[Phosphodiesterase inhibition as a new positive-inotropic principle].
Explore the source record for details and available documents.
2,2'-Dipyridyl↗
Biomedical subjects
R J Bing
Publications and source records attributed to R J Bing.
Compartmentation and functional mechanisms in myocardial failure and myocardial infarction.
Changes in compartmentation and specific mechanism in acute myocardial failure due to global ischemia and in regional myocardial ischemia in dog hearts are described. Ischemic failure was produced by periodic arrest of flow to supported heart preparations perfused with a fluorocarbon (FC-43). Sarcolemmal vesicles (SL) prepared from ischemic failing heart preparations exhibited diminished Ca++ binding and phosphorylation. TA-064, a beta-1-agonist partially abolished the reduction in Ca++ binding and phosphorylation of SL vesicles. The addition of cyclic-AMP (cAMP) and of protein kinase (PK) increased phosphorylation of SL vesicles obtained from non failing heart preparations. Combination of cAMP and of PK had the greatest effect. In contrast to myocardial failure, myocardial infarction is known to produce a large variety of specific disturbances in intermediary cardiac metabolism. Apparently in ischemic failing heart preparations, Ca++ binding and phosphorylation by SL are deficient. The results with TA-064 and isoproterenol suggest that phosphorylation of SL may play a role in the positive inotropic effect of beta-1-agonists.
Adenosine Triphosphate↗
Effect of 8-bromo-cyclic guanosine monophosphate (cGMP) on coronary artery constriction in isolated rabbit hearts.
The vasodilator 8-bromo-guanosine 3':5'-monophosphate (8-bromo-cGMP) effectively counteracts vasopressin-induced coronary artery constriction in a supported perfused working rabbit heart. In this preparation, the coronary arteries remain in contact with the beating heart. The obtuse marginal artery and portions of the left anterior descending coronary artery were deprived of endothelium. Perfusion was carried out with Krebs-Henseleit solution, oxygenated with a disposable infant oxygenator. The internal diameter of large coronary arteries was determined by color arteriography (injection of patent blue dye and gated photography). The effect of vasopressin with and without the addition of 8-bromo-cGMP on cardiac performance (cardiac output, left ventricular systolic pressure, left ventricular end-diastolic pressure, maximal rate of rise in left ventricular pressure [dP/dtmax], mean aortic pressure) and large coronary vessel and total coronary vascular resistance was determined in nine experiments. In addition, changes in coronary sinus partial pressure of carbon dioxide (PCO2) and pH were observed. Vasopressin alone caused a significant decline in coronary flow, myocardial oxygen consumption and coronary sinus pH. Cardiac performance declined, probably because of myocardial ischemia. Large coronary vessel and total coronary vascular resistance rose. The vasodilator 8-bromo-cGMP strongly inhibited the vasoconstrictor action of vasopressin, counteracted the increase in large and total coronary vascular resistance, prevented the fall in myocardial oxygen consumption and eliminated changes in pH or PCO2 of coronary sinus effluent. Because of the elimination of myocardial ischemia by 8-bromo-cGMP, cardiac performance was normalized.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The effect of cardiopulmonary bypass on cerebral blood flow.
The experiments dealth with the effect of total cardiopulmonary bypass on global and regional cerebral blood flow. Global cerebral blood flow was determined with radioactive microspheres, regional cerebral flow by direct observation through transillumination and high-speed cinematography. The latter permitted observations of changes in caliber of cerebral arterioles and of red cell velocity. Arterial blood gas tension and pH were continuously monitored. Measurements were carried out prior to and immediately following cardiopulmonary bypass. Studies on global cerebral flows showed that during cardiopulmonary bypass cerebral blood flow rose and cerebral vascular resistance declined while blood pressure did not change significantly. During bypass, cerebral blood flow and blood pressure in animals treated as a group became interdependent and showed direct proportionally. Direct observations of the cortical microvasculature by means of high-speed cinematography revealed dilatation of cerebral cortical arterioles. Even though blood pressure remained unchanged, the diameter of cortical arterioles increased. Volume flow calculated from red cells velocity and arteriolar diameter showed a tendency of arteriolar flow to increase. The condition is reminiscent of the 'luxury perfusion syndrome' (overabundant cerebral flow relative to metabolic needs of cerebral tissue).
