bluuebunny/crossref_metadata_2025 huggingface dataset:
Myocardial stretch stimulates phosphatidylinositol turnover.
Authors: von Harsdorf R , Lang R E , Fullerton M , Woodcock E A
Published: June 2012

The mammalian myocardium responds to stretch by increasing both contractility and the release of atrial natriuretic peptide. These effects are observed in isolated perfused heart preparations as well as in vivo. That atrial natriuretic peptide release can be stimulated by activation of the phosphatidylinositol turnover pathway suggests a possible mechanism by which stretch might activate a biological response. Accordingly, experiments were performed to examine the effect of dilatation of the right atrium on the phosphatidylinositol turnover pathway measured in isolated perfused hearts. Dilatation of the right atrium caused a stimulation of the phosphatidylinositol turnover pathway as measured by an increase in the accumulation of inositol phosphates. In right atria, increases were detected after 1 minute of dilatation, and maximal increases were observed after 10 minutes. Dilatation for 10 minutes caused an increase in inositol monophosphate, inositol bisphosphate, and inositol trisphosphate from 23.3 +/- 0.9, 15.4 +/- 0.4, and 9.5 +/- 0.3 cpm/mg tissue (mean +/- SEM, n = 7) to 74.6 +/- 2.3, 20.2 +/- 1.3, and 13.6 +/- 1.5 cpm/mg tissue (n = 8), respectively (p less than 0.01 for all inositol phosphates). Smaller increases were observed in the other chambers of the hearts. Perfusion with propranolol, prazosin, and atropine (all 1 microM) did not alter the inositol phosphate response to dilatation, indicating that it was not secondary to release of norepinephrine or acetylcholine. Dilatation of the right ventricle also caused a stimulation of inositol phosphate accumulation, but this was lower than after dilatation of the right atrium. These results show that the myocardium can respond to dilatation by an activation of the phosphatidylinositol turnover pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
Quantification of myocardial infarct size after coronary reperfusion by serum cardiac myosin light chain II in conscious dogs.
Authors: Isobe M , Nagai R , Yamaoki K , Nakaoka H , Takaku F , Yazaki Y
Published: June 2012

The effects of early coronary artery reperfusion on the relation between the extent of myocardial infarction and serum levels of cardiac myosin light chain II or plasma creatine kinase levels were evaluated in the conscious dog. Hydraulic occluders were placed on the left anterior descending arteries of 38 dogs. Seven to 10 days later, myocardial infarction was produced. Coronary reperfusion was performed 3 hours (group A1, n = 13) and 6 hours (group A2, n = 12) after the occlusion. In the other 13 dogs, coronary occlusion was sustained throughout the course of the experiment (group B). Seven days after the occlusion, the heart was cut from the apex to the base into 4-mm slices, and infarct size was determined macroscopically. Rapid appearance and early peaking of creatine kinase were observed in group A. Cumulative release of creatine kinase significantly correlated with infarct size in group A (infarct size ranged from 0.1 to 20.1 g, r = 0.90) and group B (from 0.6 to 26.8 g, r = 0.91). However, since creatine kinase release in group A was greater in comparison with that from infarcts of the same size in group B, the slope of the regression line for group A was significantly steeper (p less than 0.05). Cardiac myosin light chain II appeared as early as creatine kinase did and continued to be elevated for 7 days. A very close relation was observed between infarct size and total cardiac myosin light chain II release (r = 0.87 for group A, and r = 0.88 for group B) or peak level of light chain II (r = 0.85 for group A, and r = 0.81 for group B). In addition, the slopes of the regression lines for infarct size and both peak and total release of light chain II did not differ between group A and group B. On histological examination, viable myocardium was frequently observed in the epicardium of the ischemic area in group A1; therefore, infarct size was greater in group B than in group A1 (p less than 0.05). Also, myocardial creatine kinase content in the epicardium of the center of the ischemic area in group A1 was greater than that in group B. Cardiac myosin light chain II release in group A1 was less than that in group B, whereas no difference was found in plasma creatine kinase release among groups A1, A2, and B.(ABSTRACT TRUNCATED AT 250 WORDS)
Current fluctuations and oscillations in smooth muscle cells from hog carotid artery. Role of the sarcoplasmic reticulum.
Authors: Désilets M , Driska S P , Baumgarten C M
Published: June 2012

