bluuebunny/crossref_metadata_2025 huggingface dataset:
Natriuretic peptide responses to acute and chronic ventricular pacing in sheep
Authors: Rademaker M. T. , Charles C. J. , Espiner E. A. , Frampton C. M. , Nicholls M. G. , Richards A. M.
Published: December 2017

The responses of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were investigated in six conscious sheep paced at 120, 155, 190, and 225 beats/min for 1.5 h at each rate and at 180, 225, and 180 beats/min for 4 days at each rate. Increased pacing reduced arterial pressure, cardiac output, and urine and Na excretion and increased left atrial pressure and plasma ANP, BNP, and C-type natriuretic peptide, with delayed activation of the renin-angiotensin system (RAS). Acute pacing increased plasma ANP and BNP levels 8.6- and 3.6-fold, respectively (both P < 0.001), whereas chronic pacing increased ANP and BNP 7.8- and 9-fold, respectively (both P < 0.001). Thus the ANP-to-BNP ratio increased during acute pacing (P < 0.001) and decreased proportionately during chronic pacing (P < 0.05). Reduction in pacing improved hemodynamic status, reduced natriuretic peptides (BNP less than ANP), normalized the RAS, and induced diuresis and natriuresis. In conclusion, BNP is less responsive than ANP to acute changes in intracardiac pressure but is proportionately more responsive to chronic hemodynamic changes such as occur in congestive heart failure.
Pharmacological probes for A1 and A2 adenosine receptors in vivo in feline pulmonary vascular bed
Authors: Neely C. F. , Matot I.
Published: December 2017

Under conditions of controlled pulmonary blood flow and constant left atrial pressure, adenosine produces dose-dependent, tone-dependent responses in the pulmonary vascular (PV) bed of intact-chest, spontaneously breathing cats. The potency profile for adenosine receptor agonists to produce vasoconstriction at low baseline PV tone is 5'-(N-ethylcarboxamido)adenosine > or = CGS-21680 > or = 2-chloroadenosine (2-CADO) > or = [R]-N6-(2-phenylisopropyl)adenosine (R-PIA) > or = N6-cyclopentyladenosine > adenosine > > CV-1808. After an increase in PV tone with the use of an intralobar infusion of the thromboxane mimic U-46619, the potency profile for adenosine receptor agonists to produce vasodilation at elevated PV tone is 2-CADO > or = CV-1808 > or = CGS-21680 > R-PIA > or = adenosine. The selective A1 adenosine receptor antagonists xanthine amine congener (XAC) and 8-cyclopentyl-1,3-dipropylxanthine (DP-CPX) significantly antagonize the vasoconstrictor responses of adenosine and R-PIA at low baseline PV tone while having less effect on the vasodilator responses of adenosine, 2-CADO, and R-PIA at elevated PV tone. DPCPX antagonizes the vasoconstrictor responses of CGS-21680 at low baseline PV tone. The nonselective A1 and A2 adenosine receptor antagonist BWA-1433U significantly antagonizes vasoconstrictor responses of R-PIA and vasodilator responses of adenosine, 2-CADO, and R-PIA. These data support that adenosine produces vasoconstriction at low baseline PV tone and vasodilation at elevated PV tone in the feline PV bed by acting on A1 and A2 adenosine receptors, respectively. Compared with the adenosine receptor agonists tested in this in vivo model, R-PIA and CV-1808 are the most selective adenosine receptor agonists for A1 and A2 adenosine receptors, respectively, in the feline PV bed. R-PIA, CV-1808, DPCPX, and XAC may be used in this in vivo model to define the roles of A1 and A2 adenosine receptors in acute lung injury and pathophysiological changes in the pulmonary vasculature associated with pulmonary hypertension and edema formation in the same animal model.
Direct measurement of transverse residual strains in aorta
Authors: Han H. C. , Fung Y. C.
Published: December 2017

