ventricle. Qualitative inspection of cineangiograms confirmed this impression and demonstrated that a residuum of contrast medium failed to mix with the incoming blood from the left atrium.

4. In addition, there is evidence for the possibility of overestiination of stroke volumes from dilution curves recorded immediately proximal to the injection chamber.

5. Incomplete mixing of the left artial blood with the residual volume of the ventricle precludes accurate quantitation of the changes of volume in the ventricle by the simple formulas proposed by previous authors. This phenomenon may serve to explain the considerable variability that is found in the present study and in the literature.
Effects of Fat on Coronary Circulation in Dogs
Authors: KUO PETER T. , WHEREAT ARTHUR F. , ALTMAN ARTHUR A. , WEST JAMES W.
Published: June 2012

The effects of lipemia upon the coronary circulation and myocardial oxygenation, and arterial oxygen and carbon dioxide contents were studied in 13 control dogs and 20 animals with myocardial scars. Acutely induced lipemia caused a significant decrease in the cardiac output, coronary blood flow and myocardial oxygen consumption in both groups of animals. These changes were similar to those observed in experimental coronary artery embolization. The slow intravenous fat infusion did not cause a significant drop in the mean arterial pressures of these dogs. All animals in this series developed hyperpnea during fat infusion. There was a simultaneous lowering of the arterial oxygen saturation and carbon dioxide content. These changes were in some ways similar to those observed by other investigators in experimental pulmonary embolization. However, the slow fat infusion did not produce a significant elevation of the pulmonary arterial pressures of these dogs. These data suggest that the chylomicra, like most macromolecular substances, may produce mechanical interference to the coronary blood flow and impose a limitation to myocardial oxygenation, while the total oxygen consumption of the animal is unaltered by lipemia.
Mechanisms of Inhibition of Heart Rate by Phenylephrine
Authors: VARMA SARLA , JOHNSEN S. D. , SHERMAN D. E. , YOUMANS W. B.
Published: June 2012

Studies were performed to determine the effects of phenylephrine in dogs under chloralose as influenced by mechanical buffering of blood pressure, adrenergic blockade produced by injection of phenoxybenzamine, and combination of the mechanical buffering of blood pressure and phenoxybenzamine administration. Chloralose did not interfere with and possibly mildly sensitized the cardioinhibitory response to phenylephrine. Tachyphylaxis did not occur when moderate doses of phenylephrine were injected at intervals of not less than 15 minutes. Either mechanical buffering or administration of phenoxybenzamine partially prevented the pressor response to phenylephrine, and the cardioinhibitory response correspondingly was less. When the increase in blood pressure was prevented entirely by mechanical buffering of blood pressure combined with phenoxybenzamine administration, phenylephrine caused either no change in heart rate or a mild acceleration. It is concluded that the decreases in heart rate which are observed following injection of phenylephrine, in the doses used in this study, are secondary to the adrenergic actions of the compound.
Mechanisms of Coronary Microvascular Dilation Induced by the Activation of Pertussis Toxin–Sensitive G Proteins Are Vessel-Size Dependent
Authors: Komaru Tatsuya , Tanikawa Toshinori , Sugimura Akihiko , Kumagai Toshinobu , Sato Kouichi , Kanatsuka Hiroshi , Shirato Kunio
Published: June 2012

