bluuebunny/crossref_metadata_2025 huggingface dataset:
Reentrant ventricular arrhythmias in the late myocardial infarction period in the dog. 13. Correlation of activation and refractory maps.
Authors: Gough W B , Mehra R , Restivo M , Zeiler R H , el-Sherif N
Published: June 2012

Isochronal maps of ventricular activation were analyzed in dogs 3-5 days after ligation of the left anterior descending coronary artery utilizing a 64-channel multiplexer. Isochronal maps of the effective refractory period were determined from 62 epicardial sites and correlated with the activation maps. The ischemia occurring in the surviving epicardial layer prolonged refractoriness in a spatially nonuniform manner. The resulting pattern of refractoriness on the epicardial surface resembled concentric rings of isorefractoriness which increased in duration from the normal zone to the center of the ischemic zone. The formation of an arc of functional unidirectional conduction block occurred along the gradient of refractoriness and the exact location of the arc depended on the S1-S2 interval. When a short S1-S2 failed to induce reentry, fewer adjacent sites with sufficiently disparate refractoriness formed a smaller arc of block. A subsequent S3 encountered further nonuniformly shortened refractoriness (normal areas had shortened refractoriness greater than ischemic areas) and the arc of block was lengthened. This required a longer time for the wavefront to circulate around the arc. When it then reached the distal side of the arc, refractoriness had expired proximal to the arc and reentry occurred. Similarly, nonuniform shortening of refractoriness explained why one reentrant beat may or may not produce successive reentrant beats. Therefore, the spatial pattern of refractoriness forms the substrate for the arc of unidirectional conduction block that is fundamental to the development of ventricular reentry in this experimental model.
Thyroxine-induced left ventricular hypertrophy in the rat. Anatomical and physiological evidence for angiogenesis.
Authors: Chilian W M , Wangler R D , Peters K G , Tomanek R J , Marcus M L
Published: June 2012

We examined anatomical and physiological responses of the left coronary vascular system to thyroxine-induced myocardial hypertrophy. Wistar-Kyoto rats (1 and 5 months old) were administered thyroxine (0.25 mg/kg per day) or the saline vehicle (sham-treated controls) for 2 months. At the ages of 3 and 7 months, each group of animals was used for one of three experimental protocols: determination of numerical capillary density in perfusion-fixed hearts, measurement of coronary reactive hyperemic responses following a 20-second coronary occlusion (peak-to-resting blood flow velocity) as an index of coronary reserve, and assessment of myocardial perfusion under resting conditions and during maximum coronary dilation (dipyridamole infusion) for the calculation of minimum coronary resistance per unit weight of the left ventricle or minimum coronary resistance of the total left ventricle. In both groups of thyroxine-treated animals, the left ventricular weight-to-body weight ratio increased by 35-40%. Capillary density of the 3- and 7-month-old Wistar Kyoto controls was 4467 +/- 352 (mean +/- SEM) and 4029 +/- 143 capillaries/mm2, respectively, but was increased significantly in the thyroxine-treated animals to 6052 +/- 409 capillaries/mm2 (3-month) and 4654 +/- 201 capillaries/mm2 (7-month). In both age control groups, the peak-to-resting blood flow velocity ratio was about 2.2. This index of coronary reserve was not changed in the thyroxine-treated animals. Myocardial perfusion measurements were limited to the 7-month-old animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Characterization of a potentially reversible increase in beta-adrenergic receptors in isolated, neonatal rat cardiac myocytes with impaired energy metabolism.
Authors: Buja L M , Muntz K H , Rosenbaum T , Haghani Z , Buja D K , Sen A , Chien K R , Willerson J T
Published: June 2012

Previous studies have reported that the numbers of beta- and alpha-adrenergic receptors increase in ischemic myocardium. In vivo studies have raised questions regarding the mechanisms involved in the adrenergic receptor alterations and the consequences of these alterations. The purpose of this study was to evaluate potential relationships among beta-adrenergic receptor changes, high energy phosphate reduction, and severity of cell injury in cultured neonatal rat myocytes treated with metabolic inhibitors. The potential for reversal of the receptor changes also was addressed. Binding parameters were measured using [125I]iodocyanopindolol. After 4 hours incubation in potassium cyanide and 2-deoxyglucose, there was a 43% increase in beta-adrenergic receptor number, 41% decrease in adenosine triphosphate, and minimal morphological change in myocytes. Twenty-four hours after removal of the inhibitors, myocytes exhibited a return to normal of the receptor number and adenosine triphosphate level. Iodoacetate treatment for up to 3 hours resulted in marked reduction in adenosine triphosphate and increasing severity of cell injury. The number of beta-adrenergic receptors was unchanged at 1.2 hours, increased at 1.5-2 hours, and decreased at 3 hours. Thus: beta-adrenergic receptor density increases during relatively early stages of injury in metabolically impaired myocytes with reduced adenosine triphosphate levels and decreases subsequently, after the myocytes become irreversibly injured; the increased beta-adrenergic receptor density in moderately injured myocytes can be reversed upon removal of the injurious agent and restoration of the cellular adenosine triphosphate level; and changes in catecholamines mediated by an intact nervous system are not required for an increase in beta-adrenergic receptor density in the setting of impaired energy metabolism.
Afferent renal nerve-dependent hypertension following acute renal artery stenosis in the conscious rat.
Authors: Faber J E , Brody M J
Published: June 2012