Electrical activity of enzymatically isolated, smooth muscle cells from hog carotid arteries was recorded under current clamp and voltage clamp. Under the experimental conditions, membrane potential usually was not stable, and spontaneous hyperpolarizing transients of approximately 100-msec duration were recorded. The amplitude of the transients was markedly voltage dependent and ranged from about 20 mV at a membrane potential of 0 mV to undetectable at membrane potentials negative to -60 mV. Under voltage clamp, transient outward currents displayed a similar voltage dependency. These fluctuations reflect a K+ current; they were abolished by 10 mM tetraethylammonium chloride, a K+ channel blocker, and the current fluctuations reversed direction in high extracellular K+ concentration. Modulators of intracellular Ca2+ concentration also affected electrical activity. Lowering intracellular Ca2+ concentration by addition of 10 mM EGTA to the pipette solution or suppressing sarcoplasmic reticulum function by superfusion with caffeine (10 mM), ryanodine (1 microM), or histamine (3-10 microM) blocked the rapid voltage and current spikes. However, caffeine and histamine induced a much slower hump of outward current before blocking the rapid spikes. This slower transient outward current could be elicited only once after external Ca2+ was removed and is consistent with an activation of K+ channels by Ca2+ released from internal stores. In contrast, removal of external Ca2+ alone failed to abolish the rapid spikes. These results suggest that 1) a Ca2+-dependent K+ conductance can markedly affect the electrical behavior of arterial smooth muscle cells and 2) internal Ca2+ stores, probably the sarcoplasmic reticulum, can support rapid and frequent releases of Ca2+. Exposure to a low concentration of histamine (3 microM) caused synchronization of the irregular, rapid fluctuations giving rise to slow, periodic oscillations of Ca2+-activated K+ conductance with a frequency of 0.1-0.3 Hz. These regular oscillations are reminiscent of periodic Ca2+-induced Ca2+ release, were inhibited by 10 mM caffeine, and point to a modulation of sarcoplasmic reticulum Ca2+ release by histamine.
Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Possible involvement of H+-Na+ and Na+-Ca2+ exchange.
Authors: Tani M , Neely J R
Published: June 2012

The roles of H+-Na+ and Na+-Ca2+ exchange in the depression of ventricular function were studied in the reperfused isolated ischemic rat heart. Zero-flow global ischemia was induced for either 15 or 30 minutes and was followed by 30 minutes of aerobic reperfusion. Intracellular Na+ (Na+i) and 45Ca2+ uptake were measured during ischemia and reperfusion. Accumulation of Na+i was modified by prior glycogen depletion and by treatment with amiloride, a H+-Na+ exchange inhibitor, or monensin, a Na+ ionophore. Na+i rose continuously during ischemia and rapidly during the first two minutes of reperfusion. The larger inhibitory effect of amiloride and preischemic glycogen depletion was on Na+i accumulation during reperfusion; this finding suggests that the uptake occurs by H+-Na+ exchange. Reduction of Na+i accumulation by glycogen depletion was associated with less lactate and, presumably, H+ production and accumulation during ischemia. The rapid increase in Na+i during early reperfusion may reflect the readjustment of the low intracellular pH resulting from ischemia. The level of Na+i at the end of ischemia and especially after two minutes of reperfusion were linearly correlated with 45Ca2+ uptake and depression of ventricular function during subsequent reperfusion. This highly significant correlation between Na+i and 45Ca2+ uptake when Na+i was varied by several independent procedures, including monensin, strongly suggests that reperfusion 45Ca2+ uptake occurs at least in part by Na+-Ca2+ exchange. The rate of 45Ca2+ uptake during reperfusion was linearly and highly significantly correlated with elevation of diastolic pressure, reduced developed pressure, and decreased recovery of ventricular function. The data strongly support a mechanism of ischemic cell damage that involves excessive production and accumulation of H+ during ischemia that exchanges for extracellular Na+ during ischemia and rapidly during the first few minutes of reperfusion. Increased Na+i then causes excessive 45Ca2+ uptake and depressed recovery of cellular functions with continued reperfusion. Increased levels of Na+i may be a major event that couples a decreased intracellular pH during ischemia to excessive 45Ca2+ uptake and depressed recovery of cellular function with reperfusion.
Contractile shortening response of ventricular cells to extracellular acidosis. Evidence for two-site control of H+-Ca2+ interaction.
Authors: Langer G A , Rich T L , Ji S
Published: June 2012

The effect of extracellular acidosis on contraction of single isolated ventricular cells from rabbit was measured in a system in which pHo could be changed in less than 200 msec. The contractile response to acidotic levels was complete within 25 seconds. The response was measured 30 seconds after pHo was decreased to 7.0, 6.5, 6.0, and 5.5 at each of 8 [Ca]o levels (0.125-4.0 mM). Cell shortening versus [Ca]o was plotted to construct a curve for each pHo level, with each point relative to shortening at pH 7.5, [Ca]o = 1 mM (100% value). Calcium current (1 mM [Ca]o) was also measured 30 seconds after pHo was decreased from 7.5 to 6.5 with single-cell patch clamp technique. The contractile response to extracellular acidosis is accurately predicted by assuming two (probably sarcolemmal) sites at which H+ ions affect calcium binding and/or flux: (equation; see text) The first factor represents a set of sites that are proposed to control access, dependent on the degree of their ionization, to sites represented by the second factor. The latter sites are proposed to accept calcium according to mass-action law. The response of calcium channel current to extracellular acidosis was also complete and reversible within 25 seconds. The current response indicates that the two-site model could be predictive for the effect of extracellular acidosis on calcium current in ventricular cells.
Stereoselective block of cardiac sodium channels by RAC109 in single guinea pig ventricular myocytes.
Authors: Clarkson C W
Published: June 2012