G proteins are critically important mediators of many signal transduction systems. In the present study, we investigated the effect of direct activation of pertussis toxin (PTX)–sensitive G protein (G
PTX
) on coronary arterial microvascular tone in 37 open-chest anesthetized dogs in vivo. Coronary arterial microvessels on the surface of the beating left ventricle were visualized by performing fluorescence coronary microangiography using an intravital microscope with a floating objective system. Microvessels were divided into two groups, small microvessels (inner diameter, ≤130 μm) and large microvessels (inner diameter, >130 μm). Topically applied mastoparan (G protein activator, 10, 30, and 100 μmol/L) produced homogeneous microvascular dilation in a concentration-dependent manner (10 μmol/L, 7.9±2.0%; 30 μmol/L, 10.3±2.4%; and 100 μmol/L, 16.7±4.5% in small microvessels; 10 μmol/L, 5.3±1.2%; 30 μmol/L, 9.8±2.5%; and 100 μmol/L, 15.5±3.9% in large microvessels). These dilations were reversed to constriction by pretreatment with PTX (300 ng/mL, 2 hours) in both microvessel groups. Blockade of nitric oxide production by
N
ω
-nitro-
l
-arginine (LNNA, 300 μmol/L) offset the mastoparan-induced dilation in large microvessels but not in small microvessels. Cosuperfusion of glibenclamide (10 μmol/L) with LNNA produced constriction of all sizes of microvessels in response to mastoparan, whereas charybdotoxin (10 nmol/L) did not affect the mastoparan effect. Pretreatment with glibenclamide alone reversed mastoparan dilation to constriction in small microvessels, whereas it only offset the dilation without producing constriction in large microvessels. We conclude that the activation of G
PTX
produces homogeneous coronary arterial microvascular dilation and that the underlining mechanisms of the dilation are vessel size dependent. The
l
-arginine–nitric oxide pathway mediates the dilation only in large microvessels, whereas ATP-sensitive K
+
channel activation plays a central role in the dilation of small microvessels when G
PTX
is directly activated. ATP-sensitive K
+
channels are also involved in the dilation of large microvessels in a synergistic fashion with nitric oxide production.
Mechanical Strain Tightly Controls Fibroblast Growth Factor-2 Release From Cultured Human Vascular Smooth Muscle Cells
Authors: Cheng George C. , Briggs William H. , Gerson David S. , Libby Peter , Grodzinsky Alan J. , Gray Martha L. , Lee Richard T.
Published: June 2012

Although fibroblast growth factor-2 (FGF-2) participates in the response to vascular injury, the role of cellular deformation in FGF-2 release is incompletely understood. To test the hypothesis that mechanical strain tightly controls FGF-2 release, a novel device was used to impose homogeneous and uniform biaxial strain to human vascular smooth muscle cells. Release of FGF-2 increased with the number of cycles of strain (14%, 1 Hz); 1, 9, and 90 cycles of strain, respectively, released 0.55±0.06%, 2.9±0.3%, and 5.5±1.3% of the total cellular FGF-2 (versus 0.00±0.40% for control,
P
<.05), but release was not further increased for strain of 90 to 90 000 cycles. Mechanical release of FGF-2 depended on both the frequency and amplitude of deformation. For example, strain (90 cycles, 1 Hz) at 4% amplitude released only 0.1±0.1% of the total FGF-2, but strain at 14% and 33% amplitudes, respectively, released 5.7±0.5% and 19.0±3.0% of the FGF-2 cellular pool (
P
<.05), suggesting a strain amplitude threshold for FGF-2 release. Injury to a subpopulation of cells increased with the frequency and amplitude of strain, but cells were not injured by strains below 10% amplitude. Strain following pretreatment with heparin released 12.6±1.6% of the total FGF-2 (versus 15.8±0.9% for strain alone,
P
<.05), indicating that most FGF-2 was liberated from the nuclear or cytoplasmic pools and not from low-affinity extracellular receptors. Conversely, strain in the presence of heparin released 25.2±3.5% of the total FGF-2 (versus 15.6±2.6% for strain alone,
P
<.05). Thus, cellular strain closely modulates the release of intracellular FGF-2 from human vascular smooth muscle cells, but FGF-2 release is negligible in response to the smaller strains that occur in the normal artery. In addition, larger mechanical strains lead to transfer of intracellular FGF-2 to the extracellular low-affinity receptors, where FGF-2 may be displaced by heparin. These observations provide insight into the mechanisms by which deforming vascular injury, such as that produced by arterial interventions, may elicit a proliferative response.
Exogenous Oxidized Low-Density Lipoprotein Injures and Alters the Barrier Function of Endothelium in Rats In Vivo
Authors: Rangaswamy Shanthini , Penn Marc S. , Saidel Gerald M. , Chisolm Guy M.
Published: June 2012

