bluuebunny/crossref_metadata_2025 huggingface dataset:
Adrenergic and cholinergic responsiveness of isolated canine bronchial arteries
Authors: O'Rourke S. T. , Vanhoutte P. M.
Published: December 2017

The purpose of this study was to characterize the adrenergic and cholinergic responsiveness of isolated rings of canine bronchial arteries. Electrical stimulation of the vessels produced frequency-dependent contractions that were inhibited by phenoxybenzamine, tetrodotoxin, and phentolamine but not by atropine. Norepinephrine caused concentration-dependent contractions of the rings; the concentration-response curve to norepinephrine was shifted to the right by phentolamine and prazosin, whereas rauwolscine had no effect. Isoproterenol, norepinephrine, tyramine, and electrical stimulation (in the presence of phentolamine) failed to elicit relaxation in rings contracted with prostaglandin F2 alpha. Contracted rings relaxed to acetylcholine in an endothelium- and concentration-dependent manner. At concentrations up to 10(-4) M, acetylcholine did not evoke contractions in these tissues. Endothelium-dependent relaxation to acetylcholine was inhibited by atropine and 4-diphenyl-acetoxy-N-methyl piperidine methiodine but not by pirenzepine. These results suggest that alpha 1-adrenoceptors mediate contraction to norepinephrine, and M3-muscarinic receptors mediate endothelium-dependent relaxation to acetylcholine in the canine bronchial artery. Moreover, the smooth muscle of these vessels does not respond directly to beta-adrenergic- or cholinergic-receptor stimulation.
Hypertension and hemodilution during cerebral ischemia reduce brain injury and edema
Authors: Cole D. J. , Drummond J. C. , Osborne T. N. , Matsumura J.
Published: December 2017

The extent of cerebral injury and edema was determined in isoflurane-anesthetized rats (n = 32) after 180 min of middle cerebral artery occlusion (MCAO) and 120 min of reperfusion. One of the following was employed during the occlusion period only: 1) control, mean arterial pressure [MAP = 131 +/- 7 (SD) mmHg] and hematocrit (43 +/- 2%) were not manipulated; 2) hemodilution, the hematocrit was reduced to 30% with 5% albumin (MAP = 104 +/- 19 mmHg); 3) hemodilution-normotension, hemodilution was established, and MAP was maintained at 131 +/- 9 mmHg with phenylephrine; 4) hemodilution-hypertension, hemodilution was established, and MAP increased to 161 +/- 2 mmHg with phenylephrine. Brain injury was determined with 2,3,5-triphenyltetrazolium chloride, and cerebral edema was assessed by microgravimetry. Brain injury and cerebral edema were less in both phenylephrine groups, compared with the control and hemodilution groups (P less than 0.05). These results are consistent with the premise that if normotension is maintained, hemodilution reduces ischemic brain injury and edema. They also indicate that the addition of phenylephrine-induced hypertension to hemodilution therapy results in a further reduction of ischemic injury without exacerbating cerebral edema.
Halothane anesthesia causes active flow-independent pulmonary vasoconstriction
Authors: Chen B. B. , Nyhan D. P. , Fehr D. M. , Goll H. M. , Murray P. A.
Published: December 2017

We utilized multipoint pulmonary vascular pressure-flow (P/Q) plots to investigate the effects of halothane anesthesia on the pulmonary circulation. Our first objective was to assess the extent to which the P/Q relationship measured in conscious dogs is altered during halothane anesthesia. P/Q plots were constructed by stepwise constriction of the thoracic inferior vena cava to decrease venous return and Q. Compared with conscious dogs, halothane (approximately 1.2% end-tidal) resulted in active, flow-independent pulmonary vasoconstriction (P less than 0.01) at all levels of Q. Halothane also decreased (P less than 0.01) systemic arterial pressure and Q. Thus our second objective was to determine whether the halothane-induced pulmonary vasoconstriction was mediated by reflex neurohumoral activation or by metabolites of the cyclooxygenase pathway. However, the magnitude of halothane-induced pulmonary vasoconstriction was not significantly reduced by sympathetic alpha-adrenoreceptor block, angiotensin converting-enzyme inhibition, combined arginine vasopressin V1 + V2 receptor block, or by cyclooxygenase inhibition. Finally, halothane-induced pulmonary vasoconstriction (P less than 0.01) was also observed when compared with pentobarbital-anesthetized dogs during controlled ventilation. Thus, compared with the conscious state, halothane anesthesia causes active flow-independent pulmonary vasoconstriction that is not mediated by reflex neurohumoral activation, by metabolites of the cyclooxygenase pathway, nor is it due to the effects of general anesthesia and controlled ventilation.
Calculated intra- and extracellular PO2 gradients in heavily working red muscle
Authors: Groebe K. , Thews G.
Published: December 2017

A recently introduced three-dimensional analytical model of O2 diffusion to heavily working muscle that considers myoglobin-facilitated O2 diffusion inside the muscle fiber and a carrier-free layer separating erythrocytes and fiber is able to furnish the following new insights in O2 supply to red muscle at high performance. 1) Fiber PO2 profiles are essentially flat, and the major PO2 gradients are located in the perierythrocytic region, in good agreement with experimental findings [T. E. J. Gayeski and C. R. Honig, Am. J. Physiol. 251 (Heart Circ. Physiol. 20): H789-H799, 1986]. No specialized anatomical pericapillary barrier structure is required to explain these results. 2) A functional barrier to O2 diffusion has been identified that consists of the carrier-free layer and of the pericapillary muscle fiber portions. There are three reasons that make these structures act as a diffusion barrier: a “geometric reason,” a “diffusivity-related reason,” and a “myoglobin-related reason.” 3) PO2 fields of adjacent red blood cells (RBCs) practically do not interact. 4) Small scale heterogeneities in capillary and RBC spacing are compensated for by high myoglobin-facilitated fiber diffusivity. Limiting factor for diffusional O2 transport is the number of RBCs present on the fiber surface.
Fetal blood volume restoration following rapid fetal hemorrhage
Authors: Brace R. A. , Cheung C. Y.
Published: December 2017