Animals↗
Effect of intact endothelium against platelet-induced coronary artery spasm in isolated rabbit hearts.
Effects of collagen-activated washed rabbit platelets on coronary arteries with and without intact endothelium were studied in a supported rabbit heart preparation using a perfluorocarbon (FC-43) as perfusate. The vascular diameter of obtuse marginal coronary arteries was determined by means of gated color arteriography (injection of patent blue dye). Endothelial denudation of the obtuse marginal artery was accomplished by scraping the lumen with a roughened plastic tubing. Injection of washed platelets (10 ml with about 500,000 platelets/microliters) not treated with collagen failed to constrict coronary arteries either with intact or denuded endothelium. In contrast, injection of platelet suspension immediately after activation with collagen caused vasoconstriction of denuded obtuse marginal coronary arteries in 10 of 14 cases. In 6 preparations occlusion was complete, lasting up to 16 minutes. In arteries with intact endothelium, no coronary vasoconstriction occurred. In hearts with coronary artery spasm, total coronary vascular resistance increased significantly. This study furnishes additional evidence that endothelial lesions are a contributory factor for large coronary artery spasm and that endothelial cells possess a protective function against vasoconstrictor substances released from aggregating platelets.
Animals↗
A model for the study of coronary spasm induced changes in cardiac metabolism.
A model is described which permits the study of localized and generalized arterial spasm in the intact working perfused rabbit heart with a perfluorochemical (FC-43) as perfusate. Coronary arteries were visualized by intraatrial injection of Patent Blue Dye with gated photography. Localized spasm resulted from topical spray of histamine (40 mumols) on the epicardial surface overlying an obtuse marginal artery. Before and following topical administration of histamine, regional coronary flow was determined using radioisotope-labeled microspheres. Generalized arterial spasm was initiated by intraatrial injection of histamine (10 mumols). After topical administration, abtuse marginal artery diameter decreased by 57%; large vessel resistance rose 32 fold; 20% rise of total coronary resistance resulted in a slight reduction of total coronary flow (16%). Heart rate, cardiac output, dP/dtmax and myocardial oxygen consumption did not change. However, regional coronary flow in the myocardium supplied by the affected artery diminished 21% resulting in ischemic changes in redox pairs. After intraatrial injection of histamine, changes were more pronounced. Obtuse marginal artery diameter declined by 88% resulting in 3300-fold rise of large vessel resistance. Total coronary resistance increased 150%, coronary flow and cardiac output diminished (56% and 24%). Both heart rate and dP/dtmax increased (16% and 17%). Generalized coronary spasm after intraatrial histamine injection resulted in severe metabolic effects: Myocardial oxygen consumption (-48%); ATP (-29%); creatine phosphate (-34%); redox ratios, alpha-glycerophosphate/dihydroxyacetone phosphate and lactate/pyruvate, increased by 449% and 114%, respectively. The findings illustrate that localized and generalized coronary spasm can be produced and quantitated in a working heart model.
Animals↗
The effect of ischemia and reperfusion on sarcolemmal function in perfused canine hearts.
