bluuebunny/crossref_metadata_2025 huggingface dataset:
Adenosine inhibits ischemia-reperfusion-induced leukocyte adherence and extravasation
Authors: Grisham M. B. , Hernandez L. A. , Granger D. N.
Published: December 2017

Ischemia and reperfusion (I/R) of the small intestine initiates a series of events that result in neutrophil-mediated microvascular injury. Recent reports suggest that adenosine possesses anti-inflammatory properties by virtue of its ability to inhibit neutrophil (PMN) superoxide (O2-.) and hydrogen peroxide (H2O2) production and to interfere with PMN adherence to cultured endothelium. In an attempt to further characterize the anti-inflammatory properties of adenosine in vivo we assessed the influence of exogenous adenosine on 1) I/R-induced PMN-mediated microvascular injury in the feline small intestine, 2) feline PMN superoxide production, and 3) I/R-induced PMN adherence to feline mesenteric venular endothelium. We found that intra-arterial administration of adenosine (2 microM) significantly attenuated the I/R-induced increases in intestinal capillary permeability. This protective effect of adenosine could not be explained entirely on its ability to inhibit PMN O2-. (or H2O2) production, since adenosine was effective in inhibiting feline PMN O2-. production by only 20%. Using intravital microscopic techniques in cat mesentery, we found that adenosine did not alter the responses of venular blood flow, shear rate, leukocyte rolling velocity, and leukocyte adherence to I/R when compared with control animals. However, the number of extravasated leukocytes during the ischemic period was significantly reduced by adenosine. Adenosine reduced the number of adherent leukocytes by 25% at 10 and 60 min of reperfusion while leukocyte extravasation was reduced by 65-70% during the same period. Our data indicate that the adenosine-induced suppression of leukocyte extravasation cannot be explained solely by an attenuation in leukocyte adherence to venular endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)
Absent effect of plasma vasopressin on rat brain blood flow during hemorrhage
Authors: Nakai M. , Yamane Y. , Umeda Y. , Inada M. , Yamamoto J. , Kawamura M.
Published: December 2017

We investigated whether a reflex increase in plasma vasopressin level due to hemorrhagic hypotension affects brain blood flow. In 60 lightly anesthetized, artificially ventilated rats, the flow was determined with radiolabeled microspheres. We found excellent maintenance of blood flow throughout all brain regions during the hypotensive state (71 mmHg on average), and such maintenance of flow was not modulated at all by a supramaximal intravenous dose of the selective vasopressin V1-receptor antagonist [d(CH2)5 Tyr-(Me)]AVP. The latter finding also implies that the V1 antagonist failed to unmask the vasodilator type actions of V2 receptors on the maintenance of flow during hemorrhagic hypotension. These were true also when the cervical sympathetic bundles were severed bilaterally. The plasma level of endogenous vasopressin was increased during hypotension, ranging from 118 to 973 pg/ml. Despite this increase, the brain blood flow was entirely independent of the plasma vasopressin level in all the brain regions studied. We conclude that the brain circulation of rats can maintain its blood flow during hemorrhagic hypotension without any apparent contribution from a concomitant reflex increase in plasma vasopressin. Despite our negative results for the brain blood flow, the possible segmental effects of circulating vasopressin on the brain arterial caliber remain to be clarified under conditions of hemorrhagic hypotension.
Reductions in central venous pressure improve carotid baroreflex responses in conscious men
Authors: Pawelczyk J. A. , Raven P. B.
Published: December 2017

To test the hypothesis that unloading cardiopulmonary receptors improves human carotid baroreceptor responsiveness we measured heart rate (HR) and mean radial artery blood pressure (BP) responses elicited by trains of neck pressure and neck suction from +40 to -65 Torr during graded lower body negative pressure (LBNP) at -5, -10, -15, -20, -35, and -50 Torr in eight healthy men. Gain of the carotid baroreflexes was determined from logistic modeling of the HR [expressed as R-R interval (RRI)] and BP responses to neck pressure and neck suction. Central venous pressure (CVP) decreased progressively from control values of 6.2 +/- 0.6 (SE) Torr to -0.8 +/- 0.1 Torr at -50 Torr LBNP (P less than 0.001). HR changed little from control values of 62.7 +/- 2.1 beat/min to 65.9 +/- 2.8 beat/min at -15 Torr (P = NS), but increased significantly to 80.6 +/- 2.6 beats/min at -50 Torr (P less than 0.001). Maximum gain of the HR and BP stimulus-response curves was linearly and inversely related to decreases in CVP and could be described by the relationships Max RRI gain = -0.694 (CVP) + 11.6 [r2 = 0.94, standard error of estimate (SEE) = 0.45, P less than 0.001] and Max BP gain = -0.0292 (CVP) + 0.391 (r2 = 0.81, SEE = 0.038, P less than 0.001). We suggest that reductions in central venous pressure and/or central blood volume augment both HR and BP carotid baroreflex responses in man by reducing an inhibitory influence from cardiopulmonary receptors.
Dynamic exercise in senescent beagles: oxygen consumption and hemodynamic responses
Authors: Haidet G. C.
Published: December 2017