In a previous study, we found that ovine fetal blood volume returned to normal in 3 h after a slow hemorrhage of 31% over 2 h; volume was slightly elevated at 24-25 h. In the present study, we explored the time required for blood volume restoration in late gestation fetal sheep following a rapid hemorrhage over 10 min. The rate of hemorrhage was constant within each fetus but varied among fetuses from 13.5 to 32.2%. Two fetuses that were hemorrhaged 32% of their initial blood volume over 10 min underwent cardiovascular collapse during the hemorrhage. In 10 fetuses that were hemorrhaged 21.0 +/- 1.7% (SE) over 10 min, 6.5 h were required for blood volume to return to control. Fetal arterial pressure, venous pressure, and heart rate decreased during and immediately after the hemorrhage and returned to normal within 1 h. Plasma arginine vasopressin (AVP) concentration and plasma renin activity (PRA) underwent large increases following the rapid hemorrhage. Volume restoration at 5-7 h posthemorrhage correlated negatively with PRA and norepinephrine (NE) concentration immediately after the hemorrhage. Three of the 10 fetuses died overnight, and in the remaining seven fetuses blood volume was 8.8 +/- 3.3% below control (P less than 0.01) at 24-25 h posthemorrhage. The fetuses were also hypoxic, acidotic, and had greatly elevated plasma AVP and NE concentrations at this time. We conclude that ovine fetuses are less able to survive a rapid hemorrhage compared with a slow hemorrhage of the same extent. In addition, fetal blood volume restoration is delayed after rapid hemorrhage, and the impaired restoration is to the detriment of the fetus.(ABSTRACT TRUNCATED AT 250 WORDS)
Coronary flow by left atrial and left ventricular microsphere injection in the rat
Authors: Schrock G. D. , Krahmer R. L. , Ferguson J. L.
Published: December 2017

Previous studies have reported significantly higher variability in coronary blood flow (CBF) measurements obtained by microsphere injection into the left ventricle (LV) as compared with microsphere injection into the left atrium (LA) of the rat. Questions have arisen concerning whether or not some of the variability may have been due to successive rather than simultaneous injections at the two sites, thereby giving measurements at different cardiovascular states. To address this question, we measured cardiac output (CO) and CBF as well as other systemic organ blood flows by employing simultaneous injection of two different sets of radiolabeled microspheres into the left atrium and left ventricle of semiconscious rats. Using this technique, CBF values (ml.min-1.g-1) of 5.45 +/- 0.43 and 5.24 +/- 0.46 for LA and LV injection sites, respectively, were measured (all values reported as means +/- SE). CO values (ml/min) of 67.5 +/- 3.5 for LA and 67.6 +/- 3.4 for LV were obtained. Paired left atrial and left ventricular measurements of CBF, CO, and other systemic organ blood flows using tracer microsphere methodology were not significantly different. All variabilities in these measurements by LA and LV injection were not significantly different. Our procedure did not significantly alter physiological parameters such as heart rate, mean arterial pressure, hematocrit, or blood gases. These findings indicate that, in our rat model, measurements made by LV microsphere injection are not only adequate for determining systemic blood flow at distal beds but provide coronary blood flow data with variability not significantly different from that of left atrial injection.
Functional anatomical site of intramural collaterals in dogs
Authors: Scheel K. W. , Daulat G. , Williams S. E.
Published: December 2017

The objectives of the present study were to determine quantitatively whether the retrograde flow measurement reflects the total flow from collateral vessels or overestimates or underestimates collateral flow, and to determine the functional anatomical origin of intramural collaterals in the native dog heart. In an isolated heart preparation, three experimental procedures were used. 1) The left circumflex coronary artery was embolized with microspheres of different sizes; then retrograde flows and the peripheral coronary pressures were measured. 2) Epicardial collaterals were cauterized, and retrograde flows were measured before and after cautery. 3) Epicardial collaterals were cauterized followed by embolization of the circumflex coronary artery with different size spheres. We found that 1) the retrograde flow measurement underestimates the total collateral flow to the circumflex coronary artery by approximately 25%, 2) intramural collateral flow constitutes 58 +/- 3.5% of the retrograde flow measurement, 3) the antegrade component of blood flow that is not measured during a retrograde flow measurement is from the intramural collateral circulation, and 4) the functional site of origin of intramural collaterals is greater than 25 microns but less than 80 microns in diameter. We conclude that, in our preparation, retrograde flow underestimates total collateral flow, and that intramural collateral flow is a major component of retrograde flow in the native dog heart.
Cyclooxygenase blockade attenuates responses of group IV muscle afferents to static contraction
Authors: Rotto D. M. , Hill J. M. , Schultz H. D. , Kaufman M. P.
Published: December 2017

