bluuebunny/crossref_metadata_2025 huggingface dataset:
Microvascular volume contribution to hemorrhage compensation
Authors: Price R. J. , Lee J. S. , Skalak T. C.
Published: December 2017

Regulation of systemic blood pressure during small changes in blood volume is partially achieved by blood volume shifts from microcirculation to macrocirculation that cause a decrease in systemic hematocrit [LaForte, A., L. Lee, G. Rich, T. Skalak, and J. Lee. Am. J. Physiol. 262 (Heart Circ. Physiol. 31): H190–H199, 1992]. Diameters of 4–100 microns arterioles and 5–80 microns venules in spinotrapezius muscles of anesthetized rats were measured during control conditions and immediately after a 13% (of total blood volume) hemorrhage to determine the role of the microvasculature in hemorrhage compensation. The Strahler orders, mean control diameters (microns), and posthemorrhage diameters (% of control) were as follows: TA2, 5.7 (91.2%); TA3, 8.7 (90.4%); TA4, 12.5 (85.4%); TA5, 31.4 (95.8%); AA, 39.6 (94.6%); CV2, 8.0 (94.7%); CV3, 14.8 (93.7%); CV4, 24.6 (95.2%); CV5, 41.5 (98.8%); and AV, 47.8 (97.8%), where TA, AA, CV, and AV designate transverse arteriole, arcade arteriole, collecting venule, and arcade venule, respectively. The diameter reductions were heterogeneous for arterioles and venules, with significant variation in small arterioles (< 25 microns), which exhibited dimensions ranging from 61 to 100% of control, whereas larger arterioles ranged from 81 to 100% of control. The data were used with an anatomic model to estimate the systemic hematocrit decrease (0.73%) and the blood volume shifted from the microcirculation to the macrocirculation (3.74% of total control blood volume). These results agree well with direct measurements of the systemic hematocrit decrease and thus provide the microvascular basis for the rapid blood volume shift during moderate hemorrhage.
Hemodynamic variability and circadian rhythm in rats with heart failure: role of locomotor activity
Authors: Teerlink J. R. , Clozel J. P.
Published: December 2017

Heart rate variability is known to be decreased by heart failure; however, the influences of concomitant diseases, changes in activity level, evolution through time, and abnormalities in the circadian rhythm are unknown. This study evaluated the influence of these factors by assessing hemodynamic variability in rats with heart failure (n = 8) and sham-operated controls (n = 8) through telemetric monitoring of heart rate, blood pressure, and locomotor activity for 8 wk. Hemodynamic variability was assessed by the standard deviation as well as hourly standard deviations and coefficients of variation of these variables over 48 h at 2, 4, and 8 wk after myocardial infarction. The circadian rhythm was investigated through power spectral analysis. Heart failure was associated with marked decreases in heart rate and mean arterial pressure variability and circadian rhythm without any differences in activity and no change through time. Heart failure in rats due to myocardial infarction in the absence of any confounding diseases is associated with marked abnormalities in hemodynamic variability and circadian rhythm independent of locomotor activity.
Tumor necrosis factor is a mediator of phospholipase release during bacteremia in baboons
Authors: Redl H. , Schlag G. , Schiesser A. , Davies J.
Published: December 2017

Phospholipase A (PLA) activity is elevated in plasma after polytrauma and in sepsis. During both situations, tumor necrosis factor (TNF) and free fatty acids (FFAs) are also increased. To determine whether there is a relationship between the changes in PLA and in TNF that occur during sepsis, we used a primate model of bacteremia. Live Escherichia coli (5 x 10(8) colony-forming units/kg) was injected into anesthetized baboons (n = 10). Four of these animals were pretreated with an anti-TNF antibody (anti-TNF Ab, 15 mg/kg). After the administration of bacteria (2 h), the plasma TNF was 10.2 +/- 3.2 ng/ml. PLA and FFA reached their maximum values of 191 +/- 14 U/l and 1.5 +/- 0.3 mM at 10 and 24 h after the injection of bacteria, respectively. In the animals treated with anti-TNF Ab, plasma TNF was undetectable; the highest values recorded for PLA and FFA were 71 +/- 23 U/l and 0.7 +/- 0.3 mM, respectively. Thus TNF appears to be an important mediator of PLA release during sepsis.
Endothelium, vasopressin receptors, and resistance to DOCA-salt hypertension
Authors: Bockman C. S. , Jeffries W. B. , Pettinger W. A. , Abel P. W.
Published: December 2017

Mesenteric artery rings from Wistar and Wistar-Furth rats subcutaneously treated with deoxycorticosterone acetate (DOCA) and 1% NaCl drinking water were used to measure endothelial modulation of contractile sensitivity and vasopressin receptor function and affinity. DOCA-salt hypertension reduced contractile sensitivity to arginine vasopressin (AVP) and did not affect contractile sensitivity to norepinephrine in arteries from Wistar rats. Endothelial removal caused a threefold increase in contractile sensitivity to AVP and norepinephrine in DOCA-salt hypertensive Wistar rats. In Wistar-Furth rats, DOCA-salt treatment did not affect contractile sensitivity to AVP, lysine vasopressin, oxytocin, and norepinephrine or the affinity of the vasopressin receptor for agonists or antagonists. Removal of endothelium did not affect vasopressin contractile sensitivity but caused a 15-fold increase in contractile sensitivity to norepinephrine in untreated or DOCA-salt-treated Wistar-Furth rats. These data show that reduced vasopressin receptor function and increased endothelial function that compensate for increased contractile sensitivity in arteries from DOCA-salt hypertensive Wistar rats are not the cause of resistance of DOCA-salt-treated Wistar-Furth rats to the development of enhanced contractile sensitivity and hypertension.
Induction of heat shock response leads to apoptosis in endothelial cells previously exposed to endotoxin
Authors: Buchman T. G. , Abello P. A. , Smith E. H. , Bulkley G. B.
Published: December 2017

