bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanism of action of carbocyclic thromboxane A2 and its interaction with prostaglandin I2 and verapamil in isolated arteries.
Authors: Toda N
Published: June 2012

Carbocyclic thromboxane A2 (10(-9) to 10(-7) M) produced a concentration-dependent contraction of helical strips of dog cerebral, coronary, mesenteric, renal, and femoral arteries and of monkey cerebral, coronary, and mesenteric arteries. Contraction induced by low concentrations of carbocyclic thromboxane A2 tended to be greater in cerebral arterial strips. Even after 60 minutes of exposure to Ca++-free media, approximately one-half of the contractile response of dog cerebral and mesenteric arteries to 10(-8) M carbocyclic thromboxane A2 was retained. The contractile response was attenuated by diphloretin phosphate, a prostaglandin antagonist, and was potentiated by aspirin. In dog cerebral arterial strips contracted with carbocyclic thromboxane, the relaxant response to prostaglandin I2 was less than the response seen in mesenteric and coronary arteries, whereas, in contrast, the response to verapamil was greater in cerebral arteries. Concentration-relaxation curves for papaverine did differ appreciably. It may be concluded that contractions induced by carbocyclic thromboxane are associated with the release of Ca++ from intracellular storage sites and, in addition, the increase in transmembrane Ca++ influx. Greater susceptibility of cerebral arteries to verapamil may indicate that the Ca++ antagonist is of use to relieve the persistent contraction of cerebroarterial smooth muscle. Prostaglandin I2 appears to counteract effectively the action of potent vasoconstrictors, such as thromboxane A2 and its carbocyclic analog, in various vascular beds.
Augmented tissue oxygen supply during striated muscle contraction in the hamster. Relative contributions of capillary recruitment, functional dilation, and reduced tissue PO2.
Authors: Klitzman B , Damon D N , Gorczynski R J , Duling B R
Published: June 2012

To investigate the relative contributions of alterations in blood flow, capillary density, and tissue PO2 to elevated oxygen delivery in working muscle, we conducted experiments on the suffused hamster cremaster muscle, using in vivo microscopic techniques. Muscle PO2 was measured during striated muscle twitch contraction at 1 Hz. Tissue oxygenation was changed by using suffusion solutions equilibrated with 0%, 5%, 10%, 21%, or 50% oxygen. Contraction caused an increase in capillary density (capillary recruitment), whose magnitude was related to the equilibration gas and, thus, to the suffusate PO2. Capillary recruitment first increased as the oxygen content was raised, peaked with 10% oxygen, and then diminished with higher oxygen content. Arteriolar functional dilation was also observed; when oxygen was raised above 21%, dilation was decreased. The data suggest that oxygen supply is increased primarily by arteriolar conductance changes with low suffusion solution oxygen (0% to 5%), and by capillary recruitment and increased PO2 gradients above 10% oxygen. When vasomotor tone was increased by addition of norepinephrine to the suffusion medium, the changes observed were similar to those observed when oxygen was increased. Therefore, we propose that the altered microvascular responses during vasoconstriction are a function of vascular tone rather than the levels of tissue PO2. A model is proposed which may partially explain the relations among vascular tone, functional dilation, and capillary recruitment. Our data also suggest that tissue PO2 may not be precisely regulated about a narrowly defined set point in this striated muscle but that, instead, tissue PO2 is a dependent variable controlled by the integrated effects of capillary recruitment, functional vasodilation, and altered metabolism.
The arachidonic acid metabolic capacity of canine myocardium is increased during healing of acute myocardial infarction.
Authors: McCluskey E R , Corr P B , Lee B I , Saffitz J E , Needleman P
Published: June 2012

The relative capacity for metabolizing [14C]arachidonic acid into biologically active products was studied in microsomes prepared from both normal and infarcted regions of myocardium at three different times after circumflex coronary artery occlusion in the dog. At 3 days after infarction, when polymorphonuclear leukocytes were the predominant invading cell, the ability of infarcted left ventricle microsomes to produce arachidonic acid metabolites was greater than that of microsomes from normal areas of the same hearts. At 3 weeks after infarction, when macrophages were the predominant infiltrating cell and there was a proliferation of blood vessels and fibroblasts, there continued to be significant increases in the production of both prostacyclin (measured as 6-keto PGF1 alpha) and thromboxane (measured as TxB2). This enhanced production was still seen at 3 months after infarction at a time when histological examination of the tissue showed that it was still healing with both blood vessels and fibroblasts present. The production of 6-keto PGF1 alpha was 31.7 +/- 4 picomoles per milligram protein per hour (pmol/mg per hr) in noninfarcted regions of left ventricle, whereas the production was significantly increased to 71.7 +/- 15 at 3 days, 64.1 +/- 10 at 3 weeks, and 67.2 +/- 15 even at 3 months after infarction. The thromboxane synthetase activity rose significantly from 30.1 +/- 5 pmol mg per hr in noninfarcted regions to 73.7 +/- 18 at 3 days, 71.2 +/- 5 at 3 weeks, and 92.4 +/- 40 at 3 months. The enhanced ability to metabolize arachidonic acid may result from the inflammatory cell invasion or fibroblast activation which accompany healing of acute infarcts.
Heat production during hypoxic contracture of rat myocardium.
Authors: Holubarsch C , Alpert N R , Goulette R , Mulieri L A
Published: June 2012