Anatomical and electrophysiological evidence indicates that the kidneys contain both mechano- and chemoreceptor nerve endings. We conducted the present study to determine whether conditions of reduced renal blood flow elicit cardiovascular alterations that are dependent on afferent renal nerves. Removal of the renin-angiotensin system with the angiotensin I-converting enzyme inhibitor, captopril, and/or reduction in baroreflex gain by sinoaortic denervation, were combined in conscious rats with acute renal artery stenosis to prevent these systems from potentially obscuring any afferent renal nerve-dependent effects. One week after sinoaortic denervation or sham sinoaortic denervation, each rat was chronically instrumented with Doppler flow probes on the lower abdominal aorta and superior mesenteric and right renal arteries, as well as with intravascular catheters, and a perivascular balloon occluder on the right renal artery. After surgical recovery, sham sinoaortic-denervated animals responded to a 60-minute period of stenosis (50% reduction in renal blood flow) with increases in arterial pressure, regional resistance, and plasma renin activity. Captopril abolished the increases in arterial pressure, hindquarters, and left renal resistance, but both bradycardia and increased mesenteric resistance persisted, indicating that baroreflex activation might be buffering a non-renin-angiotensin system pro-hypertensive mechanism. In support of this, sinoaortic-denervated animals during captopril administration responded to stenosis with substantial increases in arterial pressure (25-30 mm Hg) and regional resistance (30-50%) that were unrelated to the renin-angiotensin system, but which were abolished after denervation of the stenotic kidney. The data suggest that acute reductions in renal blood flow activate an afferent renal nerve-dependent cardiovascular response that is strongly expressed under conditions of reduced gain of the renin-angiotensin and baroreflex systems. We speculate that this reflex may assume particular importance in chronic renal hypertension when baroreflexes become impaired and activation of the renin-angiotensin system is reduced.
Effect of alteration of left ventricular activation sequence on the left ventricular end-systolic pressure-volume relation in closed-chest dogs.
Authors: Park R C , Little W C , O'Rourke R A
Published: June 2012

We investigated the effect of pacing from the atrium and various ventricular sites on the left ventricular end-systolic pressure-volume relation following autonomic blockade in a total of 10 dogs chronically instrumented to measure left ventricular pressure and determine left ventricular volume from three ultrasonic endocardial dimensions. During ventricular pacing, left ventricular end-diastolic volume, stroke volume, and end-systolic pressure were decreased, while the end-systolic volume was relatively unchanged. Left ventricular end-systolic pressure-volume relations were generated by vena caval occlusions during pacing at a constant rate from the left atria, and the epicardium of the right ventricular free wall, right ventricular apex, and left ventricular free wall. The left ventricular end-systolic pressure-volume relations were described by straight lines for each site (r greater than 0.96 and SEE less than 2.9 mm Hg in all but one instance). Compared to atrial pacing, the left ventricular end-systolic pressure-volume relations were shifted (P less than 0.001) to the right during pacing from ventricular sites. During atrial pacing, the volume intercept of the left ventricular end-systolic pressure-volume relation was 16.0 +/- 7.2 ml (mean +/- SD), and increased to 18.7 +/- 7.8 ml (P less than 0.05) during pacing from the right ventricular free wall, to 19.6 +/- 7.7 ml (P less than 0.05) during pacing from the right ventricular apex, and to 20.0 +/- 7.5 ml (P less than 0.05) during pacing from the left ventricular free wall. These volume intercepts correlated roughly with the extent of dyssynchronous activation as estimated by the QRS duration (r = 0.59 to 0.93) and the time for left ventricular endocardial activation (r = 0.92 and 0.95). During ventricular pacing, the slope of the left ventricular end-systolic pressure-volume relation changed only slightly. Similar results were obtained during pacing from right ventricular endocardial sites. We conclude that alterations of the normal activation sequence produced by ventricular pacing depress left ventricular pumping function independent of loading conditions, as indicated by a rightward shift of the left ventricular end-systolic pressure-volume relation. The extent of this shift appears to be in proportion to the degree of dyssynchronous activation. The decreased stroke volume during ventricular pacing is due both to a decreased end-diastolic volume (decreased preload) and the rightward shift of the end-systolic pressure-volume relation (decreased pump function).
Regulation of adenosine formation by the heart.
Authors: Sparks H V , Bardenheuer H
Published: June 2012

We think that the available data on adenosine formation suggest the two signals are responsible for adenosine release from cardiac myocytes: (1) the ratio of oxygen supply to demand and (2) agonist-triggered release of extracellular adenine nucleotides. We do not believe that the available data support the oxygen consumption hypothesis. The few studies which allow us to judge the relative importance of these two signals suggest that both hypoxia and sympathetic nerve stimulation release adenosine primarily by decreasing O2 supply:demand. Agonist triggered nucleotide release may be quantitatively important in situations in which decreased O2 supply/demand cannot explain increased release, i.e., isoproterenol and acetylcholine administration.
Regional changes in intracellular potassium and sodium activity after healing of experimental myocardial infarction in cats.
Authors: Kimura S , Bassett A L , Gaide M S , Kozlovskis P L , Myerburg R J
Published: June 2012