Cyclooxygenase products of arachidonic acid might be some of the substances that accumulate in contracting muscle to cause the reflex increases in arterial pressure and ventilation that are evoked by exercise. Recently, cyclooxygenase blockade has been shown to attenuate the reflex cardiovascular responses to static muscular contraction in anesthetized cats. Group IV afferents are believed to comprise part of the afferent arm of the reflex arc, the activation by which static muscular contraction causes these cardiovascular effects. We therefore examined the effects of indomethacin and aspirin, two cyclooxygenase-blocking agents, on the responses to static contraction of group IV afferents with endings in the triceps surae muscles of anesthetized cats. We found that indomethacin (5 mg/kg iv) decreased the responses to contraction of each of eight group IV afferents tested. Likewise, aspirin (50 mg/kg iv) decreased the responses to contraction of each of four group IV afferents tested. On the other hand, we found that arachidonic acid (2 mg) injected into the femoral artery did not increase the responses to contraction of four group IV afferents that were stimulated by this maneuver. In addition, arachidonic acid injection did not cause any of seven group IV afferents not stimulated by static contraction to become responsive to this maneuver. Nevertheless, arachidonic acid injection with the muscle at rest stimulated five of seven contraction-insensitive and two of four contraction-sensitive group IV afferents. Our data suggest that cyclooxygenase metabolites of arachidonic acid are needed for the full expression of the responses of group IV muscle afferents to static contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
Inosine transiently decreases coronary flow but potentiates vasodilation by adenosine
Authors: Van der Meer P. , de Jong J. W.
Published: December 2017

To test whether inosine interferes with the action of adenosine, we investigated the effects of intracoronary administration of inosine, adenosine, 8-phenyltheophylline, and adenosine deaminase on isolated rat heart. Inosine did not change heart rate or developed tension but increased the effluent adenosine concentration. Inosine also decreased exogenous adenosine uptake and breakdown. After the start of the inosine infusion (20 microM), a transient 30% decrease of coronary flow took place within 0.5 min. The nucleoside caused sustained vasodilation, dependent on the concentration (30-400 microM). After the infusion we observed a transient vasodilation. A nonvasoactive inosine concentration (10 microM) combined with an adenosine concentration that increased flow by 60% (0.1 microM) raised vasodilation by another 60%. Infusion of adenosine, adenosine deaminase, or 8-phenyltheopylline did not influence the inosine-induced transient decrease of flow, suggesting that this decrease is independent of adenosine and its receptor. We conclude that inosine 1) potentiates the vasodilation induced by adenosine and 2) is a coronary vasodilator but probably also a vasoconstrictor.
Effects of acute coronary artery occlusion on the coronary microcirculation
Authors: Dellsperger K. C. , Janzen D. L. , Eastham C. L. , Marcus M. L.
Published: December 2017

The exact microvascular site of coronary vasodilation after coronary artery occlusion has not been clearly established. We sought to determine 1) the microvascular site of recruitable vasodilator reserve after a critical stenosis as assessed by adenosine and EDTA, 2) the coronary microvascular site responsible for vasodilatation after total coronary artery occlusion, and 3) the microvascular site for recruitable vasodilator reserve after coronary artery occlusion as assessed by adenosine and EDTA. Hemodynamics and coronary epicardial microvascular diameter were measured in 33 dogs by means of intravital epiillumination microscopy at control conditions, during a critical stenosis, or 30, 60, and 120 min following coronary artery occlusion. To evaluate the site of pharmacologically recruitable vasodilator reserve, EDTA or adenosine was suffused onto the epicardial surface. After a critical stenosis EDTA dilated all sizes of microvessels, whereas adenosine only dilated small microvessels (less than 150 microns). After coronary artery occlusion there was vasodilation that was inversely proportional to the control microvascular diameter. Coronary microvascular diameter did not change during 2 h after coronary artery occlusion. In addition, intravenous or topically applied adenosine or topically applied EDTA had no additional effect on the coronary arteriolar diameter. We concluded that in response to sudden coronary artery occlusion, the coronary microvascular dilation was inversely related to the control microvascular diameter, and in contrast to the response after a critical stenosis, there was no pharmacologically recruitable vasodilator reserve to adenosine or EDTA following acute coronary artery occlusion.
Connections between hypothalamus and medullary reticular formation mediate coronary vasoconstriction
Authors: Gutterman D. D. , Bonham A. C. , Gebhart G. F. , Marcus M. L. , Brody M. J.
Published: December 2017

We have recently identified discrete sites within the lateral hypothalamus and medullary reticular formation that, when stimulated electrically, produce neurally mediated coronary vasoconstriction. This study examined whether these sites are part of the same coronary vasomotor pathway. The neuronal tracing dye fast blue was injected in cats into the coronary vasoconstrictor site within medullary reticular formation. Fluorescence microscopy revealed major afferent projections originating from within the same region of midbrain ventrolateral periaqueductal gray that receives projections from lateral hypothalamus. To determine the functional importance of the proposed connections between the hypothalamic and medullary sites, anesthetized cats were prepared for continuous hemodynamic measurements. Constant current electrical stimulation within lateral hypothalamus produced significant increases in heart rate (21 +/- 6%), arterial pressure (11 +/- 3%), and femoral (36 +/- 18%) and coronary resistances (14 +/- 9%) with no change in coronary flow velocity (-1.1 +/- 2.5%). After beta-adrenoreceptor blockade, significantly greater increases in arterial pressure (35 +/- 8%) and coronary resistance (39 +/- 5%) with transient decreases in coronary flow velocity (21 +/- 6%) were seen. Microinjections of lidocaine into the medullary site blocked coronary constriction produced by lateral hypothalamic stimulation (39 +/- 5% increase in coronary resistance to electrical stimulation before and 2.4 +/- 2% increase after lidocaine in medullary reticular formation). These data provide evidence that specific regions of lateral hypothalamus and medullary reticular formation are part of a common central vasomotor projection that mediates coronary vasoconstriction in addition to other hemodynamic effects.
Activation of furosemide-sensitive K+ fluxes in myocytes by ouabain and recovery from metabolic inhibition
Authors: Kohmoto O. , Krueger J. A. , Barry W. H.
Published: December 2017