The homeostatic response of complex eukaryotes to the challenge of environmental stress includes the induction of several programs of gene expression; among them are those for the acute phase genes and those for the heat shock genes. In some systems, the heat shock response, which is often elicited by more severe stimuli, preempts the acute phase response, which is seen in response to less severe challenges, as well as constitutive gene expression. Nevertheless, each response appears to provide a natural selective advantage for survival of the organism in a toxic environment. However, when cultured porcine endothelial cells were exposed first to a nonlethal level of bacterial endotoxin lipopolysaccharide (LPS), an inducer of the acute phase response, and then, simultaneously to standard stimuli, which normally elicit a salutary heat shock response, the cells died manifesting a pattern of DNA fragmentation (nucleolysis) characteristic of programmed cell death (apoptosis). The treatment of LPS-exposed cells with cycloheximide to block protein synthesis reproduced the lethal apoptosis that had been elicited by the induction of heat shock gene expression. Therefore, the preemption of other programs of stress gene expression by the prioritized expression of heat shock genes is associated with apoptosis.
Age-associated increase in rat cardiac opioid production
Authors: Boluyt M. O. , Younes A. , Caffrey J. L. , O'Neill L. , Barron B. A. , Crow M. T. , Lakatta E. G.
Published: December 2017

Several lines of evidence suggest that opioid peptide production in the heart may increase during aging from adulthood through senescence. We tested the hypothesis that cardiac opioid peptides and preproenkephalin (PNK) mRNA would increase with advancing age. Ventricles and atria from male Wistar rats, aged 2, 6, 18, and 22–24 mo of age, were acid extracted and assayed for methionine enkephalin (ME) and leucine enkephalin (LE). Total RNA was extracted from hearts of age-matched rats and probed for PNK mRNA by Northern blot analysis using a cDNA probe. ME and LE peptides were significantly elevated with advancing age in both ventricles [P < 0.001; by analysis of variance (ANOVA)]. Ventricular ME concentration exhibited a biphasic increase with approximately twofold higher peaks at 6 and 22–24 mo of age compared with the 2 mo value of 1.04 +/- 0.05 (SE) pmol/g wet wt. In contrast, ventricular LE concentration was largely unchanged until 22–24 mo of age when it increased approximately threefold over the 2-mo value of 2.19 +/- 0.14 pmol/g wet wt. Left ventricular PNK mRNA increased approximately fivefold between 2 and 18 mo of age (P < 0.01; ANOVA). Thus both enkephalins and the mRNA coding for them were increased in hearts of older vs. younger rats. Because opioid receptor stimulation can negatively modulate several characteristics of cardiac myocyte contraction, these results may have important functional implications for the senescent heart.
Left ventricular adaptation to gradual renovascular hypertension in dogs
Authors: Nguyen T. N. , Chagas A. C. , Glantz S. A.
Published: December 2017

The left ventricle hypertrophies in response to chronic pressure overload. To determine whether increased beta-adrenergic stimulation, wall mass, intrinsic contractility, or a combination of these factors is responsible for improved left ventricular (LV) pump function during early development of pressure-overload hypertrophy and whether hypertrophy normalizes peak-systolic wall stress, as is commonly believed, we induced pressure overload in intact-chest dogs by gradual constriction of one renal artery and implanted radiopaque markers, via a catheter, in the LV endocardium to measure dimensions. Changes in hemodynamics, LV dimensions, contractility indexes, and circumferential wall stress were measured before and after acute beta-blockade for 12 wk. LV function improved over time in the unblocked state, indicated by increased cardiac output, systolic pressures, stroke work, and maximal elastance (Emax). Acute beta-blockade reduced stroke work, Emax, and maximal LV rate of pressure over time (dP/dtmax) relative to the unblocked state but all still increased significantly over time. dP/dtmax and Emax did not vary with increases in LV mass, but stroke work was borderline dependent on LV mass. These results suggest that beta-adrenergic stimulation contributes to improved LV pump function and that the remaining improvements are due to both increased intrinsic contractility and wall mass. In contrast to accepted theory, LV systolic wall stresses decreased significantly over time. End-diastolic wall stress increased after renal artery constriction, then returned to baseline values as the heart hypertrophied. These results suggest that hypertrophy normalizes end-diastolic, not peak-systolic, wall stress.
Effect of upright tilt on ventricular/vascular coupling in chronically instrumented primates
Authors: Tran C. C. , Latham R. D. , Self D. A. , Fanton J. W. , White C. D. , Owens R. W.
Published: December 2017

Studies of the hydraulic loading conditions on the heart in humans, especially pulsatile load, have primarily been limited to the supine state. Therefore, we have chosen a nonhuman primate model, the baboon, to assess left ventricular/vascular coupling in both supine and upright positions. Primate subjects were studied by catheterization under sedation and then after surgical implantation of transducers. This allowed the evaluation of postural stress in the chronically instrumented conscious baboon and then after light dissociative doses of ketamine. Basic hemodynamic variables were evaluated for baboons in supine and upright positions. Fourier analysis was applied to aortic pressure and flow to obtain input and characteristic impedance and the ratio of pulsatile (Wp) to total (Wt) left ventricular power (Wp/Wt). The aortic reflected, or backward, pressure was also calculated. Peripheral resistance increased (P = 0.01) and reflected pressure decreased (17.74 +/- 1.50 vs. 15.21 +/- 2 mmHg; P < 0.01) in upright subjects. Characteristic impedance and Wp/Wt were unchanged. Postoperatively, peripheral resistance increased (2,651 +/- 311 vs. 3,667 +/- 276; P < 0.05) and mean power and Wt decreased (P < 0.01) without changes in reflected pressure. All variables were unchanged after light dissociative doses of ketamine. Thus there is no significant change in efficiency of left ventricular/vascular coupling formulated in terms of Wp/Wt or input impedance with postural stress.
Altered cerebrovascular responsiveness to N-methyl-D-aspartate after asphyxia in piglets
Authors: Busija D. W. , Wei M.
Published: December 2017

