bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduction of ischemic depolarization by the calcium channel blocker diltiazem. Correlation with improvement of ventricular conduction and early arrhythmias in the dog.
Authors: Clusin W T , Buchbinder M , Ellis A K , Kernoff R S , Giacomini J C , Harrison D C
Published: June 2012

Calcium channel blockers suppress early ischemic arrhythmias, possibly by diminishing intracellular calcium overload and its effect on the ventricular action potential. To explore this, we compared the effects of diltiazem on ischemic "injury" potentials and ventricular fibrillation during serial coronary artery occlusions in dogs. Injury potentials and ventricular fibrillation were elicited every 15-25 minutes by simultaneous occlusion of the left anterior descending and circumflex arteries during rapid atrial pacing. DC epicardial electrograms were recorded differentially between the ischemic region and a small nonischemic region supplied by a proximal branch of the left anterior descending artery. Injury potentials developed with a uniform time course during five control occlusions, but were reduced by diltiazem infusion (0.5 mg/kg over 25 minutes) in each of eight dogs. The mean diastolic injury potential (T-Q depression) at 150 seconds of ischemia was 9.1 +/- 2.7 mV before diltiazem and 6.1 +/- 1.6 mV afterward (P less than 0.001). Diltiazem increased the mean time between coronary occlusion and ventricular fibrillation from 186 to 366 seconds (P less than 10(-5), but did not change the magnitude of the diastolic injury potential at onset of ventricular fibrillation. Diltiazem also delayed ischemia-induced conduction impairment to the same extent that it delayed injury potential development. In five dogs, the effect of diltiazem on regional blood flow near the epicardial electrodes was measured by infusion of radionuclide-labeled microspheres. Coronary occlusion reduced flow to the ischemic zone from 0.86 to 0.05 ml/min per g (P = 0.001). Diltiazem increased preocclusion flow by 11% (P = 0.03), but did not significantly alter flow during occlusion. Hemodynamic measurements show that diltiazem did not diminish cardiac work. Diltiazem therefore produced a flow-independent reduction of cellular depolarization during ischemia, which may be due to relief of calcium overload, and which may explain the antifibrillatory effect.
Influence of vasopressin and angiotensin on baroreflexes in the dog.
Authors: Cowley A W , Merrill D , Osborn J , Barber B J
Published: June 2012

Cardiovascular responses to step-changes of carotid sinus pressure were evaluated at normal and elevated levels of plasma arginine vasopressin in anesthetized neurohypophysectomized dogs (n = 12). Arginine vasopressin influenced autonomic function in two ways: first, maximum carotid reflex gain increased; second, cardiac output was decreased. The enhancement of reflex strength was observed only in response to decreases of intrasinus pressure below the equilibrium point (pressures of between 60 and 105 mm Hg). Aortic pressure rose twice as high for a given decrease of intrasinus pressure, elevations of total peripheral resistance responses were triple those observed at normal plasma arginine vasopressin. In this way, arginine vasopressin more than doubled the ability of the carotid reflexes to return a drop in arterial pressure to normal. Arginine vasopressin enhancement of reflex gain was not observed with elevations of intrasinus pressures above the equilibrium point. Elevation of aortic pressure expected from the vasoconstrictor actions of infused arginine vasopressin were buffered by associated reductions in cardiac output. Vagally mediated bradycardia was consistently observed with elevated arginine vasopressin, but the reflex response of heart rate to step-changes of intrasinus pressure was unchanged. Time control studies in five neurohypophysectomized dogs indicated no significant change in carotid reflex response over the 3- to 4-hour protocol. Comparison of reflex responses in anephric dogs (n = 8) at low and elevated levels of angiotensin II indicated that this vasoactive peptide did not significantly alter reflex responsiveness. We conclude that arginine vasopressin enhances the ability of the carotid reflexes to normalize decreases of arterial pressure, but buffers a rise in pressure from its own vasoactive properties by initiating a fall of cardiac output.
Ventricular receptors activated following myocardial prostaglandin synthesis initiate reflex hypotension, reduction in heart rate, and redistribution of cardiac output in the dog.
Authors: Hintze T H , Kaley G
Published: June 2012

Arachidonic acid (250 micrograms) injected into the left circumflex coronary artery of anesthetized dogs, with carotid arteries tied to reduce baroreflex-induced changes, caused a reduction in heart rate (-15 +/- 1.6 beats/min), mean arterial pressure (-27 +/- 3.4 mm Hg), and left ventricular dP/dt (-939 +/- 138 mm Hg/sec). In contrast, injection of arachidonic acid into the left anterior descending coronary artery caused smaller changes in heart rate (-4.6 +/- 1.6 beats/min), arterial pressure (-14 +/- 2.8 mm Hg), and left ventricular dP/dt (-118 +/- 131 mm Hg/sec). The hypotension following the injection of arachidonic acid results from an increase in perfusion of the kidney and skeletal muscle (as measured by radioactive microspheres), and is entirely reflex, since the changes in renal blood flow, as well as the reduction in heart rate and the hypotension, are eliminated by bilateral vagal section. Increasing the dose of arachidonic acid results in dose-related changes in heart rate, arterial pressure, and left ventricular dP/dt. Prostacyclin and prostaglandin E2, the two principle coronary vasodilator metabolites of arachidonic acid, but not nitroprusside, cause a fall in blood pressure and heart rate, establishing that coronary vasodilation per se is not responsible for initiating the reflex fall in arterial pressure and heart rate. In two dogs with sinoaortic denervation, circumflex injection of arachidonic acid caused larger reductions in heart rate (-21 +/- 1.5 beats/min) and mean arterial pressure (-51 +/- 3.5 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)
Activation sequence and potential distribution maps demonstrating multicentric atrial impulse origin in dogs.
Authors: Boineau J P , Miller C B , Schuessler R B , Roeske W R , Autry L J , Wylds A C , Hill D A
Published: June 2012