The effects of the optical stereoisomers of the local anesthetic RAC109 (RAC109-I and RAC109-II) on sodium current in isolated guinea pig ventricular myocytes were investigated by use of the whole-cell variation of the patch-clamp technique. RAC109-I and RAC109-II produced similar levels of tonic block, but RAC109-I produced a significantly larger use-dependent block on repetitive pulsing to potentials positive to -60 mV. Definition of the time courses of block development at -20 mV and recovery at -140 and -160 mV indicated that RAC109-I had a higher affinity for activated and inactivated channels and dissociated more slowly at hyperpolarized potentials compared with RAC109-II. Removal of fast inactivation by alpha-chymotrypsin intensified tonic block but did not reduce use-dependent block by RAC109-I; this finding suggests that channel inactivation is not necessary for use-dependent block. The guarded-receptor model was used to calculate apparent rate constants of drug binding and unbinding. According to the model, RAC109-I and RAC109-II have significantly different unbinding rate constants for channels when they exist predominantly in rested, activated, or inactivated states, as well as significantly different binding rate constants when channels are activated. However, the apparent rates of drug binding to closed (rested and inactivated) channels are not significantly different for the two isomers; this finding indicates that drug binding to closed channels is not markedly stereospecific, in contrast to unbinding. The effects of RAC109 stereoisomers on cardiac sodium channels were also qualitatively similar to those previously reported in nerve; these findings suggest that the binding sites for local anesthetics in both tissue types have a similar structural topography.
Renal vasoconstriction by the endothelial cell-derived peptide endothelin in spontaneously hypertensive rats.
Authors: Hirata Y , Matsuoka H , Kimura K , Fukui K , Hayakawa H , Suzuki E , Sugimoto T , Sugimoto T , Yanagisawa M , Masaki T
Published: June 2012

The effects of endothelin on systemic and renal hemodynamics in anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats were examined. Endothelin (500 ng i.v. +1,000 ng/hr per 300-g rat) elevated mean blood pressure by 13% (p less than 0.02) and decreased renal blood flow by 71% and glomerular filtration rate by 66% (both p less than 0.01), resulting in a 430% (p less than 0.05) increase in renal vascular resistance (RVR) in SHR. This rise in blood pressure was associated with a significant increase in hematocrit (+8%), but a decrease in urinary sodium excretion (-51%). This dose of endothelin reduced cardiac output by 40% (p less than 0.001) and brought about a 96% (p less than 0.01) rise in systemic vascular resistance (SVR). However, the SVR increase was significantly smaller than the RVR increase. These changes in systemic and renal hemodynamics were observed in a dose-dependent manner, and the degrees of change did not differ between the two strains. Additional infusion of atrial natriuretic peptide (0.33 microgram/kg/min) into SHR completely reversed the changes in blood pressure and renal hemodynamics caused by endothelin, resulting in pronounced natriuresis (+760%). The renal vascular casting study revealed that endothelin mainly constricted the arcuate and interlobular arteries, as well as afferent arterioles. These results suggest that endothelin may be involved in blood pressure and body fluid volume regulation through systemic and renal vasoconstriction.
The linear relation between oxygen consumption and pressure-volume area can be reconciled with the Fenn effect in dog left ventricle.
Authors: Nozawa T , Yasumura Y , Futaki S , Tanaka N , Suga H
Published: June 2012

We studied the Fenn effect in 12 excised cross-circulated dog left ventricles in control contractility and in a contractility enhanced by dobutamine or depressed by propranolol. The additional oxygen consumption (Vo2) in an ejecting contraction compared with that found in an isovolumic contraction at a comparable end-systolic pressure was considered to constitute the cardiac Fenn effect. We examined whether this load-dependent Vo2 could be reconciled with the linear relation between Vo2 and pressure-volume area (PVA) common for both ejecting and isovolumic contractions that has so far been consistently observed and was presently confirmed. PVA is a specific area in the pressure-volume diagram, represents the total mechanical energy generated by each contraction, and consists of external mechanical work (EW) and mechanical potential energy. Because potential energy is common in the isovolumic and ejecting contractions producing the same end-systolic pressure, PVA of the ejecting contraction is greater by EW than that of the isovolumic contraction. Despite this difference in PVA by EW, the Vo2-PVA relation was always linear and load independent regardless of the isovolumic and ejecting contractions in a given heart in any given contractile state. By contrast, the upward convex Vo2-end-systolic pressure relation was higher for ejecting contractions than the downward convex Vo2-end-systolic pressure relation for isovolumic contractions in each contractile state. The difference of Vo2 between the ejecting and isovolumic contractions was proportional to EW at comparable end-systolic pressure. The slope of the additional Vo2 of ejecting contractions plotted against their EW had a slope close to the slope of the Vo2-PVA relation. Thus, the load-independent linear Vo2-PVA relation can be reconciled with the cardiac Fenn effect.
Multiple regional differences in cellular properties that regulate repolarization and contraction in the right atrium of adult and newborn dogs.
Authors: Spach M S , Dolber P C , Anderson P A
Published: June 2012

