bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial heterogeneity of local blood flow and metabolite content in dog hearts
Authors: Franzen D. , Conway R. S. , Zhang H. , Sonnenblick E. H. , Eng C.
Published: December 2017

Spatial variation (heterogeneity) of myocardial blood flow was studied under basal conditions in relation to four biochemical markers: creatine kinase (CK), lactate dehydrogenase (LDH), ATP, and glycogen. A total of 508 individual 0.5-g samples from the left ventricular free wall was studied in 12 dogs. Myocardial blood flow was measured by radioactive microspheres (15 micron diam) injected via a pigtail catheter into the left ventricle during light sedation (closed-chest flow measurements); following thoracotomy, a second set of microspheres was injected via a catheter into the left atrium (open-chest flow measurements, n = 5). In 27-54 samples/heart, myocardial blood flow, CK, LDH, protein, ATP, and glycogen were determined, permitting a direct correspondence between local blood flow and metabolic markers in each sample and an assessment of the spatial heterogeneity of flow and metabolite content. Correlations between myocardial blood flow per gram tissue and metabolite concentration per gram tissue in pooled data were weak but significant: partial correlation coefficients were 0.137 for CK (P = 0.024), 0.167 for LDH (P = 0.006), 0.341 for ATP (P less than 0.001), 0.123 for glycogen (P = 0.053), but not significant for protein vs. myocardial blood flow. The coefficient of variation, which defines the extent of spatial heterogeneity, averaged 20% for closed-chest flow measurements, 19% for open-chest flow measurements, 22% for CK, 17% for LDH, 15% for protein, 8% for ATP, and 18% for glycogen; these values are over and above the variability due to the technique error, indicating a definite physiological spatial variability. The correlation between local blood flow and the studied metabolites can only explain a minor portion of the spatial heterogeneity of myocardial blood flow. Although a physiological link between blood flow and metabolite content for small regions of the heart is demonstrated, the true local variability of blood flow may be modulated predominantly by other factors.
Direct G protein gating of ion channels
Authors: Brown A. M. , Birnbaumer L.
Published: December 2017

Guanine nucleotide binding (G) proteins couple a variety of receptors to ionic channels. Until recently the pathway was thought to be indirect via cytoplasmic second messengers; now the heterotrimeric G proteins are known to act directly on K+ and Ca2+ channels. Here we summarize recent developments concerning this widespread mechanism which we call G protein gating of ion channels. A specific pertussis toxin-sensitive G protein called Gk, purified from human red blood cells, activates a unique K+ channel and Gk, or a similar G protein, couples this channel to muscarinic atrial receptors. The alpha-subunit (alpha k) at less than 10 pM mediates the effects, and alpha k also activates K+ channels directly in neurosecretory cells. The G protein stimulatory to adenylyl cyclase, Gs, gates directly through its alpha-subunit, specific Ca2+ channels in heart and skeletal muscle T tubules. Hence, one G protein can have two distinct effectors.
Effects of New World scorpion toxins on single-channel and whole cell cardiac sodium currents
Authors: Yatani A. , Kirsch G. E. , Possani L. D. , Brown A. M.
Published: December 2017

Purified toxins from a North American scorpion, Centruroides noxius (Cn II-10), and a South American scorpion, Tityus serrulatus (Ts-gamma), were tested on cardiac sodium channels using patch-clamp methods to record whole cell and single-channel currents. The two toxins produced similar effects on sodium currents; potassium and calcium currents were not affected. Macroscopic sodium current amplitudes, measured at test potentials greater than -20 mV where the opening probability was high, decreased in a concentration-dependent manner with a half maximum inhibitory concentration of 6 X 10(-8) M. Block was unchanged by repetitive depolarizing pulses. In the presence of scorpion toxin, the currents were rapidly blocked by tetrodotoxin (3 X 10(-5) M). Both toxins shifted the voltage dependence of sodium channel inactivation to more negative potentials. At test potentials between -50 and -70 mV, where the sodium channel opening probability is normally low, both toxins produced an increase in sodium current and slowed the rates of activation and inactivation. At intermediate potentials between -50 and -20 mV the currents in the presence of toxins crossed over the control currents. At a test potential of -20 mV, the toxins decreased single-channel activity and increased the latency to first opening. At a test potential of -60 mV, the toxins significantly prolonged channel open time. The unitary current amplitudes were unchanged at either potential. We conclude that New World scorpion toxins produce apparently complex effects on whole cell currents primarily by retarding activation gating of cardiac sodium channels.
Pressure overload changes cardiac skinned-fiber mechanics in rats, not in guinea pigs
Authors: Ventura-Clapier R. , Mekhfi H. , Oliviero P. , Swynghedauw B.
Published: December 2017

The mechanical properties of detergent-treated skinned fibers from pressure-overloaded rat and guinea pig hearts have been compared with those of sham-operated animals. Overload was obtained 4 wk after abdominal aortic stenosis, an intervention that increases ventricular weight by 56% in rats and 57% in guinea pigs. The time constant (T, in ms) for tension recovery after a quick stretch was significantly lower in normal guinea pig than in rat. It was lengthened by the process of overload in both species, but this was much more pronounced in rats where T increases by 84% than in guinea pig where it was only slightly augmented by 14% for a doubling of the heart weight. By contrast the maximum tension obtained at pCa 4.5, the stiffness, and the sensitivity to calcium of the fibers were unmodified by chronic overload. In rat, not in guinea pig, a slight decrease in MgATP sensitivity was also observed, whereas no change in creatine kinase efficiency was seen. These results are interpreted as indicating that the slowing of the turnover rate of cross-bridge cycling explains the drop in shortening velocity observed on papillary muscles in rat but not in guinea pig; a species in which membrane modifications must be predominant in the process of adaptation.
Rapid in vivo determinations of instantaneous right ventricular pressure and volume in dogs
Authors: Schwiep F. , Cassidy S. S. , Ramanathan M. , Johnson R. L.
Published: December 2017