Contracture due to hypoxia, to both oxygen and glucose deficiency, and to potassium chloride was induced in rat left ventricular papillary muscle preparations. Under contracture conditions, the sum of resting heat plus contracture heat was measured using Hill-type, planar vacuum-deposited thermopiles. On the basis of the measured total and initial heat output and the corresponding tension-time integral during single twitches under control conditions (Lmax, 21 degrees C, stimulus frequency 12/min), the expected heat output during contracture was calculated, assuming that the contracture tension is maintained by the same calcium-induced cross-bridge cycling as occurs in the single twitch response. With potassium chloride, the contracture tension was 1.33 +/- 0.27 g/mm2, a value which is similar to those found in hypoxic contracture and in contracture due to both oxygen and glucose deficiency. There was no significant difference between measured and calculated values for resting heat plus contracture heat (8.40 +/- 2.84 mW/g measured, 8.55 +/- 2.50 mW/g calculated); there was a linear correlation (r = 0.99) between predicted and measured values (P less than 0.05). The measured value for resting plus contracture heat in hypoxic contracture was 1.88 +/- 0.37 mW/g, whereas a value of 4.80 +/- 1.09 mW/g (P less than 0.005) was calculated on the basis of the twitch heat per tension-time integral and contracture tension (1.09 +/- 0.31 g/mm2). Contracture tension was 1.80 +/- 0.78 g/mm2 in contracture due to oxygen and glucose deficiency, whereas the value for resting plus contracture eat was 1.61 +/- 0.56 mW/g. The calculated resting plus contracture heat value for this preparation was significantly higher (7.45 +/- 3.75 mW/g; P less than 0.05). There was no significant regression between predicted and measured resting heat plus contracture heat in the hypoxic contracture preparations (slope not different from zero). In contracture due to oxygen and glucose deficiency, the linear regression had a slope of 6.06 (P less than 0.05). The results suggest that the potassium chloride contracture relies on cross-bridge cycling as in a twitch contraction, whereas hypoxic contracture and that due to oxygen and glucose deficiency may be explained by cross-bridge formations with no, or very low, heat production, i.e., contracture tensions due to hypoxia and to oxygen and glucose deficiency are maintained by rigor-like cross-bridge formation or by slowly cycling cross-bridges with a long time of cross-bridge attachment.
Interaction of verapamil and other calcium channel blockers with alpha 1- and alpha 2-adrenergic receptors.
Authors: Motulsky H J , Snavely M D , Hughes R J , Insel P A
Published: June 2012

To determine the specificity of the previously demonstrated competition of verapamil with radioligand binding to alpha-adrenergic receptors, we examined the interaction of calcium channel blockers with alpha 1- and alpha 2-adrenergic receptors on several tissues. Verapamil competed for [3H] prazosin binding to alpha 1-adrenergic receptors and for [3H]yohimbine binding to alpha 2-adrenergic receptors in several tissues (human platelets, rat kidney and heart, and cultured muscle cells) with dissociation constants of 0.6-6 microM. The calcium channel blockers D600, D591, fendiline, and prenylamine--which are structural analogues of verapamil--also competed for [3H]yohimbine binding to human platelets. Two other calcium channel blockers, diltiazem and nifedipine, did not compete for [3H] yohimbine binding to human platelets or [3H]prazosin binding to membranes prepared from rat ventricles. We used [3H]nitrendipine binding to identify putative calcium channels on rat myocardial membranes. Nifedipine and verapamil blocked these [3H]nitrendipine-binding sites on ventricular membranes, but epinephrine and prazosin did not, indicating that the ventricular alpha 1 receptors and calcium channels are distinct. We found no specific [3H]nitrendipine binding to human platelets. We conclude that the interaction of verapamil with alpha-adrenergic receptors is not receptor subtype or tissue specific, that interaction with alpha-adrenergic receptors is not a property of all calcium channel blockers, and that the interaction of verapamil with alpha-adrenergic receptors and its interaction with calcium channels occur at at least two distinct sites.
Reflex chronotropic and inotropic effects of calcium channel-blocking agents in conscious dogs. Diltiazem, verapamil, and nifedipine compared.
Authors: Nakaya H , Schwartz A , Millard R W
Published: June 2012