Recent studies of isolated cardiac myocytes have generated the need for detailed information about regional electrophysiological differences in the atrium. We measured the spatial distribution of action potentials in adult and newborn canine right atria. Multiple regional differences in action potential shape and duration were found. The multiple regional differences produced an overall simple pattern: the longest action potentials occurred in the area of the sinus node, and the action potential duration decreased with increasing distance from the sinus node area. To account for the overall pattern, we tested factors considered important in causing atrial action potential shape differences (e.g., electronic interactions). None of the factors tested accounted for the regional differences. We then found regional differences in the responses to pauses, which suggested that differences in the properties of individual cells accounted for the regional repolarization differences. If so, genetic regulation of the regional differences may produce the overall pattern on a developmental basis. Experiments in newborn atria showed that only in the upper crista was the spatial pattern similar to that of the adult; there was little variability in action potential shape and duration in the other areas. As a further test for associated regional differences in cell properties, we examined for differences in the isoform expression of troponin T (TnT1, TnT2, TnT3, and TnT4), a protein important in excitation-contraction coupling. In adults, the greatest proportion of TnT1 occurred in the area of the sinus node, and its proportion decreased with increasing distance from the sinus node area in association with a relative increase in the proportion of TnT2. In newborn atria the relative amount of TnT1 was greatest in the upper crista (similar to adult), but little difference was found in the distribution of the isoforms in the other regions. The correspondence between the regional differences in repolarization and in the expression of the troponin T isoforms in adult and newborn atria suggests that 1) cellular ionic mechanisms vary regionally to coordinate differences in action potential configuration with differences in cell properties that regulate contractility and 2) genetic expression of the systems that regulate repolarization and mechanical cellular properties are under similar developmental and regional control.
Polymorphonuclear leukocytes induced vasoconstriction in isolated canine coronary arteries.
Authors: Nishida M , Kuzuya T , Hoshida S , Kim Y , Kitabatake A , Kamada T , Tada M
Published: June 2012

To assess how polymorphonuclear leukocytes (PMNs) act on coronary vasoactivity, we measured the changes in isometric tension of isolated rings of canine coronary arteries upon addition of autologous PMNs to organ chambers in which the rings were suspended. When PMNs isolated by the colloidal polyvinylpyrrolidone-coated silica (Percoll) gradient method were added to the chambers, ring preparations of left circumflex coronary arteries developed isometric tension. The increase in tension was dependent on the amount of PMNs (1 X 10(4) to 5 X 10(6) cells/ml). Maximal tension obtained by an optimal amount of PMNs (5 X 10(5) cells/ml) was almost comparable to that produced by prostaglandin F2 alpha (5 microM). Integrity of endothelial cells was not disrupted after the addition of PMNs because the developed tension could be reversed by the addition of acetylcholine in an endothelium-dependent manner. Mechanical rubbing of endothelium abolished the PMN-induced vasoconstriction, which was regained by placing an endothelium-unrubbed ring inside a rubbed ring ("sandwich preparation"). When PMN suspensions were pretreated with 5-lipoxygenase inhibitors of arachidonate, PMN-induced vasoconstriction was greatly suppressed, although the pretreatment of vascular preparations did not alter the development of isometric tension. These findings indicate that PMNs induce the contraction of coronary arterial rings in the presence of intact endothelial cells. The mechanism by which PMNs induce the contraction is the release of vasoconstrictive substances by metabolic interaction between PMNs and endothelial cells. Vasoconstrictive substances produced by the PMN-endothelial system, such as 5-lipoxygenase metabolites through a "leukotriene A4 steal" mechanism, may contribute to the contraction of vascular smooth muscle.
Effects of endothelin on coronary flow, mechanical performance, oxygen uptake, and formation of purines and on outflow of prostacyclin in the isolated rabbit heart.
Authors: Karwatowska-Prokopczuk E , Wennmalm A
Published: June 2012

Endothelin is a 21-residue peptide formed during incubation of isolated porcine endothelial cells. Due to its pronounced vasoconstrictor activity, endothelin has been proposed to play a role in the regulation of vascular tone. We studied the effects of synthetic endothelin (0.1-10 nM) on coronary flow, mechanical performance, myocardial oxygen uptake, and formation of purines, and outflow of 6-ketoprostaglandin F1 alpha (metabolite of prostacyclin) in rabbit hearts perfused with saline by the Langendorff method. Endothelin dose-dependently decreased the coronary flow, at 10 nM, by about 75%. Heart rate, ventricular contractility, myocardial oxygen uptake, and purine release were affected by endothelin no more than by a corresponding mechanical reduction of the coronary flow. In contrast, the diastolic relaxation appeared to be directly diminished by endothelin. The concentration of 6-ketoprostaglandin F1 alpha in the cardiac effluent was dose-dependently elevated by about 14 times by endothelin (10 nM) (p less than 0.001). A corresponding mechanical restriction of the coronary flow insignificantly affected the effluent concentration of 6-ketoprostaglandin F1 alpha. The calcium channel blocker nifedipine (1 microM) completely abolished the decrease in diastolic relaxation induced by endothelin and markedly counteracted the peptide-induced increase in effluent concentration of 6-ketoprostaglandin F1 alpha, but did not affect the vasoconstrictor activity. These data demonstrate that endothelin induces vasoconstriction and facilitates the outflow of prostacyclin in the rabbit heart. In addition, the peptide appears to affect diastolic relaxation in this organ.
Spatial domain analysis of late ventricular potentials. Intraoperative and thoracic correlations.
Authors: Lacroix D , Savard P , Shenasa M , Kaltenbrunner W , Cardinal R , Pagé P , Joly D , Derome D , Nadeau R
Published: June 2012

