bluuebunny/crossref_metadata_2025 huggingface dataset:
Response of the hypertrophied left ventricle to tachycardia: importance of maturation
Authors: Fujii A. M. , Aoyagi T. , Flanagan M. F. , Takahashi T. , Bennett-Guerrero E. , Colan S. D. , Izumo S.
Published: December 2017

Pressure overload left ventricular (LV) hypertrophy (LVH) induces ventricular dysfunction during stress, which is commonly attributed to diminished myocardial capillary density and ischemia. Immature hearts with LVH have a normal coronary flow reserve and capillary density. The purpose of this study was to determine 1) whether young lambs with LVH had an abnormal response to chronotropic stress, 2) whether nonischemic mechanisms contributed to the abnormal response, and 3) whether the age at which LVH was induced affected the response. We assessed LV endomyocardial function, perfusion, and Ca(2+)-adenosinetriphosphatase (ATPase) mRNA levels in chronically instrumented lambs with and without LVH and adult sheep with and without LVH. Rapid pacing induced diastolic dysfunction, increased time constant of isovolumic relaxation using an iterative fit (tM), and elevated LV diastolic pressures in young lambs and adult sheep with LVH. During pacing, tM was greater in the adult sheep with LVH than in the young lambs with LVH. Ca(2+)-ATPase mRNA levels were 79% less in adult sheep with LVH than in those without. Ca(2+)-ATPase mRNA levels in lambs with and without LVH and adult sheep without LVH were similar. Diastolic dysfunction occurred in the absence of subendomyocardial hypoperfusion, suggesting a nonischemic mechanism. In adult sheep with LVH diastolic dysfunction was associated with a marked reduction in Ca(2+)-ATPase mRNA levels.
Fluorescent properties of rat cardiac trabeculae microinjected with fura-2 salt
Authors: Backx P. H. , Ter Keurs H. E.
Published: December 2017

We have measured force, sarcomere length, and Ca2+ during twitches in rat cardiac trabeculae. To avoid the difficulties associated with fura-2/acetoxymethyl ester (AM), fura-2 salt was iontophoretically microinjected into the preparation using a single impalement site; this is possible because fura-2 diffuses through the gap junctions between cells. By use of this method, the estimated peak of the [Ca2+] transient during a twitch was not statistically different at different sarcomere lengths: 875 +/- 92 nM at a sarcomere length of 2.15 microns vs. 905 +/- 67 nM at a sarcomere length of 1.65 microns (means +/- SD, n = 10). When trabeculae were loaded using fura-2/AM, the estimated peak of the [Ca2+] transient at a sarcomere length of 2.15 microns was 540 +/- 180 nM (means +/- SD, n = 5). The time course of the Ca2+ transients at different sarcomere lengths is qualitatively similar, but small systematic differences were observed during the relaxation period. On the other hand, the duration of twitch force increases dramatically as the muscle length is increased. As a result, when the trabeculae were held at short muscle lengths, the temporal relationship between force and the Ca2+ transient resembled the relationship between cell shortening and the Ca2+ transient measured in isolated myocytes. At longer lengths the temporal relationship between force and the Ca2+ transient more closely resembles that obtained in papillary muscles using aequorin.
2-Chloroadenosine prevents phorbol ester-induced depletion of protein kinase C in porcine coronary artery
Authors: Marala R. B. , Ways K. , Mustafa S. J.
Published: December 2017

In this study we investigated the role of the adenosine analogue 2-chloroadenosine (CAD) in the regulation of protein kinase C (PKC) in porcine coronary artery. Arterial rings were contracted with endothelin-1 (ET-1; 10(-10) to 10(-7) M) and phorbol 12,13-dibutyrate (PDBu; 10(-7) M) after incubating them for 1 and 2 days with PDBu (200 nM) in the presence and absence of CAD (10(-4) M). Chronic exposure to PDBu alone attenuated ET-1-induced contractions, while inclusion of CAD during incubation protected against the PDBu-induced blunting of ET-1-induced contraction. Similarly, PDBu (10(-7) M)-induced contraction of the arterial rings was attenuated upon chronic incubation with PDBu, and once again, inclusion of CAD showed an improved response to PDBu-induced contraction when compared with PDBu alone. Incubation with PDBu (200 nM) for 20 min caused the PKC translocation from cytosol to membrane, whereas CAD totally blocked this translocation. Chronic (1 and 2 days) incubation with PDBu caused a substantial depletion of PKC activities in cytosol and membrane. The presence of CAD protected the PDBu-induced depletion of PKC in both cytosol and membrane. To replete PKC, after incubation with the drugs, the arteries were incubated in the absence of drugs for another 2 days. Arteries incubated with PDBu in the presence and absence of CAD recovered significantly in their response to ET-1 as well as PDBu. These results indicate that CAD protects against the PDBu-induced activation and depletion of PKC in porcine coronary artery.
Differential sensitization of cardiac actions of adenosine in rats after chronic theophylline treatment
Authors: Lee H. T. , Thompson C. I. , Linden J. , Belloni F. L.
Published: December 2017