We have developed a method for measuring in vivo canine right ventricular (RV) volume at a frequency of 60 Hz. In six dogs (17-22 kg), under pentobarbital anesthesia, 18 radiopaque markers were surgically implanted in the RV myocardium to maximally represent the RV shell. The xyz-coordinates of the markers were obtained from biplane cineradiographic recordings. RV volume was calculated from the polyhedron created by the markers by decomposing the polyhedron into 24 tetrahedrons, each of whose volumes could be solved from the xyz-coordinates of markers. RV volume was obtained each 16.7 ms, permitting detailed representation if RV volume dynamics. RV end-diastolic volume, end-systolic volume, and ejection fraction averaged 41.3 +/- 10.9, 23.0 +/- 5.8, and 0.44 +/- 0.05 ml, respectively. By simultaneously measuring RV pressure, RV pressure-volume loops were constructed that demonstrated that RV ejection occurred without significant isovolumic contraction, although isovolumic relaxation occurred at end systole. RV systolic elastance was determined in two dogs by imposing four levels of RV afterload. Maximal systolic elastance averaged 4.14 mmHg/ml under control conditions and 9.20 mmHg/ml during dobutamine infusion.
Effect of afterload resistance on end-systolic pressure-thickness relationship
Authors: Aversano T. , Maughan W. L. , Sunagawa K. , Becker L. C.
Published: December 2017

The influence of afterload resistance on the end-systolic pressure-thickness relationship (ESPTR) was assessed in six isolated canine left ventricles made to eject into a simulated arterial system. An increase of simulated peripheral resistance from 1.5 to 6.0 mmHg.s.ml-1 resulted in a modest but significant shift of the ESPTR upward and to the right, indicating augmented contractile performance. A relationship between the extent of systolic wall thickening and end-systolic performance was also observed: increased wall thickening impairing and decreased wall thickening enhancing end-systolic performance. The dependence of end-systolic performance on wall thickening history in this setting is consistent with shortening deactivation. This phenomenon appears to account at least in part for the observed shift in the ESPTR with altered afterload resistance.
Dissociation of hypoxia-induced calcium gain and rise in resting tension in isolated rat hearts
Authors: Nayler W. G. , Elz J. S. , Buckley D. J.
Published: December 2017

When isolated hearts are perfused with substrate-free hypoxic buffer for prolonged periods of time, resting tension and tissue Ca increase. These two events may be interrelated. Isolated rat hearts were used to establish whether the hypoxia-induced increase in tissue Ca can be dissociated from the rise in resting tension. Tension generation was inhibited at the start of hypoxic perfusion by adding 2,3-butanedione monoxime (BDM, 30 mM). In other experiments the Ca2+ in the hypoxic buffer was reduced from 1.3 to 0.1 mM. After 30-120 min of hypoxia, ventricular muscle was assayed for ATP, creatine phosphate, Ca, and Na, and the perfusion defect was established. Resting tension was recorded before and throughout the hypoxic perfusion. Sixty minutes of perfusion with 1.3 mM Ca2+ glucose-free hypoxic buffer caused the tissue Ca to increase (P less than 0.01). Resting tension increased by 7.9 +/- 0.6 g (P less than 0.01). Sixty minutes of perfusion with 0.1 mM Ca2+ glucose-free hypoxic buffer failed to cause an increase in tissue Ca, but resting tension increased (P less than 0.01). During perfusion with glucose-free hypoxic buffer containing 2.6 mM Ca2+ and 30 mM BDM, resting tension remained low for up to 120 min, but after 60 min Ca accumulation occurred. After 120 min of BDM-hypoxic perfusion, tissue Ca reached 11.8 +/- 0.9 mumol/g dry wt. With or without BDM, hypoxia caused an early increase in tissue Na ahead of any increase in tissue Ca.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of experimental heart failure on peripheral sympathetic vasoconstriction
Authors: Wilson J. R. , Matthai W. , Lanoce V. , Frey M. , Ferraro N.
Published: December 2017

To investigate whether heart failure impairs peripheral sympathetic vasoconstriction, hindlimb vascular responses to lumbar chain stimulation (0.5-20 Hz) were studied in normal dogs and in dogs with chronic heart failure produced by rapid ventricular pacing. At lumbar chain stimulation rates of 0.5-3 Hz, hindlimb vascular responses were comparable in both groups. However, at stimulation rates of 5-20 Hz, vascular responses were significantly attenuated in the dogs with heart failure. Vascular responses to norepinephrine (0.1, 1, and 10 micrograms/min) were not altered. These findings suggest that chronic heart failure results in impaired sympathetic vasoconstriction, probably because of reduced neurotransmitter release. This abnormality may interfere with the capacity of the failing circulation to compensate for a low cardiac output and thereby intensify the severity of heart failure.
Norepinephrine effects on fetal cardiovascular and endocrine systems
Authors: Cheung C. Y. , Brace R. A.
Published: December 2017