Seven senescent beagles and seven younger mature beagles were studied at rest, as well as during maximal and submaximal exercise on a motor-driven treadmill. Maximal exercise capacity was significantly (P less than 0.05) reduced, and maximal total body O2 consumption (VO2 max) was 31% lower in senescent beagles. VO2 was also significantly reduced in old dogs, when directly compared at the same relative workloads in old and younger mature dogs. However, VO2 was very similar in both groups during each of the absolute levels of directly comparable exercise. The observed age-related reduction in VO2 max was associated with a significant 25% reduction in maximal cardiac output (CO) in senescent beagles, and with an 11% reduction in maximal arteriovenous O2 difference. CO was also significantly reduced in old dogs at the same relative levels of submaximal exercise evaluated. Combined effects of reductions in stroke volume and in heart rate both contributed to the observed reductions in CO observed in senescent dogs during maximal exercise, as well as during relative levels of submaximal exercise. However, CO responses at each absolute level of submaximal exercise were similar in senescent and younger mature beagles, and the relationship between CO and VO2 was also similar in both groups. Increases in stroke volume significantly contributed to observed increases in CO beginning at the same relative level of exercise in both old and young dogs. Results of this study demonstrate that significant age-related changes in VO2max and in other associated hemodynamic parameters occur during maximal exercise. Many of these changes are also apparent when relative levels of submaximal exercise are directly compared in senescent and in younger mature beagles. However, most hemodynamic responses during absolute levels of exercise are similar in both groups, unless these parameters reflect the relative workload performed, indicating that these responses are appropriate for each absolute level of work that can be performed in the senescent dogs.
Altered microvascular reactivity in streptozotocin-induced diabetes in rats
Authors: Hill M. A. , Larkins R. G.
Published: December 2017

This study examined the effect of short-term streptozotocin-induced diabetes in rats on the response of cremaster muscle arterioles to angiotensin II (ANG II) and vasodilatory prostaglandins. Topically applied ANG II (10(-10) to 10(-6) M) caused significantly greater vasoconstriction of third-order arterioles in diabetic animals in comparison with controls. For example, in response to 10(-6) M ANG II arterioles of the diabetic animals constricted to 43 +/- 10% of basal diameter compared with controls' 67 +/- 6% (P less than 0.05). Furthermore, the magnitude of the secondary vasodilatation after ANG II-induced constriction was decreased in diabetic animals (108 +/- 4 and 131 +/- 9%, P less than 0.025). Cyclooxygenase inhibition resulted in marked arteriolar constriction, with this effect being less evident in diabetic animals. In response to indomethacin (2.8 x 10(-5) M), arterioles of the diabetic animals constricted to 84 +/- 7% of basal diameter compared with 56 +/- 4% in controls (P less than 0.01). Arterioles of the diabetic animals were less responsive to exogenous prostaglandin I2 (PGI2) and PGE2 (10(-12) to 10(-6) M) despite evidence of increased in vitro PGI2 production. The data demonstrate potentiation of the vasoconstrictor response and a diminution of the secondary vasodilator response to ANG II in experimental diabetes. These alterations may be due, in part, to decreased responsiveness of skeletal muscle arterioles to vasodilatory prostaglandins.
Acute aortic coarctation hypertension: role of vasopressin and angiotensin II
Authors: Salgado H. C. , Salgado M. C.
Published: December 2017

The role of vasopressin (AVP) and angiotensin II (ANG II) in the onset of acute (45 min) aortic coarctation hypertension was studied in conscious rats. Changes in mean carotid pressure (MCP) and heart rate (HR) were measured in four groups of rats. Control rats presented a hypertensive response that attained a plateau 5 min after coarctation and remained near this level throughout the experiment. Rats treated with AVP V1-vascular receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-(O-methyl)tyrosine]arginine vasopressin [d(CH2)5Tyr(Me)AVP] presented a prompt rise in MCP similar to the control rats, but in contrast to this group, the MCP started to decline progressively. Rats treated with saralasin presented a delay in the onset of hypertension right after coarctation but slowly attained values similar to those for control rats. In contrast, the rats treated with AVP antagonist plus saralasin showed a blunted MCP elevation throughout the experiment. Reflex bradycardia observed in the rats treated with saralasin or the AVP antagonist plus saralasin was similar to that observed in the control rats, whereas for the group treated only with AVP antagonist, the reflex bradycardia was more intense than for the other three groups, indicating an increased sensitivity of the baroreflex. These data demonstrate that in addition to the mechanical effect of aortic constriction, both ANG II and AVP participate in the onset of acute aortic coarctation hypertension. Moreover, the results indicate that ANG II acts on the prompt (5 min) rise in pressure, whereas AVP is responsible for the maintenance (30-45 min) of the arterial pressure elevation.
Membrane cytochemistry of the atrial peptide secretory pathway
Authors: Severs N. J.
Published: December 2017

The characteristics of the principal membrane systems involved in atrial peptide secretion are explored in rabbit and rat atrial muscle cells using freeze-fracture electron microscopy combined with cytochemistry. Structural features of the Golgi apparatus and secretory granule membrane are described, and two features of the membranes' composition, cholesterol content and terminal glycocomponents, are probed in situ in the cell. Both the secretory granule membrane and the plasma membrane contain morphologically detectable cholesterol, and both are rich in the terminal sugar residues (sialic acid and N-acetyl glucosamine) of membrane glycocomponents. Some cisternal membranes of the Golgi apparatus reveal detectable cholesterol but others do not, and only focal labeling of terminal glycocomponents in Golgi membranes is observed, usually adjacent to the accumulation of secretory product. Nuclear membranes, endoplasmic reticulum, and mitochondria contain virtually no detectable cholesterol nor terminally glycosylated components. The Golgi apparatus, which is exclusively equipped with the enzymes responsible for terminal glycosylation of membrane glycoproteins, appears actively to modify the chemical composition of the membrane segments in which it packages atrial peptide. This ensures that the composition of the atrial granule membrane resembles that of the plasma membrane into which it is ultimately incorporated.
Xanthine oxidase-induced injury to endothelium: role of intracellular iron and hydroxyl radical
Authors: Kvietys P. R. , Inauen W. , Bacon B. R. , Grisham M. B.
Published: December 2017