For investigation of late potentials seen on the signal-averaged electrocardiogram, intracardiac and thoracic distributions of terminal activity were analyzed in 16 patients undergoing cryosurgery for ventricular tachycardia after remote myocardial infarction. The body surface potentials measured with 63 time-averaged unipolar leads were compared with epicardial and endocardial potential maps in six patients without and 10 patients with bundle-branch block. Intracardiac post-QRS activity, defined as extending beyond the thoracic QRS offset, was found in five of six patients without bundle-branch block (83%) and in five of 10 patients with bundle-branch block (50%), corresponding to 4 +/- 5% of the total number of electrograms in each patient. Fragmentation, double deflections, and single deflections were observed in 27%, 34%, and 39%, respectively, of these post-QRS electrograms. Post-QRS activation patterns that were stable from beat to beat showed slow propagation around or within areas of conduction block. Post-QRS activity was most often observed on both epicardial and endocardial surfaces (five of 10 patients). In the six patients without post-QRS activity, an area of late activity displaying low-amplitude deflections that were masked by the terminal activation of the normal myocardium was identified. Isopotential maps of the high-pass-filtered (55-Hz) thoracic and intracardiac signals demonstrated a close spatial correlation between the location, amplitude, and orientation of the potential extrema observed over the thoracic, epicardial, or endocardial surfaces during post-QRS activity. The thoracic patterns were generally dipolar with close extrema for anteroseptal or apical sites of post-QRS activity and more distant extrema for other sites.(ABSTRACT TRUNCATED AT 250 WORDS)
Renal-endocrine adaptations to endogenous atrial natriuretic factor during tachycardia-induced reductions in renal perfusion pressure.
Authors: Miller W L , Edwards B S , Zimmerman R S , Burnett J C
Published: June 2012

Atrial pressure, atrial natriuretic factor (ANF), the renin-angiotensin-aldosterone system, and renal hemodynamic functions were examined during and after right ventricular pacing in anesthetized dogs (n = 9). Mean arterial pressure, cardiac output, and renal blood flow decreased during tachycardia while right and left atrial pressures increased. ANF markedly increased during tachycardia but urinary and fractional excretion of sodium were unchanged from control. Plasma renin activity was not increased during pacing despite the decrease in renal perfusion pressure. After tachycardia and restoration of mean arterial pressure to control, ANF declined but remained elevated above control despite a return of atrial pressure to control level. After tachycardia, urinary and fractional sodium excretion increased significantly in the absence of an increase in glomerular filtration rate. These findings support the following conclusions: 1) tachycardia increases ANF in association with increased atrial pressure; however, an elevation of ANF persists following tachycardia despite the absence of the persistent stimulus of elevated atrial pressures; 2) the increase in ANF during tachycardia may contribute to the absence of a decrease in sodium excretion and activation of the renin-angiotensin system that occurs with reduction in renal perfusion pressure; and 3) tachycardia-induced natriuresis may be dependent on an increase in ANF and the maintenance of renal perfusion pressure.
Dexamethasone selectively attenuates prostanoid-induced vasoconstrictor responses in vitro.
Authors: Sessa W C , Nasjletti A
Published: June 2012

Glucocorticoids bind to specific vascular receptors resulting in a variety of functional consequences that may affect vascular smooth muscle behavior. We, therefore, examined in rabbits the effect of treatment with dexamethasone (2.5 mg/kg) for 6 days on vascular responses to pressor prostanoids in aortic and carotid arterial rings and in the isolated perfused kidney. Isometric tension development to prostaglandin F2 alpha and U46619, a thromboxane/prostaglandin endoperoxide mimetic, was markedly reduced in vessels from dexamethasone-treated rabbits. The inhibitory effect of dexamethasone on vascular reactivity was manifested by an increase in the concentration of agonist for threshold tension development and a reduction in the maximal response to prostaglandin F2 alpha and U46619. In contrast, reactivity to phenylephrine, potassium, histamine, or endothelin was not affected by dexamethasone treatment. In addition, pressor responses to prostaglandin F2 alpha and U46619 in Krebs'-perfused kidneys from dexamethasone-treated rabbits were also diminished. These data suggest that dexamethasone selectively interferes with the expression of receptor-mediated contractile responses to eicosanoids.
Influence of beta-adrenergic stimulation and contraction frequency on rat heart interstitial adenosine.
Authors: Fenton R A , Tsimikas S , Dobson J G
Published: June 2012

Adenosine (ADO) has an antiadrenergic action in the heart that causes an attenuation of contractile and metabolic responses elicited by beta-adrenergic stimulation. The effect of an increase in oxygen consumption elicited by either beta-adrenergic stimulation or an increase in contraction frequency on interstitial fluid and coronary effluent ADO levels was investigated in isolated perfused isovolumically contracting rat hearts. ADO in left ventricular surface transudates and coronary effluents was rendered fluorescent with chloroacetaldehyde, and the formed ethenoadenosine derivative was quantitated with high-performance liquid chromatography fluorescence detection. Heart preparation integrity was verified by determining the activities of lactate dehydrogenase and ADO deaminase in the transudates. Isoproterenol (10(-8) M) elicited a 45% increase in oxygen consumption and a 54% increase in developed left ventricular pressure in hearts paced at 240 beats/min. With isoproterenol the control transudate ADO concentration (304 pmol/ml) increased 493%, and the control effluent ADO concentration (48 pmol/ml) increased 259%. Increasing the contraction frequency from 180 to 300 beats/min in the presence of 10(-6) M propranolol increased oxygen consumption by 45% and decreased left ventricular pressure by 29%. With the increase in contraction frequency, the transudate ADO concentration did not increase significantly. However, the ADO concentration in the effluent was an average of 269% greater in hearts contracting at the higher frequency. Increasing the contraction frequency of hearts treated with both 10(-6) M propranolol and 10(-5) M atropine also had no significant effect on the level of transudate ADO. The effluent level of ADO increased only 78%. Levels of ADO in transudates were not significantly affected by mesothelial cell metabolism. These results suggest that the beta-adrenergic stimulation the interstitial level of ADO in the heart increases to levels that are sufficient to manifest its antiadrenergic effects. Furthermore, there is not always a correlation between the levels of ADO found in the interstitial and effluent fluid compartments.
Pulmonary venous responses to thromboxane A2 analogue and atrial natriuretic peptide in lambs.
Authors: Raj J U , Anderson J
Published: June 2012