We examined effects of prior asphyxia and reventilation on pial arteriolar responses to arterial hypercapnia, topical application of forskolin, and topical application of N-methyl-D-aspartate (NMDA) in newborn pigs. Piglets were anesthetized and ventilated with a respirator. Pial arteriolar diameter was determined using a closed cranial window and intravital microscopy. After baseline diameter was determined, the respirator was turned off for 10 min. Then the respirator was turned on, and the piglet was ventilated for 4 h. At 1, 2, and 4 h after asphyxia, arteriolar diameter was determined during control conditions and during arterial hypercapnia (inspiration of 10% CO2 in air; n = 4), topical application of 2.4 x 10(-8) M forskolin (n = 6), and topical application of 10(-5) M NMDA (n = 6). At 1 h after asphyxia, arterial hypercapnia dilated pial arterioles by 39 +/- 3%, topical forskolin dilated pial arterioles by 24 +/- 3%, and NMDA dilated pial arterioles by 10 +/- 1%. For arterial hypercapnia and forskolin application, arteriolar responses were not different from 1 h at 2 and 4 h postasphyxia. In contrast, for NMDA, arteriolar responses were greater at 2 h (23 +/- 6%) and 4 h (30 +/- 5%) than at 1 h. In time-control animals, NMDA dilated arterioles by 20 +/- 5% at 1 h, by 24 +/- 8% at 2 h, and by 21 +/- 4% at 4 h (n = 5). Indomethacin administration (5 mg/kg iv) before asphyxia resulted in a 23 +/- 3% arteriolar dilation in response to NMDA at 1 h (n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)
VIP and NPY in canine hearts. Distribution and effect of total and selective parasympathetic denervation
Authors: Anderson F. L. , Hanson G. R. , Reid B. , Thorpe M. , Kralios A. C.
Published: December 2017

The hypotheses that vasoactive intestinal peptide (VIP) is evenly distributed throughout atrial and ventricular myocardium and is present in postganglionic parasympathetic neurons in the regions of the sinoatrial and atrioventricular nodes were tested in three groups of dogs. Neuropeptide Y (NPY) tissue concentrations were determined in each group. In six sham dogs VIP and NPY concentrations were evenly distributed and were higher in atria compared with ventricles. In nine parasympathectomized dogs, VIP concentrations in sample sites from regions of the sinoatrial and atrioventricular nodes were comparable to those in sham-operated controls. In nine denervated dogs VIP concentrations were significantly decreased in three adjacent sample sites along the atrioventricular groove. In these dogs NPY concentrations were not detectable or were significantly decreased at all sample sites of both atria and ventricles. These data suggest that VIP neurons are evenly distributed in atrial and ventricular myocardium but do not originate in parasympathetic ganglia supplying the sinoatrial and atrioventricular nodes. The data also demonstrate the possible presence of extrinsic VIP neurons in the canine right ventricle and indicate that NPY may be a useful marker of myocardial adrenergic innervation.
A method of determining electrical potential gradient across mitochondrial membrane in perfused rat hearts
Authors: Wan B. , Doumen C. , Duszynski J. , Salama G. , LaNoue K. F.
Published: December 2017

The electrical potential gradient across the mitochondrial membrane (delta psi m) in perfused rat hearts was estimated by calculating the equilibrium distribution of the lipophilic cation tetraphenylphosphonium (TPP+), using measured kinetic constants of uptake and release of TPP+. First-order rate constants of TPP+ uptake were measured during 30-min perfusions of intact rat hearts with tracer amounts (5.0 nM) of tritium-labeled TPP+ ([3H]TPP+) in the perfusate. This was followed by a 30-min washout, during which the first-order rate constant of efflux was estimated. Values of [3H]TPP+ outside the heart and total [3H]TPP+ inside the heart at equilibrium were calculated. From this information and separately estimated time-averaged plasma membrane potentials (delta psi c) it was possible to calculate free cytosolic [3H]TPP+ at equilibrium. It was also possible to calculate free intramitochondrial [3H]TPP+ at equilibrium as the difference between total tissue [3H]TPP+ minus free cytosolic TPP+ and the sum of all the bound [3H]TPP+. Bound [3H]TPP+ was determined from [3H]TPP+ binding constants measured in separate experiments, using both isolated mitochondria and isolated cardiac myocytes under conditions where both delta psi m and delta psi c were zero. Delta psi m was calculated from the intramitochondrial and cytosolic free TPP+ concentrations using the Nernst equation. Values of delta psi m were 144.9 +/- 2.0 mV in hearts perfused with 5 mM pyruvate and 118.2 +/- 1.4 mV in hearts perfused with 11 mM glucose, in good agreement with delta psi m obtained from isolated rat heart mitochondria.(ABSTRACT TRUNCATED AT 250 WORDS)
Increase in endogenous antioxidant enzymes protects hearts against reperfusion injury
Authors: Kirshenbaum L. A. , Singal P. K.
Published: December 2017