The major objective of the present study was to characterize the sequence of events leading to endothelial cytotoxicity induced by oxidants generated extracellularly by xanthine oxidase. 51Cr-labeled monolayers of calf pulmonary artery endothelial cells were exposed to a reaction mixture containing hypoxanthine, xanthine oxidase, and chelated iron (HX/XO) and endothelial cell injury was quantitated as 51Cr release into the media. Catalase, but not mannitol or superoxide dismutase, prevented endothelial cell injury induced by HX/XO, indicating that H2O2 was the mediator of the cytotoxicity. Pretreatment of the cells with free deferoxamine (an iron chelator), but not with deferoxamine bound to dextran (mol wt 40,000), prevented endothelial cell injury induced by HX/XO or H2O2. Of the membrane-permeant hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea, only dimethylthiourea prevented 1) HX/XO or H2O2-induced endothelial cytotoxicity and 2) deoxyribose degradation by hydroxyl radicals (.OH) generated by an iron-catalyzed reaction on the sugar (site-specific reaction). The concentration of ferritin required to produce significant quantities of .OH was much greater than that present in endothelial cells, and ferritin-catalyzed .OH formation was not affected by deferoxamine, indicating that ferritin-bound iron is most likely not the physiologically active catalyst. We conclude that extracellularly generated H2O2 can enter the cell and interact with nonferritin iron to produce the cytotoxic .OH via a site-specific reaction.
Regional myocardial flow heterogeneity explained with fractal networks
Authors: Van Beek J. H. , Roger S. A. , Bassingthwaighte J. B.
Published: December 2017

There is marked heterogeneity in regional myocardial blood flow. To explain how the distribution of flow broadens with an increase in the spatial resolution of the measurement, we developed fractal models for vascular networks. A dichotomous branching network of vessels represents the arterial tree and connects to a similar venous network. A small difference in vessel lengths and radii between the two daughter vessels, with the same degree of asymmetry at each branch generation, predicts the dependence of the relative dispersion (mean +/- SD) on spatial resolution of the perfusion measurement reasonably well. When the degree of asymmetry increases with successive branching, a better fit to data on sheep and baboons results. When the asymmetry is random, a satisfactory fit is found. These models show that a difference in flow of 20% between the daughter vessels at a branch point gives a relative dispersion of flow of approximately 30% when the heart is divided into 100-200 pieces. Although these simple models do not represent anatomic features accurately, they provide valuable insight on the heterogeneity of flow within the heart.
Effects of endothelium regeneration on canine coronary artery function
Authors: Cox R. H. , Haas K. S. , Moisey D. M. , Tulenko T. N.
Published: December 2017

During coronary catheterization under general anesthesia, the endothelium of a portion of the proximal left circumflex coronary artery of dogs was removed (injured). Segments from the denuded and normal (distal circumflex and left anterior descending coronary) regions were removed immediately in some animals (acute studies) or 5 wk after the injury in other animals (chronic studies). No significant differences in passive mechanics or active stress normalized to medial thickness were found between segments from normal and denuded regions in acute studies or normal and injured segments in chronic studies. Intimal thickening was found in the chronically injured segments, which averaged 32% of the total media-adventitia thickness. No significant differences were found in potassium dose-response relations in acute or chronic studies. Maximum responses to serotonin were increased in acutely denuded but not in chronically injured segments. Sensitivity to serotonin was increased in chronically injured but not acutely denuded segments. Endothelium-dependent relaxation responses produced by acetylcholine, bradykinin, and the Ca2+ ionophore A23187 were all depressed in chronically injured segments compared with normal, as were relaxation responses to sodium nitroprusside. In acutely denuded segments, the former agents produced only small contractions at high doses, whereas nitroprusside relaxations were augmented compared with sites with intact endothelium. Relaxation responses to isoproterenol and forskolin were not significantly affected by acute denudation or by chronic injury. The results of this study suggest a "chronic" depression of relaxation responses mediated by the guanosine 3',5'-cyclic monophosphate pathway and increased serotonin vasoconstriction sensitivity in arteries 5 wk after an endothelial denudation injury.
An oximeter for measuring hemoglobin concentration and oxygen content
Authors: Shepherd A. P. , Randal V. T. , Steinke J. M. , Schmalzel J. L.
Published: December 2017