To determine the effect of chronic adenosine receptor blockade on atrial responsiveness, we administered theophylline to rats in their drinking water (0.6 mg/ml) for 2 wk. Inotropic and chronotropic responses to the adenosine receptor agonists N6-cyclopentyladenosine (CPA) and 5'-(N-ethylcarboxamido)-adenosine (NECA) were then measured in isolated atria from treated and control animals. The indirect (antiadrenergic) actions of CPA and NECA on force and rate, measured during beta-adrenergic receptor stimulation by isoproterenol, were markedly sensitized (2- to 10-fold reductions in the agonist concentration needed to obtain a half-maximal response) after theophylline. The sensitization was homologous because inotropic and chronotropic responses to carbachol were not affected by theophylline. The direct negative inotropic and chronotropic actions of CPA and NECA, measured without concomitant beta-adrenergic stimulation, were not sensitized after theophylline. The number of atrial A1-receptors, measured by antagonist radioligand binding (maximum specific binding at saturation), was increased by 22% in theophylline-treated rats [66.2 +/- 3.4 vs. 54.3 +/- 1.9 (control) fmol/mg protein, P < 0.05]. Competition binding indicated that the fraction of coupled (high-affinity) receptors was unchanged. The number of ventricular A1-receptors was increased to a similar extent without any change in coupling. Thus chronic dietary theophylline upregulated cardiac A1-adenosine receptors without changing coupling state or affinity and sensitized rat atria to the indirect, antiadrenergic, inhibitory inotropic and chronotropic actions of adenosine receptor agonists.
Nonlinear heart model predicts range of heart rates for 2:1 swinging in pericardial effusion
Authors: Sacks E. , Widman L. E.
Published: December 2017

We analyze two mathematical models of Rigney and Goldberger (14) of heart swinging in large pericardial effusions. Both models represent the torques due to the outflow of blood from the heart. The first assumes that the duration of systole does not vary with heart rate (in beats/min), whereas the second assumes that it varies linearly with heart rate. We examine the motion of the heart for heart rates between 50 and 200 and for a range of initial positions and velocities. Both models predict that the heart swings once every other beat (2:1 swinging, giving rise to electrical alternans) in a discrete range of heart rates and swings once per beat otherwise; both models explain the appearance and disappearance of 2:1 swinging mathematically. The first model predicts a rate range from 105 to 116 for the occurrence of 2:1 swinging. The second model predicts the same qualitative behavior but with 2:1 swinging occurring at heart rates between 88 and 119, which agrees well with published clinical data showing 2:1 swinging at heart rates between 90 and 144. We describe an analysis program for ordinary differential equations that analyzed the models quickly and automatically.
Evidence that heterogeneity of cerebral blood flow does not involve vascular recruitment
Authors: Williams J. L. , Shea M. , Jones S. C.
Published: December 2017

Recent studies indicate that blood flow to cerebral cortex is not homogeneous but may vary both spatially and temporally. In addition, some investigators have reported that capillaries and arterioles can be recruited to increase cerebral blood flow, an issue that is extremely controversial. The goal of this study was to determine whether recruitment of cerebral blood vessels is an important mechanism in spatial and temporal heterogeneity of cerebral blood flow. In seven anesthetized ventilated rats, different fluorescent tracers were injected 45 and 10 s before decapitation. In addition, [14C]iodoantipyrine also was injected 10 s before decapitation. After the brains were sectioned, fields in the cerebral cortex were examined microscopically for fluorescence and processed for measurement of cerebral blood flow with techniques of quantitative autoradiography and image analysis. With examination of 24 +/- 2 (SE) points in cerebral cortex of each rat, similar numbers of small blood vessels (< or = 10 microns) were counted that contained fluorescent tracers injected 45 and 10 s before decapitation (346 +/- 48 and 355 +/- 42 vessels/mm2, respectively; P > 0.05). Large blood vessels (20-60 microns; 73 +/- 6 vessels in each rat) contained both fluorescent tracers. In addition, adjacent regions of high and low blood flow contained similar numbers of small and large vessels. Our findings indicate that vascular recruitment is not an important mechanism in temporal or spatial heterogeneity of cerebral blood flow.
Modification of vascular reactivity by alteration of intimal permeability: effect of TNF-alpha
Authors: Matsuki T. , Beach J. M. , Klindt R. L. , Duling B. R.
Published: December 2017

We investigated the effects of alterations in intimal permeability on microvascular reactivity to small hydrophilic agents in isolated, cannulated, perfused arterioles (65 +/- 6 microns ID) from hamster cheek pouches. Arterioles are 300-fold less responsive to the hydrophilic alpha 1-agonist, phenylephrine, applied to the lumen than when applied to the adventitia. Luminal treatment with tumor necrosis factor-alpha (TNF-alpha, 0.625 micrograms/ml, 1–2 h) potentiated reactivity to luminally applied phenylephrine, but the treatment did not change reactivity to adventitially applied phenylephrine. Similar results were obtained with a brief treatment with the detergent, 3-[(3-cholamidopropyl)dimethylammonio]-1- propanesulfonate (CHAPS; 0.3%, < 30 s). To confirm that a change in permeability had occurred, we measured the movement across the arteriolar wall of a low-molecular-weight hydrophilic fluorescent molecule, fluorescein, before and after luminal treatment with TNF-alpha or CHAPS. Either TNF-alpha or CHAPS significantly increased the rate of movement of fluorescein across the arteriolar wall. These data suggest that one element in the pathophysiology of TNF-alpha is an increase in arteriolar permeability to small, water-soluble agents, which may modify reactivity to circulating vasoactive substances.
Copper deficiency alters collagen types and covalent cross-linking in swine myocardium and cardiac valves
Authors: Vadlamudi R. K. , McCormick R. J. , Medeiros D. M. , Vossoughi J. , Failla M. L.
Published: December 2017