Oxidation converts low-density lipoprotein (LDL) into a cytotoxin in vitro. Oxidized LDL exists in vivo in atherosclerotic lesions and possibly in plasma. Many cell functions are altered in vitro by oxidized LDL, but few have been examined in vivo. To test whether oxidized LDL could injure endothelial cells and alter endothelial permeability to macromolecules in vivo, we infused oxidized LDL, native LDL, or their solvent intravenously into rats. Subsequently, endothelial cell injury and proliferation were measured, and the transport into the aorta wall of the macromolecule horseradish peroxidase (HRP) was quantified. Transport data were analyzed using mathematical models of macromolecular transport; parameters were estimated by optimally fitting model-predicted HRP concentrations to experimental data. Compared with native LDL or solvent control infusion, oxidized LDL infusion increased (1) the number of injured aortic endothelial cells fivefold to sixfold at 36 hours, (2) proliferation of endothelial cells at 48 hours, (3) intimal and medial accumulations of HRP twofold to threefold at 48 hours, and (4) the permeability coefficient of the endothelium to HRP fourfold to fivefold at 48 hours. Hence, oxidized LDL administered in vivo can injure the endothelium, despite the presence of endogenous antioxidants, compromising the function of the endothelium as a permeability barrier.
Residence Time of Low-Density Lipoprotein in the Normal and Atherosclerotic Rabbit Aorta
Authors: Tozer Eileen Collins , Carew Thomas E.
Published: June 2012

Previous results from this laboratory found that the arterial low-density lipoprotein (LDL) residence time in lesion-prone aortic sites was longer in hyperlipidemic rabbits before lesion formation than in the corresponding sites in normolipidemic rabbits. The calculation of residence time in the previous study assumed that the arterial wall was homogeneous; the present study reexamines the issue using a method that does not require such an assumption. The concentration of radiolabeled arterial LDL was measured in New Zealand White rabbits killed at several different times (0.5 to 72 hours) after injection of labeled LDL. Using a stochastic analysis, arterial LDL residence time was calculated from the pooled labeled arterial LDL measurements from these rabbits. In these studies, the arterial LDL residence times in normolipidemic and hyperlipidemic rabbits before lesion formation were similar in both the lesion-prone and -resistant sites. However, immediately upon development of early fatty streak lesions, the arterial LDL residence time increased dramatically. After only 16 days of cholesterol feeding, the residence time was 10 times longer in the lesioned aortic arch compared with similar tissue from normolipidemic rabbits (4 to 45 hours). After 21 days of cholesterol feeding, the residence time of LDL in the lesioned aortic arch increased to >25-fold that of normolipidemic tissue. Similar results were observed in the lesioned tissue of the abdominal branchings. This early retention of LDL suggests that significant changes are taking place within the arterial wall during this critical stage of early lesion development.
Integrin Signaling Transduces Shear Stress-Dependent Vasodilation of Coronary Arterioles
Authors: Muller Judy M. , Chilian William M. , Davis Michael J.
Published: June 2012

A direct relationship exists between shear stress and endothelium-dependent NO-mediated vasodilation of blood vessels. The transduction of shear stress to the biochemical signals resulting in the production of NO is, however, unknown. We tested the hypothesis that integrin binding to Arg-Gly-Asp (RGD) peptide sequences in extracellular matrix proteins is a critical step in initiation of the signaling sequence whereby shear stress activates endothelial tyrosine kinase(s) and induces vasodilation of isolated arterioles. Isolated coronary arterioles were exposed to increasing shear stress under control conditions and in the presence of a synthetic peptide, GRGDNP, to competitively inhibit integrin binding to extracellular matrix proteins containing RGD peptide sequences. Intraluminal GRGDNP (0.1, 0.5, and 1.0 mmol/L) inhibited shear stress-induced vasodilation in a concentration-dependent manner. Application of GRGDNP had no effect on endothelium-dependent relaxation to substance P (10 sup -12 to 10 sup -8 mol/L). An inactive structural analogue, GRGESP, did not alter shear stress-induced vasodilation. To further elucidate the integrin involved in shear stress-induced vasodilation, we administered a blocking antibody to the integrin beta
3
chain (F11) and observed significant attenuation of the vasodilation. Shear stress was also associated with an increase in tyrosine kinase activity, as assessed by anti-phosphotyrosine binding. Application of GRGDNP significantly decreased anti-phosphotyrosine binding during shear stress, suggesting a link between tyrosine kinase activation and integrin signaling during this vasodilatory response. Taken together, these results indicate that integrin-matrix interactions, possibly at focal adhesions, are of cardinal importance in the signaling pathway of shear stress-induced vasodilation. (Circ Res. 1997;80:320-326.)
Arrhythmogenicity of IgG and Anti-52-kD SSA/Ro Affinity-Purified Antibodies From Mothers of Children With Congenital Heart Block
Authors: Boutjdir Mohamed , Chen Long , Zhang Zhi-Hao , Tseng Chung-E , DiDonato Francis , Rashbaum William , Morris Alan , El-Sherif Nabil , Buyon Jill P.
Published: June 2012