Coarctation of the abdominal aorta in rats for 10 wk increased the heart weight-to-body weight ratio by 36% and peak left ventricular systolic pressure by 75%; there was no apparent change in the end-diastolic pressure, and animals did not show any clinical signs of heart failure. These hypertrophied (H) hearts showed increased activities of superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) with no change in catalase. Lipid peroxide content as indicated by the malondialdehyde (MDA) level was lower in H hearts. There was no apparent difference in either Na+ and Ca2+ content or high-energy phosphates between sham (S) and H hearts. Control and H hearts were subjected to 10 min of ischemia (I) and 15 min of reperfusion (R). Contractile failure and rise in resting tension due to I, in both S and H hearts, were comparable. On reperfusion, H hearts showed better recovery of the developed force and resting tension as well as reduced incidence of arrhythmias when compared with corresponding S hearts. Both SOD and GSHPx activities were depressed due to I-R, but these activities were significantly higher in reperfused H hearts. Reperfused H hearts also showed a better maintenance of the ultrastructure and Na+ and Ca2+ contents, recovery of high-energy phosphates, and reduced MDA levels compared with S hearts. Supplementation of the perfusion medium with SOD (120 U/ml) and catalase (80 U/ml) significantly attenuated the I-R injury in S hearts, and the response in many ways was comparable to H hearts. The study documents the therapeutic potential of increased myocardial endogenous antioxidants against oxidative stress.
Influence of endothelial surface on flow velocity in vitro
Authors: Reinhart W. H. , Boulanger C. M. , Luscher T. F. , Haeberli A. , Straub P. W.
Published: December 2017

The influence of the endothelial surface and its interaction with various plasma components on flow velocity was investigated in vitro. The falling velocity of microcarrier beads with and without cultured porcine aortic endothelial cells in a vertical tube containing different media was recorded with a video system attached to a light microscope. The falling velocity of the beads was in agreement with values predicted from Stokes's law. Endothelium did not affect the falling velocity in various media, except in plasma, where it was slower than expected. Fibrinogen was found to have a strong surface tension effect, disturbing viscosity measurements, and to bind to endothelial cells and collagen-coated surfaces. We conclude that the endothelial surface may interact with plasma and plasma constituents such as fibrinogen in a way that affects blood flow.
Capillary perfusion during incomplete forebrain ischemia and reperfusion in rat brain
Authors: Theilen H. , Schrock H. , Kuschinsky W.
Published: December 2017

Previous studies have shown a complete plasma perfusion of all capillaries in the rat brain under normal physiological conditions. This raises the question under which experimental conditions nonperfused capillaries may show up in the brain. Two experimental models were investigated in rats. 1) Reduced cerebral blood flow (CBF) during incomplete forebrain ischemia: hemorrhagic hypotension was maintained for 30 min at a mean arterial blood pressure of 41 mmHg. During the final 5 min of hypotension both carotid arteries were ligated. 2) Reperfusion after incomplete forebrain ischemia: reperfusion lasted for 4 h after either 15 or 30 min of incomplete forebrain ischemia. Under both experimental conditions, the density of the existing as well as the plasma-perfused brain capillary network was quantified using fluorescent double staining. Local CBF was measured during incomplete forebrain ischemia using the quantitative autoradiographic 4-iodo-[N-methyl-14C]antipyrine technique. The results showed a decrease in CBF during incomplete forebrain ischemia, which amounted up to 94%. Whereas normotensive control animals showed a complete staining of all capillaries within 5 s after the intravenous injection of Evans blue, this period of time was increased to 10 s during incomplete forebrain ischemia, indicating a delayed capillary perfusion. Four hours of reperfusion after 15 min of incomplete forebrain ischemia resulted in a complete capillary staining, whereas reperfusion after 30 min of ischemia was followed by intracerebral bleedings and a few nonperfused capillary areas (circulation time of Evans blue: 10 s).(ABSTRACT TRUNCATED AT 250 WORDS)
Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in dogs
Authors: Pelleg A. , Hurt C. M. , Soler-Baillo J. M. , Polansky M.
Published: December 2017

To test the hypothesis that afferent traffic of the ATP-triggered vagal reflex travels mainly in the right vagus nerve, we quantitated the response of the sinus node pacemaker activity and atrioventricular (AV) nodal conduction to increasing doses of intra-atrial ATP under baseline conditions, in the presence of aminophylline, and subsequently after either right followed by left cervical vagotomy or vice versa. In addition, the effect of right vagal C-fiber afferent blockade on the action of ATP in the sinus node was also determined. Because vagal efferent traffic to the sinus and AV nodes travels mainly via the right and left vagus nerves, respectively, the working hypothesis predicted that left vagotomy would have a much smaller effect than right vagotomy on the negative chronotropic action of ATP in the sinus node and predicted similar effects of left vs. right vagotomy on the negative dromotropic action of ATP on AV nodal conduction. ATP suppressed sinus node automaticity and AV nodal conduction in a dose-dependent manner. The attenuation of the action of ATP on the sinus node by right vagotomy was much more pronounced than that caused by left vagotomy, while the negative dromotropic action of ATP in the AV node was similarly attenuated by right vs. left vagotomy. In addition, sinus node automaticity, which was only mildly attenuated by left vagotomy, was markedly suppressed by right vagal C-fiber afferent blockade. It was concluded that in the dog, afferent vagal traffic triggered by intra-right atrial ATP travels under these experimental conditions mainly via the right vagus nerve.
Calcitonin gene-related peptide mediates hypotension and tachycardia in endotoxic rats
Authors: Huttemeier P. C. , Ritter E. F. , Benveniste H.
Published: December 2017