Residual strains were measured in the porcine aorta. Segments were cut from the aorta perpendicular to its longitudinal axis. Microdots of water-insoluble black ink were sprinkled onto the transverse sectional surface of the segments in the no-load state. The segments were then cut radially, and sectional zero-stress states were approached. The coordinates of selected microdots (2-20 microns) were digitized from photographs taken in the no-load state and the zero-stress state. Residual strains in the transverse section were calculated from the displacement of the microdots. The circumferential residual strains on the inner wall and outer wall were calculated from the circumferential lengths in the no-load state and the zero-stress state. Results show that the circumferential residual strain is negative (compressive) in the inner layer of the aortic wall and positive (tensile) in the outer layer, whereas the radial residual strain is tensile in the inner layer and compressive in the outer layer. This residual strain distribution reduces the stress concentration in the aorta under physiological load. The experimental results compared well with theoretical estimations of a cylindrical model. Regional difference of the residual strain exists and is significant (P < 0.01), e.g., the circumferential residual strains on the inner wall of the ascending, descending thoracic, and abdominal regions of the aorta are -0.133 +/- 0.019, -0.074 +/- 0.020, and -0.046 +/- 0.017 (mean +/- SD), respectively. More radial cuts of a segment produced no significant additional strains. This means that an aortic segment after one radial cut can be considered as the zero-stress state.
Kininogen changes in human plasma following a test meal or insulin administration
Authors: Rothschild A. M. , Boden G. , Colman R. W.
Published: December 2017

The effect of food intake and of insulin on plasma bradykinin (BK) reserves [total (TK), high-molecular-weight (HK), and low-molecular-weight kininogen (LK)] was followed by determining (by enzyme-linked immunosorbent assay) the amount of BK released by trypsin from plasma collected before and after a test meal or hyperinsulinemic clamping. LK was kininogen remaining in plasma after in vitro kaolin treatment, which removes all HK. HK was the difference between TK and LK. Thirty minutes after a test meal, TK and HK decreased by 8.0 +/- 0.6 and 39.7 +/- 6.6%, respectively, in six of seven subjects. Return to prealimentary levels occurred after 90-120 min. Hyperinsulinemia, comparable to that arising after the test meal, partly reproduced such treatment's effect on TK and HK but did not affect blood or plasma kininogen in vitro. Observed postprandial hypotension and increased leg blood flow could be caused, in part, by BK released from plasma HK after cleavage at vascular, possibly endothelial, sites activated by insulin.
Tumor necrosis factor-alpha-induced expression of heat shock protein 72 in adult feline cardiac myocytes
Authors: Nakano M. , Knowlton A. A. , Yokoyama T. , Lesslauer W. , Mann D. L.
Published: December 2017

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that is elaborated in a myriad of cardiac disease states. Although the biological role for TNF-alpha in the adult heart is not known, a recent study in fetal myocardial cells has shown that this cytokine increases the synthesis of low-molecular-weight stress proteins. These findings suggested the interesting possibility that TNF-alpha might play a functional role in the adult heart by increasing the expression of stress proteins in cardiac myocytes. Accordingly, the purpose of this study was to determine whether TNF-alpha would modulate the expression of heat shock protein 72 (HSP 72), a stress protein that is thought to exert protective effects in the adult heart. Stimulation of adult feline cardiac myocytes with a range of TNF-alpha concentrations (10-1,000 U/ml) for 12 h showed that concentrations of TNF-alpha < or = 10 U/ml had no effect on HSP 72 expression: increased HSP 72 expression was detected 3 h following cytokine stimulation, peaked by approximately 12 h, and then returned toward baseline by 48 h. Additional studies indicated that stimulation of the type 1 TNF receptor was responsible for the increase in HSP 72 expression. In summary, these studies constitute the initial demonstration that TNF-alpha exerts concentration- and time-dependent effects on the expression of HSP 72 in the adult mammalian cardiac myocytes, thus suggesting the interesting possibility that the elaboration of TNF-alpha may enable the heart to better withstand certain forms of stress.
Characteristics and mechanisms of the effects of heart rate history on transient AV nodal responses
Authors: Zhao J. , Billette J.
Published: December 2017