We have developed an oximeter that measures both the total hemoglobin concentration in whole blood and the percentage of the hemoglobin saturated with oxygen. The oximeter uses red and infrared light-emitting diodes to illuminate a capillary tube filled with a sample of whole blood. Light scattered by the blood travels a short distance down the length of the capillary tube and reaches a photodetector, the output of which is amplified, digitized, and fed into a microprocessor. The microprocessor computes the total hemoglobin concentration as a nonlinear function of the infrared light intensity. Oxyhemoglobin saturation is computed from the ratio of the logarithms of the intensities of red and infrared light. Our instrument has the following advantages over existing oximeters: 1) it provides a measurement of total hemoglobin concentration, 2) it is immune to the calibration shifts that fluctuations in total hemoglobin concentration cause in other oximeters, 3) it is accurate over a wide range of oxygen saturation, and 4) the blood samples are not diluted and can thus be preserved for further analysis. A detailed parts list and circuit diagram are presented, and sources of error are discussed.
Arteriovenous oximeter for O2 content difference, O2 saturations, and hemoglobin content
Authors: Suga H. , Futaki S. , Ohgoshi Y. , Yaku H. , Goto Y.
Published: December 2017

We combined two spectrophotometric oximeters to measure continuously and simultaneously arteriovenous O2 content difference (AVOD) as well as arterial and venous oxyhemoglobin saturations (SaO2, SvO2) and total hemoglobin concentration (Hb). AVOD of the flowing arterial and venous whole blood was determined by the method of Guyton et al. (J. Appl. Physiol. 10: 158-163, 1957) and Shepherd and Burgar [Am. J. Physiol. 232 (Heart Circ. Physiol. 1): H437-H440, 1977]. The new arteriovenous oximeter was tested in dog experiments in which SaO2, SvO2, Hb, and AVOD were variously changed by temporary suffocation, electric muscle stimulation, hemorrhage and transfusion, and hemodilution with saline. AVOD, SaO2, SvO2, and Hb were compared with the data of the arterial and venous blood sampled near the oximeter cuvettes and measured with an IL282 CO oximeter. In one dog experiment and one in vitro blood experiment, AVOD data of the same arterial and venous blood were compared by connecting the present oximeter in series with an A-VOX Systems oximeter developed by Shepherd and Burgar. The results showed that the new arteriovenous oximeter can continuously measure AVOD, SaO2, SvO2, and Hb over wide ranges with reasonable accuracy.
Intracellular Ca2+ and force determined simultaneously in isolated resistance arteries
Authors: Bukoski R. D. , Bergmann C. , Gairard A. , Stoclet J. C.
Published: December 2017

A method is described for the simultaneous measurement of intracellular Ca2+ ([Ca2+]i) and force generation in isolated resistance arteries using the fluorescent Ca2+ indicator fura-2. Branch II mesenteric resistance arteries were isolated from 12-wk-old Wistar-Kyoto rats and mounted in a wire myograph. The myograph was placed on the stage of a compound microscope interfaced with a dual excitation wavelength fluorometer, and the tissue was loaded with fura-2 by incubation over a 30-min period with the cell-permeable form of the dye. When stimulated with physiological salt solution containing 100 mM KCl and 10 microM norepinephrine, a rapid and transient increase in [Ca2+], was observed to precede active force development and plateau at approximately 60% of the maximal level after 50 s. Washout of the agonists induced relaxation of these small arteries, consisting of an 85% decline in active tension over 100 s and a fall in [Ca2+]i to 50% of prerelaxation level over the same time period. Forskolin (1 microM), which increases intracellular adenosine 3',5'-cyclic monophosphate, induced a 50% relaxation over a 150-s period that was preceded by a fall in [Ca2+]i. Nearly identical results were obtained with 100 microM sodium nitroprusside, which stimulates intracellular guanosine 3',5'-cyclic monophosphate production. These findings indicate that the initiating event of forskolin- and sodium nitroprusside-induced relaxation may be a reduction of [Ca2+]i. The method described is useful for examining basic physiological events and Ca2+-related mechanisms of action of vasoactive compounds in isolated resistance arteries.
Modulation of effect of extracellular calcium buffering in cardiac muscle
Authors: Ginsburg S. , Shimoni Y.
Published: December 2017

The buffering of extracellular calcium by citrate, with identical free calcium levels in the buffered and unbuffered medium, was previously found to markedly reduce tension in frog and guinea pig atria. We now report the following results. 1) In guinea pig, postest contractions are not reduced by citrate. 2) In frog the negative inotropic effect of citrate is greatly attenuated by partially replacing extracellular sodium concentration ([Na+]o) with lithium or sucrose. In contrast, in low [Na+]o, sodium salts of weak acids (which cause intracellular acidosis) still reduce tension. These findings strongly support the suggestion that citrate does not reduce tension directly, e.g., by causing intracellular acidosis or by reducing voltage-dependent calcium currents. 3) Higher stimulation rates also decrease the effect of citrate. 4) Treatment with neuraminidase or phospholipase D, both of which alter sarcolemmal calcium binding, dose not change the effect of citrate. 5) The positive inotropic effect of strophanthidin is reversibly lost in the presence of citrate. Our results provide a different, novel approach to support earlier suggestions that the extracellular matrix and/or the sarcolemma contain abundant calcium-binding sites that supply some of the calcium for contraction. Citrate presumably binds calcium more strongly, thereby "trapping" calcium released from the extracellular "stores," so that less calcium is made available for contraction. The inotropic effect of cardiac glycosides may also depend on the calcium that is bound to these stores.
Contractility is the main determinant of coronary systolic flow impediment
Authors: Krams R. , Sipkema P. , Zegers J. , Westerhof N.
Published: December 2017