Circulating calcitonin gene-related peptide (CGRP) concentrations are elevated in experimental and clinical sepsis. CGRP causes hypotension and tachycardia, suggesting that the peptide might mediate the acute circulatory changes in sepsis. To test this hypothesis we administered Escherichia coli endotoxin (8 mg/kg iv) to Nembutal- (pentobarbital sodium; 50 mg/kg) anesthetized rats. Endotoxin caused hypotension and tachycardia within 60 min that stabilized for 90 min. After 2 h more severe hypotension developed, and 80% of rats died spontaneously after 3 h. In other endotoxic rats we administered 20 nmol of the CGRP receptor antagonist hCGRP (8-37) intravenously at 60 min. hCGRP (8-37) transiently reversed tachycardia (from 469 +/- 11 to 407 +/- 7 beats/min, P < 0.05) and increased mean blood pressure (from 63 +/- 4 to 93 +/- 11 mmHg, P < 0.05) over 30 min, after which hemodynamics and survival rates were no different from untreated animals. The results suggest that CGRP plays an important role in the acute circulatory changes of endotoxemia. More detailed work is necessary to determine the effects of CGRP antagonism on cardiac function, regional blood flow, and overall survival rates in sepsis.
Stress and cocaine elicit similar cardiac output responses in individual rats
Authors: Knuepfer M. M. , Branch C. A. , Mueller P. J. , Gan Q.
Published: December 2017

Cocaine use and behavioral stress elicit variable cardiovascular responses in individuals. In the present study, we examined the effects of cocaine or stress on arterial pressure, heart rate, and cardiac output in conscious rats. Rats were instrumented for determination of ascending aortic blood flow as an index of cardiac output using pulsed Doppler flow-metry. Cocaine administration elicited consistent decreases in cardiac output in some rats, whereas others had increases. In contrast, the pressor and heart rate responses were similar in these two groups of animals. Air jet stress also elicited a decrease in cardiac output only in a subset of conscious rats, yet produced equivalent pressor responses in all rats. Cardiac output responses to cocaine and air jet stress were closely correlated in individual rats, indicating that these stimuli evoke similar hemodynamic responses in individual rats. These observations suggest that the rat may provide a model for understanding differential cardiovascular sensitivity to cocaine and/or stress in humans.
Tyrosine kinase inhibitors suppress endotoxin- and IL-1 beta-induced NO synthesis in aortic smooth muscle cells
Authors: Marczin N. , Papapetropoulos A. , Catravas J. D.
Published: December 2017

Nitric oxide (NO) formation via the expression of an endotoxin- and cytokine-inducible NO synthase (iNOS) within the vascular smooth muscle is thought to be responsible for the cardiovascular collapse that occurs during septic shock and antitumor therapy with cytokines. Because the molecular mechanisms that underlie induction of iNOS are still unclear and because tyrosine kinases are implicated in interleukin-1 beta (IL-1 beta)-induced prostaglandin synthesis in mesangial cells and in NO generation by an insulinoma cell line, we investigated the influence of tyrosine kinase inhibitors on iNOS induction in cultured rat aortic smooth muscle cells (RASMC). The production of biologically active NO was demonstrated by L-arginine-dependent guanosine 3',5'-cyclic monophosphate (cGMP) accumulation after a 3-h exposure to either IL-1 beta or lipopolysaccharide (LPS). Pretreatment of RASMC for 30 min with the tyrosine kinase inhibitor genistein prevented both IL-1 beta- and LPS-elicited cGMP accumulation in a concentration-dependent manner. Geldanamycin, a chemically different tyrosine kinase inhibitor, also blocked cGMP formation in response to both LPS and IL-1 beta at nanomolar concentrations. Genistein and geldanamycin inhibited cGMP accumulation even when added 90 min after LPS exposure, but no inhibition was observed when they were included at later time points (120-180 min), suggesting that the inhibitors had no direct effect on iNOS activity after its induction. Formation of cGMP in response to sodium nitroprusside and to NO released from bovine aortic endothelial cells remained virtually unaffected by genistein and geldanamycin.(ABSTRACT TRUNCATED AT 250 WORDS)
Curvilinearity of LV end-systolic pressure-volume and dP/dtmax-end-diastolic volume relations
Authors: Noda T. , Cheng C. P. , De Tombe P. P. , Little W. C.
Published: December 2017

We investigated the effect of contractile state (CS) on the curvilinearity of the left ventricular (LV) end-systolic pressure-volume (Pes-Ves) and the dP/dtmax-end-diastolic volume (dP/dtmax-Ved) relations in eight anesthetized open-chest dogs. LV volume was determined from three orthogonal diameters measured by sonomicrometry. The Pes-Ves relation and dP/dtmax-Ved relation were assessed during transient vena caval occlusion and aortic constriction, while CS was altered with dobutamine. At all CS, both relations were linear when volumes were decreased by caval occlusion. However, at higher volumes obtained by aortic constriction, the relations became nonlinear. At enhanced CS, the nonlinearity of both the Pes-Ves relation and the dP/dtmax-Ved relation increased. The dP/dtmax-Ved relation began to deviate from linearity at larger volumes, but closer to baseline operating volume, than the Pes-Ves relation. The relation between end-systolic mean circumference stress and wall strain (sigma es-epsilon es) was linear at control CS when the Pes-Ves relation was nonlinear but became nonlinear with enhanced CS. We conclude that both the Pes-Ves relation and the dP/dtmax-Ved relation are nonlinear, saturating at higher volumes. With increased CS, the nonlinearity of both relations increases. This CS-dependent curvilinearity of the Pes-Ves relation is due to both CS-dependent nonlinearity of the sigma es-epsilon es relation (consistent with length-dependent activation) and geometric factors that alter the relation between Pes and sigma es.
Nitric oxide does not mediate the attenuated pulmonary vascular reactivity of chronic pneumonia
Authors: Yaghi A. , Paterson N. A. , McCormack D. G.
Published: December 2017