To characterize pulmonary venous vasoactivity and the factors that modulate it, we determined venous responses to a vasoconstrictor agent, thromboxane A2 (TXA2) analogue U46619, and to a vasodilator agent, atrial natriuretic peptide (ANP), in 28 isolated blood-perfused lamb lungs under conditions of varying vascular tone and intraluminal pressures. TXA2 was given in a 5 micrograms/kg bolus followed by a steady infusion of 1 micrograms/kg/min to three groups of lungs: group 1, n = 4, with low vasomotor tone; group 2, n = 8, with moderate vasomotor tone; and group 3, n = 7, with moderate vasomotor tone and high venous intraluminal pressures. Group 3 lungs were reverse-perfused to obtain high venous pressures. ANP was given as two 10 micrograms/kg bolus injections, 5 minutes apart, to three groups of lungs: group 4, n = 4, with low vasomotor tone; group 5, n = 5, with moderate vasomotor tone; and group 6, n = 8, with high vasomotor tone. Group 6 lungs were vasoconstricted with TXA2 infusion. In all lungs, we measured blood flow and pressures in the pulmonary artery and left atrium and partitioned the venous segment by measuring pressures in 20-80-microns venules by micropuncture. We found that the venous constrictor response to TXA2 was greatest in lungs with moderate basal vasomotor tone and low venous intraluminal pressures. In lungs with low vasomotor tone or high venous intraluminal pressures, the venous response to TXA2 was attenuated. The vasodilator response to ANP was negligible in lungs with low vasomotor tone, probably because they were already maximally vasodilated, but similar in lungs with moderate and high vasomotor tone.(ABSTRACT TRUNCATED AT 250 WORDS)
Supernormal excitability as a mechanism of chaotic dynamics of activation in cardiac Purkinje fibers.
Authors: Chialvo D R , Michaels D C , Jalife J
Published: June 2012

Supernormality, which can be defined as greater than normal excitability during or immediately after action potential repolarization, has been observed in a variety of cardiac preparations. However, as yet, no description of the dynamics of tissue response to repetitive stimulation in the presence of supernormal or relatively supernormal excitability has appeared. Isolated sheep cardiac Purkinje fibers (2-5 mm in length) were superfused with Tyrode's solution and stimulated with depolarizing current pulses through a suction pipette. Recovery of excitability, restitution of the action potential duration, and response patterns were measured in each fiber for a wide range of current amplitudes and stimulation frequencies. When the potassium chloride concentration of the Tyrode's solution was decreased from 7 to 4 mM, the excitability recovery function consistently changed from monophasic ("normal") to triphasic ("supernormal'). During repetitive stimulation at increasing rates, normal preparations responded only with gradual changes in the activation ratio, expressed as periodic phase-locked responses (i.e., Wenckebach-like patterns, etc.). Supernormal preparations showed a nonmonotonic change in the activation ratio, as well as complex aperiodic response patterns. Numerical results from an analytical model gave a quantitative basis for the relation between nonmonotonicity in the excitability function and the development of complex rhythms in cardiac Purkinje fibers. Both our experimental and theoretical results indicate that the presence of supernormality and the slope of the action potential duration restitution curve at short diastolic intervals are responsible for the development of chaotic dynamics. Moreover, our results give an accurate description of the supernormality phenomenon, predict the behavior expected under such conditions, and provide insight about the role of membrane recovery in determining regular and irregular frequency-dependent rhythm and conduction disturbances.
Effect of loading conditions, contractile state, and heart rate on early diastolic left ventricular filling in conscious dogs.
Authors: Cheng C P , Freeman G L , Santamore W P , Constantinescu M S , Little W C
Published: June 2012