Norepinephrine (NE) was infused intravenously into near-term chronically catheterized sheep fetuses for 30 min. Infusions of 0.39, 1.2, 3.9, 12, and 39 micrograms/min caused a 1- to 300-fold increase in plasma NE concentration. Fetal arterial pressure increased in a dose-dependent manner up to a maximum of 72 +/- 5% above basal levels at 6-7 min and gradually declined thereafter. Venous pressure increased during the four highest infusion rates to a maximum at 6-7 min followed by a return toward normal. Fetal blood volume underwent a rapid dose-dependent decrease by a maximum of 12 +/- 1% during 39-micrograms/min infusions of NE. Heart rate initially decreased by up to 40 beats/min during the 3.9-, 12-, and 39-micrograms/min infusions, returned to normal within 10 min, and increased to 50 beats/min above control by the end of the 30-min infusion. Plasma concentrations of arginine vasopressin, epinephrine, and plasma renin activity did not change during or after the four lowest infusion rates. Thus fetal vascular pressures and blood volume are altered in a dose-dependent manner over a broad range of plasma NE concentrations. In addition, NE does not appear to affect other circulating vasoactive hormones within its physiological range of concentrations.
Peripheral chemoreceptor control of neurohypophysial blood flow
Authors: Hanley D. F. , Wilson D. A. , Feldman M. A. , Traystman R. J.
Published: December 2017

Neurohypophysial blood flow responses to hypoxic hypoxia were studied under conditions of vagotomy, carotid sinus denervation, and combined vagotomy and carotid sinus denervation. Arterial O2 tension was lowered from 128 +/- 3 to 31 +/- 1 Torr, whereas pH and arterial CO2 tension remained constant. Denervation of either carotid sinus or aortic arch chemoreceptors alone does not attenuate the dilation of neurohypophysial vessels that accompanies hypoxic hypoxia. Combined denervation, however, completely blocks this response for the neurohypophysis but not for any other brain region studied. Hypoxic hypoxia resulted in an increase in plasma vasopressin (AVP) from approximately 8 to approximately 40 pg/ml. This increase occurred in the intact, vagotomy, and carotid sinus-denervation conditions. This neurosecretory response was also completely inhibited by combined denervation. For most brain regions peripheral chemoreceptors are not involved in the blood flow response; however, the response of the neurohypophysis appears to be mediated via these chemoreceptors, presumably by altering the neuroeffector activity to this region. In addition our data suggest a temporal relationship between neurohypophysial vasodilation and neurosecretion of AVP.
Microvascular control of capillary pressure during increases in local arterial and venous pressure
Authors: Davis M. J.
Published: December 2017

The extent to which capillary hydrostatic pressure might be protected from increases in local arterial and venous pressure was examined in the wing microcirculation of unanesthetized pallid bats (Antrozous pallidus). Arterial inflow and venous outflow pressures to the wing were elevated using a box technique to increase pressure around the body of the animal in steps of 12 mmHg between 0 and +60 mmHg for 3-min periods. During this time, hydrostatic pressure, diameter, and red cell velocity in single microvessels were continuously recorded. All branching orders of arterioles constricted significantly during increases in box pressure (Pb), while capillaries and venules dilated. First-order arteriole and venule pressures increased 1:1 with Pb. Capillary pressures increased by only a fraction of Pb up to +36 mmHg, but at higher Pb, the change in capillary pressure was equivalent to the change in Pb. Calculations of vascular resistance indicate that changes in both pre- and postcapillary resistance in this tissue act to prevent increases in capillary pressure during moderate, but not during large, increases in arterial and venous pressure.
A new fabrication technique for directly coupled transmural cardiac electrodes
Authors: Witkowski F. X. , Penkoske P. A.
Published: December 2017

Many current attempts at electrophysiological elucidation of cardiac arrhythmia mechanisms have centered around activation sequence mapping. This is most commonly performed with polarized unipolar or bipolar metal electrodes, which, because of unstable direct current (DC) base-line potentials, necessitate alternating current (AC)-coupled amplification. An ideal nonpolarizable unipolar electrode offers unhindered exchange of charge allowing for stable DC recordings of biological electrical activity. In addition to activation information, DC unipolar recordings enable quantitation of systolic and diastolic potentials, other low-frequency phenomena of interest such as repolarization, as well as rapid recovery from such rapid extreme potential shifts such as defibrillation. Previous attempts to apply nonpolarizable electrodes to transmural cardiac investigations required complex wick electrode techniques to prevent mechanical movement of the fluid-metal interface when chlorided silver wire was used. We have developed a technique to fabricate miniature sintered Ag-AgCl electrodes that are mounted at various locations on a 20-gauge stainless steel needle permitting stable transmural DC unipolar electrogram recordings in vivo. The electrodes are low noise, rugged, sterilizable, and reusable and should prove useful in three-dimensional electrophysiological characterization of the heart.
Long-term hemodynamic actions of atrial natriuretic factor (99-126) in conscious sheep
Authors: Parkes D. G. , Coghlan J. P. , McDougall J. G. , Scoggins B. A.
Published: December 2017

The hemodynamic and metabolic effects of long-term (5 day) infusion of human atrial natriuretic factor (ANF) were examined in conscious chronically instrumented sheep. Infusion of ANF at 20 micrograms/h, a rate below the threshold for an acute natriuretic effect, decreased blood pressure by 9 +/- 1 mmHg on day 5, associated with a fall in calculated total peripheral resistance. On day 1, ANF reduced cardiac output, stroke volume, and blood volume, effects that were associated with an increase in heart rate and calculated total peripheral resistance and a small decrease in blood pressure. On days 4 and 5 there was a small increase in urine volume and sodium excretion. On day 5 an increase in water intake and body weight was observed. No change was seen in plasma concentrations of renin, arginine vasopressin, glucose, adrenocorticotropic hormone, or protein. This study suggests that the short-term hypotensive effect of ANF results from a reduction in cardiac output associated with a fall in both stroke volume and effective blood volume. However, after 5 days of infusion, ANF lowers blood pressure via a reduction in total peripheral resistance.
Endotoxemia and neutrophil activation in vivo
Authors: Grisham M. B. , Everse J. , Janssen H. F.
Published: December 2017