In chronically instrumented, conscious dogs, rapid injection of equihypotensive doses of three calcium channel-blocking agents, verapamil (250 micrograms/kg), diltiazem (200 micrograms/kg) and nifedipine (50 micrograms/kg), produced disparate chronotropic and inotropic responses. Although they all decreased mean arterial pressure by about 10%, heart rate (93 +/- 4 beats/min) was markedly increased to 175 +/- 12 with nifedipine, to 163 +/- 15 with verapamil, and only slightly increased to 118 +/- 7 with diltiazem. Contractile responses measured before (left ventricular dP/dtmax, 2749 +/- 131 mm Hg/sec) and during left ventricular ejection (endocardial dimension dD/dtmax, 57 +/- 4 mm/sec) were increased by 24% and 14% with nifedipine, decreased by 26% and 22% with verapamil, and were unchanged with diltiazem. These chronotropic and inotropic responses to rapid intravenous administration of the three drugs were increased in a dose-dependent manner. Similar results also were observed after slow infusion of these drugs. To determine the extent to which autonomic reflexes participated in these cardiac responses, propranolol (0.5 mg/kg) or propranolol plus atropine (0.1-0.2 mg/kg) was administered prior to injection of each calcium channel-blocking agent. Propranolol abolished the positive inotropic response to nifedipine and potentiated the negative inotropic response to verapamil. Positive chronotropic responses to verapamil, nifedipine, and diltiazem were attenuated by propranolol plus atropine. These results suggest that equihypotensive doses of the three prominent calcium channel-blocking agents exert different degrees of autonomic reflex activation in awake, unsedated dogs. These reflexes, which modulate the direct effects of calcium channel-blocking agents on chronotropic and inotropic variables of the heart, may have important clinical implications.
Systolic mechanical properties of the left ventricle. Effects of volume and contractile state.
Authors: Hunter W C , Janicki J S , Weber K T , Noordergraaf A
Published: June 2012

To characterize the mechanical properties of the contracting left ventricle, we studied the changes in left ventricular systolic pressure following step-like perturbations (+/- 3 ml) in ventricular volume, using an isovolumically beating, isolated canine heart preparation. Three mechanical properties (elasticity, resistance, and a deactivation effect) were identified. The elastic property differs from the traditional parallel and series elastic elements; it is a time-varying elasticity that includes active and passive effects of volume changes. Furthermore, it could not be represented by a simple time-varying elasticity, but required a second factor to express the dependence of end-systolic elasticity on the timing of the volume step. This effect was represented by a "volume influence factor," which may arise from length-dependent activation. The resistive property appeared to be related to force-velocity behavior of the myocardium. Each mechanical property reacted characteristically to steady state changes in ventricular filling volume or contractile state produced by dobutamine (2-13 micrograms/min). Our findings indicate that elasticity was the property most sensitive to changes in contractile state; these changes increased peak isovolumetric pressure 54% on average, and raised elastic stiffness 40% above control (which was 5.1 mm Hg/ml). Changes in ventricular filling volume only prolonged, but did not alter, the level of elastic stiffness attained at peak pressure. These results support the view that elasticity--or the end-systolic pressure-volume relationship--serves in a given heart to quantify contractility. The "volume influence factor" was not affected by either filling volume or contractile state. Resistance increased in direct proportion with ventricular pressure, but this linear relation was not altered greatly by changes in contractile state or in ventricular filling volume. At 100 mm Hg, ventricular resistance averaged 0.11 mm Hg/ml per sec. Finally, deactivation was greater the later in systole a volume step was imposed, and this pattern was independent of changes in ventricular filling volume and in contractile state.
Effects of sympathetic stimulation and changes in arterial pressure on segmental resistance of cerebral vessels in rabbits and cats.
Authors: Baumbach G L , Heistad D D
Published: June 2012

The purpose of this study was to determine directly segmental cerebral vascular resistance during sympathetic stimulation and changes in arterial pressure. We measured pressure in pial arteries in anesthetized rabbits and cats with a servo-null pressure-measuring device. Cerebral blood flow was measured with microspheres. Using these measurements we calculated large artery resistance and small vessel resistance. Under control conditions, large artery resistance accounted for approximately 40% of total cerebral vascular resistance. Sympathetic stimulation increased large artery resistance and reduced pial artery pressure. Cerebral blood flow and total cerebral vascular resistance did not change significantly. To examine constrictor responses of small cerebral vessels, we raised cerebral perfusion pressure by obstructing the descending aorta. During increases in arterial pressure from 70 to 110 mm Hg, large artery resistance tended to increase and small vessel resistance increased significantly. We conclude that, although sympathetic stimulation has little effect on total cerebral vascular resistance under normal conditions, it has important effects on segmental vascular resistance and cerebral microvascular pressure, and that sympathetic stimulation and increases in systemic arterial pressure within the physiological range have markedly different effects on segmental resistance; i.e., sympathetic stimulation produces constriction only in large arteries, and increases in systemic arterial pressure within the physiological range produce constriction primarily in small vessels.
Tissue PO2 in the intestinal muscle layer of rats during chronic diabetes.
Authors: Bohlen H G
Published: June 2012