We examined the onset of atrial epicardial excitation by recording unipolar potentials from 360 electrodes arranged in templates affixed to the superior vena cava and right atrium in dogs. Both activation sequence and potential distribution maps were obtained for the period of impulse origin beginning before the surface P wave and continuing through the first 15-20 msec of atrial depolarization. The activation maps demonstrated impulse origin from multiple widely separated sites, resulting in two to three individual wavefronts that merged to form a single widely disseminated wavefront spread over a 50 X 20 mm area by 10-15 msec. Atrial potential maps obtained for the same time periods revealed multiple sites of primary negativity corresponding to the points of impulse origin in the activation maps. The potential distributions and evolution of these maps also indicated the presence of multiple wavefronts originating from widely separated locations, and suggested an extensively dispersed source of impulse origin. One of these sites at the superior cavo-appendicular junction corresponded to the rostral portion of the sinus node and the site of classical unifocal origin. Additional sites of impulse origin and primary negativity distant to the sinus node were noted either concurrently in the same map or in other maps associated with different patterns of impulse initiation. Classical physiological and pharmacological interventions were used to alter adrenergic and cholinergic input to the atrium, and resulted in coincident changes of both the patterns of impulse origin and heart rate. In addition, we examined spontaneous changes in the patterns of impulse initiation which accompanied beat-to-beat changes in cycle length (sinus arrhythmia). There was close agreement between activation and potential maps over the entire steady state and dynamic range of impulse origin. The data can be explained by the concept of a widely distributed system of functionally differentiated but coordinated atrial pacemakers.
Removal of adenosine from the rabbit pulmonary circulation, in vivo and in vitro.
Authors: Catravas J D
Published: June 2012

The contributions of pulmonary endothelial and blood cells to the removal of adenosine during a single passage through the rabbit pulmonary circulation were investigated. In the isolated, blood-free perfused rabbit lung in situ, single pass pulmonary removal of [3H]-adenosine injected into the pulmonary artery was accomplished by a low-affinity, saturable process yielding apparent Michaelis-Menten constants of Km = 498 +/- 36 microM and Vmax = 39 +/- 4 mumol/min per lung. Similar experiments in the intact, anesthetized animal, in vivo revealed a rapid, high-affinity removal of [3H]adenosine from plasma with apparent Michaelis-Menten constants of Km = 3.3 +/- 0.5 microM and Vmax = 6.5 +/- 2.4 mumol/min per lung. However, complete recovery of the injected adenosine was achieved upon lysing of cells from blood collected during a single transpulmonary passage of the substrate, indicating that blood cells were responsible for adenosine removal in vivo. The rate of disappearance of adenosine from plasma, observed by incubating the substrate with whole rabbit blood in vitro, was comparable to that found in vivo. We conclude that although, in the absence of circulating blood, rabbit lung is able to extract adenosine in vitro, this mechanism is of little significance in vivo where blood cells appear to be primarily responsible for such removal.
The effect of coronary inflow pressure on coronary vascular resistance in the isolated dog heart.
Authors: Hanley F L , Messina L M , Grattan M T , Hoffman I E
Published: June 2012

The shape of the coronary arterial pressure-flow relationship results from the interaction of a number of poorly understood physiological factors. Experiments in which coronary inflow and outflow pressures were coupled so that driving pressure was held constant showed that changes in inflow or outflow pressures altered coronary blood flow: coronary vascular resistance varied inversely with changes inflow pressure below 50 mm Hg and with changes in outflow pressure below 80 mm Hg. The magnitude of the influence of inflow pressure on resistance also depended on the fixed level of outflow pressure, the influence being large when the outflow pressure was low, and small when it was high. Inflow and outflow pressures, then, are two physiological factors which are determinants of the shape of the pressure-flow relationship, and their interaction contributes to the degree of curvature found in a particular relationship. These findings suggest that the use of linear regression in the interpretation of pressure-flow relationships results in poor estimation of resistance and zero-flow pressure. Other experiments measuring regional coronary blood flow using radionuclide-labeled microspheres resulted in the same inverse relationship between inflow pressure and resistance, regardless of mural depth, indicating that inflow pressure may influence resistance by distending vessels, rather than by causing sequential cessation of perfusion in successive transmural layers.
Forskolin potentiates the coronary vasoactivity of adenosine in the open-chest dog.
Authors: Kusachi S , Bugni W J , Olsson R A
Published: June 2012