Dietary copper deficiency induces alterations of connective tissue metabolism that are associated with lesions in cardiovascular and other organ systems. To determine the impact of copper deficiency on characteristics of collagen in porcine myocardium and cardiac valves, weaned pigs were fed diets with adequate or deficient levels of copper. Although dietary copper did not affect the concentration of collagen in either myocardium or bicuspid valves, the degree of collagen cross-linking, as assessed by the level of hydroxylysylpyridinoline, was lower in both tissues of copper-deficient pigs. Proportions of type III collagen were increased in the left ventricle and bicuspid valves of copper-deficient pigs. Copper deficiency induced extensive remodeling, however, of the collagen fraction of cardiac interstitium. Reduction in left ventricular collagen cross-linking may provide the stimulus for the development of cardiac hypertrophy, which characterizes severe copper deficiency, by increasing the compliance of the ventricular wall. The shift in the phenotypic profile of collagen that is associated with this cardiac hypertrophy indicates synthesis of new collagen, which could affect collagen cross-linking irrespective of copper status.
Left ventricular stroke volume by single and dual excitation of conductance catheter in dogs
Authors: Steendijk P. , Van der Velde E. T. , Baan J.
Published: December 2017

The conductance method employs a multielectrode catheter to measure intracavitary electric conductance from which left ventricular volume is estimated. A dual-excitation method introduced by us uses a more homogeneous electric field and thereby should enable more accurate volume estimation. In six anesthetized open-chest dogs we compared stroke volume obtained from electromagnetic flow probes with the conventional single-excitation method and with the new dual-excitation conductance method. Caval occlusion and left atrial hemorrhage were used to obtain a wide range of stroke volumes. The slope of the relation between stroke volume calculated from the flow probes and from the conductance catheter increased significantly (P < 0.001) from 0.635 with single excitation to 0.835 with dual excitation, but the interanimal variability was not reduced. The linearity of the relation was substantially improved.
Continuous, on-line, real-time spectral analysis of systemic arterial pressure signals
Authors: Kuo T. B. , Chan S. H.
Published: December 2017

We present in this communication an algorithm that offers continuous, on-line, real-time analysis of the power spectrum (CORAPS) of systemic arterial pressure (SAP) signals. Based on direct fast Fourier transform of raw SAP signals into power spectral density, it is suitable for the delineation of acute SAP spectral changes over time after physiological or pharmacological perturbations. Thus it is an improvement over most current methods, which only generate the spectra off-line or from intermittent data. Furthermore, all executions can be accomplished economically with a general-purpose personal computer. We demonstrated and quantified vivid sequential alterations in the low-frequency components (< 3 Hz) of the SAP spectrum, which purportedly reflect the influence of vasomotor, baroreceptor, and respiratory activity on SAP during pentobarbital administration or transient hypertension. Three window options incorporated into the algorithm further improved the frequency or temporal resolution and discrimination of the spectral changes during abrupt hypertension or hypotension. Thus our CORAPS algorithm may be useful as an on-line monitor for acute hemodynamic changes.
Regulation of diaphragmatic oxygen uptake by endothelium-derived relaxing factor
Authors: Chang H. Y. , Ward M. E. , Hussain S. N.
Published: December 2017

The role of endogenous nitric oxide (NO) in the regulation of phrenic blood flow (Qphr) and O2 consumption (VO2) of the in situ isolated left hemidiaphragms was assessed in two groups of anesthetized, mechanically ventilated dogs. Saline was infused into the phrenic artery for 20 min in one group, whereas N omega-nitro-L-arginine (L-NNA, 6 x 10(-4) M) was infused in the other (L-NNA) group. Qphr and diaphragmatic VO2 were measured at rest and during 2 min of continuous 3-Hz stimulation of the left phrenic nerve. The animals were progressively hemorrhaged, and the measurements were repeated at various arterial pressures (Pa). For the resting diaphragm, Qphr at a mean Pa of 145 mmHg was lower in the L-NNA group than in the saline group; however, diaphragmatic VO2 values were similar in both groups. Qphr decreased with the decline in Pa in both groups, but O2 extraction ratios obtained at mean Pa of 25–45 mmHg were similar in both groups (71 vs. 73%). For the contracting diaphragm, Qphr and diaphragmatic VO2 values at a given Pa were lower in the L-NNA group than in the saline group (except at mean Pa < 75 mmHg). O2 extraction ratios obtained at a given Pa were similar in both groups. We concluded that 1) EDRF inhibition limits diaphragmatic blood flow both at rest and during 3-Hz stimulation; 2) diaphragmatic O2 extraction is unaffected by EDRF inhibition; and 3) the effect of EDRF release on diaphragmatic VO2 is dependent on the level of metabolic demands.
Presynaptic effects of epinephrine on norepinephrine release from cardiac sympathetic nerves in dogs
Authors: Boudreau G. , Peronnet F. , De Champlain J. , Nadeau R.
Published: December 2017

The possible functional role of tissue epinephrine in the modulation of norepinephrine release from cardiac sympathetic nerve endings in anesthetized dog was investigated. Observations were carried out under control conditions and after a short- (10 min) and long-term (180 min) epinephrine infusion (92 ng.kg-1.min-1). An increase in the stimulation-induced release of norepinephrine after intravenous administration of a selective beta 2-agonist (fenoterol, 0.5 micrograms/kg) indicated the presence of the beta 2-facilitatory mechanism. Furthermore, the facilitatory effect of fenoterol was inhibited by intravenous administration of a selective beta 2-antagonist (ICI 118551, 1 mg/kg). Short-term epinephrine infusion did not facilitate the stimulation-induced release of norepinephrine, when tissue epinephrine content in the left ventricle was increased 1.5-fold, without, as well as with, alpha 2-blockade (yohimbine, 0.3 mg/kg). However, stimulation-induced release of norepinephrine from the myocardium was significantly potentiated in animals in which tissue epinephrine in the left ventricle was greatly increased (5.6-fold) by a prolonged infusion of epinephrine (180 min). It is concluded that a facilitatory mechanism mediated by presynaptic beta 2-adrenoceptors is present in cardiac sympathetic nerve endings of the dog. Some of our observations support the hypothesis that this mechanism may be influenced by locally released epinephrine and, thus, by tissue epinephrine content.
Effect of adenosine on heart rate in isolated muskrat and guinea pig hearts
Authors: McKean T. A. , Sterling H. , Streeby D. R. , Lynch A. E. , Lacroix C. , Vestal R. E.
Published: December 2017