The characteristics and functional origin of the changes in transient atrioventricular (AV) nodal responses with heart rate history were studied in isolated rabbit heart preparations. For this purpose, ramp stimulation sequences were applied to the atrium from different initial conditions. A ramp decrease and increase in the His-stimulus interval and a reverse sequence consisting of a ramp increase and decrease were performed starting from a control basic cycle length, after 5 min of fast rate, or with 5 min of fast rate inserted between the two ramps. The nodal conduction times (NCT) obtained during the ramp stimulations formed hysteresis loops, the direction, shape, and magnitude of which varied markedly with the nodal history. That is, the nodal response to a given ramp took a variety of forms, depending on the initial condition. The effects of the initial condition also depended on ramp direction and sequence. A paradoxical NCT-recovery relationship (decrease in NCT with shortening His-atrial interval) was consistently observed at the onset of any ramp decrease performed after 5 min of fast rate. These effects also varied with the rate used to change the nodal history. The insertion of a control cycle at every 20th beat during repeated ramp protocols allowed the determination of the contribution of the nodal property of fatigue to these effects. Fatigue was found to account for all observed hysteresis patterns. In conclusion, heart rate history can, by modulating beat-to-beat changes in fatigue, transform transient nodal responses and hysteresis observed during stimulation ramps. Interpretation of transient nodal responses thus requires exact knowledge of previous nodal history.
Recovery of glycolysis and oxidative metabolism during postischemic reperfusion of hypertrophied rat hearts
Authors: Schonekess B. O. , Allard M. F. , Lopaschuk G. D.
Published: December 2017

We investigated the source and extent of recovery of ATP production during postischemic reperfusion of isolated working hearts from abdominal aortic-banded rats. Rates of glycolysis, glucose oxidation, lactate oxidation, and palmitate oxidation were measured in hypertrophied and control hearts [perfused with (in mM) 11 glucose, 0.5 lactate, and 1.2 palmitate] during and after 30 min of no-flow ischemia. In the initial aerobic period glycolytic rates were 1.87-fold higher in hypertrophied hearts compared with control hearts (P < 0.05), with rates of carbohydrate and palmitate oxidation being similar. During reperfusion, hypertrophied hearts recovered 40% of preischemic function compared with 71% in control hearts. Rates of glycolysis during reperfusion of hypertrophied hearts remained accelerated compared with control hearts (2.01-fold higher, P < 0.05), whereas oxidative metabolism returned to preischemic values in both groups. The efficiency of converting ATP production into mechanical work decreased to 29% of preischemic values in hypertrophied hearts during the postischemic reperfusion compared with a decrease to only 59% of preischemic values in control hearts. This suggests that the recovery of glycolysis and oxidative metabolism in the hypertrophied heart during postischemic reperfusion is not impaired, but rather the efficiency of converting ATP produced into mechanical function decreases.
L-arginine augments nitric oxide production and mesenteric blood flow in ovine endotoxemia
Authors: Allman K. G. , Stoddart A. P. , Kennedy M. M. , Young J. D.
Published: December 2017

We studied the effects of administrating the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), or the nitric oxide precursor, L-arginine, on hemodynamic variables and serum nitrate concentrations in an anesthetized ovine model of endotoxemia to assess the effects on regional visceral blood flow and to determine whether L-arginine availability limits nitric oxide production. Animals received Escherichia coli endotoxin (2 micrograms/kg) followed 2 h later by L-NAME (25 mg/kg), L-arginine (0.575 g/kg), or saline administered over 1 h followed by an infusion of the same dose over 8 h (n = 6 per group). Renal and mesenteric blood flow were measured by placement of electromagnetic flow probes, and serum nitrate concentrations were determined using vanadium III chloride or nitrate reductase reduction to nitric oxide or nitrite, respectively. The results showed L-NAME significantly increased systemic vascular resistance (P < 0.01), decreased serum nitrate concentrations (P < 0.05), and caused a transient reduction in mesenteric blood flow (P < 0.05). L-Arginine caused a reduction in systemic vascular resistance (P < 0.01), increased mesenteric blood flow (P < 0.001) and conductance (P < 0.05). There were no significant changes in renal arterial blood flow in either group. We conclude that the availability of L-arginine limits nitric oxide production in endotoxemia and, furthermore, that L-arginine administration in this model causes significant mesenteric vasodilatation. L-NAME administration had only limited effect on visceral blood flow despite a marked increase in systemic vascular resistance and a reduction in nitric oxide production.
Transfer function analysis of ventilatory influence on systemic arterial pressure in the rat
Authors: Kuo T. B. , Yang C. C. , Chan S. H.
Published: December 2017