The report deals with the effect of ischemia and reperfusion on purified sarcolemma obtained from canine myocardium of perfused supported heart preparations. Perfusion was carried out with a perfluorochemical (FC-43). Ischemia was produced by intermittent total clamping of inflow and outflow followed by release until the decrease in dP/dtmax had become stabile. Purity of sarcolemmal vesicles was ascertained with marker enzymes: succinate cytochrome c reductase (for mitochondria), K+-stimulated p-nitrophenylphosphate (K+-pNPPase), (Na+/K+)ATPase and adenylate cyclase (for SL). In addition Na+/Ca2+-exchange characteristics for SL were determined. Sidedness of vesicles was ascertained by means of adenylate cyclase activity using sarcolemmal preparations treated and untreated with alamethicin. Emphasis was placed on ATP-dependent Ca2+ uptake, phosphorylation of sarcolemmal vesicles and yield of SL proteins. Ischemia and reperfusion resulted in a significant reduction in adenylate cyclase activity. This decline was significant following ischemia and reperfusion. The yield of protein recovered from SL vesicles from ischemic-reperfused heart preparations was also significantly decreased. Both initial rate of ATP-dependent Ca2+ uptake and maximal Ca2+ uptake fell significantly following ischemia and reperfusion. The initial rate of phosphorylation also dropped significantly. These disturbances in SL Ca2+ transport following ischemia and reperfusion are probably a part of the general deficit in Ca2+ translocation.
4-Nitrophenylphosphatase↗
Crystalloid and perfluorochemical perfusates in an isolated working rabbit heart preparation.
Krebs-Henseleit buffer (KH) and a perfluorochemical (FC-43) were compared as perfusates in an isolated working rabbit heart preparation. Both perfusates were oxygenated in an identical manner using an infant bubble oxygenator. After 60 min of perfusion, no difference could be detected in the ratio of wet to dry heart weight between KH- and FC-43-perfused hearts (KH, 6.25 +/- 0.3; FC-43, 5.99 +/- 0.20). Left ventricular systolic pressure, maximal rate of left ventricular pressure rise, mean aortic systolic pressure, cardiac output, aortic flow, left ventricular power, and myocardial O2 consumption (MVO2) were significantly higher in FC-43-perfused hearts throughout the time of perfusion. However, there were no differences in resistance to cardiac output and heart rate. In KH- and FC-43-perfused hearts, MVO2 and left ventricular power were closely correlated (KH, r = 0.793; FC-43, r = 0.831). Significantly higher coronary flow of KH-perfused hearts could be attributed to the lower viscosity of KH (1.05 Pa . s) compared with FC-43 (1.91 Pa . s). Increased O2 extraction during KH perfusion could not compensate for low O2-carrying capacity of KH buffer (345 compared with 705 nmol O2 X ml-1 in FC-43 emulsion). A postischemic increase of coronary flow was observed only in FC-43-perfused hearts (28%). These results demonstrate a different response of perfused heart preparations to FC-43 and KH buffer.
Animals↗
A new method for the visualization of subepicardial coronary arteries in small isolated mammalian hearts.
A model is described which permits direct visualization of large coronary arteries in a supported modified perfused heart preparation, using a perfluorochemical (FC-43) as perfusate. Filling of a large coronary artery with Patent Blue Dye is recorded by gated photography (color arteriography). The technique is applicable to the study of reactivity (spasm) of coronary arteries in hearts of small and large animals (rats, rabbits, dogs). The technique has the following advantages: preservation of vascular endothelium, adequate oxygenation, avoidance of major surgical intervention to implant sensors for the detection of changes in coronary diameter, quantitative evaluation of time dependent changes in geometry of large coronary arteries and simultaneous measurement of large coronary vessel and total coronary vascular resistance.
Animals↗
Red cell velocity and autoregulation in the cerebral cortex of the cat.