After healing of experimental myocardial infarction in cat hearts, endocardial cells demonstrate persistent regional electrical changes. These include long action potential duration in surviving cells over the infarct scar, and short action potential duration and low membrane potential in border zone cells between the scar and normal tissue. We studied the basis for these electrophysiological changes by measuring intracellular potassium and sodium activity with ion-sensitive microelectrodes in normal, border, and infarct zone cells of the cat left ventricle 2-6 months after ligation of multiple distal tributaries of the left anterior descending and circumflex coronary arteries. In normal zone cells, intracellular potassium activity was 89.6 +/- 12.3 mM (mean +/- SD, n = 9), and sodium activity was 10.8 +/- 2.2 mM (n = 5). Neither was significantly different from infarct zone cells (91.2 +/- 15.0 and 10.5 +/- 3.0 mM, respectively). In contrast, border zone cells had significantly reduced intracellular potassium activity (71.4 +/- 5.1 mM, P less than 0.01, compared to normal and infarct zone cells) and increased intracellular sodium activity (19.1 +/- 5.9 mM, P less than 0.05, compared to normal and infarct zone cells). The membrane potential in border zone cells was more positive to calculated potassium equilibrium potential, and less sensitive to the change in the extracellular potassium concentration in the range between 2 and 10 mM, compared to normal and infarct zone cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Platelet-activating factor and the release of a platelet-derived coronary artery vasodilator substance in the canine.
Authors: Jackson C V , Schumacher W A , Kunkel S L , Driscoll E M , Lucchesi B R
Published: June 2012

Platelet-activating factor (acetyl-glyceryl-ether-phosphorylcholine; 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphorylcholine), which is released by stimulated neutrophils and platelets, possesses the ability to alter vascular tone and permeability and to activate various formed blood elements. We have characterized the hemodynamic effects of intracoronary injections of platelet-activating factor and the influences of pharmacological blockade and platelet depletion on its activity. Intracoronary injections of platelet-activating factor produced maximum increases in left circumflex coronary artery blood flow of 55 +/- 8, 52 +/- 8, and 52 +/- 7 ml/min at 0.5, 1.0, and 2.0 nM, respectively. Only modest changes in systemic arterial blood pressure and regional developed isometric contractile force were associated with the intracoronary artery administration of platelet-activating factor over the range of doses studied. The increase in left circumflex coronary artery blood flow in response to platelet-activating factor was attenuated (44%), but not prevented, by pretreatment with diphenhydramine, (4 mg/kg, iv), and was not affected by pretreatment with aspirin (20 mg/kg, iv) or the systemic administration of the serotonin receptor antagonist, methysergide. The coronary vasodilator response to platelet-activating factor was reduced significantly by the induction of thrombocytopenia (95 +/- 3% platelet depletion) through the administration of sheep-derived canine platelet antiserum. The intracoronary artery injection of platelet-rich plasma activated with platelet-activating factor into thrombocytopenic dogs produced a significantly greater increase in coronary artery blood flow than the injection of either non-activated platelet-rich plasma or platelet-depleted plasma to which platelet-activating factor was added. Similar changes in coronary artery blood flow could be obtained with the intracoronary artery injection of cell-free supernates from washed platelets activated with platelet-activating factor. The observed results suggest that circulating platelets, when exposed to platelet-activating factor, can release a coronary dilator substance, and that the coronary artery dilation is not prevented by pharmacological receptor antagonists for histamine, serotonin, or inhibitors of cyclooxygenase.
A dual function for adenosine 5'-triphosphate in the regulation of vascular tone. Excitatory cotransmitter with noradrenaline from perivascular nerves and locally released inhibitory intravascular agent.
Authors: Burnstock G , Kennedy C
Published: June 2012

A dual function for adenosine 5'-triphosphate in the regulation of vascular tone is considered. Adenosine 5'-triphosphate can cause vasodilation, acting via P2-purinoceptors located on vascular endothelial cells to release an endothelium-derived relaxing factor which diffuses to the vascular smooth muscle and induces vasodilation. The main source of intraluminal adenosine 5'-triphosphate is likely to be endothelial cells, and its release can be measured during pathophysiological conditions such as ischemia and hypoxia, in amounts likely to be sufficient to activate endothelial P2-purinoceptors. Adenosine 5'-triphosphate can also be released during intravascular platelet aggregation and from intact and damaged vascular smooth muscle cells, and so may play a role in the complex physiological mechanisms controlling local vascular tone under normoxic conditions and during vessel injury. Evidence is also presented for adenosine 5'-triphosphate acting as an excitatory cotransmitter with noradrenaline from sympathetic perivascular nerves, to cause vasoconstriction via excitatory P2-purinoceptors located on vascular smooth muscle. The postjunctional mechanical and electrical responses of a number of blood vessels following perivascular nerve stimulation contain a component that is resistant to blockade of the alpha-adrenoceptor. This nonadrenergic response is mimicked by adenosine 5'-triphosphate and can be blocked by selective desensitization of the P2-purinoceptor by alpha,beta-methylene adenosine 5'-triphosphate. Vesicular storage of adenosine 5'-triphosphate and its release from sympathetic perivascular nerves has also been demonstrated. The functional significance of adenosine 5'-triphosphate acting intraluminally as a vasodilator and extraluminally as a vasoconstrictor neuronal agent in the control of vascular tone is discussed.
Atrial reentry around an anatomic barrier with a partially refractory excitable gap. A canine model of atrial flutter.
Authors: Frame L H , Page R L , Hoffman B F
Published: June 2012