We evaluated the hypothesis that fluctuations in systemic arterial pressure (SAP) are under the influence of the respiratory pumping mechanism subjected to a modulatory action by the autonomic nervous system that is exerted primarily on the heart. Computer-generated broad-band mechanical ventilation (0-3 Hz) was applied to Sprague-Dawley rats that were anesthetized with ketamine and paralyzed with pancuronium. We observed excellent coherence between lung volume and SAP signals at ventilatory rates between 0.5 and 2.5 Hz; this coherence was unaffected by phentolamine, propranolol, atropine, bilateral vagotomy, or ventilatory stroke volume at 2-4 ml. Whereas bilateral vagotomy exerted no discernible effect, propranolol elicited a significant frequency-dependent (0.5-1.5 Hz) reduction in the magnitude of lung volume-SAP and lung volume-pulse pressure transfer functions. There was also a shift toward 0 degree for the phase of the lung volume-SAP transfer function over the same frequency range. We conclude that the high-frequency component (0.8-2.4 Hz) of the SAP spectrum may be generated by the respiratory pumping mechanism. However, the lower-frequency end of this mechanical influence is subjected to additional amplification by the autonomic nervous system, in which the beta-adrenergic system played a major role via its influence on the heart.
ATP-sensitive potassium channels regulate stimulated ANF secretion in isolated rat heart
Authors: Xu T. , Jiao J. H. , Pence R. A. , Baertschi A. J.
Published: December 2017

Perfused hearts (n = 127) were exposed to acute hypoxia (10% O2 for 12 or 20 min) or left atrial stretch (increase in atrial pressure) in the presence or absence of 100 mumol/l ATP-sensitive potassium channel blocker (tolbutamide) or openers (pinacidil and diazoxide). Hypoxia alone elicited a prolonged atrial natriuretic factor (ANF) release, peaking at 74% over baseline (P < 0.01); with tolbutamide, ANF secretion peaked at 132% over baseline (P < 0.01). Pinacidil and diazoxide abolished the ANF response to hypoxia (P < 0.01). Atrial stretch alone (1 mmHg) transiently (2 min) increased ANF by 56% (P < 0.05); with tolbutamide, ANF increased transiently by 124% and showed a prolonged increase of 52% (P < 0.05). With tolbutamide, graded stretch (0.5-2.3 mmHg) induced a bell-shaped transient (2-min) increase of ANF release [-3% at 0.5 mmHg, 124% (P < 0.05) at 1.0 mmHg, 80% (P < 0.05) at 1.48 mmHg, and 14% at 2.22 mmHg] and a saturating prolonged ANF response. Tolbutamide increased the ANF response nonsignificantly at lower doses (30 mumol/l) and had no effect at 1 mumol/l. Pinacidil abolished the stretch-induced ANF release. These results suggest that ATP-sensitive potassium channels are extremely potent modulators of stimulated ANF secretion.
Oxidized low-density lipoproteins and microvascular responses to ischemia-reperfusion
Authors: Liao L. , Harris N. R. , Granger D. N.
Published: December 2017

The objective of this study was to determine whether ischemia and reperfusion (I/R) and/or chronic arterial hypertension potentiates the leukocyte-endothelial cell adhesion (LECA) and microvascular dysfunction elicited by oxidized low-density lipoproteins (ox-LDL). Mast cell degranulation, leukocyte adherence and emigration, and albumin leakage were monitored in postcapillary venules of rat mesentery. Intra-arterial infusion of copper-oxidized LDL (Cu-LDL), at a concentration that does not directly affect the microvasculature, significantly enhanced the I/R-induced recruitment of adherent and emigrated leukocytes but does not affect the increased albumin leakage and mast cell degranulation responses normally observed after I/R. Infusion of a higher concentration of Cu-LDL in nonischemic mesentery of either normotensive Wistar-Kyoto or spontaneously hypertensive rats elicited significant yet similar increases in LECA, mast cell degranulation, and albumin leakage. These findings indicate that 1) ox-LDL act synergistically with I/R to promote leukocyte recruitment in postcapillary venules but without an accompanying exacerbation of albumin leakage, and 2) ox-LDL do not elicit a more intense inflammatory response in the microvasculature of hypertensive versus normotensive animals.
Protection of ischemic myocardium by inhibition of contracture in isolated rat heart
Authors: Tani M. , Hasegawa H. , Suganuma Y. , Shinmura K. , Kayashi Y. , Nakamura Y.
Published: December 2017