An important advance in the description and understanding of congenital heart block (CHB) came in the 1970s with the observation that mothers of affected infants frequently had autoimmune diseases and, in particular, that many maternal sera contained antibodies to SSA/Ro and SSB/La ribonucleoproteins. Although the molecular biology of the candidate antigens has been extensively defined, the arrhythmogenic and electrophysiological effects of their cognate antibodies on the human fetal heart are unknown. In the present study, we provide evidence that IgG-enriched fractions and anti-52-kD SSA/Ro antibodies affinity-purified from sera of mothers whose children have CHB induce complete atrioventricular (AV) block in the human fetal heart perfused by the Langendorff technique and inhibit L-type Ca
2
+ currents at the whole-cell and single-channel level. Immunization of female BALB/c mice with recombinant 52-kD SSA/Ro protein generated high-titer antibodies that crossed the placenta during pregnancy and were associated with varying degrees of AV conduction abnormalities, including complete AV block, in the pups. These findings strongly suggest that anti-52-kD SSA/Ro antibodies are causally related to the development of CHB.
Unilateral Vitelline Vein Ligation Alters Intracardiac Blood Flow Patterns and Morphogenesis in the Chick Embryo
Authors: Hogers B. , DeRuiter M.C. , Gittenberger-de Groot A.C. , Poelmann R.E.
Published: June 2012

Abstract
To study the role of blood flow in normal and abnormal heart development, an embryonic chicken model was developed. The effect of altered venous inflow on normal intracardiac blood flow patterns was studied by visualization of blood flow with India ink. At stage 17, India ink was injected into a capillary or small venule within a specific yolk sac region. After determination of the normal intracardiac flow pattern, the right lateral vitelline vein was ligated, and the new intracardiac flow pattern was studied. Ligation resulted in disturbance of normal intracardiac flow patterns, which was most obvious in the conotruncus. The long-term effect of these abnormal intracardiac flow patterns on the development of the heart and pharyngeal arch arteries was investigated by permanent ligation in ovo with a microclip at stage 17 and subsequent evaluation at stages 34, 37, and 45. These experiments revealed anomalies of the vascular system in 58 of the 91 ligated embryos studied. We observed intracardiac malformations consisting of subaortic ventricular septal defects (n=52), semilunar valve anomalies (n=19), atrioventricular anomalies (n=7), and pharyngeal arch artery malformations (n=32). It is concluded that abnormal intracardiac blood flow, resulting from hampered venous inflow, may result in serious intracardiac and pharyngeal arch artery malformations comparable to defects observed in embryonic chicken models subjected to neural crest ablation, cervical flexure experiments, and excessive retinoic acid treatment.
Collagen VIII Is Expressed by Vascular Smooth Muscle Cells in Response to Vascular Injury
Authors: Sibinga Nicholas E. S. , Foster Lauren C. , Hsieh Chung-Ming , Perrella Mark A. , Lee Wen-Sen , Endege Wilson O. , Sage E. Helene , Lee Mu-En , Haber Edgar
Published: June 2012

Abstract
To identify genes involved in vascular remodeling, we applied differential mRNA display analysis to the rat carotid artery balloon injury model. One polymerase chain reaction product showing increased expression at days 2 to 14 after vascular injury was nearly identical to the mouse α
1
chain of type VIII collagen, a heterotrimeric short-chain collagen of uncertain function expressed by a limited number of cell types. By Northern analysis, expression of both chains of the type VIII collagen heterotrimer increased: collagen α
1
(VIII) mRNA expression was almost 4-fold higher than control by 7 days after vascular injury, and collagen α
2
(VIII) mRNA expression reached a maximum of almost 6-fold above baseline by 3 days after injury. By immunohistochemical analysis, type VIII collagen expression increased in the media and neointima in a localized pattern consistent with the distribution of activated dedifferentiated vascular smooth muscle cells (VSMCs). Cultured VSMCs expressed higher levels of type VIII collagen in response to serum and growth factors, notably platelet-derived growth factor (PDGF)-BB. VSMCs adhered significantly less to type VIII collagen than to type I collagen substrata and showed greater PDGF-BB–stimulated migration (by 2.2-fold) on type VIII collagen than on type I collagen. We hypothesize that increased expression of type VIII collagen by VSMCs after arterial injury may contribute to vascular remodeling through the promotion of VSMC migration.
Neuronal Nitric Oxide Reduces Sympathetic Excitability by Modulation of Central Glutamate Effects in Pigs
Authors: Zanzinger Johannes , Czachurski Jürgen , Seller Horst
Published: June 2012