There is a growing body of data to suggest that marginated granulocytes mediate much of the pulmonary damage observed during endotoxemia. The mechanism(s) by which endotoxemia initiates neutrophil margination and cytotoxicity remain either controversial or unknown. The objectives of this study were 1) to determine the temporal relationship between endotoxin-induced decreases in mean arterial pressure and circulating neutrophils, 2) to monitor neutrophil activation in vivo by measuring myeloperoxidase (MPO) activity in the plasma and lymph, and 3) to assess the interaction between endotoxin and complement in activation of neutrophilic oxidative metabolism in vitro. We found that a bolus injection of endotoxin causes a concurrent decrease in both mean arterial pressure and circulating neutrophils at 2 min postinfusion. Blood pressure recovered to approximately 70% of control values by 180 min, whereas circulating neutrophils remain depressed at 20% of control values for the entire experimental period. Using MPO as a marker for neutrophil activation, we found that infusion of endotoxin produces a dramatic increase in plasma and lymph MPO activity, suggesting activation of neutrophilic metabolism in vivo. In vitro data showed that both endotoxin and plasma were required for optimal neutrophilic degranulation and superoxide formation. We conclude that 1) the appearance of MPO in the plasma (or lymph) may be a useful neutrophil marker for neutrophil activation in vivo and may prove useful in following the course of neutrophil-mediated tissue injury during endotoxemia, and 2) endotoxin-activated complement (C5a) activates neutrophils to produce cytotoxic oxidants.
Cardiopulmonary responses to continuous administration of endotoxin
Authors: Traber D. L. , Redl H. , Schlag G. , Herndon D. N. , Kimura R. , Prien T. , Traber L. D.
Published: December 2017

The cardiopulmonary response to continuous administration of lipopolysaccharide (LPS) was studied in chronically instrumented sheep. LPS was administered in doses of 0 (sham), 6, 9, 12, and 24 ng.kg-1.h-1 for 24 h. No significant changes in the measured variables occurred in the sham group and in the 6 ng.kg-1.h-1-LPS group. With 9, 12, and 24 ng.kg-1.h-1-LPS, cardiac index rose and peripheral resistance fell to the same extent in all three groups. Lung lymph flow (QL) increased with increasing concentration of LPS. These elevations in QL occurred in the presence of only minor increases in the pulmonary artery pressure, which rose to the same extent in the 9, 12, and 24 ng.kg-1.h-1 groups. Consequently, the changes in QL were attributable to changes in fluid conductance of the pulmonary microvasculature rather than variations in hydrostatic pressure. The increase in QL correlated with a decrease in prekallikrein levels (r = 0.97), indicating that the changes in fluid conductance might have been kinin mediated.
Dobutamine modifies myocardial infarct size through supply-demand balance
Authors: Miura T. , Yoshida S. , Iimura O. , Downey J. M.
Published: December 2017

We investigated dobutamine effect on infarct size during permanent coronary artery occlusion in dogs. The coronary artery of closed-chest dog was embolized by a 2.5-mm Teflon bead. Regional flow was measured 8 min after embolization with microspheres and, in drug-treated animals, again 20 min after starting dobutamine infusion (10 micrograms.kg-1.min-1 for 5 h immediately after the first microsphere measurement). The percent of the ischemic region progressing to infarct was determined 48 h later in each animal. Percent necrosis in the control group correlated closely with collateral flow to the epicardial one-third of the ischemic zone normalized against flow to the corresponding layer in the nonischemic zone. This flow should reflect an index of supply (collateral flow) and demand (flow to the nonischemic region determined by autoregulation). Percent necrosis in the drug-treated group did not correlate with normalized collateral flow measurement made before drug infusion, indicating that dobutamine had modified the course of infarction. Percent necrosis correlated well with normalized collateral flow measured during drug infusion, and that relationship was not different from that in the control group. Dobutamine increased infarct size over that expected from the predrug flow measurement in some dogs and reduced it in others. In all cases, however, the drug effect on infarct size was clearly reflected in normalized collateral flow measurement during drug infusion. Percent necrosis correlated with absolute collateral flow but less closely than with the normalized one.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood pressure increases after injection of neuropeptide Y into posterior hypothalamic nucleus
Authors: Martin J. R. , Beinfeld M. C. , Westfall T. C.
Published: December 2017

Unilateral microinjection of neuropeptide Y (NPY; 0.235-2.35 nmol) into the posterior hypothalamic nucleus was found to evoke a concentration-dependent increase in mean arterial pressure (MAP) of Urethane-anesthetized rats. Concentration-dependent pressor responses were also elicited by unilateral administration of histamine (0.543-17.9 nmol) into the posterior hypothalamic nucleus. Administration of 30 nmol of the histamine H1-receptor antagonist, chlorpheniramine, but not 43.5 nmol of the histamine H2-receptor antagonist, cimetidine, into the posterior hypothalamic nucleus 10 min before 5.43 nmol histamine administration, significantly attenuated the histamine-induced pressor response. These concentrations of chlorpheniramine or cimetidine did not affect the increase in MAP, which could be evoked by the administration of 5.48 nmol of the cholinergic muscarinic agonist carbachol into the posterior hypothalamic nucleus. The carbachol-induced increase in MAP was, however, completely blocked by administration of 12 nmol of the cholinergic muscarinic antagonist atropine into the posterior hypothalamic nucleus 10 min before carbachol administration. This concentration of atropine did not affect the histamine-induced pressor response. Administration of atropine or chlorpheniramine into the posterior hypothalamic nucleus 10 min before 2.35 nmol NPY significantly attenuated the pressor response evoked by NPY. Cimetidine, on the other hand, was unable to significantly affect the increase in MAP evoked by NPY. These results demonstrate that NPY administered into the posterior hypothalamic nucleus can elicit a pressor response, and that this pressor response might involve local histaminergic and cholinergic neuronal pathways.
Effect of pathological blood histamine levels on canine coronary vascular permeability
Authors: Pilati C. F. , Maron M. B.
Published: December 2017