We have characterized, in dogs, a model of inducible regular atrial tachycardia that resembles atrial flutter. The model involves creating a Y-shaped lesion comprised of an intercaval incision and a connected incision across the right atrium. It is suitable for serial studies of the effects of pacing or antiarrhythmic drugs in chronically instrumented animals studied in the awake state for at least several months. The postoperative cycle length of the induced tachycardia varies from 143 to 188 msec, depending on the size of the dog. The tachycardia cycle length was consistent for each dog, and the rhythm--once induced--was very stable until terminated by pacing. The mechanism of the tachycardia was reentry due to circus movement based on the ability to induce and terminate it by premature impulses or overdrive, the ability to reset the tachycardia by single premature stimuli, the pattern of entrainment during overdrive stimulation, and the ability to terminate the tachycardia by interrupting the conduction pathway. The window of reset determined by the range of coupling intervals of premature stimuli that were able to enter and reset the tachycardia ranged from 56 to 82 msec. There appears to be incomplete recovery of excitability by the end of the excitable gap as evidenced by the fact that even late premature impulses that enter the reentrant circuit conduct more slowly than the tachycardia impulse, and because stimulation of muscarinic receptors that shortens the duration of the action potential and refractoriness also reduces the cycle length of the tachycardia. Epicardial and endocardial activation mapping during tachycardia showed the reentrant pathway does not merely encircle the lesion, particularly over the left atrial epicardium near the intercaval lesion. Rather, the impulse appears to travel around the atrial tissue just above the tricuspid ring, including a portion that travels through the right side of the lower intraatrial septum. Thus, the model involves circus movement around an anatomic barrier through normal tissue that contains no depressed segments. During the circus movement, there is a relatively long excitable gap during which there is incomplete recovery of excitability. This model should be useful for studies of the mechanism of antiarrhythmic drug action and the responses to premature stimulation in this particular subclass of reentrant rhythms, and for comparison with the behavior and responses of other forms of reentry.
Stimulation of soluble guanylate cyclase by an acetylcholine-induced endothelium-derived factor from rabbit and canine arteries.
Authors: Förstermann U , Mülsch A , Böhme E , Busse R
Published: June 2012

The present study was designed to investigate the hypothesis that, during acetylcholine-induced endothelium-dependent relaxation, a factor(s) is released from endothelial cells which directly activates soluble guanylate cyclase. We attempted to determine what similarities or differences existed between this factor and endothelium-derived relaxing factor. The study was performed on segments of rabbit aorta and canine femoral artery. Purified soluble guanylate cyclase was injected into the lumen of these vascular segments, together with its substrate, for intraluminal incubation of the enzyme. In endothelium-intact vascular segments, the activity of guanylate cyclase was enhanced over control values obtained by incubation in test tubes. The stimulation was further increased by acetylcholine in concentrations which caused relaxation of the vascular segments. The stimulating principle could not be transferred from the vessel lumen to an external solution of guanylate cyclase, indicating a short life-time. Removal of the endothelium prevented formation and release of the guanylate cyclase stimulating factor(s). Atropine, mepacrine, or nordihydroguaiaretic acid, which inhibit acetylcholine-induced endothelium-dependent relaxations, also inhibited acetylcholine-induced endothelium-mediated activation of guanylate cyclase. The results support the hypothesis that acetylcholine-induced endothelium-derived relaxing factor increases cyclic guanosine monophosphate levels of vascular smooth muscle by a stimulation of soluble guanylate cyclase.
Effect of hypercholesterolemia on vascular reactivity in the rabbit. I. Endothelium-dependent and endothelium-independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits.
Authors: Verbeuren T J , Jordaens F H , Zonnekeyn L L , Van Hove C E , Coene M C , Herman A G
Published: June 2012

We studied the effects of hypercholesterolemia on vascular responsiveness in different arteries isolated from rabbits: control groups of rabbits and groups receiving the atherogenic diet consisted of eight animals each. In the arteries, 16 weeks of cholesterol-rich (0.3%) diet evoked intimal lesions which were more pronounced than those noted after 8 weeks of hypercholesterolemia; the aortic arch was affected significantly more by the lesions than the abdominal aorta and the pulmonary artery. Segments of the arteries were mounted in organ chambers for isometric tension recording or for measurement of the endothelium-derived relaxant factor. Contractions caused by acetylcholine and prostaglandin F2 alpha were not altered by the hypercholesterolemia; those evoked by serotonin were moderately augmented only in the aortic arch of hypercholesterolemic rabbits. As the degree of intimal lesion formation increased, the contractions to norepinephrine and clonidine were progressively inhibited. The endothelium-independent relaxations to nitroglycerin were inhibited in only the most severely affected arteries; the endothelium-dependent relaxations to acetylcholine and adenosine triphosphate were progressively inhibited as the degree of fatty streak formation augmented. Thus, in the aortic arch, the relaxations to 3 X 10(-6) M acetylcholine, expressed as percent of the initial contraction, decreased from 86.7 +/- 3.3% in control tissues to 16.3 +/- 8.6% in the 16-week hypercholesterolemic vessels; in the abdominal aortas these relaxations averaged 93.5 +/- 2.2% in control vessels and 72.0 +/- 6.9% in the hypercholesterolemic tissues. The acetylcholine-induced release of endothelium-derived relaxant factor from the abdominal aorta was not significantly affected by the hypercholesterolemia. We conclude from these studies that in arteries obtained from hypercholesterolemic rabbits: the contractions caused by serotonergic mechanisms tend to be augmented, while those to alpha-adrenergic activation are decreased, the endothelium-independent relaxations are modified only in the more severely affected arteries, and the endothelium-dependent relaxations are progressively inhibited as the degree of fatty streak formation augments, probably because a step subsequent to the release of endothelium-derived relaxant factor is altered.
The influence of pressure overload left ventricular hypertrophy on diastolic properties during hypoxia in isovolumically contracting rat hearts.
Authors: Lorell B H , Wexler L F , Momomura S , Weinberg E , Apstein C S
Published: June 2012