Forskolin, a plant diterpene, directly stimulates adenylate cyclase and also potentiates receptor-mediated stimulation of this enzyme by many stimulatory--but not inhibitory--agonists. We exploited the potentiating effect of forskolin to test the hypothesis that adenosine initiates coronary relaxation through activation of adenylate cyclase. In six open-chest dogs, intracoronary forskolin infusions which produced plasma concentrations between 0.15 and 0.48 microM barely changed coronary flow and had no effect on cardiac performance or oxygen metabolism, and did not cause hypotension. Under these conditions, the EC50 of adenosine, 0.66 microM (range 1.3-2.4), P less than 0.05. In five of the six dogs, higher doses of forskolin, 0.6-6.3 microM, produced the previously described positive inotropic, chronotropic, and systemic hypotensive effects of this drug. These larger doses of the drug increased coronary flow and MVO2 but decreased oxygen extraction, reflecting a combination of direct and metabolic vasodilation. The potentiation of the vasoactivity of adenosine by forskolin supports the hypothesis that the coronary receptor is an adenylate cyclase stimulatory (Ra or A2) receptor.
Binding of charged ferritin to alveolar wall components and charge selectivity of macromolecular transport in permeability pulmonary edema in rats.
Authors: Brody J S , Vaccaro C A , Hill N S , Rounds S
Published: June 2012

Rat lungs were inflated and incubated in either anionic or cationic ferritin, and alveolar and capillary basement membranes were examined by electron microscopy. Cationic ferritin bound to heparan sulfate proteoglycans on the external surface of the alveolar basement membrane, whereas cationic ferritin bound to the lamina densa of the capillary basement membranes. Anionic and cationic ferritin was also perfused through the pulmonary circulation of lungs isolated from control rats and rats previously injected with alpha-naphthylthiourea, which produces permeability pulmonary edema. Neither anionic nor cationic ferritin leaked from the pulmonary capillaries in perfused controls; cationic, but not anionic, ferritin adhered to endothelial cell surfaces. In lungs with alpha-naphthylthiourea pulmonary edema, perfused for 2-15 minutes, anionic ferritin leaked from pulmonary capillaries into the alveolar interstitium and alveolar space, while cationic ferritin remained within the capillary lumen. Five times as much anionic ferritin appeared in the capillary basement membranes on the thick side of the alveolar wall, as in the alveolar basement membranes on the thin side of the alveolar wall. In alpha-naphthylthiourea lungs perfused for 45-60 minutes, cationic ferritin also leaked through the injured endothelium and bound twice as much to the alveolar as the capillary basement membranes. The negatively charged pulmonary capillary endothelium, the positively charged capillary basement membranes, and the negatively charged alveolar basement membranes may influence the transport of macromolecules from the pulmonary circulation in permeability pulmonary edema.
Pressure-dependent membrane depolarization in cat middle cerebral artery.
Authors: Harder D R
Published: June 2012

This study was undertaken to examine the effect of increasing transmural pressure on membrane electrical properties of cat middle cerebral arterial muscle. Middle cerebral arteries were removed from the cat brain, cannulated, and prepared so that transmural pressure within a segment could be manipulated. Intracellular membrane potential was recorded with glass microelectrodes at various transmural pressures. There was a positive slope relating changes in intracellular membrane potential as a function of transmural pressure with a correlation coefficient of 0.79. Blockade of nerve excitation with tetrodotoxin and inhibition of alpha-adrenergic receptors with phentolamine not only did not block the pressure-induced depolarization, but increased the slope of the intracellular membrane potential vs. pressure relationship. This slope was increased upon elevation of extracellular calcium concentration from 2.5 to 4.0 mM and was significantly reduced upon reduction of extracellular calcium concentration to 0.5 mM. When arterial preparations were equilibrated at 0 mm Hg prior to pressurization, action potentials were recorded only when pressure was initially elevated, while a sustained depolarization was recorded during the pressure plateau. However, when arteries were equilibrated at a transmural pressure of 100 mm Hg for 90 minutes, spontaneous action potentials were recorded which increased in frequency as a function of pressure until they were inactivated when intracellular membrane potential approached -30 mV at high transmural pressures. Photomicrographs demonstrated that these vessels either maintained or decreased diameter upon pressurization. These findings provide a cellular mechanism for myogenic regulation of cerebral arterial diameter.
Metabolic and mechanical properties of aortas from aldosterone-salt hypertensive rats.
Authors: McMahon E G , Paul R J
Published: June 2012

Aortas from aldosterone-salt treated hypertensive rats and vehicle-infused normotensive controls were compared with respect to mechanical properties, metabolism, and energy turnover. Passive wall stress at any given circumference was slightly higher in aortas from the hypertensive rats, whereas active isometric force normalized to cross-sectional area was similar in vessels from the two groups at their respective optimal circumference for active tension developments [hypertensive rats: (n = 14), 19.73 +/- 1.98; controls: (n = 13), 22.57 +/- 2.13 mN/mm2). Metabolic parameters were measured with the aortas held at optimal circumference for active tension development, the optimal length for tension development (n = 6), 5.67 +/- 0.17 and (n = 7), 5.29 +/- 0.18 mm for control and aldosterone-salt groups, respectively. Basal oxygen consumption rate was elevated significantly in aortas from the hypertensive rats [(n = 14), 0.457 +/- 0.026 vs. (n = 13), 0.267 +/- 0.028 mumol/min per g; P less than 0.001]. Under resting conditions, lactate production rate similar in aortas from the two groups [hypertensive rats: (n = 20), 0.129 +/- 0.010; controls: (n = 21), 0.112 +/- 0.008 mumol/min per g]. Upon activation with added KCl, the rate of oxygen consumption and lactate production increased with tension development in both groups, but the stimulated rate of oxygen consumption was higher in hypertensives compared to controls [(n = 14), 0.580 +/- 0.031 vs. (n = 13), 0.441 +/- 0.049 mumol/min per g; P less than 0.025]. The stimulated rates of lactate production were similar in the two groups [hypertensive rats: (n = 20), 0.172 +/- 0.009; controls: (n = 21), 0.118 +/- 0.009].(ABSTRACT TRUNCATED AT 250 WORDS)
Blockade of central nervous system GABAergic tone causes sympathetic-mediated increases in coronary vascular resistance in cats.
Authors: Segal S A , Jacob T , Gillis R A
Published: June 2012