The purpose of this study was to compare the responses of isolated hearts of the diving muskrat with the nondividing guinea pig (GP) to determine the contribution of adenosine (ADO) to the profound bradycardia that was seen in isolated muskrat hearts during exposure to hypoxia. Muskrat hearts were more sensitive than GP hearts to the heart rate-lowering effects of exogenously applied ADO or a stable ADO analogue, (R)-N6-(phenylisopropyl)adenosine. The hearts of both species were unpaced, and the bradycardia appeared to be due to high degree of atrioventricular block. Radioligand binding with 8-cyclopentyl-1,3-[3H]dipropylxanthine to A1-ADO receptors was greater in cardiac membranes prepared from GP hearts than from muskrat hearts. Nucleoside transporter antagonist binding was also greater in GP hearts compared with muskrats. This was determined by membrane binding of [3H]-nitrobenzylthioinosine, an antagonist of nucleoside transport. Both muskrat and GP hearts responded to 30 min of hypoxic perfusion by releasing ADO into the coronary effluent; however, the muskrat hearts released approximately five times more than the GP hearts. When hearts were subjected to hypoxia in the presence of ADO deaminase, theophylline, or 8-(p-sulfophenyl)theophylline, the hypoxia-induced bradycardia was blocked in the GP hearts and either slightly reduced or not affected in muskrat hearts. In contrast to GP hearts, muskrat hearts release larger amounts of ADO during hypoxia and are more sensitive to the negative chronotropic effects of exogenously administered ADO; yet the hypoxia-induced bradycardia does not appear to be exclusively mediated by ADO in the muskrat as it is in the isolated GP heart.
Pressure-related capillary leukostasis following ischemia-reperfusion and hemorrhagic shock
Authors: Hansell P. , Borgstrom P. , Arfors K. E.
Published: December 2017

Although the receptor-dependent venular adhesion of leukocyte adherence has been relatively well characterized, less is known about capillary leukostasis. With the use of fluorescence intravital microscopy, leukocyte behavior in the capillaries of rabbit tenuissimus muscle was evaluated after ischemia-reperfusion or hemorrhage. After fixed volume hemorrhage or 4 h of total ischemia, inflammatory injury was manifest by broken fibrils, edema, leukocyte infiltration, and margination along the postcapillary venular walls. Nevertheless, as long as arterial perfusion pressure was between 27 and 72 mmHg, the frequency of capillary leukostasis was low (4-8 cells/mm2) and similar in all groups, including animals treated with the antiadhesion antibody IB4. In contrast, when perfusion pressure decreased to 20 mmHg, capillary leukostasis increased similarly (to 16–21 cells/mm2) in controls (with or without IB4) and in those subjected to ischemia. Furthermore, when perfusion pressure was increased to more than 27 mmHg, (27–72 mmHg) stationary leukocytes returned to the original low level (4–5 cells/mm2). These results are consistent with the conclusion that during some inflammatory injuries, capillary leukostasis is a pressure-related phenomena that is not receptor dependent and is freely reversible with the early restoration of perfusion pressure.
Magnesium influences incorporation of [3H]arachidonic acid in perfused rabbits hearts
Authors: Weis M. T.
Published: December 2017

Ca(2+)-free perfusion of rabbit hearts produces a 50% loss of tissue Ca2+ and Mg2+ and results in reduced incorporation of arachidonic acid into tissue lipids. This work was undertaken to determine whether the reduced incorporation was specific for arachidonic acid and whether it was correlated to the loss of either (or both) cation(s). Single 170-pmol bolus doses of [3H]arachidonic or [3H]oleic acid were given to perfused hearts with or without Ca2+ in the perfusate. The experiment was terminated, and the lipids were extracted 1-15 min after administration of label. At all time points, significantly less arachidonate was incorporated into total tissue lipids in the absence of than in the presence of Ca2+. The presence or absence of Ca2+ had no effect on the incorporation of oleate. When [3H]arachidonate was administered to hearts perfused with buffer containing 104 mM Li+ and 35 mM Na+ (which reduces tissue Mg2+ by approximately 25% and increases tissue Ca2+ by approximately 35%), the incorporation into lipids was reduced from 0.882 +/- 0.0739 to 0.598 +/- 0.0722 pmol/mg lipid (P < 0.05; n = 6). The incorporation of [3H]oleate during 104 mM Li+ and 35 mM Na+ was not different from control. These data suggest that the incorporation of arachidonic, but not oleic, acid into tissue lipids is dependent on the tissue Mg2+ content.
Glucose use in neonatal rabbit hearts reperfused after global ischemia
Authors: Itoi T. , Huang L. , Lopaschuk G. D.
Published: December 2017