We evaluated the effect of systemically administered histamine on coronary vascular permeability (CVP) of pentobarbital-anesthetized, open-chest dogs with and without beta-receptor blockade. We determined changes in CVP by comparing prenodal cardiac lymph flow and lymph-to-plasma protein concentration ratio before and after 30 min of histamine infusion. Histamine was infused into the left ventricle at 150 micrograms/min to produce pathological blood histamine concentrations of approximately 0.5 micrograms/ml. Histamine increased CVP in only one of seven dogs without beta-receptor blockade but increased CVP in four of seven beta-blocked animals. In a second series of experiments, the effect of histamine on CVP was assessed in an in situ isolated heart-lung preparation. In this preparation, similar blood histamine concentrations increased CVP in the same fraction of experiments (4 of 7) as was observed for beta-blocked dogs. Therefore, isolating the heart from the effects of all systemically derived histamine antagonistic substances did not appear to make the coronary vessels any more vulnerable to histamine than only blocking the actions of catecholamines. We conclude that 1) catecholamines provide protection for the coronary microvasculature against histamine-induced increases in the CVP; and 2) the probability that vascular permeability will increase in the heart when histamine exposure occurs through the general circulation is remote. Thus, if histamine-induced increases in CVP occur, then they probably result from the release of histamine from myocardial storage sites.
Periarteriolar and tissue PO2 during sympathetic escape in skeletal muscle
Authors: Boegehold M. A. , Johnson P. C.
Published: December 2017

The purpose of this study was to determine whether vascular escape from sympathetic nerve stimulation in skeletal muscle is caused by a fall in the tissue O2 level. O2 microelectrodes were used to measure PO2 at the wall of arterioles (periarteriolar PO2) and near the venous end of capillary networks (parenchymal tissue PO2) in the exteriorized cat sartorius muscle during sympathetic nerve stimulation. Measurements were made under a low O2 suffusate (equilibrated with 5% CO2-95% N2) and under a high O2 suffusate (10% O2-5% CO2-85% N2). During sympathetic stimulation under low O2, mean diameter of proximal (second-order) arterioles decreased from 55 to 32 micron before returning to 37 micron (sympathetic escape). Mean periarteriolar PO2 fell from 50 to 25 mmHg with no secondary increase. Distal (fifth-order) arterioles initially constricted from 7 to 4 micron before relaxing to 6 micron. Periarteriolar PO2 of these vessels fell from 40 to 13 mmHg with no secondary increase. During stimulation under high O2, periarteriolar PO2 levels of both proximal and distal arterioles were similar to those under low O2, yet escape was substantially reduced. The lack of relationship between periarteriolar PO2 and vascular escape argues against a role of vascular wall PO2 in this behavior. Parenchymal tissue PO2 fell to 9 mmHg during stimulation under low O2 but did not fall below 22 mmHg during stimulation under high O2. The attenuation of escape under conditions where tissue PO2 did not fall is consistent with the hypothesis that sympathetic escape in skeletal muscle is mediated through a fall in parenchymal cell PO2.
Evidence for lack of importance of oxygen free radicals in Escherichia coli endotoxemia in dogs
Authors: Novotny M. J. , Laughlin M. H. , Adams H. R.
Published: December 2017

Reactive oxygen species have been proposed as pathophysiological factors responsible for the hypodynamic circulatory response to gram-negative endotoxin. To test this hypothesis, we examined the cardiorespiratory effects of mechanistically different oxygen free radical scavenging agents during Escherichia coli endotoxemia in beagle dogs. Pentobarbital-anesthetized dogs were instrumented for repeated sampling of cardiorespiratory, hematologic, and tissue blood flow (radiolabeled 15-micron microspheres) indexes. Four groups were studied: 1) time-matched control dogs (n = 6); 2) dogs receiving only endotoxin (1.5 mg/kg; n = 6); 3) dogs receiving endotoxin and combination therapy with allopurinol (150 mg/kg) plus superoxide dismutase (5 mg/kg) and catalase (5 mg/kg; n = 6); and 4) dogs receiving endotoxin and deferoxamine (30 mg/kg; n = 5). Measured variables in control dogs were constant during the 4-h study, whereas endotoxin-injected dogs consistently demonstrated the following: 1) maintained reductions in blood pressure (greater than 45%), left ventricular systolic pressure (greater than 43%), left ventricular maximum rate of pressure development (+/- dP/dtmax) (greater than 41%), cardiac index (greater than 33%), and blood flow in all sampled tissues except liver and skeletal muscle; 2) transient tachypnea, bradycardia, and arterial acidosis; and 3) persistent neutropenia and hemoconcentration. Neither of the free radical scavenging protocols significantly improved measured variables during endotoxemia (P greater than 0.05). This lack of efficacy suggests that superoxide anion, hydrogen peroxide, and hydroxyl radical may lack primary pathophysiological importance during the development of E. coli endotoxicosis in intact dogs.
Adenosine potentiates insulin-stimulated myocardial glucose uptake in vivo
Authors: Law W. R. , Raymond R. M.
Published: December 2017