We measured the relation between coronary flow amplitude (delta F = Fd-Fs; where d is diastolic and s is systolic) and developed left ventricular pressure (delta PLV = Ps-Pd) at a constant perfusion pressure of 75 mmHg (10 kPa) in the maximally vasodilated blood-perfused isolated cat heart for different steady-state levels of contractility (protocol A) and during transients in contractility (protocol B). Contractility was defined as the slope of the end-systolic pressure-volume relation (Emax). From protocol A it appeared that the coronary flow amplitude was only weakly related to left ventricular pressure at each steady-state level of contractility studied. However, the coronary flow amplitude was strongly related to the different levels of contractility. In protocol B, contractility was changed over a wide range of values (0-100%) but developed pressure and contractility changed simultaneously. Using multiple linear regression analysis, we found that contractility has approximately 10 times (range: 2.8-57.3) stronger effect than left ventricular pressure on coronary flow amplitude (n = 10 experiments). These data and our earlier observations suggest that it is the difference in stiffness of cardiac muscle between systole and diastole that determines coronary flow amplitude.
Ventricular remodeling induced by acute nonocclusive constriction of coronary artery in rats
Authors: Capasso J. M. , Jeanty M. W. , Palackal T. , Olivetti G. , Anversa P.
Published: December 2017

To determine the consequence of acute nonocclusive constriction of the epicardial coronary artery on the adaptation of the left ventricle and its impact as a function of age, the left main coronary artery was narrowed in rats 4 and 12 mo of age, and the animals were killed 45 min later. Similar reductions in the luminal diameter, averaging 4%, were obtained in both groups of animals, and this change resulted in an increase in left ventricular end-diastolic pressure and a decrease in positive and negative change in pressure overtime (dP/dt) and in peak-developed ventricular pressure. Left ventricular volume increased by 66% and 56% at 4 and 12 mo because of increases in both the longitudinal and transverse chamber diameters. In contrast, wall thickness decreased by 27% and 35%, whereas sarcomere length increased only by 8.0% and 6.0%, respectively. These changes implied the occurrence of side-to-side slippage of myocytes within the wall to accommodate the larger chamber volume. The alterations in myocardial performance combined with the variations in ventricular size and wall thickness produced a marked elevation in diastolic and systolic wall stress. Moreover, myocyte cell damage in the form of contraction bands and disorganization of the intercalated disc region was seen. No consistent difference was found in any of the parameters measured as a function of age. Measurements of resting coronary blood flow across the left ventricular wall before coronary artery narrowing were comparable with those obtained 45 min after constriction. In conclusion, acute nonocclusive coronary artery stenosis has profound detrimental effects on the function and structure of the myocardium in the absence of an impairment of resting coronary blood flow.
Evaluation of systolic effectiveness and its determinants: pressure/midwall-volume relations
Authors: Regen D. M.
Published: December 2017

It is generally agreed that systolic performance of a heart chamber is the fractional inward displacement of its wall during contraction and that this depends on preload, afterload, and characteristics of the relation between afterload and end-ejection dimensions. However, there is no consensus on the details of this statement. How can one define and identify the wall element, the displacement of which best expresses performance? What is preload? What parameters best characterize the relation between afterload and end-ejection dimensions? Dividing a thick-wall compliance equation by a thick-wall pressure equation reveals the midwall element, the normalized displacements of which depend consistently on normalized pressure changes according to wall properties regardless of wall-to-cavity ratio. This midwall element's reference dimensions best express chamber size, its reference-normalized dimensions best express wall stretch or distension, and its fractional displacements best express systolic performance. The hydraulically unloaded state is a poor reference for expressing size, normalizing dimensions, and defining chamber characteristics; it is inaccessible, immeasurable, acutely variable, and not a mechanically unloaded state. Therefore stiffness is neither a characteristic nor an expression of systolic vigor. A better reference state is the "average basal end-diastolic distension to which the chamber is accustomed"; it is accessible, measurable, and a state where stretches throughout the wall are near a characteristic value. End-diastolic midwall dimension relative to its average basal value is a valid expression of preload. There are two main hydrodynamic characteristics expressing systolic vigor: 1) peak isovolumic pressure at reference distension and 2) displacement from reference distension if afterload were zero. An additional characteristic is shape of the pressure-volume relation. It appears possible to account for systolic performance in terms of preload, afterload, and these hydrodynamic characteristics.
Activation of ATP-sensitive K channels in heart cells by pinacidil: dependence on ATP
Authors: Arena J. P. , Kass R. S.
Published: December 2017

We have investigated the effects of pinacidil on channel activity recorded from inside-out patches of membrane excised from guinea pig ventricular cells. If the cytosolic ATP concentration is greater than 0 but less than 500 microM, pinacidil increases the activity of a channel identified as the ATP-sensitive K channel (IKATP) by its single-channel conductance, its inhibition by ATP, and its sensitivity to glybenclamide. When ATP is greater than 3.0 mM the effects of pinacidil are inhibited. Our experiments show that pinacidil enhances the activity of IKATP in heart cells, but that the action of the drug depends on the ATP concentration of the cytosolic solutions. The results suggest that pinacidil acts indirectly, perhaps at an ATP-binding site that regulates this channel.
Lipoproteins are inhibitors of endothelium-dependent relaxation of rabbit aorta
Authors: Takahashi M. , Yui Y. , Yasumoto H. , Aoyama T. , Morishita H. , Hattori R. , Kawai C.
Published: December 2017