In this study, we measured both glycolysis and glucose oxidation during reperfusion of previously ischemic hearts obtained from 7-day and 6-wk-old rabbits. Isolated working hearts perfused with 11 mM [3H/14C]glucose, 0.4 mM palmitate, 0.5 mM lactate, and 100 microU/ml insulin were subjected to either 30 or 40 min of global ischemia followed by a 60-min period of reperfusion. Recovery of mechanical function was 58% in 7-day-old hearts subjected to 40 min of ischemia. In 6-wk-old rabbits, a 45% recovery of function was seen after only 30 min of ischemia. Addition of 1 mM dichloroacetate (DCA) to the perfusate at reperfusion increased glucose oxidation rates during reperfusion in both 7-day and 6-wk-old hearts (from 102 +/- 22 to 262 +/- 27 and from 280 +/- 63 to 523 +/- 97 nmol.min-1.g dry wt-1, respectively). Addition of DCA, however, resulted in a significant improvement in recovery of mechanical function only in 6-wk-old hearts (from 45 to 67% of preischemic function). These results demonstrate that fatty acid-perfused neonatal rabbit hearts are more able to tolerate ischemia than the matured rabbit hearts. However, our data suggest that there may be less potential to improve mechanical recovery in neonatal hearts during the actual reperfusion period by stimulating glucose oxidation.
Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries
Authors: Ku D. D. , Zaleski J. K. , Liu S. , Brock T. A.
Published: December 2017

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), has recently been shown to increase cytosolic free calcium in endothelial cells. In the present study, we investigated the coronary vascular effects of recombinant human and native guinea pig VEGF/VPF in isolated canine coronary arteries in the presence and absence of intimal endothelium, indomethacin, and NG-monomethyl-L-arginine, a competitive nitric oxide synthase inhibitor. Addition of recombinant VEGF/VPF (1-660 pM) in coronary arteries that had been previously contracted with prostaglandin F2 alpha induced a slow, dose-dependent relaxation, reaching a maximum of -59.1 +/- 6.7% (mean +/- SE, n = 19). Mechanical disruption of the intimal endothelium completely abolished the observed relaxation. No direct vascular effect of recombinant VEGF/VPF on the endothelium-disrupted coronary arteries was noted. Pretreatment of endothelium-intact coronary arteries with 5 microM of indomethacin did not alter the observed relaxation (-57.3 +/- 7.0%, n = 18), whereas pretreatment with either NG-monomethyl-L-arginine or 10 microM of genistein, a known inhibitor of tyrosine kinase, significantly inhibited the relaxation. Addition of native VEGF/VPF (1-100 pM) also induced an endothelium-dependent relaxation in the isolated coronary arteries. Heating of recombinant VEGF/VPF (70 degrees C, 25 min) or prior incubation with a specific antibody raised against a VEGF/VPF peptide completely abolished the relaxation. Finally, recombinant VEGF/VPF stimulated a slow rise in cytosolic free calcium in cultured human endothelial cells that was qualitatively similar to that of native VEGF/VPF.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiac effects of injections of epinephrine into the spinal intermediolateral column
Authors: Malhotra V. K. , Kachroo A. , Sapru H. N.
Published: December 2017

Small doses of epinephrine (0.008, 0.05, and 0.1 pmol, i.e., 20-nl volumes of 0.40, 2.5, and 5 microM solutions) produced a dose-dependent increase in heart rate when micro-injected into the right intermediolateral column (IML) at T2 spinal level. These effects were mediated via alpha 1-adrenergic receptors because prazosin blocked them. The presence of alpha 1-adrenergic receptors at this site was confirmed by microinjections of phenylephrine (a specific agonist for these receptors); phenylephrine elicited tachycardia. Larger doses of epinephrine (320, 2,000, and 3,200 pmol, i.e., 20-nl volumes of 16, 100, and 160 mM solutions) caused bradycardia when microinjected into the IML. These effects were mediated via alpha 2-adrenergic receptors because idazoxan blocked them. The presence of alpha 2-adrenergic receptors at this site was confirmed by microinjections of clonidine (a specific agonist for these receptors); clonidine elicited bradycardia. Injections of the vehicle (20 nl of normal saline containing 0.3% ascorbic acid, pH 7.4) did not evoke a response. Epinephrine, prazosin, or idazoxan did not alter the responses to L-glutamate. None of the doses of epinephrine elicited any response when injected intravenously. The aforementioned results provide pharmacological evidence for the presence of alpha 1- and alpha 2-adrenergic receptors in the IML at T2. Thus a basis is provided for investigating the role, if any, of alpha-adrenergic receptors in the IML in mediating cardiovascular responses elicited by the stimulation of different brain stem areas.
Control of resting bronchial hemodynamics in the awake dog
Authors: Hennessy E. , White S. , van der Touw T. , Quail A. , Porges W. , Glenfield P.
Published: December 2017

In the resting awake dog a continuous-wave Doppler flow transducer on the right bronchoesophageal artery inscribes a sharp early systolic spike and low flow in late systole and throughout diastole, indicating a highly resistive bed. An analysis of autonomic factors using intravenous, cumulative, and randomly applied cholinoceptor, beta 1- and beta 2-adrenoceptor, and alpha 1- and alpha 2-adrenoceptor antagonists indicates that the low vascular conductance is due to cholinoceptor and alpha 1- and alpha 2-adrenoceptor effects in a ratio 3.6:1. No beta-adrenoceptor tone is present. Sighing behavior invokes a transient (< 2 s) fall in intrapleural pressure (and thus rise in bronchovascular transmural pressure) of 10-30 mmHg, which is followed by a two- to threefold increase over 30 s in bronchial flow and conductance, an effect simulated in 50% of dogs when bronchovascular transmural pressure is acutely raised and maintained over 40-60 s by inflating an intra-aortic balloon distal to the origin of the bronchial artery. Autonomic blockade has no effect on bronchovascular dilatation evoked either by sighing or by balloon inflation. It is concluded that, in the resting bronchial circulation, there exists strong cholinoceptor and alpha-adrenoceptor-based vasoconstrictor activity which can be overpowered by strong nonadrenergic noncholinergic local vasodilator reflexes evoked by sudden changes in intrathoracic transmural pressure possibly acting on stretch-sensitive sensory nerve endings containing substance P, calcitonin gene-related peptide, and neurokinins. The tonic vasoconstrictor but not the sigh-evoked vasodilator effects are sensitive to pentobarbital sodium anesthesia.
Endothelium-dependent vasorelaxing activity of wine and other grape products
Authors: Fitzpatrick D. F. , Hirschfield S. L. , Coffey R. G.
Published: December 2017