Myocardial adenosine (ADO) has long been regarded as a regulator of coronary blood flow. In other tissues, such as adipose and skeletal muscle, much attention has focused on the role of ADO as a metabolic regulator of the actions of insulin. In the present study, we determined the effect of ADO infusion on insulin-stimulated myocardial glucose uptake (MGU). Mongrel dogs of either sex were instrumented to obtain arterial-coronary sinus differences for glucose, lactate, and oxygen. These were multiplied by circumflex artery blood flow (Q) to obtain uptake values. Measurements were made before and during hyperinsulinemic (4 U/min)-euglycemic clamp (clamp) with intracoronary infusions of saline, ADO, adenosine deaminase (ADA), or nitroprusside (NP). During clamp, MGU increased from a basal value of 3.0 +/- 0.8 mg/min (mean +/- SE) to 5.53 +/- 0.8 mg/min. Adenosine infusion potentiated this response, raising MGU further to 9.02 +/- 1.1 mg/min while not significantly affecting lactate or oxygen uptakes. Infusion of ADA confirmed the specificity of the response by blocking the metabolic effect of exogenously infused ADO. When NP was infused, Q increased significantly without altering MGU, indicating that the metabolic response to ADO was independent of the changes it caused in Q. A dose-response relationship existed between ADO and insulin-stimulated MGU. The metabolic response to ADO was more sensitive than the vasodilator response. It is concluded that ADO acts as a regulator of insulin in heart. This metabolic regulation occurs independent of changes in coronary blood flow.
Vasorelaxation and vascular binding sites for atrial natriuretic peptide in pregnant rats
Authors: St-Louis J. , Parent A. , Gutkowska J. , Genest J. , Schiffrin E. L.
Published: December 2017

To investigate the role of atrial natriuretic peptide (ANP) in pregnancy, we measured, in cyclic and pregnant female rats (9- and 21-days pregnant), the vascular responsiveness to ANP using helical strips of the thoracic aorta, the binding characteristics of 125I-labeled ANP in a membrane preparation of the mesenteric vascular bed, and the plasma level and the atrial content of immunoreactive ANP (IR-ANP). On aorta strips, concentration-response (C-R) curves to phenylephrine (PE) were measured and were slightly displaced to the right in the aorta of both groups of pregnant rats in comparison with the cyclic rats. There was a potentiation of the relaxant response of ANP on the PE-precontracted aortic strips of 9-day pregnant rats but it was not statistically modified in tissues of 21-day pregnant rats in comparison with strips from cyclic rats. The number of binding sites (Bmax) for ANP in the mesenteric vascular bed was similar in cyclic rats and the two groups of pregnant rats. The dissociation constant (KD) of ANP was lower in 9-day pregnant rats than in cyclic and 21-day pregnant ones. Plasma IR-ANP was not different in 9-day pregnant rats and cyclic rats but was markedly decreased at the end of gestation. Atrial content of IR-ANP increased at the end of gestation, but not in midpregnancy in comparison with cyclic rats. These results indicate that despite the reported important increase in blood volume during gestation the secretion of ANP is not increased and suggest that the ANP-volume relationship is reset during pregnancy in the rat.
Functional consequences of acute anterior vs. posterior wall ischemia in canine left ventricles
Authors: Hoit B. D. , Lew W. Y.
Published: December 2017

We compared the consequences of acute anterior and posterior wall ischemia on regional left ventricular function in seven open-chest dogs. Circumferentially oriented sonomicrometers were implanted in the midwall of the anterior and posterior left ventricle. The left anterior descending (LAD) and left circumflex (LCX) coronary arteries were each occluded for 3 min, with 45 min of reperfusion between the two occlusions. The ischemic areas at risk, as assessed by postmortem perfusion techniques, were similar for anterior (34.5 +/- 12.5 g) and posterior (32.3 +/- 9.4 g) wall ischemia. Both occlusions produced a similar increase in end-diastolic pressure. After LAD occlusion, total segment shortening (end diastole to aortic valve closure) in the nonischemic posterior wall increased from 8.0 +/- 3.9 to 10.8 +/- 4.4%, solely caused by increased isovolumic shortening. In contrast, with LCX occlusion, total segment shortening in the nonischemic anterior wall increased significantly more, from 10.5 +/- 3.8 to 14.6 +/- 4.2% caused by nearly equal increases in isovolumic and ejection phase shortening. Thus, with both LAD and LCX occlusions, there was increased shortening in nonischemic areas during isovolumic systole, which was “wasted” in paradoxically stretching the ischemic zone. However, a compensatory increase in nonischemic area ejection phase shortening occurred only with LCX occlusions. These findings may explain the greater functional impairment that occurs with LAD than LCX occlusions.
Basis for tetrodotoxin and lidocaine effects on action potentials in dog ventricular myocytes
Authors: Wasserstrom J. A. , Salata J. J.
Published: December 2017