We investigated left ventricular (LV) early diastolic filling in 10 normal conscious dogs that had been previously instrumented to measure LV and left atrial (LA) pressures and three orthogonal LV internal dimensions. LV volume was calculated as a general ellipsoid. The pressure within a passive structure increases as it is filled. If myocardial relaxation is rapid enough to substantially aid LV diastolic filling, it may overcome this effect and cause LV pressure to fall despite an increase in volume. Thus, we defined the amount of LV filling that occurred while LV pressure was falling as relaxation filling, which is a measure of the importance of LV relaxation during early diastolic filling. The time constant of relaxation (T) was derived from the exponential fall of LV pressure during isovolumic relaxation. While LV pressure was falling early in diastole (the relaxation filling period), all three LV diameters increased. Autonomic blockade with hexamethonium (5 mg/kg) and atropine (0.1 mg/kg) reduced relaxation filling from 21 +/- 6% (mean +/- SD) to 12 +/- 3% of the stroke volume (p less than 0.01). The mean LA pressure also was significantly decreased (from 12 +/- 2 to 10 +/- 5 mm Hg, p less than 0.05), while the duration of the relaxation filling period and T were unchanged. Positive inotropic stimulation with dobutamine (10 micrograms/kg/min) shortened T without changing LA pressure. The maximum LA-LV pressure gradient, dV/dtmax, and relaxation filling all increased. Augmented preload produced by dextran infusion (500 ml/10 min) caused an increase in LA pressure (from 11 +/- 3 to 21 +/- 8 mm Hg, p less than 0.05) without altering T. This also increased the maximum LA-LV pressure gradient, dV/dtmax, and relaxation filling. Augmented afterload produced by methoxamine (10 mg/3 min i.v.) significantly increased LA pressure (from 9 +/- 4 to 15 +/- 10 mm Hg, p less than 0.05) and lengthened T (from 35 +/- 4 to 50 +/- 7 msec, p less than 0.05) and the duration of relaxation filling (from 36 +/- 5 to 44 +/- 9 msec, p less than 0.01) without altering the maximum LA-LV pressure gradient, dV/dtmax, or LV relaxation filling. Incremental changes in heart rate induced by atrial pacing (from 100-180 beats/min) resulted in progressive decreases in the time constant of LV relaxation and the duration of relaxation filling. The LA pressure was also decreased. There was no corresponding increase in the amount of active LV filling until the heart rate reached 180 beats/min. During all these interventions, T correlated with the duration of LV relaxation filling (r = 0.99. p less than 0.05). The amount of relaxation filling and dV/dtmax both correlated with the maximum LA-LV pressure gradient.(ABSTRACT TRUNCATED AT 400 WORDS)
Interaction between endothelin-1 and endothelium-derived relaxing factor in human arteries and veins.
Authors: Lüscher T F , Yang Z , Tschudi M , von Segesser L , Stulz P , Boulanger C , Siebenmann R , Turina M , Bühler F R
Published: June 2012

Endothelin-1 is a 21-amino acid endothelial vasoconstrictor peptide that may be the physiological antagonist of endothelium-derived relaxing factor (EDRF). Endothelin-1 (10(-11)-3 x 10(-7) M) evoked potent contractions of isolated internal mammary arteries, internal mammary veins, and saphenous veins, which were enhanced in internal mammary veins as compared with internal mammary arteries (concentration shift, 6.3-fold; p less than 0.05) but not in the saphenous veins. Endothelial removal augmented the response to the peptide (at 3 x 10(-7) M) in internal mammary arteries (p less than 0.05) but not in veins. In the artery, EDRF released by acetylcholine or bradykinin reversed endothelin-1-induced contractions; in saphenous veins, both agonists were much less effective compared with the artery and veins contracted with norepinephrine (p less than 0.005-0.01). This inhibition of endothelium-dependent relaxations in veins occurred at half-maximal contractions but was most prominent at maximal contractions to the peptide. Nitric oxide similarly inhibited contractions to endothelin-1 and norepinephrine in internal mammary arteries, whereas in veins that were contracted with endothelin-1 but not with norepinephrine, the relaxations were blunted (p less than 0.005). The nitric oxide donor SIN-1 and sodium nitroprusside induced complete relaxations of internal mammary arteries but were less effective in veins contracted with endothelin-1 (p less than 0.005). Thus, in normal human arteries, EDRF inhibits endothelin-1-induced contractions, whereas the peptide specifically attenuates the effects of EDRF and nitrovasodilators in veins. This may be important in pathological conditions associated with increased levels of endothelin-1 and in veins used as coronary bypass grafts.
Differences in myosin isoform expression in the subepicardial and subendocardial myocardium during cardiac hypertrophy in the rat.
Authors: Bugaisky L B , Anderson P G , Hall R S , Bishop S P
Published: June 2012

We have investigated myosin isoform expression during progressive cardiac hypertrophy and the development of congestive heart failure in young male rats. Cardiac enlargement was produced by placing a constricting band (0.024-inch diameter) around the ascending aorta of 25-day-old animals, which resulted in progressively increased stenosis as the rat matured. A 57% and 77% cardiac hypertrophy was observed at 2 and 8 weeks, respectively, with signs of congestive failure at the latter time point. Myosin isoform expression was examined in the subendocardial and subepicardial myocardium of the left ventricle and the free wall of the right ventricle by use of native gel electrophoresis. The percentage of the V3 isoform increased dramatically in both ventricles. In the subendocardial myocardium of the left ventricle, expression of the V3 isoform increased (p less than or equal to 0.05) relative to the subepicardial myocardium at 2, 4, and 8 weeks (17.1% vs. 10.2%, 29.4% vs. 18%, and 46.6% vs. 36.2%). In addition to regional differences within a given transmural segment, we also observed a high degree of heterogeneity in myosin isoform expression throughout a given layer (particularly the subendocardial myocardium) when small (less than or equal to 10-15 mg) adjacent samples were examined. This variability illustrated a potential danger in interpretation of gel results obtained from a single small tissue sample. Thus, cardiac hypertrophy produced by pressure overload in 25-day-old rats resulted in significantly increased V3 myosin in both the left and right ventricles. Furthermore, within the hypertrophied left ventricle, the subendocardial myocardium contained a significantly greater percentage of V3 myosin than the subepicardial myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
Detection of oxygen-derived free radical generation in the canine postischemic heart during late phase of reperfusion.
Authors: Kuzuya T , Hoshida S , Kim Y , Nishida M , Fuji H , Kitabatake A , Tada M , Kamada T
Published: June 2012