Picrotoxin, an antagonist of gamma-aminobutyric acid, produces an increase in coronary vascular resistance, S-T segment elevation, and ventricular arrhythmias after an intravenous injection of 2 mg/kg in chloralose-anesthetized cats. To determine whether these responses were due to blockade of central nervous system GABAergic mechanisms leading to an increase in sympathetic outflow to the coronary vasculature, several types of experiments were performed. First, picrotoxin was injected directly into the brain in a dose of 600 micrograms while coronary blood flow and S-T segment changes were monitored. Central nervous system administration of this agent resulted in a significant increase in coronary vascular resistance, S-T segment elevation, and arrhythmias. Second, animals were pretreated with the gamma-aminobutyric acid receptor agonist drug, muscimol, prior to central administration of picrotoxin. Pretreatment prevented the usual increase in coronary vascular resistance, S-T segment elevation, and arrhythmias. Third, animals were subjected to acute bilateral cardiac sympathetic denervation prior to picrotoxin administration. Denervation attenuated the picrotoxin-induced increase in coronary vascular resistance (mean = 11.6 +/- 2.1% vs. 26.1 +/- 7.1%, P less than 0.05) and elevation in S-T segment (mean = 0.09 +/- 0.03 mV vs. 0.29 +/- 0.04 mV, P less than 0.05), and prevented arrhythmias. Pretreatment with the alpha-receptor blocking agent, phentolamine, produced even more pronounced antagonistic effects. These results suggest that blockade of central nervous system GABAergic tone leads to enhanced sympathetic outflow to the coronary vasculature, resulting in an increase in coronary vascular resistance of sufficient intensity to cause S-T segment elevation and arrhythmias.
Changes in vascular capacity in awake dogs in response to carotid sinus occlusion and administration of catecholamines.
Authors: Bennett T D , Wyss C R , Scher A M
Published: June 2012

Changes in cardiac filling pressure (central venous pressure) were measured following carotid occlusion and infusions of catecholamines in awake dogs while cardiac output was held constant. After carotid occlusion in dogs with vagi blocked, central venous pressure increased about 0.8 mm Hg (an estimated decrease in vascular capacity of 2.4 ml/kg). Carotid occlusion before vagal block or following vagal block and beta-adrenergic block with propranolol caused no significant changes in central venous pressure. Phenylephrine (0.1-2.0 micrograms/min per kg) caused dose-dependent increases in arterial pressure, but changed central venous pressure (ca. 2.5 mm Hg) only at the highest doses. Epinephrine in doses (0.03-0.51 micrograms/min per kg) that caused little change in arterial pressure increased central venous pressure up to 5.3 mm Hg (an estimated decrease in vascular capacity of 12.0 ml/kg); this response was attenuated about 50% by propranolol. Isoproterenol (0.01-0.40 micrograms/min per kg) decreased arterial pressure and caused changes in central venous pressure similar to those seen with epinephrine. These responses were abolished by propranolol. Vascular compliance, determined from the change in central venous pressure following known changes in vascular blood volume, averaged 3.0 +/- 0.6 ml/mm Hg per kg. In the conscious, resting dog, both alpha- and beta-adrenergic receptors are involved in the reflex control of cardiac filling pressure. The beta-adrenergic responses predominate.
Phenol topically applied to canine left ventricular epicardium interrupts sympathetic but not vagal afferents.
Authors: Barber M J , Mueller T M , Davies B G , Zipes D P
Published: June 2012