Chronic diabetes mellitus induced in rats by streptozotocin or of genetic origin in Db/Db mice is associated with a loss of capillaries, arteriolar constriction, and a decrease in resting and maximum blood flow. As a result of these vascular changes, as well as glycolysation of hemoglobin, it is possible that tissue Po2 is reduced at rest and cannot be substantially increased during dilatation. Tissue Po2 in the intestinal muscle layer was measured at rest and during maximal dilation. In addition, the spacing between capillaries with active flow and the velocity of red blood cell flow in capillaries were measured at rest and at maximum dilation. These measurements were made in normal and diabetic rats (streptozotocin) at age 26-30 weeks; the diabetic animals had been hyperglycemic (greater than 350 mg/100 ml) for 12-15 weeks. Tissue Po2 at a distance of about 15 microns from the arterial, mid-point, and venous end of capillaries in normal rats was 24.8 +/- 1.1 (SE), 23.1 +/- 1.2, and 22.4 +/- 0.9 mm Hg, respectively, compared with 25.8 +/- 0.9, 24.1 +/- 1.2, and 22.4 +/- 1.1 mm Hg, respectively, in diabetic rats. The maximum mid-capillary tissue Po2 during dilation was 27.7 +/- 1.3 mm Hg in normal rats and 29.7 +/- 1.5 mm Hg in diabetic rats. The average distance between capillaries was 37.6 +/- 2.0 microns in normal rats and 46.8 +/- 2.9 microns in diabetic animals; vasodilation did not change the capillary spacing in either group of animals. Capillary red cell velocity in normal rats increased from 0.98 +/- 0.11 mm/sec at rest to 2.1 +/- 0.4 mm/sec during dilatation. For comparable conditions in diabetic rats, the velocities were 0.41 +/- 0.07 and 1.06 +/- 0.19 mm/sec. The data presented indicate that the diabetic animals have tissue Po2 equivalent to those in normal rats, both at rest and during maximum vasodilation. The loss of capillaries and decreased resting and maximum capillary red cell velocity in diabetic rats would decrease the delivery of oxygen, but, apparently, a decrease in oxygen consumption occurred that allowed the intestinal tissue to have a normal Po2.
Developmental changes in the cardiac effects of amrinone in the dog.
Authors: Binah O , Legato M J , Danilo P , Rosen M R
Published: June 2012

Amrinone, a bipyridine compound, has been shown to exert a positive inotropic effect on the heart, without producing cardiac arrhythmias. Because of preliminary observations suggesting that the actions of amrinone might change significantly with growth and development, we studied its effects on the contractility and electrophysiology of isolated cardiac muscle of 0- to 96-day-old beagles and Purkinje fibers of 5-year-old beagles. Amrinone's effects on ventricular muscle contractility were age-related. A significant decrease in contractility of right ventricular trabeculae and papillary muscles (not associated with changes in action potential characteristics) was observed in the 0- to 3-day newborn, whereas, by day 4-10, amrinone increased contractility. The magnitude of the increase became greater through day 96 of life. The negative inotropic effect of amrinone is unassociated with changes in the action potential plateau, suggesting that the slow inward current is not involved in this mechanism.
Role of adenosine in the maintenance of coronary vasodilation distal to a severe coronary artery stenosis. Observations in conscious domestic swine.
Authors: Gewirtz H , Brautigan D L , Olsson R A , Brown P , Most A S
Published: June 2012

The purpose of this study was to test the hypothesis that adenosine is required to maintain arteriolar vasodilation distal to a severe coronary stenosis. Eight closed-chest conscious pigs were prepared by placing a 7.5-mm long stenosis (82% lumenal diameter reduction) in the proximal left anterior descending coronary artery. Regional myocardial blood flow (microsphere technique) was measured at control 1, after 10 minutes of intracoronary infusion of adenosine deaminase (7-10 U/kg per min) distal to the stenosis, and 20-30 minutes after stopping adenosine deaminase infusion. Studies with 125I-labeled adenosine deaminase were conducted in six additional pigs to document the extent to which infused adenosine deaminase penetrated the interstitial space. 125I-labeled adenosine deaminase was infused for 10 minutes (10-11 U/kg per min) into the left anterior descending coronary artery. Calculated interstitial fluid concentrations of adenosine deaminase ranged between 71 and 272 U/ml and were at least one order of magnitude greater than that required to deaminate all the adenosine which would be released into the interstitium in response to 15-30 seconds of coronary occlusion. In the primary group of animals (n = 8), endocardial flow (ml/min per g) distal to stenosis at control 1 (1.15 +/- 0.33) was reduced vs. endocardial flow in the nonobstructed circumflex zone (1.59 +/- 0.38, P less than 0.05). Flows in epicardial layers were comparable at control 1 (distal zone = 1.40 +/- 0.36 vs. circumflex zone = 1.45 +/- 0.41). Distal zone endocardial and epicardial flows did not change vs. control 1 in response to infusion of adenosine deaminase. However, the distal: circumflex epicardial flow ratio declined vs. control 1 (0.98 +/- 0.14) during adenosine deaminase infusion (0.87 +/- 0.17, P less than 0.05). The distal:circumflex endocardial flow ratio during adenosine deaminase (0.72 +/- 0.20) was unchanged vs. control 1 (0.76 +/- 0.22) but was less than control 2 (0.80 +/- 0.18, P less than 0.05). Thus, destruction of all or most interstitial adenosine caused only slight relative reduction in regional myocardial blood flow distal to a severe coronary artery stenosis. Accordingly, adenosine contributes only modestly to maintenance of arteriolar vasodilation in this setting or else its absence is almost fully compensated for by another mechanism(s).
Hyperreactivity of coronary arterial smooth muscles in response to ergonovine from rabbits with hereditary hyperlipidemia.
Authors: Yokoyama M , Akita H , Mizutani T , Fukuzaki H , Watanabe Y
Published: June 2012