Protection of the ischemic myocardium by pretreatment with a high dose of 2,3-butanedione monoxime (BDM) is attributed to the enhancement of glycolytic ATP production rather than to the inhibition of contracture during mild ischemia. Our objective was to investigate whether the inhibition of contracture would protect the arrested heart during prolonged ischemia. Isolated perfused rat hearts were subjected to 30 min of low-flow ischemia followed by reperfusion. Ischemic hearts were treated with BDM (5 mmol/l) after beating stopped. BDM ameliorated the increase in intraventricular pressure after ischemia without significant changes in ATP levels and with a decreased accumulation of lactate. BDM treatment accelerated the recovery of function and high-energy phosphates with reduced myocardial Ca2+ overload. The results of this study suggested that inhibition of contracture can protect the heart from ischemia-reperfusion injury.
Cerebral arteriolar dilation to hypoxia: role of prostanoids
Authors: Leffler C. W. , Parfenova H.
Published: December 2017

Experiments addressed the hypothesis that dilator prostanoids contribute to maintenance of low cerebral microvascular tone during hypoxia in the newborn. Anesthetized newborn pigs equipped with closed cranial windows were used to measure responses of pial arterioles (approximately 60 microns) to treatments. Hypoxia (Pao2 approximately equal to 25 mmHg) caused dilation of pial arterioles (approximately 50% increase in diameter). Hypoxia (5 min) caused an increase in cortical cerebrospinal fluid 6-ketoprostaglandin F1 alpha concentration from 907 +/- 171 (normoxia) to 1,408 +/- 213 pg/ml (hypoxia). Pretreatment with indomethacin (5 mg/kg) did not affect pial arteriolar dilation to hypoxia. Conversely, indomethacin treatment during hypoxia caused a rapid decrease in arteriolar diameter to nearly the normoxia diameter within 3 min, returning to the original hypoxia diameter by 10 min. Ibuprofen treatment (30 mg/kg) had no effect on pial arteriolar diameter during normoxia or hypoxia, and pretreatment did not alter dilation to hypoxia. However, pretreatment with ibuprofen abolished the constrictor effect of indomethacin given during hypoxia. These data suggest that the primary mechanism by which hypoxia produces cerebral vasodilation does not involve prostanoids, but prostanoids can contribute to cerebral vasodilation in response to hypoxia.
Contribution of red blood cell aggregation to venous vascular resistance in skeletal muscle
Authors: Cabel M. , Meiselman H. J. , Popel A. S. , Johnson P. C.
Published: December 2017

The effects of red blood cell aggregation on venous vascular resistance and conductance were examined in the cat lateral gastrocnemius muscle. During perfusion with blood of normal hematocrit, venous conductance fell linearly by 41% when blood flow was reduced from 5 to 1 ml x min(-1) x 100 g tissue(-1) and increased linearly by 155% when flow was increased from 5 to 20 ml x min(-1) x 100 g tissue(-1). This effect was not seen when the muscle was perfused with an acellular solution of 12% Dextran 40 in Ringer solution and was greatly reduced or absent with a nonaggregating suspension of red blood cells in Ringer solution + Dextran 40. Also, the venous vascular conductance at a control flow of 5 ml x min(-1) x 100 g tissue(-1) during perfusion with the nonaggregating red blood cell suspension was twice that with normal blood of the same hematocrit. The effect of flow on venous conductance was significantly reduced when red blood cell aggregation was increased by addition of Dextran 250 to the blood (200 mg/kg body wt) and was also reduced in animals with systemic hematocrit >50%. These findings suggest that red blood cell aggregation contributes importantly to venous vascular resistance in resting muscle.
A model for the initiation and growth of extracellular lipid liposomes in arterial intima
Authors: Yin Y. , Lim K. H. , Weinbaum S. , Chien S. , Rumschitzki D. S.
Published: December 2017