Modulation of transsarcolemmal K+ flux mediated by the furosemide-sensitive K(+)-Cl- (or Na(+)-K(+)-Cl-) cotransport carrier was studied in cultured chick embryo ventricular cells. We defined at least three distinct K+ efflux pathways: 1) a Ba2(+)-sensitive efflux component, probably reflecting K+ movement through K+ channels; 2) a furosemide-sensitive component, reflecting K(+)-Cl- cotransport; and 3) a component insensitive to both Ba2+ and furosemide. With respect to K+ influx, there were 1) a ouabain-sensitive K+ uptake presumably mediated by Na(+)-K(+)-adenosinetriphosphatase and 2) a furosemide-sensitive K+ uptake. The effects of elevation of intracellular calcium concentration ([Ca2+]i) on Ba2+ and furosemide-sensitive K+ flux pathways were studied. Elevation of [Ca2+]i had minor effects on Ba2(+)-sensitive K+ flux. However, elevation of [Ca2+]i produced by exposure to ouabain for 60 min activated a furosemide-sensitive 42K+ efflux and a ouabain-resistant, furosemide-sensitive 42K+ influx. The activation of K+ influx, caused by an increase in [Ca2+]i, was completely inhibited by ATP depletion (produced by exposure to ouabain and metabolic inhibitors simultaneously) and was partially inhibited by the calmodulin inhibitor W7. Activation of the furosemide-sensitive K+ flux was also produced by washout of metabolic inhibitors, a condition in which ATP resynthesis occurs in the presence of an increased [Ca2+]i. Activation of furosemide-sensitive K+ fluxes by exposure to ouabain or washout of metabolic inhibitors caused a net K+ loss, which accounts in part for the cell shrinkage noted during recovery from metabolic inhibition in previous studies. These results suggest that [Ca2+]i and intracellular ATP concentration are important in the regulation of furosemide-sensitive K+ flux in these cells, perhaps via the involvement of a Ca2(+)-calmodulin-dependent protein kinase.
Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway
Authors: Julou-Schaeffer G. , Gray G. A. , Fleming I. , Schott C. , Parratt J. R. , Stoclet J. C.
Published: December 2017

The involvement of L-arginine-dependent nitric oxide (NO) production in the vascular failure observed in endotoxemia was investigated in male Wistar rats treated with Escherichia coli lipopolysaccharide (LPS). Contractile responses to norepinephrine (NE) were measured ex vivo in aortas isolated from rats treated with LPS (20 mg/kg ip, 4 h before experiments) and pressor responses to NE were recorded in vivo in rats infused with LPS (5 mg.kg-1.h-1 iv). LPS pretreatment induced a rightward shift of the concentration-response curve to NE and a reduction of the maximal contraction by approximately 43% and 54% (P less than 0.05) in aortic rings with and without functional endothelium, respectively. This was not modified by the presence of indomethacin (10 microM) during the contractile experiments. In contrast, in the presence of NG-monomethyl-L-arginine (L-NMMA, 300 microM) or methylene blue (10 microM), maximal contractions to NE were restored to control values whether functional endothelium was present or not. The effects of L-NMMA were reversed by L- but not by D-arginine. Additionally, the effects of LPS pretreatment on vascular contractility were potentiated by L-arginine. In vivo, LPS infusion produced a reduction in pressor responsiveness to NE (0.1-10 mg/kg), which was also abolished by L-NMMA (30 mg/kg iv). This effect of L-NMMA was reversed by L- but not by D-arginine (100 mg/kg iv). These results demonstrate that activation of the L-arginine pathway has a major role in the production of vascular hyporeactivity in endotoxemia, ex vivo as well as in vivo. Additionally, they suggest that endothelium-independent vascular production of NO may be involved.
Effect of acidosis on contractile system in skinned fibers of hypertrophied rat heart
Authors: Kimura S. , Bassett A. L. , Furukawa T. , Furukawa N. , Myerburg R. J.
Published: December 2017

Hypertrophied hearts have enhanced susceptibility to ischemia-induced contractile dysfunction. To explore the mechanisms of this phenomenon, we studied the effect of acidosis on the Ca2+ sensitivity of the contractile proteins and on Ca2+ accumulation by the sarcoplasmic reticulum (SR) in chemically (saponin) skinned cardiac fibers obtained from normal and pressure-overloaded hypertrophied rat left ventricles. Left ventricular pressure overload was induced by partial ligation of the abdominal aorta 6-8 wk before study. Age- and weight-matched normal rats served as controls. Pressure overload increased the left ventricular weight-to-body weight ratio by 48%. Reduction in pH shifted the pCa-tension curve to the right similarly in normal and hypertrophied preparations, and there was no difference in pCa-tension relationship at pH 7.0 or 6.5 between the two groups. However, reducing the pH of 1 microM Ca2(+)-loading solution from 7.0 to 6.5 decreased the amount of Ca2+ accumulated in the SR to 66.2 +/- 3.0% in normal fibers and 43.2 +/- 4.0% in hypertrophied fibers (P less than 0.01). We conclude that the enhanced susceptibility of hypertrophied hearts to ischemia-induced diastolic dysfunction may be partly explained by the greater depressing effect of acidosis on Ca2+ accumulation by the SR.
Quantitative and autoradiographic analyses of alpha-adrenergic and serotonergic receptors on aorta and coronary artery
Authors: Tsutsui H. , Tomoike H. , Nakamura M.
Published: December 2017