Current interest in the presumed benefits of wine in protecting against coronary heart disease prompted us to investigate possible effects of various grape products on vascular function in vitro. Certain wines, grape juices, and grape skin extracts relaxed precontracted smooth muscle of intact rat aortic rings but had no effect on aortas in which the endothelium had been removed. Quercitin and tannic acid, compounds known to be present in grape skins, also produced endothelium-dependent relaxation; two other grape skin compounds, resveratrol and malvidin, did not relax the rings. Phenylephrine-induced contractions were attenuated by prior exposure of aortic rings to grape skin extracts. The extracts also increased guanosine 3',5'-cyclic monophosphate (cGMP) levels in intact vascular tissue, and both relaxation and the increase in cGMP were reversed by NG-monomethyl-L-arginine and NG-nitro-L-arginine, competitive inhibitors of the synthesis of the endothelium-derived relaxing factor, nitric oxide (NO). The vasorelaxation induced by grape products therefore appears to be mediated by the NO-cGMP pathway. If such responses occur in vivo, they could conceivably help to maintain a patent coronary artery and thereby possibly contribute to a reduced incidence of coronary heart disease.
Vasoconstriction and increased flow: two principal mechanisms of shear stress-dependent endothelial autacoid release
Authors: Hecker M. , Mulsch A. , Bassenge E. , Busse R.
Published: December 2017

The mechanisms of which nitric oxide (NO) and prostacyclin (PGI2) are released from endothelium-intact rabbit femoral arteries under resting conditions and after stimulation by either shear stress or acetylcholine (ACh) were investigated. The concentration of NO in the effluate was determined by monitoring the NO-mediated stimulation of purified soluble guanylyl cyclase, and that of PGI2 was done using a specific radioimmunoassay for its stable hydrolysis product, 6-ketoprostaglandin F1 alpha, NO release under static (no-flow) conditions and in the absence of a stimulus accounted for 10-15% of the maximum release of NO from luminally perfused segments stimulated with ACh and was attenuated by removal of extracellular Ca2+. A six- to sevenfold increase in shear stress (from 0.15 to 1 dyn/cm2), generated either by vasoconstriction at constant flow or by an increase in flow at constant diameter, elicited a five- to sevenfold increase in NO release, which was correlated with increasing shear stress. The same increase in shear stress also enhanced the release of PGI2 from the femoral artery segments by 11- to 12-fold. Removal of extracellular Ca2+ abolished the shear stress-dependent PGI2 released but did not affect that of NO. In contrast, the ACh-stimulated NO release was strongly inhibited in the absence of extracellular Ca2+ (78% inhibition). Charybdotoxin, an inhibitor of Ca(2+)-activated K+ channels, and glibenclamide, an inhibitor of the ATP-sensitive K+ channel, had no effect on the shear stress-dependent release of NO.(ABSTRACT TRUNCATED AT 250 WORDS)
Functional role of Ca(2+)-activated K+ channels in resting state of carotid arteries from SHR
Authors: Asano M. , Masuzawa-Ito K. , Matsuda T. , Imaizumi Y. , Watanabe M. , Ito K.
Published: December 2017

Carotid arteries from spontaneously hypertensive rats (SHR) exhibited an active tone when exposed to a physiological salt solution; that is, the tension decreased when nifedipine was added. To determine the possible role of Ca(2+)-activated K+ (KCa) channels in the resting state of these arteries, the effects of agents that interact with these channels on tension and 86Rb efflux were compared in endothelium-denuded strips of carotid arteries from SHR and normotensive Wistar-Kyoto rats (WKY). The addition of charybdotoxin, a blocker of high-conductance KCa channels, to the resting strips produced a concentration-dependent contraction in SHR but not in WKY. In resting strips preloaded with 86Rb, the basal 86Rb efflux rate constant was significantly greater in SHR than in WKY. The addition of nifedipine to the resting strips decreased the basal 86Rb efflux rate constant only in SHR. The effect of nifedipine on tension and 86Rb efflux in 25.9 mM K(+)-contracted strips of WKY was comparable to the effect of this blocker in the resting strips of SHR. The basal 45Ca influx in resting strips of SHR was significantly increased when compared with WKY, and this increase in SHR was abolished by nifedipine. These results suggest that the transmembrane Ca2+ influx via L-type voltage-dependent Ca2+ channels was significantly increased in the resting state of carotid arteries from SHR and that the KCa channels were highly activated.
Resistance to O2 diffusion in anemic red muscle: roles of flux density and cell PO2
Authors: Honig C. R. , Gayeski T. E.
Published: December 2017