This report deals with a comparison of total and regional cerebral blood flow with red cell velocity in the microcirculation of the ecto- and suprasylvian areas of the cerebral cortex of the cat and their response to changes in systemic blood pressure. Total and regional blood flows were measured during a steady-state with radioactive microspheres; a newly devised method, based on transillumination was employed for direct visualization of the microcirculation in the cerebral cortex. Craniotomy failed to influence either autoregulation or red cell velocity under the skull opening or of the total cerebral flow. Autoregulation of total and regional cerebral flow was present. In contrast marked pressure-dependent variations in microcirculatory red cell velocity occurred. A fall in systemic pressure was accompanied by a decrease in red cell velocity; return of pressure resulted in increased red cell velocity and in some instances, in an overshoot. Considerable inhomogeneity of red cell velocity in different microcirculatory vessels was encountered. In some cases a fall in systemic pressure led to complete disappearance of red cells.
Animals↗
Microbubble dynamics visualized in the intact capillary circulation.
The potential for the use of contrast echocardiography to study myocardial perfusion has generated efforts to develop standardized echo contrast agents. The two methods used in this laboratory to generate microbubbles in solutions serving as contrast agents included the widely used hand-agitation method and the newer ultrasonic microcavitation (sonication) method. The latter has been demonstrated to generate smaller and more uniform microbubbles in an in vitro system. The present study was designed to observe, by direct microscopic examination of a cat mesentery preparation, the behavior and fate of the microbubbles in an in vivo system. The in vivo mesentery observations confirm the critical role of microbubble size in its unhindered passage through the capillary vasculature. The smaller and more uniform sonicated microbubbles passed rapidly through the microcirculation along with the red blood cells, whereas the larger microbubbles were observed to coalesce and interrupt the flow of blood and subsequently collapse or shrink.
Animals↗
Effect of serotonin on albumin and low density lipoprotein uptake in perfused rabbit femoral arteries.
Uptake by the arterial wall of plasma constituents has considerable clinical implication; thus, uptake of low density lipoprotein (LDL) plays an important role in the development of atherosclerosis. Serotonin and other vasoactive material may result in changes in the arterial wall leading to increased uptake of albumin or low density lipoprotein. This study was conducted to determine the effect of serotonin (10(-5)M 5-hydroxytryptamine) and serotonin-induced arterial constriction on albumin and low density lipoprotein uptake rates in perfused rabbit femoral arteries. The results show that the presence of serotonin inhibits the rate of uptake of both albumin and LDL. The effect on albumin uptake does not have a direct dose response dependence and is linearly dependent on transmural pressure. In contrast, LDL uptake rates are only slightly affected by pressure. Thus, albumin and LDL uptake processes appear to be due to separate mechanisms.
Animals↗
The effect of 5-hydroxytryptamine and arterial blood withdrawal on cerebral microcirculation in the cat, arterial permeability in the rabbit.
Studies dealing with the effect of 5-HT on cerebral cortical microcirculation of cats and on permeability of femoral arteries to RISA of rabbits are presented. The effect of 5-HT on cerebral cortical microcirculation was compared to that of arterial blood withdrawal and blood reinfusion. The effect of topical administration of 5-HT was also studied. Cortical microcirculation was observed by transillumination using a microtransilluminator. Motion pictures were taken at a speed of 400 frames/sec. and a magnification of 3000X. Permeability was investigated using arterial RISA uptake in vessels perfused in vitro, with continuous recording of perfusion pressure. Microcirculatory studies revealed that arterial blood withdrawal and injection of 5-HT diminished red cell velocity, although to a different degree. With blood withdrawal and reinjection, good correlation existed between blood pressure and red cell velocity. In contrast, no correlation between blood pressure and red cell velocity was found after intracarotid injection of 5-HT. Reactive hyperemia was noted during reinfusion of blood. Both arterial blood withdrawal and 5-HT injection resulted in disappearance of red cells in individual vessels (unperfused channels). Good correlation of blood pressure with capillary red cell velocity during arterial blood withdrawal suggests absence of autoregulation in this portion of the microcirculation. Topical administration of 5-HT caused general vasoconstriction. Permeability to 5-HT to RISA followed a parabolic curve. With slight arterial vasoconstriction, permeability declined, while it rose with severe vasoconstriction.
Animals↗
The biochemical basis of myocardial failure.