Norepinephrine, epinephrine, and 5-hydroxytryptamine (5-HT) modulate the vascular tone via specific receptors on the vascular wall. Binding characteristics and localization of alpha-adrenergic and serotonergic receptors were determined in porcine aortas and coronary arteries. Radioligand binding studies were done using frozen sections of vascular tissue (10 microns thick), and the obtained data were compared with findings on microsomal fractions prepared from smooth muscle cells. Affinities [dissociation constant (Kd)] of 125I-labeled 2-[beta-(4-hydroxyphenyl)-ethylaminomethyl]-tetralone (BE 2254), an alpha 1-antagonist, for alpha-adrenergic receptors on aortic and coronary microsomal fractions were 190 and 224 pM, respectively. The Kd of 125I-labeled lysergic acid diethylamide (LSD), a serotonergic antagonist, to serotonergic receptors on the aorta was 403 pM, a value less than that obtained for the coronary artery (873 pM, p less than 0.01). The Kd of 125I-BE 2254 on tissue sections from the aorta was 164 pM and did not significantly differ from that obtained for microsomal fractions. Inhibition constants of adrenergic agonists and antagonists for specific 125I-BE 2254 binding on aortic sections were identical with those obtained for microsomal fractions. Receptor densities examined by 125I-BE 2254 and 125I-LSD were higher in the aorta than in the coronary artery. 125I-BE 2254 bound specifically to alpha 1-adrenergic and 125I-LSD to 5-HT1-like receptors. Radiodensities of 125I-BE 2254 and 125I-LSD were homogeneous macroscopically across the aortic media. Silver grains distributed homogeneously over the smooth muscle cells across the media. There was no accumulation of silver grains to the intima.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of atrioventricular relationship on ventricular refractoriness in humans
Authors: Kadish A. H. , Kou W. H. , Schmaltz S. , Morady F.
Published: December 2017

Right ventricular refractory periods obtained using atrial and ventricular pacing with an atrioventricular (AV) interval of 160 ms were compared with those obtained with an AV interval of 0 ms in a group of 53 patients. The mean right ventricular effective refractory periods were longer at an AV interval of 160 ms than at an AV interval of 0 ms at pacing cycle lengths of 600 (mean 2.5 +/- 1.8 ms difference) and 400 ms (mean 3.8 +/- 2.4 ms difference; P less than 0.01). In a subset of 10 patients, left ventricular volumes measured by two-dimensional echocardiography demonstrated that pacing with an AV interval of 160 ms was associated with a higher end-diastolic volume and stroke volume than pacing with an AV interval of 0 ms (P less than 0.001). Autonomic blockade did not alter the relationship between AV interval and ventricular refractoriness. We conclude that 1) right ventricular refractory periods are shorter at an AV interval of 0 ms than at an AV interval of 160 ms; 2) these differences are not caused by changes in autonomic tone but are associated with differences in ventricular volumes; and 3) if precise determinations of ventricular refractoriness are desired, then the timing of atrial systole should be controlled by atrial pacing.
Enhancement of red cell washout from blood clots by alteration of gel pore size and red cell flexibility
Authors: Carr M. E. , Hauge Y.
Published: December 2017

Plasma clots formed in the presence of erythrocytes have pores large enough to allow significant perfusion induced washout of red cells. Erythrocyte washout is a function of gel pore size and erythrocyte flexibility. This study evaluated the possibility of increasing cell washout by enhancing gel pore size and/or erythrocyte flexibility. Addition of increasing concentrations of Dextran 40 resulted in gels composed of large fibers with large intervening pores. Gel fiber mass-to-length ratios increased from 2.6 to 8.1 x 10(13) Da/cm as Dextran 40 concentration increased from 0 to 12 mg/ml. Over the same dextran concentration range, perfusion measurements revealed an increase in gel pore diameter from 1.4 to 3.5 x 10(-4) cm and an increase in erythrocyte washout from 8.2 to 30.4% during a 1.5 gel volume exchange. Pentoxifylline was added to blood to enhance erythrocyte flexibility. Whereas turbidity measurements indicated minimal direct impact of pentoxifylline (50 micrograms/ml) on fibrin assembly or structure, perfusion measurements indicated an increase in erythrocyte washout from 8.1 to 13.4% after a 1.5 gel volume exchange. Efforts to evaluate pentoxifylline effects at higher concentrations were hampered by decreased adhesion of the gel to the sides of the perfusion chamber. These results indicate that it may be possible to enhance erythrocyte washout and thereby increase diffusion and perfusion of materials through in situ clots.
Coronary and myocardial adaptations to high altitude in dogs
Authors: Scheel K. W. , Seavey E. , Gaugl J. F. , Williams S. E.
Published: December 2017

The objective of this study was to determine whether exposure to high altitude (hypoxic hypoxemia) induces coronary and/or collateral growth. Fourteen mongrel dogs were maintained at a simulated altitude of 18,000 ft for 1 mo and 7 dogs maintained for 3 mo. Within 2 days after their sojourn, the following data were obtained at ambient pressure: pulmonary, right heart chamber, and wedge pressures as well as cardiac output. On an isolated heart preparation, coronary and collateral flows were determined; each vessel was injected with a different color tracer; and the heart was sliced, separated by perfusion territories, and examined for myocardial hypertrophy. We found that pulmonary artery pressures in altitude-adapted animals were higher compared with controls, and coronary flow per gram was increased after 1 mo of exposure but not different from control after 3 mo. Collateral flows were not significantly different from that of control animals, and biventricular hypertrophy occurred with right ventricular dominance. Comparing these results with those that we obtained previously from anemic animals, we favor the hypothesis that oxygen availability rather than blood flow velocity is most likely linked to vascular growth.
Vascular mechanics of venous drainage in dog hindlimbs
Authors: Magder S.
Published: December 2017