Chronic Pseudomonas pneumonia is associated with decreased acute hypoxic pulmonary vasoconstriction. However, it is not known whether this is a result of a generalized reduction in contractile responsiveness. We therefore examined the effect of chronic Pseudomonas pneumonia on in vitro pulmonary vascular responsiveness to agonists. We then investigated the role of nitric oxide (NO) in the altered pulmonary vascular contractility. Control rats or rats infected with Pseudomonas (pneumonia) were killed, and small intrapulmonary arteries (100-200 microns effective lumen radius) were removed. In the pneumonia group, arteries were harvested from the pneumonic area of the lung. Vascular responsiveness was assessed in vitro by obtaining cumulative dose-response curves to contractile agonists [phenylephrine (PE), 5-hydroxytryptamine (5-HT), prostaglandin F2 alpha (PGF2 alpha), and KCl]. KCL-induced (voltage-operated) contractions were not significantly depressed in small pulmonary arteries from pneumonic lungs, suggesting that the smooth muscle contractile apparatus in these arteries was preserved. Contractile responses to the three receptor-operated agonists (PE, 5-HT, and PGF2 alpha) were significantly depressed in arteries subserving the pneumonic lobe of infected rats. NG-monomethyl-L-arginine, which blocks the synthesis of NO, caused a shift toward the left in the dose-contraction curves to PE, PGF2 alpha, and 5-HT in vessels from the sterile control lungs, but it had little effect on arteries from the pneumonic lungs. Chronic Pseudomonas pneumonia is associated with depressed pulmonary vascular contractility in vitro, particularly affecting the receptor-mediated contractile responses. Excessive NO release does not contribute to this attenuated vascular contractility.(ABSTRACT TRUNCATED AT 250 WORDS)
Transient analysis of macromolecular transport across microvascular wall and into interstitium
Authors: Kim D. , Armenante P. M. , Duran W. N.
Published: December 2017

We studied the dynamics of macromolecular transport across the microvascular wall in the hamster cheek pouch using intravital microscopy and digital video-image analysis. We used fluorescein isothiocyanate-dextrans of 70,000 and 150,000 Da (FITC-Dextran 70 and 150, respectively) as tracers. We applied our mathematical model and our in vivo calibration to determine the diffusion coefficient (D) and the average fluid velocity (V) in the microvascular wall and in the interstitium from the experimental data. The value of D for FITC-Dextran 70 was 0.90 +/- 0.04 x 10(-11) cm2/s in the wall and 1.29 +/- 0.05 x 10(-8) cm2/s in the interstitium. In both regions, V was 2.05 +/- 0.05 x 10(-8) cm/s. The transport parameters for FITC-Dextran 150 were 0.27 +/- 0.02 x 10(-11) cm2/s, 0.55 +/- 0.05 x 10(-8) cm2/s, and 1.71 +/- 0.48 x 10(-8) cm/s for D in the wall and interstitium and V, respectively. The topical application of either calcium ionophore A23187 (7 x 10(-7) M) or bradykinin (5 x 10(-7) M) increased D for FITC-Dextran 70 and 150 2-fold and V 10-fold relative to their control values. We used these values to quantify the relative importance of the diffusive and convective mechanisms in the total solute flux. Molecular diffusion dominates convective transport in both the microvascular wall and the interstitial space.
Unilateral carotid-cardiac baroreflex responses in humans
Authors: Williamson J. W. , Raven P. B.
Published: December 2017

To determine the individual contributions of the right and left carotid sinus baroreflex control of the cardiac interval, we measured heart rate [as expressed by R-R interval (RRI)] and mean arterial pressure (MAP) responses elicited by pulsed trains of neck suction or pressure in 20 healthy men. Pulses were delivered using a customized neck collar device partitioned to allow for stimulation of only one side of the neck. Maximal cardiac gains for right, left, and bilateral baroreflexes were determined from the logistic function of RRI responses to changes in estimated carotid sinus pressure (ECSP). Maximal gains for right (5.44 +/- 1.33 ms/Torr ECSP) and left (4.22 +/- 1.44 ms/Torr ECSP, P > 0.05) carotid-cardiac responses did not differ. However, the bilateral gain (6.89 +/- 1.80 ms/Torr ECSP) was less than the simple sum of the right and left gains (9.67 +/- 2.20 ms/Torr ECSP, P < 0.01). We suggest that the right and left carotid-cardiac reflex responses are quantitatively similar in humans and exhibit an inhibitory interaction when compared with the bilateral response under conditions of supine rest in normotensive subjects.
Possible paracrine facilitation of ventricular growth in oculo by atrial tissue
Authors: Love T. C. , Tucker D. C.
Published: December 2017

Load-independent growth controls were investigated in embryonic atria and ventricles cultured in the anterior eye chamber of adult rats. At embryonic day 12, the mass of atria was half that of ventricles (0.11 vs. 0.24 mg), whereas after 8 wk in oculo, atrial grafts were threefold larger than ventricular grafts (2.26 +/- 0.36 vs. 0.69 +/- 0.16 mg). To examine possible paracrine communication between atria and ventricles, two grafts were cocultured in the same eye chamber. Atrial grafts cocultured with either another atrial graft or a ventricular graft did not differ in projected area or mass from atrial grafts cultured alone. Ventricular grafts cocultured with another ventricular graft did not differ in projected area or mass from ventricular grafts cultured alone. However, ventricular grafts cocultured with an atrial graft grew larger than single ventricular grafts. At 1 wk in oculo, DNA synthesis (bromodeoxyuridine incorporation) was higher in ventricular grafts cocultured with atrial grafts than in single ventricular grafts (6.84 +/- 0.88 vs. 4.40 +/- 0.10%). Thus atria may stimulate growth, including DNA synthesis, in developing ventricles via a paracrine mechanism.
Guanethidine chemical sympathectomy: spinal cord and sciatic nerve blood flow
Authors: Kinoshita Y. , Monafo W. W.
Published: December 2017