We tested the hypothesis that there is an enhanced susceptibility in hypertrophied cardiac muscle to develop decreased diastolic distensibility of the left ventricle in response to hypoxia. The effects of brief hypoxia (3 minutes) were studied in rats with and without chronic left ventricular pressure overload hypertrophy using an isolated buffer-perfused and isovolumic (balloon-in-left ventricle) heart preparation with excised pericardium and vented right ventricle. We compared hypertrophied hearts from hearts from hypertensive uninephrectomized Wistar-Kyoto rats (n = 12) with normotensive uninephrectomized age-matched controls (n = 13). Coronary flow was held constant and adjusted so that an identical flow per gram left ventricular weight was achieved in both groups. The left ventricular balloon volume was adjusted to produce an initial left ventricular end-diastolic pressure of 10 mm Hg in both groups and was held constant thereafter so that changes in left ventricular end-diastolic pressure during hypoxia represented changes in diastolic chamber distensibility. Under aerobic conditions, left ventricular systolic pressure was 66% higher in the hypertrophied hearts than in the controls, but there was no difference in the rate or extent of left ventricular relaxation as estimated by the exponential time constant of pressure decay and the asymptote to which pressure decayed. In response to hypoxia, left ventricular end-diastolic pressure was significantly higher in the hypertrophied hearts than in the controls (37 +/- 5 vs. 22 +/- 5 mm Hg, P less than 0.001). In response to hypoxia, the rate of left ventricular relaxation was depressed to a comparable degree in both groups, but there was a greater upward shift in the asymptote to which pressure decayed in the hypertrophied hearts. Hypoxia-induced coronary vasodilation as assessed by the change in coronary vascular resistance was similar in the hypertrophied and control hearts (2.9 +/- 0.5 vs. 2.3 +/- 0.9 mm Hg/[(ml/min)/g], NS). The degree of hypoxia-induced anaerobic metabolism as estimated by the coronary arterial-venous lactate concentration difference was also similar in both groups (-0.72 +/- 0.23 vs. -0.73 +/- 0.16 mM/liter, NS). It is concluded that brief hypoxia results in a greater decrease in diastolic distensibility of the left ventricle in the presence of chronic pressure overload hypertrophy than in its absence.
Left ventricular mechanics related to the local distribution of oxygen demand throughout the wall.
Authors: Beyar R , Sideman S
Published: June 2012

The complex interactions between left ventricular mechanics and the oxygen demand is studied by relating the left ventricular transmural oxygen demand to the myocardial structural and dynamic characteristics. The study utilizes a recent model of left ventricular contraction, which is based on a nested shell spheroidal geometry, a fan-like fibrous structure, the twisting motion of the left ventricle over its long axis, a transmural electrical activation propagation and the basic laws of sarcomere dynamics. The local "axial" stress (in the direction of the fibers) and the instantaneous sarcomere length are used to calculate the spatial distribution of the intramural oxygen demand per beat Vo2(y), where y is the distance from the endocardium. The normalized local sarcomere stress-length area SLAn(y) is related linearly to Vo2(y) by: Vo2(y) = K1 X SLAn(y) + K2, where K1 and K2 are constants. The calculations show a transmural metabolic gradient which is characterized by higher values of Vo2(y) in the endocardial layers than in the epicardial layers. Shorter endocardial sarcomeres and the twisting motion of the left ventricle around the long axis decrease the metabolic gradient across the wall, while a slow transmural electrical propagation wave as well as a wider angle of distribution of the fan-like fiber architecture increases the transmural metabolic gradient. Integration of the local oxygen demand across the left ventricular wall yields global values in agreement with those based on Suga's pressure-volume area approach. The model thus provides a qualitative and quantitative tool to assess the relation of the local and global oxygen demand to the complex left ventricular structure, fiber mechanics, and the dynamics of contraction.
Atherosclerosis impairs endothelium-dependent vascular relaxation to acetylcholine and thrombin in primates.
Authors: Freiman P C , Mitchell G G , Heistad D D , Armstrong M L , Harrison D G
Published: June 2012