The time constant of venous drainage (tau v) of a vascular bed is an important determinant of the change in regional volume that will occur with a change in blood flow or venous pressure (Pv). Therefore, to measure tau v of the dog hindlimb, the vasculature was isolated and perfused with a pump. Inflow and outflow were measured with electromagnetic flow probes. Blood volume was changed (delta V) by changing flow (delta Q), and a double-occlusion procedure was used to obtain the venous elastic recoil pressure (Pel) from the plateau of Pv. Venous resistance (Rv), compliance (Cv), and tau v could then be calculated. Rv was 7.7 +/- 1.4 mmHg.ml-1.min.100 g-1 and Cv was 0.59 +/- 0.25 ml/mmHg, tau v calculated from the product of Rv and Cv was 4.20 +/- 1.58 s and from the ratio of delta V to delta Q was 4.95 +/- 1.53 s (P = NS) at a mean Pel of 17.6 +/- 3.7 mmHg. delta V was also produced by changing Pv; the average tau v (1.95 +/- 0.37 s), was shorter than that with changes in flow. Finally, a ramp increase in flow was used to calculate tau v from the time delay between inflow and outflow. tau v by this method was longer (6.06 +/- 1.70 s) and was probably influenced by the change in Pv. In conclusion, the hindlimb has a short tau v of venous drainage and would not be expected to store large volumes of blood even with large increases in blood flow.
L-arginine-dependent vascular smooth muscle relaxation and cGMP formation
Authors: Gold M. E. , Wood K. S. , Byrns R. E. , Buga G. M. , Ignarro L. J.
Published: December 2017

The objective of this study was to ascertain whether endothelium-dependent relaxation and guanosine 3',5'-cyclic monophosphate (cGMP) formation in bovine pulmonary artery are dependent on L-arginine. Arterial rings responded to acetylcholine and A23187 with increased cGMP accumulation and relaxation and showed resting L-arginine levels of approximately 300 microM. Addition of L-arginine failed to cause relaxation or cGMP accumulation. Arterial rings incubated under tension at 37 degree C for 24 h showed a three- to fourfold decline in L-arginine levels, and this decline was accompanied by a similar decline in resting cGMP levels as well as complete refractoriness to endothelium-dependent relaxation and cGMP formation in response to acetylcholine and A23187, without alteration of responsiveness to nitric oxide, s-nitrosothiols, or nitroglycerin. The endothelium in 24-h incubated arterial rings was normal morphologically, as assessed by scanning electron microscopy. L-Arginine caused endothelial-dependent relaxation and cGMP formation in L-arginine-depleted rings, which was antagonized by oxyhemoglobin and methylene blue. Bovine aortic endothelial cells grown in L-arginine-deficient medium supplemented with D-arginine during the final 24 h of growth failed to generate endothelium-derived nitric oxide, as assessed by bioassay cascade. L-Canavanine, but not L-lysine or L-ornithine, protected against the decline in L-arginine and cGMP levels and loss of endothelium-dependent relaxation that was characteristic of 24-h incubated arterial rings. The pharmacological properties of L-arginine were shared by L-arginine ethyl ester, L-arginine methyl ester, and L-homoarginine but not N-alpha-benzoyl-L-arginine ethyl ester or L-canavanine. These observations indicate that L-arginine or a structural analogue may be obligatory for endothelium-dependent relaxation and cGMP formation.
Iron-mediated radical reactions upon reperfusion contribute to myocardial "stunning"
Authors: Bolli R. , Patel B. S. , Jeroudi M. O. , Li X. Y. , Triana J. F. , Lai E. K. , McCay P. B.
Published: December 2017

Recent evidence suggests that postischemic myocardial dysfunction ("stunning") is mediated by iron-catalyzed free radical reactions, but the exact time window during which the critical iron-mediated damage develops remains unknown. Furthermore, the evidence that iron promotes free radical reactions in vivo is indirect. Thus open-chest dogs undergoing a 15-min coronary occlusion and 4 h of reperfusion were given one of the following intracoronary infusions: desferrioxamine (DF) beginning 2 min before reperfusion (group I), DF beginning 1 min after reperfusion (group II), iron-loaded DF in dosage identical to group I (group III), or vehicle (controls, group IV). Recovery of contractile function was substantially greater in group I than in controls, whereas in groups II and III it was indistinguishable from controls. To determine whether the protection afforded by DF was due to inhibition of free radical reactions, myocardial production of free radicals was directly assessed by intracoronary infusion of the spin trap alpha-phenyl N-tert-butyl nitrone (PBN). In controls (group VI), radical adducts of PBN were released in the coronary venous blood after reperfusion. DF given as in group I (group V) markedly suppressed myocardial production of PBN adducts. These results strongly suggest that a substantial portion of the damage responsible for myocardial stunning is caused by iron-catalyzed free radical reactions that develop in the initial seconds of reperfusion and can be prevented by administration of iron chelators started just before reflow. Furthermore, the results demonstrate that attenuation of postischemic dysfunction by DF is associated with attenuation of free radical reactions in vivo, thereby providing direct evidence for a pathogenetic role of iron-catalyzed free radical reactions in myocardial stunning in the intact animal.
Phosphorylated compounds and function in isolated hearts: a 31P-NMR study
Authors: Aussedat J. , Ray A. , Lortet S. , Reutenauer H. , Grably S. , Rossi A.
Published: December 2017