The spinal cord vasculature is innervated by noradrenergic nerve fibers, the role of which in the regulation of regional spinal cord blood flow (RSCBF) is presently unclear. We used the distribution of [14C]butanol to simultaneously measure RSCBF at seven cord levels and the regional blood flow in sciatic nerve (NBF), truncal skin, and biceps femoris muscle. The subjects were control rats and rats that had been given parenteral guanethidine sulfate for 5 wk to induce selective postganglionic "chemical sympathectomy." Flows were measured under basal conditions (group I) and immediately after an arterial hemorrhage (group II). The results indicate that RSCBF was unchanged from control after guanethidine administration in both groups; however, NBF was elevated after guanethidine by 47% in group I and by 41% in group II. We conclude that in the spinal cord as in the brain, sympathetic inflow does not appear to have an important role in the regulation of regional blood flow. Sympathetic inflow appears to partly regulate NBF, however, probably by varying vascular tone.
Vagal-mediated atrial premature beats: a computer model
Authors: Whitney R. T. , Rozanski G. J.
Published: December 2017

A computer algorithm is described that used experimental data to model the arrhythmogenic interaction of phasic vagal stimuli and atrial ectopic pacemakers. The model consisted of a dominant sinus node and a single ectopic pacemaker center separated by conducting atrial tissue. Its primary operation was to predict the timing and incidence of atrial premature beats resulting from transient escape of ectopic automatic impulses when vagal-induced entrance block of the sinus impulse was simulated near the ectopic focus. These predictions were based on a series of experimentally derived phase-response and corrected recovery time curves, describing the modulation of ectopic pacemaker periodicity by vagal input and overdrive suppression, respectively. Depending on the combination of curves tested, the model predicted premature beats to develop only with critically timed vagal stimuli. The coupling intervals of vagal-induced premature beats were > 300 ms and varied as a function of vagal timing and sinus cycle length. The model suggests therefore that phasic vagal stimuli within the atrium may transiently protect ectopic pacemaker foci from conducted sinus impulses and mediate the genesis of atrial extrasystoles with long coupling intervals.
Effect of tetanic myocardial contraction on coronary pressure-flow relationships
Authors: Livingston J. Z. , Resar J. R. , Yin F. C.
Published: December 2017

Cardiac contraction causes a decrease in coronary flow. Despite many studies, it is still not clear what mechanism or mechanisms are responsible for this flow decrease. The phasic nature of myocardial contraction and the complexities intrinsic to intact heart preparations make it difficult to elucidate the mechanisms. We therefore studied coronary pressure-flow relationships during steady-state (tetanic) contractions in the maximally vasodilated isolated canine interventricular septum to see whether waterfall-type behavior is present. Using ryanodine and electrical stimulation allowed the production of reproducible and reversible tetani. This preparation minimizes the difficulties associated with transmural variations and also the effects of intramyocardial capacitance. Two separate protocols were performed to delineate the pressure-flow relationships in the passive and tetanized states. The first compared diastolic and tetanized pressure-flow relationships. In the second protocol, 2,3-butanedione monoxime was added to obtain an intermediate contractile level, thus allowing the comparison of two contractile states. Both the diastolic and tetanized pressure-flow relationships were curvilinear in the low-pressure range. Linear and nonlinear fits to the data showed that the primary effect of contraction was a shift of the pressure-flow relationships to higher pressures at a given flow. This effect was graded by the level of contractility and was independent of developed stress. Although other mechanisms may also be operative, these results support the presence of waterfall behavior in the coronary vascular bed.
Rate-dependent functional properties of retrograde atrioventricular nodal conduction in experimental animals
Authors: O'Hara G. , Gendreau R. , Billette J. , Amellal F. , Nayebpour M. , Talajic M. , Nattel S.
Published: December 2017

While rate-dependent atrioventricular (AV) nodal functional properties play a major role in determining antegrade AV nodal conduction, their existence and characteristics have not been assessed during retrograde AV nodal impulse propagation. Pacing protocols were used to study selectively AV nodal recovery, facilitation, and fatigue in 6 isolated, superfused rabbit AV nodal preparations and in 11 morphine-chloralose anesthetized dogs. All three properties were identifiable during retrograde AV nodal activation in rabbits. Retrograde recovery and fatigue were clearly demonstrated in dogs, but facilitation could not be evaluated because of echo beats during retrograde premature stimulation. Functional properties were qualitatively similar during retrograde and antegrade propagation; however, important quantitative differences were noted. The time constant for recovery from activation was significantly greater in the retrograde [rabbits, 69 +/- 8 (SE) ms; dogs, 93 +/- 11 ms] compared with the antegrade direction (rabbits, 50 +/- 5 ms; dogs, 58 +/- 4 ms; P < 0.05 vs. retrograde for each species). The magnitude of fatigue resulting from sustained increases in rate was also substantially greater in the retrograde direction in both rabbits (17 +/- 2 vs. 10 +/- 1 ms antegrade, P = 0.01) and dogs (20 +/- 4 vs. 6 +/- 1 ms antegrade, P < 0.01). Conduction time and refractory period were both greater in the retrograde compared with antegrade direction, and directional differences in conduction properties were magnified as activation rate increased.(ABSTRACT TRUNCATED AT 250 WORDS)
Downregulation of C-receptor by natriuretic peptides via ANP-B receptor in vascular smooth muscle cells
Authors: Kishimoto I. , Nakao K. , Suga S. , Hosoda K. , Yoshimasa T. , Itoh H. , Imura H.
Published: December 2017