Abstract
Mechanisms of the modulation of sympathetic activity by neuronal NO were studied in vagotomized anesthetized pigs. Inhibition of neuronal NO synthase (nNOS) within the brain stem by intracerebroventricular (ICV) administration of 7-nitroindazole (7-NI, 1 mmol/L) or
S
-methyl-
l
-thiocitrulline (MeTC, 0.1 mmol/L) caused slight increases in renal sympathetic nerve activity (RSNA) but did not affect arterial blood pressure (BP) or cardiac output (CO). However, the sympathoexcitatory effects of glutamate (0.5 mL, 0.1 mol/L ICV) that were associated with marked increases in BP, CO, and heart rate were potentiated by both nNOS inhibitors. Furthermore, 7-NI and MeTC significantly enhanced the responses of RSNA, BP, and CO to activation of somatosympathetic reflexes via stimulation of the left greater sciatic nerve (nervus ischiadicus, 10 to 20 V, 30 Hz, 1-millisecond pulses). Subsequent systemic inhibition of either the neuronal (by 7-NI) or all isoforms of NOS by
N
G
-nitro-
l
-arginine-methyl ester (20 mg/kg) had no significant additional effects on these responses. The effects of NOS inhibition were effectively counteracted by the endogenous NOS substrate
l
-arginine and by
S
-nitroso-
N
-acetyl-penicillamine (SNAP), a stable analogue of endogenous
S
-nitroso factors. Disruption of sympathoinhibitory baroreflex mechanisms by bilateral cutting of the carotid sinus nerves caused increases in RSNA and slightly increased responses to all excitatory stimuli but had no effects on the actions of the NOS inhibitors or SNAP. These results suggest that modulation of glutamate effects by nNOS-derived NO may be an important mechanism by which NO affects sympathetic activity in pigs.
Enhancement of the ATP-Sensitive K
+
Current by Extracellular ATP in Rat Ventricular Myocytes
Authors: Babenko Andrey , Vassort Guy
Published: June 2012

Abstract
ATP-sensitive K
+
(K
ATP
) channels are present at high density in membranes of cardiac cells, where they regulate cardiac function during metabolic impairment. The present study analyzes the effects of extracellular ATP (ATP
e
), a P
2
-purinergic agonist that can be released under various conditions in the myocardial cell bed, on K
ATP
current (I
K-ATP
) in rat ventricular myocytes. Under the whole-cell patch-clamp configuration at a physiological level of intracellular ATP, applying ATP
e
in the micromolar range did not activate I
K-ATP
. However, dialyzing the cell with a low-ATP (100 μmol/L) pipette solution elicited a slowly, quasilinearly increasing I
K-ATP
that was markedly enhanced by applying ATP
e
in the presence of a P
1
-purinergic antagonist. The effect was reversible on washing out the agonist. The I
K-ATP
enhancement was inhibited by cholera toxin treatment of the myocytes, suggesting that a G
s
protein was involved to mediate the effect. Experiments on excised patches allowed us to exclude a membrane-delimited G protein–dependent pathway. Rather, the results suggested that ATP
e
activates the adenylyl cyclase, since its inhibition by 2′-deoxyadenosine 3′-monophosphate and SQ-22536, which respectively interact with the purine and catalytic site of the cyclase, strongly reduced the ATP
e
-induced I
K-ATP
enhancement, whereas neither compound affected I
K-ATP
in inside-out patches. Inhibition of cAMP-dependent protein kinase by protein kinase inhibitor peptide 5-24 did not alter the purinergic effect. The findings suggests that ATP
e
triggers the activation of adenylyl cyclase, which causes a subsarcolemmal ATP depletion sufficient to enhance I
K-ATP
as it develops during low-ATP dialysis of rat ventricular myocytes.