We studied the effects of tetrodotoxin (TTX) and lidocaine on transmembrane action potentials and ionic currents in dog isolated ventricular myocytes. TTX (0.1-1 x 10(-5) M) and lidocaine (0.5-2 x 10(-5) M) decreased action potential duration, but only TTX decreased the maximum rate of depolarization (Vmax). Both TTX (1-2 x 10(-5) M) and lidocaine (2-5 x 10(-5) M) blocked a slowly inactivating toward current in the plateau voltage range. The voltage- and time-dependent characteristics of this current are virtually identical to those described in Purkinje fibers for the slowly inactivating inward Na+ current. In addition, TTX abolished the outward shift in net current at plateau potentials caused by lidocaine alone. Lidocaine had no detectable effect on the slow inward Ca2+ current and the inward K+ current rectifier, Ia. Our results indicate that 1) there is a slowly inactivating inward Na+ current in ventricular cells similar in time, voltage, and TTX sensitivity to that described in Purkinje fibers; 2) both TTX and lidocaine shorten ventricular action potentials by reducing this slowly inactivating Na+ current; 3) lidocaine has no additional actions on other ionic currents that contribute to its ability to abbreviate ventricular action potentials; and 4) although both agents shorten the action potential by the same mechanism, only TTX reduces Vmax. This last point suggests that TTX produces tonic block of Na+ current, whereas lidocaine may produce state-dependent Na+ channel block, namely, blockade of Na+ current only after Na+ channels have already been opened (inactivated-state block).
Role of median preoptic area in vasopressin-mediated bradycardia
Authors: Patel K. P. , Schmid P. G.
Published: December 2017

To determine whether neural traffic through the median preoptic nucleus (MnPO) is involved in arginine vasopressin (AVP)-mediated bradycardia and sympathoinhibition, we recorded reflex decreases in heart rate (HR) and lumbar sympathetic nerve activity, in response to increases in arterial pressure induced either by intravenous phenylephrine (PE) or AVP before, during, and after local administration of lidocaine (200 nl, 2%) in the MnPO of chloralose-anesthetized rabbits. Base-line blood pressure and HR did not change in response to administration of lidocaine into the MnPO. Blockade of neural traffic (by lidocaine) in the MnPO produced an attenuation of AVP-mediated bradycardia but not the baroreflex-mediated bradycardia caused by PE. Lidocaine in the MnPO did not alter the sympathoinhibition produced with AVP. These results indicate that part of the bradycardia produced by AVP is mediated via forebrain structures such as the MnPO and is selective for bradycardia. Additionally, this response was mimicked by administration of yohimbine, an alpha 2-antagonist, into the MnPO, which suggests that noradrenergic mechanisms are involved in the baroreflex-mediated facilitation of bradycardia by AVP at the level of the MnPO.
Acute saline loading in normal and bilaterally atrial-resected conscious dogs
Authors: Cowley A. W. , Anderas P. R. , Skelton M. M.
Published: December 2017

Acute isotonic saline volume loads (400 ml) were intravenously administered to conscious, renal-denervated dogs before and after bilateral removal of the atrial free walls and atrial appendages to determine the role of atrial-mediated hormonal factors in the renal excretory response. In one group of dogs (n = 11), the volume was given in 10 min; in another group (n = 5), the volume was given in 30 min while arginine vasopressin (AVP) was infused to maintain plasma AVP at a fixed, normal level (3 pg/ml). Sodium and water excretion, mean arterial pressure, and plasma hormone levels were determined before and for 5 h after volume loads. Atrial resection resulted in a 40-50% reduction of sodium and water excretion in both groups during the first 2 h after volume expansion. The blunted renal excretory responses could not be explained by differences in arterial pressure, renal sympathetic nerve activity, or by hormonal differences of plasma immunoreactive atrial natriuretic factor (iANP), plasma AVP, plasma renin activity, or plasma aldosterone. Plasma iANP was not significantly increased by the volume load in either the normal or atrial-resected state. Atrial-resected dogs exhibited normal plasma levels of iANP. The data indicate the presence of an unidentified diuretic and natriuretic substance, which is released with volume expansion from either the cardiac atria or via the central nervous system, and that the release of this factor is removed by atrial resection.
Effects of L-propionylcarnitine on mechanical recovery during reflow in intact hearts
Authors: Liedtke A. J. , DeMaison L. , Nellis S. H.
Published: December 2017

We tested the influence of L-propionylcarnitine (LPC) in modifying mechanical stunning during reflow. Nineteen adolescent anesthetized swine were extracorporeally perfused at control coronary flows for 20 min, supplemented with excess fatty acids (average values 1.1 +/- 0.1 mumol/ml), and subjected to 45 min regional ischemia (-60 delta % decrease in anterior descending flow) followed by 35 min reperfusion. Responses in 10 placebo hearts were compared with those obtained from 9 animals treated with 50 mg/kg LPC at 0 min perfusion and 40 mg/kg at 40 min perfusion. Ischemia in placebo hearts caused a 62.6 delta % decrease in active shortening in anterior descending bed, which failed to recover (-41.4 delta % from control values) during reflow. Conversely, in LPC-treated hearts, decreases in active shortening (-38.6 and -11.6 delta %) during ischemia and reflow, respectively, were significantly smaller (P less than or equal to 0.05). This improved motion was associated with greater rates of myocardial oxygen consumption but similar levels of fatty acid oxidation and fatty acid intermediates. Thus LPC significantly reversed mechanical stunning in myocardial ischemia/reperfusion protocols, presumably because of its positive inotropic properties. This derivative, otherwise innocuous in nature, could represent an attractive new treatment choice for future clinical use.
Effects of altered left atrial pressure on pulmonary vascular pressure-flow relationships
Authors: Ducas J. , Schick U. , Girling L. , Prewitt R. M.
Published: December 2017