The natriuretic peptide system comprises at least three ligands, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) and three receptors, the ANP-A receptor, the ANP-B receptor, and the clearance (C) receptor. In the present study, the regulation of natriuretic peptide receptors by their ligands was investigated in cultured rat vascular smooth muscle cells (SMC). The treatment of vascular SMC with ANP, BNP, or CNP decreased the C-receptor density significantly, and the rank order of potency for this downregulation was CNP > ANP > BNP. This rank order was the same as that for guanosine 3',5'-cyclic monophosphate (cGMP) production by ANP, BNP, or CNP in vascular SMC and also the same as that for the ligand selectivity of the ANP-B receptor rather than the C-receptor. The incubation of vascular SMC with 8-bromoguanosine 3',5'-cyclic monophosphate significantly decreased the C-receptor density and its mRNA expression. These results suggest that the down-regulation of the C-receptor by natriuretic peptides is induced not by the binding of natriuretic peptides to the C-receptor but by the activation of the ANP-B receptor-cGMP pathway.
Coronary artery acidosis: pH and calcium pump stability
Authors: Grover A. K. , Samson S. E.
Published: December 2017

To study the effects of prolonged exposure to different pH, pig coronary artery smooth muscle subcellular fraction F3 enriched in sarcoplasmic reticulum was preincubated at 0 or 37 degrees C and pH 6.4-7.8 and then used for monitoring the rate of the oxalate-stimulated component of the ATP-dependent azide-insensitive Ca2+ uptake at constant pH (6.8) and temperature (37 degrees C). Ca2+ uptake by F3 decreased with the increasing preincubation pH. The loss of Ca2+ uptake was more rapid upon preincubation at 37 degrees C than at 0 degrees C. Dithiothreitol (DTT), when included in the preincubation solution, protected against the loss. Sucrose, KCl, ATP, and ATP plus CaCl2 protected slightly, and glutathione, catalase, superoxide dismutase, azide, ascorbate, CaCl2, ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, mannitol, mercaptopropionylglycine, and FeSO4 had only marginal or no effects. Efflux of accumulated Ca2+ was more rapid from membranes that had been preincubated at 37 degrees C than from those preincubated at 0 degrees C, but it was not affected by the preincubation pH or by DTT. The loss of Ca2+ uptake due to incubation at pH 7.8 accompanied a decrease in the 115-kDa Ca(2+)-dependent acylphosphate formation due to the Ca2+ pump. The presence of DTT in the preincubation mixture increased the acylphosphate level in the control and protected against its loss at the preincubation pH 6.8 or 7.8. Thus, in the membranes isolated from coronary artery, acidosis may protect against damage to the sarcoplasmic reticulum Ca2+ pump by protonation of a key sulfhydryl group.(ABSTRACT TRUNCATED AT 250 WORDS)
Distribution of microvascular pressure in arteriolar vessel trees of ventilated rabbit lungs
Authors: Kuhnle G. E. , Pries A. R. , Goetz A. E.
Published: December 2017

We have developed a new in vivo microscopic technique for comprehensive measurements of vessel diameter, segment length, and red blood cell velocity in discrete arteriolar vessel trees of the lung. In anesthetized and mechanically ventilated rabbits, a transparent window was implanted into the right thoracic wall. We injected fluorescently labeled red cells to visualize blood flow and to measure red blood cell velocity. The distribution of microvascular pressures was simulated in a computer model based on morphometric and microhemodynamic data. Of the total pulmonary vascular pressure drop from pulmonary artery to left atrium, on average 2.5% occurred in distal arteriolar vessel trees with main trunk diameters of 73-111 microns. Along the pathlength from main trunk to terminal arterioles (0.18-2.79 mm), the pressure drop ranged between 0.06 and 0.94 mmHg. The pressure drop along individual pathways correlated significantly with pathlength of terminal arterioles, whereas red blood cell velocity did not. The results indicate that in terminal arteriolar vessel trees of the ventilated rabbit lung the resistance to blood flow is low, and the heterogeneity of microvascular pressures in arterioles feeding capillary networks is high.
Effect of glutamate stimulation of bed nucleus of the stria terminalis on arterial pressure and heart rate
Authors: Ciriello J. , Janssen S. A.
Published: December 2017

Experiments were done in the chloralose-anesthetized, paralyzed, and artificially ventilated rat to determine the cardiovascular responses elicited during chemical stimulation of bed nucleus of the stria terminalis (BST) and to investigate the components of the peripheral autonomic nervous system that mediate these responses. Neurons in BST were selectively stimulated by the microinjection (10-20 nl) of the excitatory amino acid L-glutamate (1 M). Stimulation of BST elicited decreases in mean arterial pressure (n = 105) of -6 to -55 mmHg. These depressor responses were on occasion (n = 60) accompanied by decreases in heart rate ranging between -10 and -40 beats/min. The largest depressor responses were consistently elicited from a crescent-shaped region of BST around the dorsolateral, lateral, and ventrolateral surfaces of the anterior commissure. Intravenous administration of the muscarinic receptor blocker, atropine methylbromide, had no affect on the magnitude of the mean arterial pressure and heart rate responses. On the other hand, administration (intravenous) of the nicotinic receptor blocker, hexamethonium bromide or arfonad, abolished both the depressor response and cardiac slowing during stimulation of BST. These data suggest that the BST depressor and the bradycardia responses are mediated by inhibition of both sympathetic vasoconstrictor fibers to the vasculature and cardioacceleratory fibers to the heart, respectively.