This study was undertaken to examine the response to ergonovine, an agent used to provoke spastic constriction of large epicardial coronary arteries, to elucidate the responsible underlying mechanism, and to determine the impact of endogenous hyperlipidemia on contractile properties of isolated vessels from different beds. The isolated arteries from both control and Watanabe hereditary hyperlipidemic rabbits (WHHL rabbits) were suspended for recording isometric force in oxygenated Krebs buffer and exposed to agonists and antagonists. In atherosclerotic aortas from WHHL rabbits, the concentration-response relations for ergonovine and serotonin exhibited a marked leftward shift with significantly depressed constrictor threshold concentration and lowered one-half maximally effective concentration values. In coronary arteries with no atherosclerotic lesions detectable macroscopically from WHHL rabbits, the concentration-response relations showed a leftward shift for ergonovine but not serotonin. Coronary contraction evoked by ergonovine was remarkably inhibited by 0.1 microM cyproheptadine and 0.3 microM methysergide, serotonergic antagonists, in both groups. alpha-Adrenergic blockade with 0.1 microM prazosin was effective in inhibiting ergonovine-induced contraction of aortas from control rabbits, but not that of atherosclerotic ones. The constrictor response to ergonovine of atherosclerotic aortas was inhibited by cyproheptadine. The responsiveness to ergonovine of both carotid and femoral arteries from WHHL rabbits with no sclerotic lesions, which was suppressed by prazosin was not different from that of control rabbits. In contrast, the concentration-response relations for phenylephrine in the four different types of arteries did not differ appreciably between the two groups, and the constrictor responses to 20 mM KCl were virtually identical. Thus, aortas and coronary arteries exposed to endogenous hyperlipidemia appear to be hyperreactive to ergonovine mediated by a serotonergic mechanism.
Synergistic effects of acute hypoxemia and hypercapnic acidosis in conscious dogs. Renal dysfunction and activation of the renin-angiotensin system.
Authors: Rose C E , Kimmel D P , Godine R L , Kaiser D L , Carey R M
Published: June 2012

The effects of acute hypoxemia and hypercapnic acidosis were examined in five unanesthetized dogs in which sodium intake was controlled at 80 mEq/24 hours for 4 days prior to study. Each animal was studied during combined acute hypoxemia and hypercapnic acidosis (Pao2 = 36 +/- 1 mm Hg, Paco2 = 52 +/- 1 mm Hg, pH = 7.18 +/- 0.02), acute hypoxemia alone (Pao2 = 32 +/- 1 mm Hg, Paco2 = 32 +/- 1mm Hg, pH = 7.34 +/- 0.01), and acute hypercapnic acidosis alone (Pao2 = 82 +/- 2 mm Hg, Paco2 = 51 +/- 1 mm Hg, pH = 7.18 +/- 0.02). Although mean arterial pressure, cardiac output, and heart rate increased during combined hypoxemia and hypercapnic acidosis, effective renal plasma flow and glomerular filtration rate decreased. In addition, filtered sodium load and urinary sodium excretion decreased during combined hypoxemia and hypercapnic acidosis. Either acute hypoxemia or hypercapnic acidosis alone resulted in increased mean arterial pressure, cardiac output, and heart rate. However, in contrast to their combined effects, renal hemodynamic function was unchanged and natriuresis was observed. Measurement of plasma renin activity and angiotensin II concentrations indicated that hypoxemia or hypercapnic acidosis alone resulted in moderate activation of the renin-angiotensin system. Moreover, combined hypoxemia and hypercapnic acidosis acted synergistically resulting in major renin-angiotensin activation. Systemic angiotensin II blockade using 1-sarcosine, 8-alanine, angiotensin II (2 micrograms/kg per min) during combined acute hypoxemia and hypercapnic acidosis resulted in decreased renal hemodynamic function. We conclude that acute hypoxemia and hypercapnic acidosis act synergistically to increase mean arterial pressure, diminish renal hemodynamic function and activate the renin-angiotensin system. Systemic angiotensin inhibition studies suggest activation of the renin-angiotensin system maintains renal hemodynamic function during combined hypoxemia and hypercapnic acidosis, instead of mediating the renal vasoconstriction.
Thromboxane generation after thrombin. Protective effect of thromboxane synthetase inhibition on lung fluid balance.
Authors: Garcia-Szabo R R , Peterson M B , Watkins W D , Bizios R , Kong D L , Malik A B
Published: June 2012

We examined the role of thromboxane in mediating the alterations in pulmonary hemodynamics and in lung fluid and protein exchange after thrombin. Studies were made in control sheep and in sheep pretreated with the thromboxane synthetase inhibitor, Dazoxiben (injection of 10 mg/kg followed by infusion of 4 mg/kg per hr). Thrombin infusion caused an increase in mixed venous and aortic concentrations of thromboxane B2, a stable degradation product of thromboxane A2, whereas the concentrations of 6-keto-PGF1 alpha, a degradation product of prostacyclin, did not change significantly. In sheep pretreated with Dazoxiben, thromboxane B2 concentrations did not increase, indicating effectiveness of the thromboxane synthetase inhibitor. The blood concentrations of 6-keto-PGF1 alpha after thrombin increased in the thromboxane synthetase-inhibited group, indicating shunting towards prostacyclin synthesis. Thrombin in untreated sheep increased pulmonary lymph flow (Qlym) and the lymph protein clearance (Qlym X lymph-to-plasma protein concentration ratio). The increases in lymph parameters were due to an increase in pulmonary vascular permeability to proteins because raising left atrial pressure further increased Qlym but did not change lymph-to-plasma ratio. Dazoxiben prevented the thrombin-induced increase in pulmonary vascular permeability because the increase in left atrial pressure resulted in an increase in Qlym and a decrease in lymph-to-plasma ratio, as was the case after left atrial hypertension in normal animals. Therefore, thrombin results in selective release of thromboxane A2 which precedes the increase in pulmonary vascular permeability. Thromboxane A2 may contribute to the increased permeability after thrombin, since inhibition of thromboxane synthesis prevents the permeability change.
Salvage of myocardial function by coronary artery reperfusion 1, 2, and 3 hours after occlusion in conscious dogs.
Authors: Lavallee M , Cox D , Patrick T A , Vatner S F
Published: June 2012