To test the hypothesis that atherosclerosis impairs endothelium-dependent vascular relaxation, we examined the effect of the endothelium-dependent vasodilators acetylcholine and thrombin and the endothelium-independent vasodilator nitroglycerin on iliac arteries from normal cynomolgus monkeys and cynomolgus monkeys with diet-induced atherosclerosis. Rings of iliac artery were suspended in organ chambers at their optimal length for generating tension. After preconstriction with prostaglandin F2 alpha, cumulative concentration-response curves to acetylcholine, thrombin, and nitroglycerin were examined. The presence of endothelium was confirmed in each vessel by scanning electron microscopy. Atherosclerotic vessels showed morphologic evidence of moderate to severe atherosclerosis. Acetylcholine produced a maximal relaxation of 65 +/- 10% in the normal group and 27 +/- 10% in atherosclerotic vessels (P less than 0.05). Thrombin (10.0 U/ml) produced relaxation of 39 +/- 9% in the normal group and 13 +/- 7% in atherosclerotic iliac arteries (P less than 0.05). Nitroglycerin relaxed both normal and atherosclerotic blood vessels to an equal extent; maximal relaxation was 92 +/- 4% in normal vessels and 98 +/- 2% in atherosclerotic vessels. To determine if hypercholesterolemia alone produces an abnormality in endothelium-dependent relaxation, we performed two additional studies. First, because veins are exposed to hypercholesterolemia, but do not develop atherosclerosis, we studied relaxation responses to acetylcholine and thrombin in veins from normal monkeys and monkeys with diet-induced atherosclerosis. Veins from normal and atherosclerotic monkeys relaxed to a similar extent upon exposure to the endothelium-dependent vasodilators acetylcholine and thrombin.(ABSTRACT TRUNCATED AT 250 WORDS)
Augmented cardiopulmonary baroreflex control of forearm vascular resistance in young athletes.
Authors: Takeshita A , Jingu S , Imaizumi T , Kunihiko Y , Koyanagi S , Nakamura M
Published: June 2012

The aim of this study was to examine the effect of exercise training on reflex control of vascular resistance in human males. Forearm vascular responses to lower body negative pressure (LBNP) at -10 and -40 mm Hg were compared between highly trained young athletes (21.5 +/- 0.5 years old, n = 14) and age-matched nonathletes (20.7 +/- 0.5 years old, n = 16). Resting heart rate was lower in athletes than in nonathletes. Resting blood pressure, central venous pressure, forearm blood flow, and forearm vascular resistance were not different between the two groups. The magnitude of reflex forearm vasoconstriction in response to LBNP at -10 mm Hg, which decreased central venous pressure but did not alter blood pressure or heart rate, was greater in athletes than in nonathletes. The slope of the regression line relating changes in central venous pressure and forearm vascular resistance was steeper in athletes than in nonathletes. Vasoconstrictive responses to intraarterially administered norepinephrine and angiotensin II did not differ between athletes and nonathletes. These results suggest that the tonic inhibitory influence of the cardiopulmonary receptors is augmented in athletes. This augmentation may contribute to some of cardiovascular and endocrine adaptations that occur with exercise training.
Myocardial ischemia: platelet and thromboxane concentrations in cardiac lymph and the effects of ibuprofen and prostacyclin.
Authors: Michael L H , Hunt J R , Lewis R M , Entman M L
Published: June 2012

Blood platelets have been implicated in several mechanisms leading to and/or modifying myocardial ischemia. Cardiac lymph examination allows insight into the extracellular fluid that is in equilibrium with the capillary blood. In order to obtain an index of platelet activation during coronary artery events in the awake chronic animal, we wished to ascertain whether evaluation of cardiac lymph would detect changes in platelet activation resulting from a vascular occlusion. The study used conscious dogs in which cardiac lymph vessels had been previously cannulated by open-chest surgical protocol. The concentrations of immunoreactive thromboxane B2 and platelet counts were assessed in the cardiac lymph during the control period, the 10-60 minute occlusions, and the reperfusion periods. The same protocols were effected on another series of dogs after infusion of ibuprofen or prostacyclin. Initially, immunoreactive thromboxane B2 concentrations in the systemic blood and cardiac lymph were identical. A three-fold increase in immunoreactive thromboxane B2 concentrations occurred in untreated animals and was accompanied by a fall in platelet count in the lymph. The infusion of ibuprofen or prostacyclin, which inhibit platelet aggregation by different mechanisms, prevented both the decrease in platelets and the increase in immunoreactive thromboxane B2. In this study, intravascular events resulting from coronary occlusion invoke a rapid rise of immunoreactive thromboxane B2 in the extravascular fluid. A decrease in platelet escape into the extravascular compartment is interpreted as a result of intravascular aggregation promoting decreased platelet numbers. Thus, examination of continuously flowing cardiac lymph allows rapid detection of intravascular activation of platelets in the awake animal in the absence of surgical trauma.
Transmural distribution of myocardial infarction: difference between the right and left ventricles in a canine model.
Authors: Ohzono K , Koyanagi S , Urabe Y , Harasawa Y , Tomoike H , Nakamura M
Published: June 2012

The evolution of myocardial infarction 24 hours after ligating both the right coronary artery and the obtuse marginal branch of the left circumflex coronary artery was examined in 33 anesthetized dogs. Postmortem coronary angiography and a tracer microsphere technique were used to determine risk areas and their collateral blood flows, respectively. The mean weight of the risk areas was 11.3 +/- 0.5 g (mean +/- SEM) in the right ventricle and 10.5 +/- 0.9 g in the left ventricle (NS). The weight of infarcted tissue was 5.7 +/- 0.7 g in the right ventricle and 5.2 +/- 0.9 g in the left ventricle (NS). In both ventricles, infarct weight was linearly related to risk area size, and the percent of risk area necrosis was inversely correlated with the extent of collateral flow at 24 hours of coronary ligation, defined as the mean myocardial blood flow inside the central risk area. Ratios of infarct to risk area between the subendocardial and subepicardial layers were 0.76 +/- 0.06 and 0.28 +/- 0.05 in the right and left ventricles, respectively (p less than 0.01, between ventricles, n = 31), which coincided well with subendocardial-to-subepicardial-flow ratios at 24 hours, ie, 0.86 +/- 0.04 in the right ventricle and 0.32 +/- 0.06 in the left ventricle (p less than 0.01). The regional distribution of myocardial infarction correlated well with flow distribution inside the risk area; the slope of these relations was similar between the subendocardium and subepicardium in the right ventricle, whereas in the left ventricle it was larger in the subendocardium than in the subepicardium. Thus, in the dog, the inherent change in the regional distribution of coronary collateral blood flow is an important modifier in the evolution of myocardial infarction, especially in the left ventricle.
Effect of shear rate variation on apparent viscosity of human blood in tubes of 29 to 94 microns diameter.
Authors: Reinke W , Johnson P C , Gaehtgens P
Published: June 2012