The potential role of phosphorylated compounds in the control of myocardial cell respiration was investigated by means of 31P-nuclear magnetic resonance (NMR) spectroscopy. Isolated isovolumic rat hearts, perfused with a 9 mM glucose, 2 mM pyruvate medium at a constant beating rate (6 Hz) and temperature (37 degrees C), were subjected to changes in work load by varying the calcium concentration ([Ca2+]) in the perfusion fluid from 0.5 to 1.0, 1.5, or 2.0 mM. Each change in left ventricular developed pressure (LVDP) induced by the [Ca2+] change was accompanied by alterations in the inorganic phosphate-to-creatine phosphate ratio ([Pi]/[PCr]), with the ATP level remaining constant. The relationship between [Pi]/[PCr] and LVDP followed a Michaelis-Menten pattern with an apparent Michaelis constant (Km) of 0.09 and a maximal LVDP of 91 mmHg. This Km corresponded to intracellular concentrations of 1.2 mM for Pi and 13.0 mM for PCr. The calculated [ADP] and phosphorylation potential corresponding to these values were 44 microM and 151,000 M-1, respectively. All these values are close to those estimated under in situ physiological conditions. These results support the assumption that in the rat heart, as in skeletal muscle, mitochondrial activity could be controlled by changes in phosphorylated compound concentrations under normoxic conditions.
Contrasting preganglionic and postganglionic effects of phenylephrine on parasympathetic control of heart rate
Authors: Pardini B. J. , Lund D. D. , Schmid P. G.
Published: December 2017

Previous reports indicate that alpha-adrenergic agonists modulate vagal control of heart rate. In the rat, phenylephrine inhibition of vagal-stimulated bradycardia may be occurring at any of a number of sites along the cardiac parasympathetic pathway. The purpose of the present experiments was to localize the pre- or postganglionic sites of phenylephrine modulation of parasympathetic-mediated bradycardia in the rat. Sprague-Dawley rats were anesthetized and instrumented with arterial and venous catheters and electrocardiographic leads. The cervical vagi were sectioned, and propranolol was administered. The right cervical vagus nerve was electrically stimulated to activate preganglionic parasympathetic nerves. Carbachol was injected to activate nicotinic receptors on postganglionic parasympathetic nerves (i.e., intracardiac ganglion cells). Methacholine was injected to activate muscarinic receptors at the sinoatrial node. The heart rate responses to these three interventions were recorded before, during, and after phenylephrine infusion. Phenylephrine significantly attenuated the bradycardia produced by vagal nerve stimulation. In contrast, phenylephrine facilitated the bradycardia elicited by carbachol injection. Since carbachol has both muscarinic and nicotinic effects, the results were compared with those obtained from methacholine, a pure muscarinic agonist. Phenylephrine had no effect on methacholine-induced bradycardia, suggesting that the modulation of the carbachol response was through carbachol's nicotinic effects. Yohimbine, the alpha 2-receptor antagonist, eliminated phenylephrine-mediated facilitation of the carbachol response. These data indicate that phenylephrine has contrasting effects on pre- and postganglionic cardiac parasympathetic nerves in rats: inhibition at preganglionic sites (vagal stimulation results) and facilitation at the level of the ganglion cells (carbachol experiments).
Effects of ANP, angiotensin, vasopressin, and endothelin on ANP receptors in cultured rat vascular smooth muscle cells
Authors: Schiffrin E. L. , Turgeon A. , Tremblay J. , Deslongchamps M.
Published: December 2017

Some evidence suggests homologous and heterologous regulation of atrial natriuretic peptide (ANP) receptors. We have examined the effects of exposure to ANP, angiotensin II (ANG II), arginine vasopressin (AVP), and endothelin (ET), on binding of ANP to cultured rat vascular smooth muscle cells (VSMC) and on guanylate cyclase-coupled and -uncoupled ANP receptors. The latter were studied by examining production of guanosine 3',5'-cyclic monophosphate (cGMP) in response to ANP and binding of ANP to Triton X-100-solubilized VSMC membranes, irreversible cross-linking with disuccinimidyl suberate, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in presence of dithiothreitol, followed by radioautography. Exposure to 100 nmol/l ANP for 18 h reduced ANP sites to 43% of control. However, if acid wash of VSMC membranes at pH 5.0 was performed before binding, no decrease in density of ANP binding sites was detected. On SDS-PAGE, a 130-kDa band bound 42 vs. 46% of 125I-labeled ANP in acid-washed membranes from control vs. cells exposed to ANP; the remainder was bound to a 67-kDa band. ANG II (100 nmol/l), AVP (1 mumol/l), or ET-1 or ET-3 (100 nmol/l) did not produce changes in density of ANP sites or in binding to the 130- and 67-kDa bands. cGMP production in response to ANP showed exaggerated response in ANG II but not in AVP- or ET-treated VSMC. Effect of ANG II was abolished by the ANG II antagonist [Sar1-Ile8]ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)
Combined effects of age and dietary fat on beta 1-receptors and Ca2+ channels in rat hearts
Authors: Gudmundsdottir E. , Benediktsdottir V. E. , Gudbjarnason S.
Published: December 2017