Normal and anemic dog gracilis muscles were compared at equal O2 uptake rates (VO2) to locate the principal site of resistance to diffusive O2 transport. Anemia halved the hematocrit and the number of red blood cells per square millimeter of muscle cross section. Flow doubled in anemia, and flow times arterial O2 content, PO2 of effluent blood, and O2 extraction per red blood cell were approximately the same as control. Nevertheless, intracellular PO2 was significantly lower in anemia. At any instant the aggregate red blood cell surface area for O2 release was about half normal. Because the flux (VO2) was the same as control, the driving force for diffusion from red blood cell to myocyte should have doubled. An estimate of the total driving force from red blood cell to mitochondria was greater in anemia. This increase was much less than a factor of 2 because lower intracellular PO2 increases myoglobin-facilitated diffusion, thus decreasing resistance inside the myocyte. The role of myoglobin and the coupling of convective to diffusive transport are discussed. We conclude that the principal resistance to O2 diffusion lies outside the myocyte.
Effects of cardiac contraction and cavity pressure on myocardial blood flow
Authors: Doucette J. W. , Goto M. , Flynn A. E. , Austin R. E. , Husseini W. K. , Hoffman J. I.
Published: December 2017

Regional impairment of cardiac contraction uncouples force generation from left ventricular pressure (LVP) and may alter the determinants of the phasic pattern and transmural distribution of coronary flow. In anesthetized, open-chest dogs with maximal coronary vasodilation, we studied the effects of abolishing local contraction and changing cavity pressure on phasic myocardial inflow and net transmural flow in a region of left ventricular free wall. With contraction present, the normalized amplitude of distal phasic coronary velocity (NAmp) was not significantly different at normal vs. low LVP (1.00 vs. 0.92 +/- 0.09, respectively, intracoronary lidocaine, however, NAmp varied with LVP (1.62 +/- 0.25 at normal LVP, 0.85 +/- 0.22 at low LVP, P < 0.0001). With contraction present, inner-to-outer flow ratio was not consistently different at normal vs. low LVP (0.47 +/- 0.15 vs. 0.64 +/- 0.28, respectively, P = NS) but was consistently higher at low than at normal LVP with contraction absent (1.01 +/- 0.30 vs. 1.84 +/- 0.38, respectively, P < 0.0001). During uniform global function, contraction is the main determinant of phasic amplitude and transmural distribution of myocardial flow. When regional contraction is abolished, allowing passive deformation of the wall during systole, LVP assumes a powerful role.
Arrhythmogenic effects of catecholamines are decreased in heart failure induced by rapid pacing in dogs
Authors: Li H. G. , Jones D. L. , Yee R. , Klein G. J.
Published: December 2017

Increased circulating catecholamines are considered to be arrhythmogenic in heart failure. It is unclear whether increased circulating catecholamines contribute directly to ventricular arrhythmias or are only markers of the severity of heart failure. The present study determined the sensitivity of the failing heart to the arrhythmogenic effect of exogenous norepinephrine in a rapid pacing-induced model of heart failure in dogs (240 beats for 4 wk, n = 14). A similarly operated, non-paced group served as controls (n = 9). Cardiac sensitivity to the arrhythmogenic effect of catecholamines was determined by measuring the minimal dose of exogenous norepinephrine that induced ventricular tachycardia (arrhythmogenic threshold dose, ATD). ATD significantly increased after development of heart failure in heart-failure group (1.62 +/- 0.32 microgram/kg at baseline vs. 16.65 +/- 3.48 micrograms/kg at restudy, P < 0.01), whereas no significant change was noted in the control group (1.08 +/- 0.36 microgram/kg at baseline vs. 2.53 +/- 0.36 micrograms/kg at restudy, P > 0.10). Action potential duration was unchanged by superfusion with 10(-7) M isoproterenol in both ventricular muscles (230.2 +/- 6.1 vs. 229.7 +/- 5.3 ms, P = NS) and Purkinje fibers (273.2 +/- 6.5 vs. 283.8 +/- 4.2 ms, P = NS) from the failing hearts, although isoproterenol induced a shortening in the control group (204.8 +/- 0.9 vs. 181.3 +/- 1.6 ms in ventricular muscles, P < 0.01; 313.8 +/- 6.5 vs. 279.5 +/- 5.7 ms in Purkinje fibers, P < 0.01). We conclude that the failing heart has a decreased sensitivity to the arrhythmogenic effect of catecholamines.
Right and left ventricular O2 uptake during hemodilution and beta-adrenergic stimulation
Authors: Crystal G. J. , Kim S. J. , Salem M. R.
Published: December 2017

Myocardial O2 uptake (MVO2) and related variables were compared in right and left ventricles (RV and LV, respectively) during isovolemic hemodilution (HD) alone and combined with isoproterenol (Iso) infusion in 13 isoflurane-anesthetized open-chest dogs. Measurements of myocardial blood flow (MBF) obtained with radioactive microspheres were used to calculate MVO2. Lactate extraction (Lacext) was determined. The study consisted of two experimental series: 1) graded HD (dextran) to hematocrit (Hct) of 10% and 2) Iso (0.1 microgram.kg-1.min-1 iv) during moderate HD (Hct = 18 +/- 1%). In series 1, arteriovenous O2 content difference in both ventricles decreased in parallel with reduced arterial O2 content caused by HD, i.e., percent O2 extraction was constant; MVO2 was maintained by proportional increases in MBF. In series 2, Iso during moderate HD raised MVO2 (RV, +156%; LV, +80%). Higher MVO2 was satisfied by combination of increased MBF and O2 extraction in RV and by increased MBF alone in LV. Lacext remained consistent with adequate myocardial O2 delivery throughout study. Conclusions were that 1) both RV and LV tolerated extreme HD (Hct = 10%) because blood flow reserves were sufficient to fully compensate for reduced arterial O2 content; 2) significant cardiac reserve was evident during HD, which could be recruited Iso; and 3) because increase in MVO2 in RV caused by Iso in presence of HD was partially satisfied by increased O2 extraction, the absence of augmented O2 extraction during HD alone was not due to impaired release of O2 from diluted red blood cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Paracrine effects of endocardial endothelial cells on myocyte contraction mediated via endothelin
Authors: Mebazaa A. , Mayoux E. , Maeda K. , Martin L. D. , Lakatta E. G. , Robotham J. L. , Shah A. M.
Published: December 2017