The effects of coronary artery occlusion and reperfusion at 1 hour (1-hr group), 2 hours (2-hr group), and 3 hours (3-hr group) were compared with a permanently occluded group (P group) on measurements of overall left ventricular and regional endocardial function over a 4-week period. The studies were conducted in conscious dogs 1-2 weeks after recovery from instrumentation with solid state left ventricular pressure gauges, aortic, and left atrial catheters, hydraulic occluders, and Doppler flow transducers on the left anterior descending or left circumflex coronary arteries, and multiple pairs of ultrasonic transducers implanted in the endocardial third of the left ventricular free wall to measure endocardial segment shortening. During coronary artery occlusion, similar effects were observed in the four groups. At 1 hour after coronary artery occlusion, three classes of ischemia-induced dysfunction were observed; dyskinetic (systolic shortening completely lost and replaced by paradoxical bulging), severely hypokinetic (systolic shortening depressed by 65-95%), and moderately hypokinetic (systolic shortening depressed by 40-65%). Compared with the P group, significant (P less than 0.05) return of systolic shortening and velocity of shortening gradually occurred over the 4-week period following reperfusion in all classes of segments in the 1-hour group. In the 2-hour group, systolic shortening returned in the moderately and severely hypokinetic segments, but was slight and not significant in the dyskinetic segments. In the 3-hour group, significant systolic shortening returned only in the moderately hypokinetic segments. The effects of isoproterenol, 0.04 micrograms/kg per min, and exercise were compared on "salvaged" dyskinetic segments prior to and at 1, 2, 3, and 4 weeks after coronary artery occlusion and reperfusion. The responses to isoproterenol were significantly depressed at 1 week after reperfusion and gradually recovered over the 4-week period. At 3-4 weeks after reperfusion, severe exercise also increased shortening and velocity of shortening in "salvaged" segments. Thus, in the conscious dog, coronary artery reperfusion at 1 hour after coronary artery occlusion results in substantial return of endocardial function even in the most severely ischemic myocardium. The "salvaged" myocardium responds adequately to myocardial stress with increases in the extent and velocity of systolic shortening, as long as 3-4 weeks after reperfusion are allowed for recovery. However, after 3 hours of coronary artery occlusion, little salvage of regional myocardial function can be induced by acute reperfusion in this model.
Magnetic measurement of S-T and T-Q segment shifts in humans. Part I: Early repolarization and left bundle branch block.
Authors: Savard P , Cohen D , Lepeschkin E , Cuffin B N , Madias J E
Published: June 2012

The direct-current magnetocardiogram not only shows the features usually seen on the electrocardiogram, but also shows the T-Q (baseline) shift due to cardiac injury current. The first direct-current magnetocardiogram measurements of the human heart are presented here. The hypothesis tested is that there is no injury current associated with the S-T shift seen in two electrocardiogram abnormalities: early repolarization, and left bundle branch block. The data from three typical early repolarization subjects and one typical left bundle branch block patient are presented. It is found, in each case, that although there is appreciable S-T shift, there is essentially no baseline shift on the direct-current magnetocardiogram. The absence of baseline shift proves that the S-T shifts in these cases are not "apparent" shifts, caused by a dc injury current which is interrupted during the S-T interval; instead, these are "true" S-T shifts caused by a current flowing only during systole, presumably due to an altered repolarization of the ventricles. It is also found that the direct-current magnetocardiogram does not have routine clinical application because of a practical problem. This is the presence of false baseline shifts due to noncardiac currents, mostly in the gastrointestinal tract, which could be suppressed in only about one-third of the subjects. However, the direct-current magnetocardiogram may be useful as a research tool, for clarifying the cause of the S-T shift in selected subjects.
Magnetic measurement of S-T and T-Q segment shifts in humans. Part II: Exercise-induced S-T segment depression.
Authors: Cohen D , Savard P , Rifkin R D , Lepeschkin E , Strauss W E
Published: June 2012

The direct-current magnetocardiogram, which shows the T-Q (baseline) shift, is used to clarify the cause of S-T depression induced by stress testing in the human heart. Measurements are made of the amount of baseline shift associated with the S-T depression. Results are presented of a well-documented patient, with typical coronary artery disease, undergoing a two-step exercise test. Before exercise, there was no S-T or baseline shift. During exercise, the S-T segment became depressed and the baseline segment was simultaneously elevated, at about 70% of the S-T amplitude. After termination of exercise, the baseline elevation disappeared somewhat more rapidly than the S-T depression. These results were consistent in repeated tests of this patient. Because the baseline shift is a reflection of an injury current, these results confirm the belief that exercise-induced S-T depression is mostly due to an injury current which is interrupted during the S-T interval. The baseline shift seen here is the first non-invasive measurement of an injury current in the human heart, and its presence and time-course generally agree with measurements in the animal heart. This work also confirms that the direct-current magnetocardiogram, although not practical for clinical purposes, is useful as a research tool.
Effect of positive inotropic agents on the relation between oxygen consumption and systolic pressure volume area in canine left ventricle.
Authors: Suga H , Hisano R , Goto Y , Yamada O , Igarashi Y
Published: June 2012