In order to test the hypothesis that the increase of vascular resistance observed in vivo at low flow rates is due in part to blood rheological properties, the apparent viscosity of human blood was measured in small tubes in a range of shear rates. Pressure-flow relationships were obtained in vertical glass tubes (29 to 94 microns i.d.) perfused with blood at hematocrits between 0.13 and 0.65. Viscosity of blood and plasma was calculated using Poiseuille's law. With the exception of data obtained in the largest tube at a hematocrit of 0.6, relative blood viscosity was found to be independent of shear rate in the range between 1 and 120 s-1. Microscopic observation revealed pronounced red cell aggregation at low shear rates. Velocity profiles obtained by the use of fluorescence-labelled red cells showed increased blunting with decreasing shear rate. The Fahraeus-Lindqvist effect was evident in a reduction of viscosity with tube size at a given feed hematocrit. The observed constancy of apparent blood viscosity with decreasing shear is attributed to the opposing effects of a cell-depleted marginal layer and red cell aggregation or deformation in the cell core. The findings indicate that the increase of vascular resistance at low arterial pressure cannot be explained by shear-dependent changes of apparent blood viscosity observed in macroviscometers.
Stimulation of angiogenesis by adenosine on the chick chorioallantoic membrane.
Authors: Dusseau J W , Hutchins P M , Malbasa D S
Published: June 2012

The effect of adenosine on the vascular density of the chick chorioallantoic membrane was studied. Elvax polymer pellets containing 0.2-3.0 mg of adenosine were placed on the chorioallantoic membrane of 10-day embryos. Control pellets containing mannitol were placed at least 1 cm away. After 4 days the membrane was formalin-fixed and removed. A thin plastic coverslip, inscribed with concentric circles (4-8 mm in diameter), was placed over the pellet. A vascular density index was estimated at 20 X by counting the number of intercepts between vessels and the inscribed circles. Adenosine stimulated a dose-dependent increase (p less than 0.01) in the vascular density index with the 3-mg pellets inducing a 15% increase. Inosine, a major metabolite of adenosine, did not cause a change in the number of intercepts counted. The adenosine-stimulated increase in vascularity was blocked with 110 micrograms of methyl-isobutyl-xanthine injected daily into the albumin. Partial inhibition was observed with 55 micrograms/day. Methyl-isobutyl-xanthine by itself did not affect the vascular density index. Dipyridamole enhanced adenosine's stimulation of vascular growth an additional 52%. Given alone, however, it had no effect on the membrane's vascularity. These data support an angiogenic role for adenosine. The modest, but consistent, increase in the vascular density index stimulated by adenosine, and the fact that it may be released during tissue hypoxia, is consistent with an hypothesis that this nucleoside plays a modulatory role in vessel proliferation accompanying conditions of long-term hypoxia.
Mechanism of early contractile failure during hypoxia in intact ferret heart: evidence for modulation of maximal Ca2+-activated force by inorganic phosphate.
Authors: Kusuoka H , Weisfeldt M L , Zweier J L , Jacobus W E , Marban E
Published: June 2012

We tested the hypothesis that accumulation of H+ or inorganic phosphate (Pi) is responsible for the early contractile failure of hypoxia by measuring maximal Ca2+-activated pressure and 31P nuclear magnetic resonance spectra in Langendorff-perfused ferret hearts at 30 degrees C. Maximal Ca2+-activated pressure was identified by the saturation of pressure with respect to [Ca2+]o observed during tetani as [Ca2+]o was increased to 15 mM in HEPES-buffered, 100% O2-bubbled perfusate and during hypoxia induced by bubbling with room air or with 100% N2. Tetani were produced by pacing at 8-12 Hz following exposure to ryanodine (1-5 microM), an inhibitor of Ca2+ release from the sarcoplasmic reticulum, and were elicited once a minute to measure maximal Ca2+-activated pressure during acquisition of nuclear magnetic resonance spectra. An inverse correlation was observed between [Pi] and maximal Ca2+-activated pressure (r = -0.87 mean, n = 12), with an average decline of 8.6% in pressure per 1 mumol/g wet wt. increase in [Pi]. Intracellular pH (pHi) showed no significant correlation with maximal Ca2+-activated pressure (r = 0.49 mean, n = 12). Two other protocols, pacing at variable rates and gated measurements at two different times during the tetanus, were also used to correlate [Pi], pHi, and maximal Ca2+-activated pressure. These protocols confirmed the highly significant correlation between [Pi] and maximal Ca2+-activated pressure, as well as the lack of correlation with pHi. Acidosis induced by NH4Cl (20 mM) or by bubbling with 95% O2/5% CO2 was associated with less than 20% depression of maximal Ca2+-activated pressure in the pHi range down to 6.8, but much greater depression at lower pHi. The data are consistent with depression of maximal Ca2+-activated force during the early phase of hypoxia by Pi but not by H+.
Effect of adenosine on atrioventricular conduction. II: Modulation of atrioventricular node transmission by adenosine in hypoxic isolated guinea pig hearts.
Authors: Clemo H F , Belardinelli L
Published: June 2012