Endocardial endothelium is reported to modulate myocardial contraction by releasing diffusible factors, but the nature of the agent(s) responsible is unknown. In the present study we investigated the potential role of endothelin in these effects. Cultured sheep endocardial endothelial cells were found to express endothelin-1 mRNA and to release endothelin-1 into superfusing solution. This superfusate induced positive inotropic effects in isolated rat cardiac myocytes, associated with an increase in the cytosolic Ca2+ transient. Similar positive inotropic effects were induced by vascular endothelial cell superfusate as well as by synthesized endothelin-1, administered at concentrations similar to those present in the superfusate. Incubation of endocardial endothelial cell superfusate with endothelin-1-specific antiserum reduced the free endothelin-1 concentration to undetectable levels and abolished both the positive inotropic effect and the rise in cytosolic Ca2+. These findings indicate that endocardial endothelial cells may modulate myocardial contraction in part through the release of endothelin-1 and suggest that endocardial as well as vascular endothelium could exert potent paracrine effects on myocardium.
Hemodynamic and mechanical determinants of myocardial O2 consumption in normal human heart: effects of dobutamine
Authors: Vanoverschelde J. L. , Wijns W. , Essamri B. , Bol A. , Robert A. , Labar D. , Cogneau M. , Michel C. , Melin J. A.
Published: December 2017

The relationship of myocardial O2 consumption (MVO2) to its potential hemodynamic and mechanical determinants was investigated in eight healthy normal volunteers at rest and during infusion of dobutamine (5–10 micrograms.kg-1.min-1). MVO2 was calculated from the monoexponential myocardial clearance of [1–11C]acetate with positron emission tomography, and left ventricular mechanical function was assessed by two-dimensional echocardiography. Infusion of dobutamine increased heart rate by 53%, the tension-time index by 31%, and the rate-pressure product by 116%. Cardiac output (+70%), left ventricular ejection fraction (+24%), total mechanical energy [systolic pressure-volume area, (PVA) +84%], and left ventricular pressure-work index (+100%) also increased during infusion of dobutamine. During infusion of dobutamine, MVO2 increased from 96 +/- 17 to 233 +/- 19 J.min-1.100 g left ventricle-1, while myocardial efficiency (the ratio of PVA to MVO2) decreased from 46 +/- 8 to 35 +/- 4% (P < 0.001 each). MVO2 was best correlated (P < 0.001) with the PVA (r = 0.92) and the pressure-work index (r = 0.92). Infusion of dobutamine also resulted in a significant parallel upward shift of the PVA-MVO2 relationship, indicative of an increase in PVA-independent MVO2. Our data indicate that, in human subjects, MVO2 is mainly related to systolic PVA and that inotropic stimulation with dobutamine results in decreased efficiency of contraction, such as that previously described in isolated hearts.
Adaptation speed of cardiac mitochondrial oxygen consumption decreases with higher heart rate
Authors: Eijgelshoven M. H. , Hak J. B. , Van Beek J. H. , Westerhof N.
Published: December 2017

The purpose of the present study was to determine whether the mean response time of cardiac mitochondrial oxygen consumption after a step in metabolic demand is constant in heart muscle, as has already been found for skeletal muscle. The mean response time reflects the average delay between the change in ATP hydrolysis due to a heart rate step and mitochondrial ATP production. Isolated rabbit hearts with a water-filled balloon in the left ventricle were perfused according to Langendorff with a constant flow of Tyrode solution at 28 degrees C. The mean response time increased significantly from 7.6 s for a step in heart rate from 60 to 70 min-1 to 12.1 s for a step from 60 to 120 min-1. The mean response times for heart rate steps downward from 120 min-1 were all approximately 12 s, but for the step from 120 to 140 min-1 the response time was 16.8 s. These results demonstrate that the mean response time of cardiac mitochondrial oxygen consumption in most cases increases with heart rate. These findings are in contrast to those obtained in skeletal muscle, where the response time at which ATP synthesis adapts to a change in work load is constant.
Dynamics of myocardial lactate efflux after a step in heart rate in isolated rabbit hearts
Authors: Hak J. B. , van Beek J. H. , van Wijhe M. H. , Westerhof N.
Published: December 2017

We investigated whether a glycolytic burst contributes to the initial adaptation of ATP synthesis to increased cardiac metabolic demand. Six isolated rabbit hearts were perfused with glucose-containing Tyrode solution at 28 degrees C. In venous and arterial samples the lactate concentration was determined with a sensitive enzymatic cycling method. After the heart rate was doubled from 60 to 120 beats/min, lactate efflux increased from 0.23 +/- 0.10 (SE) to 0.45 +/- 0.12 mumol.min-1.g-1 dry weight with a mean response time of 21.3 s but without an overshoot. The transport time for lactate is longer than 15.7 s, suggesting that lactate production adapts with a mean response time of less than 6 s. Because no overshoot in lactate efflux was found, it is unlikely that a glycolytic burst after a step in heart rate contributes to the fast adaptation of ATP synthesis to demand in the isolated rabbit heart, although it might be possible that a change in cytosolic lactate production is not reflected in an increase in lactate efflux. Extrapolation of the results of this study to the in vivo situation should be done with caution.