The present study was performed to investigate plasma inhibitors of endothelium-dependent relaxation other than hemoglobin and low-density lipoprotein (LDL). We purified an inhibitor that contained a protein of 28,000 Da from human plasma by ammonium sulfate precipitation and serial chromatography. NH2-terminal sequence analysis revealed the protein to be homologous with human apolipoprotein A-I (Apo A-I), a major apolipoprotein of high-density lipoprotein (HDL). Very low-density lipoprotein (VLDL), LDL, and HDL obtained from rabbit plasma reversed endothelium-dependent relaxation of rabbit aorta induced by acetylcholine (ACh) and A23187 but did not inhibit relaxations induced by nitroglycerin or nitric oxide. These inhibitory activities were lost by delipidation of lipoproteins, and there were no differences in the inhibitory activity among these three lipoproteins on the basis of phospholipid concentration. Moreover, phospholipids such as phosphatidylcholine, phosphatidylinositol, and sphingomyelin reversed relaxations by ACh and A23187. Thus all lipoproteins inhibit endothelium-dependent relaxation, and this nonspecific inhibition seems to be due to the inhibition of production or release of endothelium-derived relaxing factor by phospholipids in the lipoprotein complex.
Preservation of cardiac metabolic capacity after acute catecholamine injury
Authors: Chen V. , Downing S. E.
Published: December 2017

High concentrations of adrenergic agonists are known to cause significant structural damage to the heart, accompanied by depressed cardiac performance. These studies were undertaken to further elucidate mechanisms that contribute to this process. Rabbits were infused with either norepinephrine (NE, 3 micrograms.min-1.kg-1 iv) for 90 min or with an equivalent volume of normal saline (controls). The heart was immediately extracted and studied as an isolated working heart preparation perfused with erythrocyte-enhanced buffer. Stroke work, coronary flow, and O2 metabolism were determined, and substrate oxidation was measured by [14C]glucose or palmitate. Stroke work performed by hearts exposed to NE was only 31% of controls (2.6 +/- 0.4 vs. 8.4 +/- 0.9 g.cm-1.g-1). This was matched by reductions in coronary flow and O2 metabolism. Glucose oxidation was reduced from 54.6 +/- 3.9 to 16.0 +/- 5.3 nmol.min-1.g-1, and palmitate oxidation from 49.8 +/- 5.3 to 21.0 +/- 4.1 nmol.min-1.g-1 in the NE group. However, ATP, creatine phosphate, glycogen, and triacylglycerol concentrations were identical with the control group. O2 delivery per unit substrate oxidation was not lower in the NE group, and O2 extraction did not differ significantly. These findings indicate that the markedly lower contractile performance of the hearts exposed to NE cannot be attributed to a deficiency of metabolic capacity or limitation of O2 or substrate availability because of vasospasm. In view of the brief time (90 min), it is unlikely that leukocyte accumulation was a major factor. The observations are consistent with NE-derived oxidant injury, possibly causing disordered excitation-contraction coupling.
Reflex inotropic responses to distension of left atrium or pulmonary veins
Authors: Kurz M. A. , Wead W. B. , Roberts A. M.
Published: December 2017

Previous investigators demonstrated that distension of the left atrium (LA) or pulmonary veins (PV) evokes reflex changes in heart rate (HR) and mean arterial blood pressure (MABP). This study was designed to determine whether stimulation of receptors in these areas could evoke reflex changes in left ventricular (LV) maximum contractility (Vmax) in anesthetized dogs. Balloons were placed in the left atrial appendage or in two right pulmonary veins to stimulate mechanoreceptors in these regions without directly altering other cardiorespiratory pressures. Distension of either the LA or PV increased LV contractility and decreased MABP. LA distension evoked a vagally mediated increase in HR when predistension HR was less than 140 beats/min but did not change HR when predistension HR was greater than 140 beats/min. Reflex changes in inotropic state and MABP were not altered by bilateral vagotomy or carotid sinus denervation. In dogs with stellate ganglia and sympathetic chains sectioned and vagi intact, PV or LA distension decreased LV contractility and MABP. Responses were eliminated when both vagal and sympathetic pathways were cut. We conclude that distension of the LA or the PV and LA junction evokes a sympathetically mediated increase in LV contractility.
Beta-receptors and adenylate cyclase: comparison of nonischemic, ischemic, and postmortem tissue
Authors: Vatner D. E. , Young M. A. , Knight D. R. , Vatner S. F.
Published: December 2017