We analyzed the effect of positive inotropic agents on the relation between left ventricular oxygen consumption and the systolic pressure-volume area. Pressure-volume area is a measure of total mechanical energy for ventricular contraction, and is a specific area in the ventricular pressure-volume diagram circumscribed by the end-systolic and end-diastolic pressure-volume relation curves and the systolic segment of the pressure-volume trajectory. Either epinephrine (1 microgram/kg per min, iv) or calcium ion (0.03 mEq/kg per min, iv) was administered to canine excised cross-circulated hearts. These agents increased an index of ventricular contractility, Emax, or the slope of the end-systolic pressure-volume line, by 70%. The regression lines of ventricular oxygen consumption on pressure-volume area in control and in enhanced contractile states were of the same formula: ventricular oxygen consumption (ml O2/beat per 100 g) equals A times pressure-volume area (mm Hg ml/beat per 100 g) plus a constant B. Coefficient A remained unchanged at 1.8 X 10(-5) ml oxygen/(mm Hg ml), but constant B increased from 0.03 ml oxygen/beat per 100 g by more than 50% with either agent. The reciprocal of A reflects the energy conversion efficiency for the total mechanical energy, and this efficiency remained near 36%. The increase in B was equal to the directly measured increment in ventricular oxygen consumption for mechanically unloaded contraction. The basal metabolism remained unchanged. We conclude that the augmented oxygen consumption under the acutely enhanced contractile state with either epinephrine or calcium was caused primarily by an increased energy utilization associated with the excitation-contraction coupling.
The dimensional characteristics of smooth muscle in rat blood vessels. A computer-assisted analysis.
Authors: Todd M E , Laye C G , Osborne D N
Published: June 2012

This investigation was undertaken to provide precise information about the dimensional characteristics of vascular smooth muscle cells as related to their paracellular matrix. The representative types of vessels were fixed at the mean blood pressures of adult male Wistar rats. The shapes, positions of the nucleus, linear dimensions, volumes, and orientation within the vessel wall were determined by a computer-assisted reconstruction of the cells from serial sections. Wall-to-lumen and cellular-to-paracellular ratios also were assessed. The smooth muscle cells were elongate, but whereas some are spindle shaped, most are not, and may be shaped like flattened triangles, paddles, boomerangs, or hourglasses, and in addition, any one of these shapes may be forked. The nucleus tended to be in the largest part of the cell, wherever that region occurred. Thus, the majority of the nuclei (61%) were not centrally located, but overlapped the middle and end thirds of the elongate cells. Of the three arteries investigated, the muscular type tail artery had cells with volumes two to three times larger (P less than 0.01) than cells in a musculoelastic (femoral) or elastic (mesenteric) artery, and six times larger (P less than 0.01) than those of the portal vein. Therefore, the smooth muscle cells of the vein were significantly smaller than those in any artery (P less than 0.01). The smooth muscle cells were aligned at a steeper angle in the vessel wall (15 degrees +/- 2 degrees) of the muscular artery than in those with more elastic tissue (9 degrees +/- 2 degrees), with a higher percentage of circumferential cells in the latter. The wall-to-lumen ratios decreased as the relative amount of paracellular matrix, particularly elastic tissue, increased in the three arteries. Therefore, irregularly shaped cells, with the nucleus in the thickest region, and having characteristic cell volumes depending on the type of vessel, form the vascular smooth muscle tissue. These factors are relevant if stereology, or measuring from two dimensions, is used to estimate size characteristics in cardiovascular disease such as hypertension. In addition, the optimum angle at which vascular strips are cut would vary, for example, when used in testing pharmacological agents.
Rabbit arterial endothelium and subendothelium. A change in interfacial free energy that may promote initial platelet adhesion.
Authors: Boyce J F , Wong P C , Schürch S , Roach M R
Published: June 2012

Endothelial damage and exposure of the subendothelium is accompanied by platelet adhesion and aggregation. Thermodynamically, adhesion will occur if this process decreases the total free energy of the system. In this investigation, we have developed a contact angle technique to measure relative changes in the surface free energy of the arterial wall, before and after the endothelium has been removed. Sections of descending thoracic aorta from seven rabbits were tested with an equilibrium two-phase system of 4% polyethylene glycol (mol wt: 20,000)/4% dextran (mol wt: 2,000,000) in Hepes-buffered physiological saline. The tissue was split longitudinally, immersed in the polyethylene glycol phase, and test droplets of the denser dextran phase were placed on its surface. Advancing contact angles of the drop were measured from photomicrographs taken with polarizing optics. After testing, the endothelium was removed with a saline jet, which we had calibrated previously with scanning electron microscopy, and the tissue was retested. We measured angles of 86.0 +/- 1.1 degree (SEM), n = 64 for the intact endothelium and 20.0 +/- 0.8 degree (SEM), n = 61 on the subendothelial surface. Since the physical behavior of blood is probably similar to our polyethylene glycol bathing medium the subendothelium may also represent a surface of high interfacial free energy in vivo. Assuming that the surface energy of platelets is low, platelet adhesion to the subendothelium could reduce the total free energy of the system, by covering this high interfacial free energy surface.
Vibratory ventilation decreases filtration of fluid in the lungs of newborn lambs.
Authors: Raj J U , Goldberg R B , Bland R D
Published: June 2012