Adenosine as well as hypoxia and ischemia are known to cause atrioventricular conduction block. To test the hypothesis that adenosine is the primary mediator of hypoxia-induced atrioventricular conduction delay in isolated perfused guinea pig hearts, we characterized a) the time courses of hypoxia-induced adenosine release and delay in atrioventricular conduction, b) the relationships between oxygen tension, adenosine concentration in the effluent, and atria-to-His-bundle interval, and c) the adenosine receptor mediating the negative dromotropic effect of hypoxia. Oxygen tension and effluent adenosine levels were linearly related with a correlation coefficient (r) of -0.85 and a slope of -6.3 +/- 0.37 pmol/min/g/torr. Likewise, oxygen tension and atria-to-His-bundle interval prolongation were linearly related with r = -0.85 and a slope of -0.180 +/- 0.013 msec/torr. The EC50 of effluent adenosine in causing atria-to-His-bundle prolongation was 0.26 +/- 0.02 microM. Adenosine deaminase, an enzyme that deaminates adenosine to inosine and is limited to the extracellular space, significantly attenuated (61%) the atria-to-His-bundle interval prolongation caused by hypoxia. This prolongation was further reduced (81%) by a combination of adenosine deaminase and theophylline, an adenosine receptor blocker. Adenosine deaminase also reduced (by 95%) the atria-to-His-bundle interval prolongation in normoxic recipient hearts caused by the effluent of hypoxic donor hearts. Several adenosine antagonists, i.e., theophylline, 8-phenyltheophylline, and 8-(p-sulfophenyl)theophylline antagonized in a dose-dependent manner the negative dromotropic effect of exogenous adenosine and hypoxia. Schild analysis of the antagonism of hypoxia-induced atria-to-His-bundle interval prolongation by 8-(p-sulfophenyl)theophylline yielded the following pA2 values: 5.30 +/- 0.25 and 5.28 +/- 0.31 using oxygen tension and effluent adenosine vs. AH interval prolongation, respectively. 8-(p-Sulfophenyl)theophylline also antagonized to an equal extent atria-to-His-bundle interval prolongations of similar magnitude caused either by adenosine or hypoxia. We conclude that 1) adenosine is the primary mediator of hypoxia-induced atrioventricular conduction delay, and 2) the adenosine receptor that mediates the negative dromotropic effect of hypoxia is similar to that of exogenous adenosine.
Acute alterations in diastolic left ventricular chamber distensibility: mechanistic differences between hypoxemia and ischemia in isolated perfused rabbit and rat hearts.
Authors: Wexler L F , Weinberg E O , Ingwall J S , Apstein C S
Published: June 2012

Changes in diastolic chamber distensibility (DCD) during hypoxemia and ischemia were studied in isolated-buffer-perfused rabbit hearts. Two minutes of hypoxemia (low PO2 coronary flow) resulted in a shift of the diastolic pressure-volume curve to the left, i.e., distensibility was decreased (hypoxemic contracture). In contrast, 2 minutes of ischemia (zero coronary flow) resulted in an initial shift of the diastolic pressure-volume curve to the right indicating increased distensibility, which was followed by a later (30 minutes) shift to the left (ischemic contracture). Two minutes of ischemia superimposed on hypoxemia caused complete reversal of contracture. A quick stretch and release applied to the myocardium reversed late ischemic contracture but did not effect early hypoxemic contracture. The role of intracellular pH in modulating changes in DCD during hypoxia and ischemia was studied using phosphorus-31 nuclear magnetic resonance spectroscopy of isolated-buffer-perfused rat hearts that demonstrated changes in DCD similar to rabbit hearts during hypoxemia and ischemia. Intracellular pH decreased from 7.03 +/- 0.02 to 6.87 +/- 0.03 (p less than .01) during 2 minutes of ischemia but did not change significantly during 4 minutes of hypoxemia. When 2 minutes of ischemia were superimposed on hypoxemia, pH decreased from 6.99 +/- 0.01 during hypoxemia to 6.88 +/- 0.02 after 2 minutes of ischemia (p less than .01), concomitant with the complete reversal of hypoxemic contracture. These results suggest different mechanisms for late ischemic and early hypoxemic contracture and also suggest an explanation for the opposite initial changes in DCD seen after brief periods of ischemia and hypoxemia. The early development of contracture during hypoxemia and rapid redevelopment of diastolic tension after quick stretching are consistent with the hypothesis that hypoxemic contracture results from persistent Ca++-activated diastolic tension secondary to impaired calcium resequestration by the sarcoplasmic reticulum. In contrast, the late development of contracture during global ischemia and reversal by quick stretching is compatible with rigor bond formation. The initial increase in distensibility during early ischemia and the reversal of hypoxemic contracture by a brief period of superimposed ischemia probably is the result of two factors present during ischemia but not during hypoxemia: the collapse of the coronary vasculature and loss of the "erectile" effect and, the rapid development of intracellular acidosis, which has been shown to affect myofibrillar calcium sensitivity, and this may lead to a decrease in Ca++ activated diastolic tension.