The intracardiac pathways carrying the cardiovascular reflex responses mediated by cardiac sympathetic and vagal afferent fibers were examined in this study. We investigated the response to epicardial applications of bradykinin (5 micrograms) and nicotine (50 micrograms) before and after regional epicardial applications of 85% phenol in chloralose anesthetized open-chest dogs. Bradykinin stimulated sympathetic afferents, while nicotine stimulated vagal afferents. Topical applications of phenol were used to interrupt these pathways. Before phenol encircling, bradykinin significantly increased--whereas nicotine significantly decreased--mean arterial blood pressure when applied at the same sites. After phenol, nicotine applied to all sites within and outside the phenol circle continued to decrease mean arterial pressure, whereas bradykinin applied to sites within the circle no longer increased mean arterial pressure. Removal of aortic and carotid baroreceptors did not significantly affect these responses. Painting horizontal stripes of phenol on the anterior and posterior left ventricular free wall basal to the site of bradykinin application eliminated the elevation in mean arterial pressure produced by bradykinin. Reapplication of bradykinin basal to the stripe restored its response. Phenol stripes eliminated the nicotine vasodepressor response only when the stripe was painted in the atrioventricular groove. When bradykinin and nicotine were injected via a nonocclusive intracoronary catheter, both drugs elicited an early depressor response (interrupted by vagotomy) and, in some animals a late pressor response (interrupted by stellectomy). Epicardial phenol encircling the flow distribution of the cannulated coronary artery interrupted most or all of the sympathetic afferents mediating pressor responses to bradykinin or nicotine, while leaving the depressor responses intact. The depressor responses were eliminated by applying phenol to the atrioventricular groove or by transecting the cervical vagi. These data suggest that sympathetic afferent fibers travel in the superficial subepicardium in an apex-to-base direction. Vagal afferent fibers travel deeper in the myocardium until they approach the atrioventricular groove, where they ascend to the superficial subepicardium.
Evidence of myogenic vascular control in the rat cerebral cortex.
Authors: Bohlen H G , Harper S L
Published: June 2012

The potential presence of myogenic regulation in the cerebral microvasculature of the rat was investigated using a method which alters intravascular pressure without appreciably changing cerebral perfusion pressure (arterial minus venous pressure). The entire rat was placed in a sealed box, with the cranial cavity open to the atmosphere and prepared for in vivo microscopy. By increasing the ambient pressure in the box, both systemic arterial and venous pressure could be changed by nearly equal amounts (+/- 20 mm Hg). Heart and respiratory rates were not influenced by changing ambient pressure by +/- 20 mm Hg. At elevated ambient pressures, cortical arterioles constricted in linear proportion to the ambient pressure, whereas subatmospheric ambient pressures caused vasodilation whose magnitude was about equal at ambient pressures of -6 to -18 mm Hg. The calculated vessel wall tension typically remained within about +/- 10-15% of control during changes of transmural pressure of +/- 20-40%. In all cases, arteriolar responses to changes in ambient and intravascular pressure reached a new steady state within 10-15 seconds and were sustained for up to 30 minutes. These data are interpreted to indicate the presence of a myogenic vascular response in the brain vasculature of the rat.
Analysis of responses to leukotriene D4 in the pulmonary vascular bed.
Authors: Kadowitz P J , Hyman A L
Published: June 2012

Pulmonary vascular responses to leukotriene D4 were investigated in the intact-chest animal under conditions of controlled pulmonary blood flow. Intralobar injections of leukotriene D4 in the sheep caused dose-dependent increases in lobar arterial and small vein pressures without influencing left atrial or systemic arterial pressure. Leukotriene D4 was very potent in increasing pulmonary vascular resistance in the sheep, with activity similar to that of U-46619, a thromboxane A2 mimic. Pulmonary vascular responses to leukotriene D4 in the sheep were similar when the lung was ventilated and when lobar ventilation was arrested. Responses to leukotriene D4 were similar when the lung was perfused with blood or with dextran. Pulmonary vascular responses to leukotriene D4 but not U-46619 in the sheep were reduced by inhibitors of cyclooxygenase and thromboxane synthesis. In contrast, leukotriene D4 had modest pressor activity in the pulmonary vascular bed of the cat whereas U-46619 had marked activity in this species. Responses to leukotriene D4 in the cat were not altered by cyclooxygenase inhibitors. It is concluded that leukotriene D4 has marked pulmonary vasoconstrictor activity in the sheep, increasing pulmonary vascular resistance by constricting intrapulmonary veins and upstream segments. In this species, responses to leukotriene D4 were independent of changes in ventilation or interaction with formed elements but were dependent on the formation of cyclooxygenase products including thromboxane A2. However, in the cat, leukotriene D4 had very modest pressor activity, and this activity was not dependent on the integrity of the cyclooxygenase pathway. These data suggest considerable species difference in responses to leukotriene D4, a major component of the slow-reacting substance of anaphylaxis, in the pulmonary vascular bed.
Independence of myocardial oxygen consumption from pressure-volume trajectory during diastole in canine left ventricle.
Authors: Suga H , Goto Y , Yamada O , Igarashi Y
Published: June 2012

We have found that myocardial oxygen consumption is linearly correlated with the systolic pressure-volume area in the canine left ventricle. This pressure-volume area is a specific area in the pressure-volume diagram that is circumscribed by the end-systolic pressure-volume relation line, the end-diastolic pressure-volume relation curve, and the systolic segment of the pressure-volume trajectory. This area is equivalent to the total mechanical energy generated by ventricular contraction, consisting of the external mechanical work and the mechanical potential energy. In the present study, we specifically changed the course of the diastolic segment of the pressure-volume trajectory without changing the systolic segment of the pressure-volume trajectory and the systolic pressure-volume area. Although the fractions of external mechanical work and mechanical potential energy in the pressure-volume area were markedly changed, the simultaneously measured left ventricular oxygen consumption remained unchanged. This result indicates that the myocardial oxygen consumption is predominantly determined by the total mechanical energy generated during systole, or the systolic pressure-volume area, independent of how the total mechanical energy is converted effectively to external mechanical work during the cardiac cycle.
An analysis of myocardial infarction. The effect of regional changes in contractility.
Authors: Bogen D K , Needleman A , McMahon T A
Published: June 2012