To compare effects of vibratory and mechanical ventilation on fluid balance in the newborn lung, we measured pulmonary arterial and left atrial pressures, pleural and airway pressures, lung blood flow and lymph flow, and concentrations of protein in lymph and plasma of 19 healthy lambs, 2-4 weeks old, during a 2- to 4-hour period of spontaneous breathing, followed by 4-8 hours of mechanical ventilation at 30 breaths/min and 4-8 hours of vibratory ventilation, in which the lambs received 1650 whiffs of air/min. In 8 of 22 studies, we increased lung microvascular pressure by filling a balloon catheter in the left atrium with saline. There was no significant difference in mean airway pressure during the two types of ventilation. Despite higher lung vascular pressures, lymph flow was less and lymph protein concentration was greater during vibratory than during mechanical ventilation. These findings are consistent with reduced lung fluid filtration, possibly from reduced pulmonary blood flow and increased perimicrovascular pressure, during vibratory ventilation. In eight lambs killed after 8 hours of vibratory ventilation, extravascular lung water was normal and microscopy showed no edema. We conclude that vibratory ventilation has no adverse effect on lung fluid balance and may benefit lambs by decreasing net filtration of fluid into their lungs.
Normothermic ischemic cardiac arrest of the isolated working rat heart. Effects of time and reperfusion on myocardial ultrastructure, mitochondrial oxidative function, and mechanical recovery.
Authors: Edoute Y , van der Merwe E , Sanan D , Kotzé J C , Steinmann C , Lochner A
Published: June 2012

The ischemic state of the myocardium of the isolated working rat heart after induction of normothermic ischemic cardiac arrest was assessed by the interrelationship among changes in myocardial ultrastructure, mitochondrial oxidative phosphorylation, and tissue high energy phosphate contents. At all time intervals (10-40 minutes) studied, the ultrastructural changes were more severe in the subendocardium than in the subepicardium. After 25-40 minutes of normothermic ischemic cardiac arrest, the mitochondrial oxygen uptake (state 3) became increasingly depressed, particularly in mitochondria isolated from the subendocardium. Mitochondrial oxidative function, as measured in vitro, did not correlate well with mitochondrial ultrastructural damage. In addition, the effects of coronary reperfusion on the ability of the ischemic heart to recover in terms of ultrastructure, mechanical, and metabolic function were evaluated. Hearts subjected to 10-40 minutes of normothermic ischemic cardiac arrest showed almost complete ultrastructural recovery of the subepicardium upon reperfusion; regression of ultrastructural changes occurred to a lesser extent in the subendocardium. Reperfusion for 30 minutes did not alleviate the depression in mitochondrial oxidative function, while tissue ATP levels did not return to control, preischemic levels. After 20 minutes of normothermic ischemic cardiac arrest, the mechanical performance of the working heart during reperfusion was significantly depressed, compared with pre-ischemic control values. Normal ultrastructure of the subendocardium always accompanied mechanical recovery, while improvement of mitochondrial oxidative function was not essential.
Energy levels at systole vs. diastole in normal hamster hearts vs. myopathic hamster hearts.
Authors: Sievers R , Parmley W W , James T , Wikman-Coffelt J
Published: June 2012

The following studies were carried out to examine energy metabolites and cardiac performance of the failing heart (hereditary cardiomyopathy) of the Syrian hamster (strain UM-X7.1) perfused either by normal or stress conditions, and to determine whether cyclical changes in energy-related metabolites occurred in the glucose-perfused hearts of both normal and heart failure animals. Hamster hearts from 250-day-old animals with moderate heart failure were removed and perfused either as nonworking hearts (Langendorff method, an afterload pressure of 90 mm Hg and 2.5 mM calcium in the perfusate) or as working hearts with stress conditions [an afterload of 110 mm Hg, high calcium concentrations in the perfusate (3.5 mM), and 10(-8) M isoproterenol]. Mechanical parameters (developed pressure and max dP/dt) and measurements of oxygen consumption indicated that both contractility and oxygen consumption had fallen 50% in myopathic hearts, compared with those of normal hamsters perfused with either of the two conditions. By means of a specially designed stimulator-triggered freeze clamp, hearts were terminated at systole and diastole, and tissue content of ATP, ADP, AMP, adenosine, phosphocreatine, creatine, pyruvate, lactate, and inorganic phosphate were analyzed. A 50% reduction in cardiac performance of the cardiomyopathic hamster hearts was associated with a corresponding reduction in systolic ATP, adenosine, and phosphocreatine values, while inorganic phosphate and lactate increased. With glucose as the sole substrate, the high energy phosphates, ATP and phosphocreatine, reached maximum values during diastole and minimum values during systole.(ABSTRACT TRUNCATED AT 250 WORDS)