To define the relation between oxygen-derived free radical (oxy-radical) generation in the reperfused ischemic myocardium and the progression of myocardial damage, we measured oxy-radical generation in the ischemic myocardium and the propagating infarct size in a model of canine coronary occlusion (90 minutes) and reperfusion. We used electron paramagnetic resonance spin-trapping techniques (5,5-dimethyl-1-pyrroline N-oxide [DMPO]) to detect oxy-radicals in the rapidly frozen myocardial samples taken by needle biopsy. There was no detectable generation of DMPO adducts in the normal myocardium before or after reperfusion. In the reperfused ischemic myocardium, electron paramagnetic resonance signals of DMPO-OOH (superoxide anion) and DMPO-OH (hydroxyl radical) were detected, with peak concentrations at 1 hour after reperfusion for DMPO-OOH and at 3 hours after reperfusion for DMPO-OH, respectively. These DMPO adducts were also detected during the early phase (15 seconds) of reperfusion, but the concentrations of these signals were much less than those during the late phase of reperfusion. Treatment with human recombinant superoxide dismutase (2.5 mg/kg/hr) and catalase (2.5 mg/kg/hr) during the course of experiments abolished DMPO-OOH formation but had little effect on DMPO-OH formation. Infarct size (percent of risk area infarcted), quantified by a dual staining method with Evans blue dye and triphenyltetrazolium chloride, was 18.3 +/- 4.8% (mean +/- SEM) at 90 minutes of occlusion. After 5 hours of reperfusion, infarct size increased to 43.6 +/- 7.2%. These results indicate that a greater magnitude of oxy-radical generation was sustained in the ischemic myocardial tissue during the late phase (1-3 hours) of reperfusion, associated with the progression of myocardial infarction. The concurrent appearance of oxy-radicals and progressive infarction may support the view that a chain reaction of oxy-radicals contributes to the propagation of myocardial cell damage in the postischemic heart.
Angiotensins and the failing heart. Enhanced positive inotropic response to angiotensin I in cardiomyopathic hamster heart in the presence of captopril.
Authors: Hirakata H , Fouad-Tarazi F M , Bumpus F M , Khosla M , Healy B , Husain A , Urata H , Kumagai H
Published: June 2012

We examined the hypothesis that the positive inotropic effect of angiotensin I (Ang I) may be retained in the presence of angiotensin converting enzyme inhibitors so that it may have a direct beneficial effect on the heart. Accordingly, isolated perfused hearts (Langendorff preparation) of 300-day-old cardiomyopathic hamsters (a model of spontaneous cardiomyopathy) and age-matched normal hamsters (controls) were infused with Ang I in the presence of captopril; propranolol was added to the perfusing medium to block catecholamine-mediated effects of angiotensins on the heart. Left ventricular developed pressure and the rate of increase in left ventricular developed pressure increased significantly (p less than 0.001) in both the cardiomyopathic and the normal hamster heart despite concomitant reduction in myocardial flow rate favoring a direct inotropic effect of Ang I in both normal and myopathic hearts; these changes were significantly higher by almost threefold in the cardiomyopathic than in the normal hamsters (p less than 0.01) and were blocked by the angiotensin II (Ang II) antagonist [Sar1,Thr8]Ang II. Comparing dose-left ventricular contractility response curves for Ang I and Ang II, ED50 for responses was identical in both normal and myopathic hearts, whereas peak responses to Ang II were double those to Ang I in normal hearts but were almost identical in the myopathic hearts. Binding of [125I]Ang II in six cardiomyopathic and four normal hamster hearts was of high affinity, but there was no evidence for Ang I-saturable high-affinity binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
Chloride efflux in cyclic AMP-induced configurational change of bovine pulmonary artery endothelial cells.
Authors: Ueda S , Lee S L , Fanburg B L
Published: June 2012

Elevation of cellular cyclic AMP by agents such as isoproterenol plus 3-isobutyl-1-methylxanthine produced rapid and reversible dendritic formation of bovine pulmonary artery endothelial cells in the monolayer. The effect did not occur with exposure of the cells to a variety of other vasoactive agents, calcium ionophore, phorbol ester, or cyclic GMP. The cyclic AMP-induced configurational change was completely inhibited by 2.5 mM N-phenylanthranilic acid or 145 mM sodium gluconate (Cl- channel inhibitors) and was partially inhibited by 2.5 mM 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS), but it was not affected by deprivation of Ca2+ or Na+ ion, 1 mM bumetanide (Cl- cotransport inhibitor), 1 mM amiloride (Na+/H+ exchange inhibitor), 0.1 mM verapamil (Ca2+ channel inhibitor), or 5 mM BaCl2 (K+ channel inhibitor), by change in cellular pH, or by pertussis toxin. Trifluoperazine (calmodulin inhibitor, 50 microM), 1 mM EGTA plus 100 microM 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8, intracellular Ca2+ antagonist), and 5 microM cytochalasin B also produced cellular retraction, but these changes were not blocked by chloride channel inhibition. In the presence of 0.1 mM ouabain plus 0.1 mM bumetanide, 36Cl- uptake was decreased by isoproterenol plus isobutylmethylxanthine while its efflux was enhanced. N-Phenylanthranilic acid inhibited the stimulated efflux. We conclude that cyclic AMP induces a configurational change of endothelial cells that is related to Cl- efflux from the cells; the cellular effects may play a role in vascular function.