Cardiac failure can begin with metabolic disturbances within the myocardial cell--in the mitochondria, contractile proteins, or other cellular organelles. It also can result from faulty adrenergic regulation of contraction. New technology is making it possible to synthesize the contributing factors into a clinical model that will greatly enhance our understanding of these mechanisms.
Cardiac Catheterization↗
Inhibitory effect of a calcium antagonist (diltiazem) on aortic and coronary contractions in rabbits.
Explore the source record for details and available documents.
Animals↗
Microcirculation of left atrial muscle, cerebral cortex and mesentery of the cat. A comparative analysis.
By means of transillumination (microtransilluminator and light pipe), comparative analyses were carried out on geometry, topography, and morphometry of microcirculation in the cerebral cortex, left atrial muscle, and mesentery of the cat using computer analysis. In addition, specific types of capillary distribution (concurrent, countercurrent, and asymmetric distribution) in these three organs were ascertained from images visualized on films. These parameters were related to their role in tissue oxygen supply. It was found that mean capillary diameter, mean intercapillary distance, total capillary length, and total capillary surface area differed significantly among the three organs. Differences in mean capillary tortuosity between cerebral and left atrial muscle and between left atrial muscle and mesentery also were significant. Mean capillary tortuosity in mesentery and cerebral cortex was of equal magnitude. In the cerebral cortex, a high degree of tortuosity and asymmetric capillary distribution favor tissue oxygenation. A similar situation exists in left atrial muscle, although some concurrent and countercurrent distribution could be detected. In the mesentery, the combination of high capillary tortuosity and concurrent capillary arrangement is unfavorable for tissue oxygenation.
Animals↗
Effect of alcohol on the heart and cardiac metabolism.
In this report the disturbances in biochemistry of the heart muscle exposed to alcohol are delineated. All elements of cellular substructures are affected. In plasma membranes, (Na+ + K+)-activated ATPase (EC 3.6.1.3) is inhibited. Mitochondrial damage consists in diminished respiratory function and calcium uptake and binding. High-energy phosphates remain intact. Alcohol also affects the malate-aspartate shuttle. Acetaldehyde, a metabolite of ethanol, has a direct effect on myocardial protein synthesis through microsomal inhibition; however, the development of cardiac hypertrophy is not affected. Malfunction of sarcoplasmic reticulum is evidenced by disturbances in calcium binding and uptake. Effects of ethanol on the contractile machinery are deficiencies in the turnover rate of chemical into mechanical energy (diminished Vmax), and in the number of cross-bridges formed (P0). It increases stiffness of series elastic elements. There is diminished fatty acid oxidation with increased esterification. The involvement of CoA synthetase (EC 6.2.1.1), palmityl-carnitine transferase (EC 2.3.1.7), and pyruvate dehydrogenase complex in disturbed fatty acid oxidation is not certain. The role of catalase in myocardial ethanol oxidation was examined. Ethanol activates myocardial catalase-H2O2 complex (EC 1.11.1.6). The biochemical basis of fetal alcohol syndrome is low hepatic alcohol dehydrogenase (EC 1.1.1.1) activity during fetal life.
Acetaldehyde↗
Incorporation of 7-ketocholesterol by plasma membranes from porcine aortic endothelial cells.
We present evidence that 7-ketocholesterol (7KC) is incorporated into the plasma membranes of endothelial cells in excised porcine aortas in molar amounts comparable to the native cholesterol present in the membrane. Our experimental findings indicate that simple adsorption of 7KC does not play a role in the results obtained. Instead 7KC appears to be inserted into the lipid bilayer of the membranes. This is largely independent of membrane cholesterol content and is not due to substitution of the native membrane cholesterol. A significant increase in the total sterol-to-phospholipid ratio is obtained with 7KC-exposure without significant changes in the cholesterol-to-phospholipid ratio.
Alkaline Phosphatase↗