We compared the effects of myocardial ischemia and postmortem changes on beta-adrenergic receptors and their coupling to adenylate cyclase activity. The effects of 1 h of left circumflex coronary artery occlusion were examined in eight conscious calves, which were then anesthetized with pentobarbital sodium, and the left ventricle was divided into nonischemic and ischemic regions. A crude membrane fraction was prepared from each region and from the nonischemic tissue 1 h postmortem. beta-Adrenergic receptor density increased (152 +/- 55%) and decreases in basal (-21 +/- 6.1%), isoproterenol-stimulated (-25 +/- 8.0%), 5'-guanylylimidodiphosphate [Gpp(NH)p]-stimulated (-17 +/- 5.8%), fluoride-stimulated (-26 +/- 5.8%), and forskolin-stimulated (-31 +/- 8.4%) adenylate cyclase activities were observed in the ischemic myocardium compared with nonischemic myocardium. Similarly, in postmortem samples, beta-adrenergic receptor density rose 58 +/- 16%, whereas decreases in basal (-48 +/- 8.7%), isoproterenol-stimulated (-61 +/- 7.8%), Gpp(NH)p-stimulated (-58 +/- 7.0%), fluoride-stimulated (-64 +/- 6.1%), and forskolin-stimulated (-52 +/- 6.2%) adenylate cyclase activities were observed. Agonist-binding competition curves with isoproterenol were shifted, indicating that beta-adrenergic receptors were binding agonists with low affinity in both the ischemic and postmortem myocardium. The marked, but directionally opposite, changes in receptor density and adenylate cyclase that occur postmortem indicate the importance of prompt processing of tissues. The striking similarity in response of beta-adrenergic receptor agonist and antagonist binding and adenylate cyclase activity in ischemic and postmortem tissue raises the speculation that similar mechanisms may operate under both conditions.
Postunclipping renal blood flow in one-kidney, one-clip hypertensive rats
Authors: Ma Y. H. , Dunham E. W.
Published: December 2017

Removal of the arterial clip (unclipping) in one-kidney, one-clip (1K, 1C) Goldblatt hypertensive rats causes rapid return of mean arterial pressure (MAP) to normotensive levels. An extracorporeal circulation was established between the renal and jugular veins to evaluate the influence of unclipping on renal blood flow (RBF) in Inactin-anesthetized 1K, 1C rats. MAP in rats with the extracorporeal circulation was 182 +/- 5 mmHg before unclipping or sham operation. MAP decreased to 113 +/- 4 mmHg within 2 h after unclipping compared with 169 +/- 13 mmHg in sham-unclipped rats. RBF increased by 2.8 ml.min-1.g-1 from a basal level of 3.8 +/- 0.3 after unclipping and was maintained approximately 40% above the basal level for 2 h, although renal vascular resistance was 94% greater than in uninephrectomized control rats. Heart rate did not change in either unclipped or sham-operated rats. Indomethacin (7 mg/kg) did not affect unclipping-induced changes in MAP, RBF, or urine output; however heart rate decreased immediately after unclipping and remained approximately 25-35 beats/min below control levels for the 2-h observation period. In rats lacking the extracorporeal circuit, MAP decreased (P less than 0.005) and heart rate increased (P less than 0.05) in response to unclipping. Nevertheless, unclipping-induced tachycardia was significantly less than that caused by nitroprusside infusions causing similar decrements in MAP. The results suggest that the sustained increment in RBF after unclipping in chronic, established 1K, 1C hypertension may be associated with postunclipping hypotension and diuresis, that blockade of prostaglandin synthesis may unmask unclipping-induced bradycardia, and that prostaglandins are not essential for postunclipping changes in renal hemodynamics.
Two dimensions describe left ventricular volume change during hemodynamic transients
Authors: Appleyard R. F. , Glantz S. A.
Published: December 2017

Left ventricular (LV) volume can be estimated from three orthogonal dimensions measured by sonomicrometry. Often, an index based on fewer than three dimensions has been substituted for volume. We consider whether a consistent relationship between LV cross-sectional area, computed as the product of the minor axes dimensions and LV three-dimensional volume, is maintained throughout the responses to application and release of vena caval, pulmonary artery, and aortic occlusions, which were held for approximately 30 beats. In six dogs, the relationship between area and volume was highly linear, with an average correlation of 0.98 and standard error of the estimate of 0.9 ml. Within each dog, there were small but statistically significant differences in the intercepts in the regression lines among the three interventions. However, the magnitude of these differences averaged only 0.5 ml. There was not a systematic difference between the relationship for vena caval and pulmonary artery occlusions, and the relationship for aortic occlusions shifted upward by an average of only 0.8 ml. We conclude that cross-sectional area can be substituted for the three-dimensional volume during the transient responses to acute alterations in the external load conditions.
Modulation of electrophysiological properties of neonatal canine heart by tonic parasympathetic stimulation
Authors: Pickoff A. S. , Stolfi A.
Published: December 2017

The effects of tonic right and left vagal stimulation (RVS and LVS) on electrophysiological properties of the immature myocardium and specialized conduction system were evaluated in 11 neonatal canines pretreated with propranolol (1 mg/kg iv). Electrophysiological studies were performed by recording intracardiac electrograms from multiple endocardial catheters during programmed electrical stimulation. Assessments were made of sinus node function, intra-atrial, atrioventricular (AV) nodal and His-Purkinje conduction, and atrial and ventricular refractoriness in the control state and during RVS and LVS at 4–12 Hz. Vagal stimulation prolonged the sinus cycle length; RVS produced a 38% increase and LVS a 25% increase at 8 Hz (P less than 0.01). There were no changes in the intra-atrial or His-Purkinje conduction times. Comparable increases occurred during RVS and LVS in the paced cycle length resulting in AV nodal Wenckebach, the AV nodal conduction time at a paced cycle length of 340 ms, and the effective and functional refractory periods of the AV node, suggesting symmetrical influences of the right and left vagus on neonatal AV nodal function. Right atrial effective and functional refractory periods shortened significantly during vagal stimulation (ERP, 36% RVS and 23% LVS; FRP, 27% RVS and 15% LVS), and in 5 of 11 neonates, a sustained regular atrial tachyarrhythmia was induced during atrial extra-stimulation. Small yet significant increases were observed in the right ventricular ERP and FRP during vagal stimulation. This study provides information regarding the functional integrity of the parasympathetic nervous system and its potential role as a modulator of the electrophysiological properties of the newborn heart.(ABSTRACT TRUNCATED AT 250 WORDS)
Pulsatile pressure can prevent rapid baroreflex resetting
Authors: Mendelowitz D. , Scher A. M.
Published: December 2017