Male Wistar rats were fed a standard diet or diets supplemented with 10% butter, 10% corn oil, or 10% cod liver oil from the age of 2 mo. At 7 and 24 mo of age, the fatty acid composition of total phospholipids was determined in ventricular crude sarcolemma preparations; binding capacity and affinity (1/Kd) of [3H]dihydroalprenolol and [3H]nitrendipine binding were also determined. The arachidonic acid level was significantly higher at 24 mo than at 7 mo of age in the membrane phospholipids in rats fed no extra fat, but in rats fed fat-supplemented diets, age had no effect. Affinity of Ca2+ channels for [3H]nitrendipine decreased significantly in all dietary groups between 7 and 24 mo of age, whereas the affinity of beta 1-receptors for [3H]dihydroalprenolol increased in corn oil-fed rats. Density of beta 1-receptors decreased significantly in corn oil- and butter-fed rats and rats fed no extra fat between 7 and 24 mo of age, whereas the density of Ca2+ channels decreased significantly in corn oil-fed rats. We conclude that the antagonist binding properties of Ca2+ channels and beta 1-adrenergic receptors in rat hearts may change with age depending on the dietary fat.
Temporary contractile blockade prevents hypercontracture in anoxic-reoxygenated cardiomyocytes
Authors: Siegmund B. , Klietz T. , Schwartz P. , Piper H. M.
Published: December 2017

Reoxygenation after 120-min substrate-free anoxia causes sudden hypercontracture in isolated rat cardiomyocytes. Reoxygenated-hypercontracted cardiomyocytes maintain their sarcolemmal integrity as indicated by the absence of enzyme release and reestablish a nearly normal free energy change of ATP hydrolysis within 15 min [Siegmund, B., A. Koop, T. Klietz, P. Schwartz, and H. M. Piper.Am J. Physiol. 258 (Heart Circ. Physiol. 27): H285-H291, 1990]. In the same model, it was now investigated whether a temporary contractile blockade by 20 mM 2,3-butanedione monoxime (BDM) can prevent reoxygenation-induced hypercontracture. When BDM was present during 120-min anoxia and the subsequent 15-min reoxygenation, hypercontracture could be prevented. The anoxic changes of high-energy phosphate contents, the free energy change of ATP hydrolysis, and the ultrastructure of the cells remained unaffected by the presence of BDM. When BDM was applied anoxically immediately before reoxygenation, it also prevented hypercontracture. Contracture still remained absent when BDM was washed out after the first 15 min of reoxygenation. These results demonstrate that a temporary contractile blockade (15 min) at the onset of reoxygenation prevents hypercontracture in anoxic-reoxygenated cardiomyocytes. This result, the energetic recovery, and the sarcolemmal integrity of cardiomyocytes in anoxia-reoxygenation demonstrate that reoxygenation-induced hypercontracture is not based on an already irreversible cell damage.
Estimated time course of Ca2+ bound to troponin C during relaxation in isolated cardiac muscle
Authors: Peterson J. N. , Hunter W. C. , Berman M. R.
Published: December 2017

We present a mechanical assay for estimating the time course of Ca2+ bound to low-affinity sites on troponin C (TnC) in twitching rabbit papillary muscle. The assay is based on a theoretical correlation between the rate of force redevelopment after detachment of all cross-bridges and the amount of Ca2+ bound to TnC. Experimentally, we applied length impulses at different times to detach all cross-bridges; the initial rate of force redevelopment after each impulse was taken as an index of bound Ca2+ at that time. Under control conditions, the magnitude of this index decreased to 10% of its maximum during early relaxation, when force had declined only slightly 78 +/- 12% of its peak isometric value. The time course of this index was examined after addition of either isoproterenol or ryanodine, which are known to shorten and prolong, respectively, the intracellular free Ca2+ transient. As expected, changes previously reported in the free Ca2+ time course were qualitatively reflected in the time course of the bound Ca2+ index. We conclude that this index constitutes a reasonable method for estimating the time course of bound Ca2+ and that bound Ca2+ declines well ahead of force in isometrically contracting rabbit myocardium at 24 degrees C.
Temperature dependence of sodium current block by lidocaine in cardiac Purkinje cells
Authors: Makielski J. C. , Falleroni M. J.
Published: December 2017

Cardiac Na current block by antiarrhythmic drugs has usually been studied at lower than physiological temperatures to achieve adequate voltage control, but the effect of temperature on block is not well characterized. Using a large suction pipette, we studied the effect of 50 microM lidocaine on blocking peak Na current between 10 and 25 degrees C in cells isolated from canine cardiac Purkinje fibers using three voltage clamp protocols: 1) development of block during a prolonged depolarization, 2) recovery from block after a prolonged depolarization, and 3) development of block during trains of depolarizations. At least two exponential components [a fast component with time constant (tau f) and relative amplitude (as) and a slow component with time constant (tau f) and relative amplitude (as)] were required to describe both development and recovery in lidocaine. For development of block between 10 and 25 degrees C, tau s decreased from 1,100 to 200 ms but tau f remained about the same (less than 30 ms), and as approximately equal to 0.8 and af approximately equal to 0.2 did not change with temperature. For recovery between 10 and 25 degrees C, tau a decreased from approximately 2,500 to 35 ms, tau f was relatively constant at approximately 25 ms, af decreased from 0.46 to 0.16, and as increased from 0.54 to 0.84. The fractional block developed during pulse trains decreased at higher temperatures (from 0.55 at 10 degrees C to 0.22 at 25 degrees C) and developed more quickly with time constant 6 pulses at 10 degrees C to 1.3 pulses at 25 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)