We studied the effects of changes in pulmonary capillary wedge pressure (PCWP) on the slope (incremental resistance) and the extrapolated pressure intercept (PI) of the mean pulmonary artery pressure (PAP)-cardiac output (CO) relationship. Multipoint plots of PAP against CO were obtained in intact anesthetized dogs. Group 1 consisted of six dogs entirely in West zone 3 and group 2 of four dogs with mixed West zone 2-3. The four conditions studied were the following: 1) fixed low PCWP, 2) fixed high PCWP, 3) variable PCWP, and 4) time-control repeat of condition 1. The PI significantly exceeded PCWP at fixed low PCWP (group 1, 9.3 vs. 11.1 mmHg, group 2, 6.6 vs. 3.9 mmHg). PI became identical to PCWP only at fixed high PCWP in group 1 (19 +/- 2.0 vs. 19 +/- 1.1 mmHg). Thus PCWP reflects the effective vascular outflow pressure when PCWP is fixed and high. For both groups of dogs in condition 3, when PCWP was varied with CO, the slope of the resulting PAP-CO plot was significantly greater than when PCWP was constant. Also in 9 of 10 dogs, PI was less than PCWP when PCWP was varied. These findings demonstrate that when changes in PCWP are allowed to occur during the generation of a pulmonary artery pressure-flow plot, the resulting slope and intercept, as defined by a Starling resistor model, do not accurately represent the incremental resistance and outflow pressure of the pulmonary vasculature.
Allopurinol does not enhance antioxidant properties of extracellular fluid
Authors: Zimmerman B. J. , Parks D. A. , Grisham M. B. , Granger D. N.
Published: December 2017

Allopurinol has been shown to provide significant protection against ischemia/reperfusion-induced microvascular and parenchymal cell injury. It has been hypothesized that the protection seen with allopurinol after ischemia/reperfusion (I/R) is caused by inhibition of xanthine oxidase. However, recent reports suggest that the beneficial effects of allopurinol in I/R may be caused by direct free radical scavenging. The objective of this study was to determine whether the regimen of allopurinol administration used in most I/R studies leads to a significant modification of the free radical scavenging properties of extracellular fluid (ECF), i.e., plasma and lymph. Plasma and intestinal lymph samples obtained from both control and allopurinol-treated cats were used to assess the following: 1) allopurinol and oxypurinol concentrations, 2) xanthine oxidase inhibition, 3) myoglobin-catalyzed linolenic acid peroxidation, 4) hypochlorous acid scavenging, and 5) protein and nonprotein sulfhydryl content. ECF from allopurinol-treated animals contained approximately 10 microM each of allopurinol and oxypurinol. Ten percent ECF resulted in 80% inhibition of xanthine oxidase activity. Comparable volumes of control ECF did not inhibit xanthine oxidase. Furthermore, allopurinol treatment did not enhance the antioxidant properties of ECF. The results of this study do not support the contention that the beneficial effects of allopurinol in I/R injury are caused by the scavenging of oxidants produced in ECF by activated granulocytes.
Nitric oxide, ACh, and electrical and mechanical properties of canine arterial smooth muscle
Authors: Komori K. , Lorenz R. R. , Vanhoutte P. M.
Published: December 2017

The effects of nitric oxide and acetylcholine (ACh) were investigated on the electrical and mechanical properties of vascular smooth muscle cells of the canine mesenteric artery. Isolated tissues with or without the endothelium were contracted with prostaglandin F2 alpha. Nitric oxide caused comparable concentration-dependent relaxations in rings with and without endothelium. ACh induced concentration-dependent relaxations only in arteries with endothelium. The relaxations to both nitric oxide and ACh were inhibited by methylene blue or oxyhemoglobin. Either in the presence or absence of prostaglandin F2 alpha, ACh caused transient hyperpolarization of the cell membrane of the vascular smooth muscle. The ACh-induced transient hyperpolarization was not observed after mechanical removal of the endothelial cells or after treatment with atropine. Nitric oxide (less than or equal to 8 X 10(-6) M) did not alter membrane potential, in either the presence or absence of the endothelium. The excitatory junction potentials generated by perivascular nerve stimulation were inhibited by ACh but not by nitric oxide. These results suggest that in the canine mesenteric artery 1) the endothelium-derived hyperpolarizing factor generated by ACh is not nitric oxide; 2) nitric oxide relaxes vascular smooth muscle by a direct effect; and 3) nitric oxide does not modify adrenergic neurotransmission.
Increased response of brachial artery diameter to norepinephrine in hypertensive patients
Authors: Laurent S. , Juillerat L. , London G. M. , Nussberger J. , Brunner H. , Safar M. E.
Published: December 2017

The hyperresponsiveness of small arteries to norepinephrine is well documented in essential hypertensive patients. Our objective was to investigate in situ the reactivity to norepinephrine of the diameter of large arteries, which are involved in the arterial disease of hypertension as well as small arteries. Brachial artery diameter, blood flow velocity, local volumic blood flow, and local vascular resistances were determined noninvasively with a pulsed Doppler system in 19 patients with essential hypertension and 9 normotensive subjects, before and after the administration of placebo (glucose) or increasing doses of norepinephrine (10, 20, and 40 ng.kg-1.min-1 iv) given in a single-blind fashion. In hypertensive patients, norepinephrine (40 ng.kg-1.min-1) induced 1) a significant decrease in brachial artery diameter, local blood velocity, volumic flow, and conductance and 2) a small increase in mean arterial pressure. These hemodynamic changes did not occur in the placebo group and were significantly greater in hypertensive patients than in normotensive subjects, although plasma norepinephrine increased to the same extent in both groups. We conclude that in hypertensive patients the increase in vascular reactivity to norepinephrine involves not only the resistive vessels but also the large arteries thus decreasing their conducting and buffering function.