In a previous study [Am. J. Physiol. 255 (Heart Circ. Physiol. 24): H673-H678, 1988] we demonstrated that baroreflex responses decay (reset) to increased static sinus pressures, but with increased pulsatile pressure, responses are maintained. To determine more conclusively whether pulsatile pressure prevents rapid baroreflex resetting in this study we examined resetting as shifts of the baroreflex (sinus pressure-arterial pressure) curve. In seven anesthesized rabbits the left sinus was vascularly isolated and conditioned for 5 min to static or pulsatile pressures of 60, 100, or 140 mmHg mean pressure, 0 or 35–40 mmHg pulse pressure. The baroreflex curve was then determined by stepwise changing sinus pressure from 40 to 160 mmHg in 20-mmHg increments. Threshold, midpoint, and saturation sinus pressures shifted 25-39% with static conditioning pressures but did not shift significantly with pulsatile pressures. Also, the baroreflex responses to step increases in static sinus pressure decayed, as resetting occurred, but did not decay with pulsatile sinus pressure increases. Thus the baroreflex rapidly resets with static pressures, but there is minimal, if any, resetting with pulsatile pressures.
Vascular washout reduces Ca2+ overload and improves function of reperfused ischemic hearts
Authors: Tani M. , Neely J. R.
Published: December 2017

Relationships between myocardial Ca2+ uptake, recovery of ventricular function, and restoration of tissue metabolites were determined during 30 min of reperfusion following ischemic and anoxic perfusion with either zero or low coronary flow, zero flow with intermittent perfusion, and low-flow perfusion without substrates. When zero-flow ischemia was maintained for 30 or 40 min, tissue lactate levels increased approximately 100-fold; with reperfusion of these hearts, developed pressure recovered to only 70 and 40% of preischemic function, respectively, and Ca2+ uptake increased by 7- and 15-fold. In contrast, 30 min of low-flow (1 ml/min) anoxic perfusion resulted in accumulation of less lactate (15-fold increase), less reperfusion Ca2+ uptake, and recovery of developed pressure to the preanoxic level. Omission of energy substrates during the low-flow anoxic perfusion caused a reduced recovery of heart rate with lower high-energy phosphate levels and increased Ca2+ uptake, but contractile function recovered to the same extent as in low-flow perfusion with substrate. Even very low flow rates (0.06-0.16 ml/min) of oxygen-deficient perfusate increased high-energy phosphate content and contractile function and decreased Ca2+ uptake. Intermittent perfusion with either oxygenated or anoxic buffer between four 10-min episodes of ischemia reduced lactate accumulation, maintained function, and left Ca2+ uptake essentially unchanged. Recovery of developed pressure during reperfusion was negatively correlated with the amount of lactate that accumulated during ischemia or anoxia and with reperfusion Ca2+ uptake, regardless of the duration or type of ischemia or anoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
Relation between left ventricular systolic resistance and contractile rate processes
Authors: Shroff S. G. , Naegelen D. , Clark W. A.
Published: December 2017

To test the hypothesis that left ventricular (LV) systolic resistance is determined by the intrinsic rate processes of the contractile system, we studied 40 spontaneously hypertensive male rats (SHR). Thyroid hormone manipulation was used to alter isomyosin composition and consequently the rate processes of the contractile system. Seven groups of rats were studied: control (SHRC, n = 9); propylthiouracil (PTU) treated for 10 days (SHRP-10, n = 5), 20 days (SHRP-20, n = 5), and 30 days (SHRP-30, n = 6); and thyroxine treated for 5 days (SHRT-05, n = 5), 10 days (SHRT-10, n = 5), and 15 days (SHRT-15, n = 5). In situ (n = 40) and isolated (n = 14; 5 SHRP-30, 5 SHRC, and 4 SHRT-15) heart experiments were performed. In comparison to SHRC, we observed the following: 1) LV pump performance was not different in any of the thyroxine-treated groups, whereas with PTU, pump performance was significantly depressed in rats with greater than 80% slow myosin. 2) Normalized LV peak elastance (Emaxn) was significantly increased in the SHRP-30, whereas it was not altered after thyroxine. These observations were further confirmed in the isolated heart on the basis of peak isovolumetric stress-strain relations. 3) Thyroxine increased and PTU decreased theoretical maximum flow (Qmax; a measure of LV resistance); thus an inverse relation between Qmax and percent slow myosin was observed (r2 = 0.86). 4) The time to peak isovolumetric pressure was increased in SHRP-30 and decreased in SHRT-15. The relaxation process was significantly slower for SHRP-30 group and was unchanged for SHRT-15 group. These observations support our hypothesis that LV systolic resistance quantifies an intrinsic rate-dependent property of the myocardium and that isomyosin composition is one of its determinants. In addition, with changes in isomyosin composition toward predominantly slow myosin, the responses in Emaxn and Qmax are discordant, which may be responsible for the preservation of pump performance. This underscores the importance of quantifying both LV systolic resistance and elastance in the assessment of the functional status of the LV as a mechanical pump.