In a preceding paper, we employed an initially spherical, modified membrane model of the infarcted ventricle to investigate the relation between ventricular function and both infarct size and infarct stiffness. In the present paper, we have applied the same model to a set of different questions, namely, the consequences of enhanced or depressed inotropic state within the noninfarcted myocardium. When infarcted ventricles containing up to 41% infarction are examined, stroke volume appears to be relatively insensitive to increases in inotropic state. However, stroke volume falls rapidly when inotropic state is depressed below 80% of normal. For the case of a ventricle with a large, weakly contracting segment which is not totally infarcted, stroke volume is impaired only when the contractility of the weak region is diminished below 50% of normal. Finally, the stress concentration around a region of infarction appears to be dependent more strongly on the inotropic state of the noninfarcted tissue than on the infarct size.
Relationship between myocardial fiber direction and segment shortening in the midwall of the canine left ventricle.
Authors: Freeman G L , LeWinter M M , Engler R L , Covell J W
Published: June 2012

Myocardial fiber orientation undergoes an orderly transition from the epicardium to the endocardium in the left ventricle, with circumferential fibers predominating in the middle one-third of the heart wall. How fibers lying at different depths in the myocardium, running in different directions, interact to produce local deformation is not known. To define the relationship between the orientation of uniaxial myocardial fibers and local wall motion, we placed three sets of ultrasonic dimension gauges in the middle one-third of the apex-to-base distance of the left ventricle of nine dogs. One pair was placed in line and two intentionally out of line with the presumed local fiber direction. The relative angle between the gauge and the local myofibers was determined by the use of postmortem radiography and histological techniques. Our results show that in the midwall of the left ventricle, myocardial segment shortening is maximal in the direction of local fibers; the shortening measured by gauges placed out of line with the local fiber axis by more than 30 degrees was significantly less than the actual in-line fiber shortening which occurred. This suggests that functional tethering between midwall fibers and endocardial or epicardial fibers does not play a major role in the pattern of midwall deformation. We also documented that an external reference line can be used to predict midwall myofiber direction. Using this line as a guide, ultrasonic dimension gauges could be placed within an average of 12 degrees (range: 0.5 to 18.5 degrees) from the local fiber axis.
Limitations of tracer oxygen uptake in the canine coronary circulation.
Authors: Rose C P , Goresky C A
Published: June 2012

Theoretical models of oxygen transport in the myocardium have failed to account for low average tissue pO2 relative to to coronary sinus pO2, measured with pO2 electrodes and myoglobin saturation, and for hypoxic contractile failure at relatively high coronary sinus pO2 levels. These findings could be explained by either arteriovenous diffusional shunting or a limiting rate of transfer of oxygen from blood to tissue, or both. To gain new insights, we performed multiple indicator dilution tracer experiments across the coronary circulation in the dog, with 18O2 as the oxygen tracer and 51Cr-labeled red cells as the reference tracer for oxygen. 125I-Albumin and 22Na+ were included to provide the relative plasma flow rate. The tracer oxygen outflow curve consisted of a large early peak related to its reference red cell curve. No tracer emerged before the labeled red cells. The downslope, which contains the returning component of the tracer curve, decreased less steeply when oxygen consumption was reduced by propranolol. Fitting the tracer oxygen outflow curve with a distributed model including irreversible sequestration behind a resistance gave a transfer rate constant which was relatively small, and a relatively large rate constant for sequestration. Relative oxygen consumption (estimated from the arteriovenous difference) correlated closely with the rate constant for sequestration. Estimated average tissue oxygen concentrations were of the order of one-third blood concentration. Dimensional analysis indicates that the low transfer rate constant derives from hemoglobin-oxygen binding; this decreases fractional tracer oxygen transfer in proportion to the ratio of plasma:red cell oxygen pools.
Effect of reperfusion late in the phase of reversible ischemic injury. Changes in cell volume, electrolytes, metabolites, and ultrastructure.
Authors: Jennings R B , Schaper J , Hill M L , Steenbergen C , Reimer K A
Published: June 2012

The acute effects of reperfusion on myocardium reversibly damaged by 15 minutes of severe ischemia in vivo, were studied. Changes in the adenine nucleotide pool, cell volume regulation, myocardial calcium, and ultrastructure were studied at the end of 15 minutes of ischemia and after 0.5, 3.0, and 20 minutes of reflow. Before reperfusion, adenosine triphosphate and the adenylate pool decreased by 63% and 44% of control, respectively, and the adenylate charge was reduced to 0.65. After 3 minutes of reperfusion, the adenylate charge was restored to control by the rephosphorylation of adenosine mono- and diphosphate, but adenosine triphosphate was still reduced by 45%. Mild tissue edema was detected after 0.5 minute of reflow and persisted throughout 20 minutes of reperfusion. The increased tissue water was accompanied by a slight increase in sodium and a marked increase in tissue potassium. Although massive calcium accumulation develops when irreversibly injured tissue is reperfused, no calcium overload was detected during early reperfusion of reversibly injured myocytes. Reperfusion for 3 minutes exaggerated the mitochondrial swelling induced by 15 minutes of ischemia but after 20 minutes of reperfusion, myocardial ultrastructure was essentially normal except for rare swollen, or disrupted, mitochondria. Thus, the cellular abnormalities associated with brief periods of ischemia persist for variable periods of time after reperfusion of reversibly injured myocytes. First: although adenine nucleotide repletion occurs very slowly, the adenylate charge was restored after 3 minutes, indicating rapid resumption of mitochondrial adenosine triphosphate production. Second: calcium overload was not detected, but myocardial edema and increased potassium persisted throughout the 20 minutes of reperfusion. Third: the ultrastructural consequences of ischemia were nearly reversed after 20 minutes of reperfusion.
Structural and electrophysiological changes in the epicardial border zone of canine myocardial infarcts during infarct healing.
Authors: Ursell P C , Gardner P I , Albala A , Fenoglio J J , Wit A L
Published: June 2012

Structural and electrophysiological properties of the epicardial muscle which survives on the surface of transmural infarcts of the canine heart (epicardial border zone) were studied at different times after occlusion of the left anterior coronary artery (LAD). Isolated preparations were superfused in vitro, transmembrane potentials recorded, and impulse propagation mapped. In preparations from subacute infarcts (1 and 5 days), resting potential, action potential amplitude, upstroke velocity, and duration were all significantly reduced. Well-defined directional differences in propagation occurred. Propagation was more rapid in the direction perpendicular to the left anterior coronary artery than in the direction perpendicular to the base of the heart, because of the uniform anisotropic structure of the surviving muscle fibers which were arranged in tightly packed bundles oriented perpendicular to the left anterior coronary artery. The only ultrastructural abnormalities found in these muscle fibers was an accumulation of large amounts of lipid droplets. As the infarcts healed, resting potential, action potential amplitude, and upstroke velocity returned to normal by 2 weeks, although action potential duration decreased further. Lipid droplets had disappeared, and connective tissue had invaded the epicardial border zone, separating the muscle bundles. By 2 months, action potentials were normal, but the muscle fibers were widely separated and disoriented by the connective tissue (parallel bundles no longer were found). In these regions with a nonuniform anisotropic structure, the well-defined directional differences in impulse propagation were lost. However, activation was very slow, perhaps because of diminished connections between cells. The persistence of slow conduction in healed infarcts may contribute to the occurrence of chronic arrhythmias.
Subfornical organ. Does it protect against angiotensin II-induced hypertension in the rat?
Authors: Bruner C A , Mangiapane M L , Fink G D
Published: June 2012

The purpose of this study was to examine the contribution of the subfornical organ to the chronic hypertension produced by intravenous angiotensin II infusion in rats. Male rats were instrumented with permanent arterial and venous catheters and housed in metabolism cages for daily measurement of arterial pressure, heart rate, water intake, water balance, and urinary electrolyte excretion. Angiotensin II was infused intravenously at a rate of 10 ng/minute for 5 consecutive days, preceded by 2 control days, and followed by 2 recovery days. Normal rats with an intact subfornical organ (n = 7), and rats with an electrolytic lesion placed such that greater than 80% of the subfornical organ was destroyed (n = 9), were studied using this infusion protocol. An additional group of eight rats did not receive angiotensin II, and, thus, served as a time control. Both groups of rats receiving angiotensin II exhibited significant elevations in arterial pressure during the 5-day hormone infusion period, but pressure in rats with subfornical organ lesions (delta 23-29 mm Hg) was increased significantly more than that of intact rats (delta 14-20 mm Hg). Water intake was significantly increased on the 3rd, 4th, and 5th days of angiotensin II infusion only in rats with lesions in the subfornical organ. In contrast to previous studies showing that an intact subfornical organ is required for normal pressor and drinking responses to acute elevations in circulating angiotensin II in the rat, the current experiments indicate that the presence of the subfornical organ actually inhibits these same responses during more chronic increases in plasma angiotensin II levels.
Fibrosis, lipids, and calcium in human atherosclerotic plaque. In vitro differentiation from normal aortic walls by ultrasonic attenuation.
Authors: Picano E , Landini L , Distante A , Benassi A , Sarnelli R , L'Abbate A
Published: June 2012

This study was designed to determine whether attenuation of ultrasound by the aortic wall is potentially useful in characterizing the atherosclerotic lesion. Measurements were made on fresh specimens taken from a human aorta at autopsy. Four hundred different sites, 4 mm in diameter each, corresponding to the dimension of the ultrasonic beam at the focal zone, were ultrasonically analyzed and histologically studied. Attenuation of ultrasound in each site was assessed by Fourier analysis of the echo produced by a specular reflector placed behind the specimen. Two parameters were measured over the range 7-11 MHz: the integrated attenuation index (per cm), and slope (per cm per MHz) of the best fit straight line relating attenuation and frequency. Histological examination--performed for each of the 400 sites where attenuation had been measured--identified four subsets (100 samples each): normal aortic walls, fibrous plaques, fibrofatty plaques, and calcified plaques. Results obtained from ultrasonic and histological analyses showed that the integrated attenuation index was lowest in normal walls (24 +/- 2.1, mean +/- SE) and progressively increased in fibrous (32 +/- 3.1), fibrofatty (82 +/- 6.5), and calcific (185 +/- 8.7) subsets (all intergroup differences were significant, except for the normal vs. fibrous comparison). The slope value was significantly lower in the fibrous than in the normal subsets: (10(-3)) 31.9 +/- 4.5 vs. (10(-3)) 99.5 +/- 9.1, respectively. Values of fibrofatty and calcific plaques overlapped: (10(-3)) 383 +/- 21 vs. (10(-3)) 320 +/- 23, respectively. Both were significantly different from normal and fibrous groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparative vascular pharmacology of the atriopeptins.
Authors: Wakitani K , Oshima T , Loewy A D , Holmberg S W , Cole B R , Adams S P , Fok K F , Currie M G , Needleman P
Published: June 2012

The atriopeptins are potent relaxants of norepinephrine-constricted aortic strips or are dilators of renal blood vessels in isolated perfused rat kidneys that are constricted by norepinephrine. This vasorelaxant property of the atriopeptins requires the presence of phenylalanine arginine (i.e., atriopeptin II, III, or ser-leu-arg-arg atriopeptin III) residues in the carboxy terminus which are considerably more effective than atriopeptin I (the 21 amino acid peptide which lacks the phe-arg C-terminus) or the core peptide (residues 3-19). However, these artificially in vitro precontracted preparations do not accurately predict the vascular effectiveness of the atriopeptins in intact rats. Intravenous administration of the atriopeptins (including atriopeptin I) to anesthetized rats produces concentration-dependent hypotension, a selective decrease in renal resistance in low doses (determined with microspheres), and pronounced diuresis. At higher doses, atriopeptins increase blood flow in other vascular beds. On the other hand, in the anesthetized dog, injection (intraarterially) of the phe-arg-containing peptides produces a concentration-dependent increase in both renal blood flow and sodium excretion, whereas atriopeptin I is inactive. Although there is a species difference in responsiveness to atriopeptin I, these data demonstrate a direct correlation between the renal vasodilation and diuresis produced by this novel family of atrial peptides.
Animal models for protecting ischemic myocardium: results of the NHLBI Cooperative Study. Comparison of unconscious and conscious dog models.
Authors: Reimer K A , Jennings R B , Cobb F R , Murdock R H , Greenfield J C , Becker L C , Bulkley B H , Hutchins G M , Schwartz R P , Bailey K R
Published: June 2012

The Animal Models for Protecting Ischemic Myocardium Study was undertaken for the purpose of developing reproducible animal models that could be used to assess interventions designed to limit infarct size. This paper describes the results obtained in an unconscious dog model and in a conscious dog model, developed in three participating laboratories. The unconscious dog model, involving reperfusion after 3 hours of ischemia in open-chest dogs, was intended to determine whether therapy followed by early reperfusion would limit infarct size more than reperfusion alone. The conscious dog model used chronically instrumented dogs and permanent coronary occlusion to better mimic myocardial infarction in man. In both models, the proximal circumflex artery was occluded, and the primary experimental endpoint was infarct size, as measured by histological techniques 3 days after the initial occlusion. Infarct size was analyzed in relation to baseline variables including the anatomic area at risk, collateral blood flow to the subepicardial zone of ischemia and hemodynamic determinants of myocardial metabolic demand. Most of the variation in infarct size in control dogs could be related to variation in the area at risk, collateral blood flow, and rate pressure product. Using multivariate analysis and groups of 15 dogs, an intervention that limited infarct size by 10-13% of the area at risk would have been detected 50% of the time. Larger treatment effects would be detected more readily, and smaller effects often would be missed, unless group sizes were larger. Two drugs, verapamil and ibuprofen, were evaluated in both models, with experimental group sizes averaging 13 and 20 dogs, in the unconscious and conscious models, respectively. Three of 15 verapamil-treated dogs in the unconscious model study had much smaller infarcts than expected from baseline parameters. With these exceptions, neither drug limited infarct size in either model.
Coronary venous perfusion of the ischemic myocardium during acute coronary artery occlusion in isolated rat hearts.
Authors: Taira Y , Kanaide H , Nakamura M
Published: June 2012

Effects of retrograde coronary venous perfusion on oxygen supply and energy metabolism of ischemic myocardium of the isolated perfused rat heart were examined by means of NADH fluorescence photography. Occlusion of the left coronary artery produced regional ischemia of the left ventricular free wall, as evidenced by the sharply demarcated increase in NADH fluorescence. During ischemia, a narrow area of minimal fluorescence (140 +/- 10 microns), indicating sufficient oxygenation for oxidative phosphorylation, was observed around the epicardial coronary veins in the ischemic lesion. Retrograde perfusion was introduced through the coronary vein (left cardiac vein) that drained off the ischemic area, which resulted in a marked reduction of the area of increased NADH fluorescence in the epicardial surface. In the cross-sectional view, although the myocardium of the entire ischemic area induced by left coronary artery occlusion could be perfused by venous retroperfusion, the effect on reduction of the area of increased NADH fluorescence was seen only in the epicardial half of the myocardium. Retrograde coronary venous perfusion also resulted in a small increase in tension development (P less than 0.05), a decrease in resting tension (P less than 0.01), and partial preservation of myocardial high energy phosphate content (P less than 0.01). We propose that coronary venous retroperfusion improves oxygenation, partially preserves oxidative phosphorylation in the epicardium, and improves contractile function in the ischemic region.