There is considerable evidence that lipoprotein cholesterol, after crossing the arterial endothelium and entering the intima from the vascular lumen, lodges in extracellular lipid packets (labeled "liposomes") bound to the extracellular matrix. These liposomes appear to form by occasional attachment of a low-density lipoprotein (LDL) to the intimal matrix and to grow in place mainly by appending available free LDL. The liposome size distributions observed in chronically hypercholesteremic (WHHL) and in short-term cholesterol-fed rabbits are quite different. We propose a hierarchy of simple nucleation-polymerization models to describe liposome formation and growth. Even the simplest of these (with only one adjustable parameter) agrees extremely well with the WHHL data. In contrast, the cholesterol-fed rabbit data seem to result from the short-term nonuniform intimal history of LDL supply, which is a consequence of the focal nature of the transendothelial LDL flow through isolated transient leakyjunctions. The same models used for the WHHL data, together with this intimal nonuniformity, superimposed on a slow uniform transendothelial seepage also account very well for this cholesterol-fed rabbit data.
Canine pulmonary vasoreactivity to serotonin: role of protein kinase C and tyrosine kinase
Authors: Barman S. A. , Pauly J. R. , Isales C. M.
Published: December 2017

The role of protein kinase C- and protein tyrosine kinase-mediated signal transduction in the canine pulmonary vascular response to serotonin (5-HT) was determined in the isolated blood-perfused dog lung. Pulmonary vascular resistances and compliances were measured with vascular occlusion techniques. 5-HT (10(-5) M) significantly increased precapillary resistance by approximately 150% and postcapillary resistance twofold and significantly decreased total vascular compliance to approximately 50% of control values by decreasing large-vessel compliance and middle-compartment compliance. The 5-HT2-receptor blocker ketanserin (10(-7) M), the protein kinase C inhibitor staurosporine (10(-7) M), the voltage-dependent Ca2+-channel blocker verapamil (10(-5) M), and the specific protein tyrosine kinase inhibitors genistein (5 x 10(-4) M) and tyrphostin 25 (5 x 10(-4) M) completely inhibited the pressor response to 5-HT, whereas the 5-HT1-receptor antagonist (-)pindolol (10(-7) M) had no significant effect on the serotonergic response. These results indicate that the canine pulmonary vascular response to 5-HT involves activation of 5-HT2 receptors and suggests that this receptor signal transduction pathway involves protein kinase C and tyrosine kinase and the activation of voltage-dependent Ca2+ channels.
Cutaneous vasodilation during dorsal column stimulation is mediated by dorsal roots and CGRP
Authors: Croom J. E. , Foreman R. D. , Chandler M. J. , Barron K. W.
Published: December 2017

Dorsal column stimulation (DCS) is used clinically to provide pain relief from peripheral vascular disease and has the benefit of increasing cutaneous blood flow to the affected lower extremities. The purpose of this study was to examine the role of dorsal roots, calcitonin gene-related peptide (CGRP), and substance P in the cutaneous vasodilation induced by DCS. Male rats were anesthetized with pentobarbital sodium (60 mg/kg ip). A unipolar ball electrode was placed unilaterally on the spinal cord at the L1-L2 spinal segment. Blood flow was recorded in each hindpaw foot pad with laser Doppler flowmeters. Blood flow responses were assessed during 1 min of DCS (either 0.2 mA subdural or 0.6 mA epidural at 50 Hz, 0.2-ms pulse duration). Dorsal rhizotomy of L3-L5 (n = 5) abolished the cutaneous vasodilation to subdural DCS, whereas removal of T10-T12 (n = 5) and T13-L2 dorsal roots (n = 5) did not attenuate the DCS-induced vasodilation. The CGRP antagonist, CGRP-(8-37) (2.6 mg/kg iv, n = 7), eliminated the epidural DCS-induced vasodilation, whereas the substance P receptor antagonist, CP-96345 (1 mg/kg iv, n = 6), had no effect. In summary, L3-L5 dorsal roots and CGRP are essential for the DCS-induced vasodilation. We propose that DCS antidromically activates afferent fibers in the dorsal roots, thus causing peripheral release of CGRP, which produces cutaneous vasodilation.
Pulmonary serotonin 5-HT3-sensitive afferent fibers modulate renal sympathetic nerve activity in rats
Authors: Veelken R. , Leonard M. , Stetter A. , Hilgers K. F. , Mann J. F. , Reeh P. W. , Geiger H. , Luft F. C.
Published: December 2017

Cardiopulmonary reflexes with vagal afferents may control volume homeostasis by influencing renal nerve activity. Such reflexes can be stimulated mechanically and chemically, e.g., by serotonin 5-HT). We have demonstrated that stimulation of epicardial 5-HT3 receptors inhibits renal sympathetic nerve activity (RSNA) by a cardiorenal reflex. We now tested the hypothesis that pulmonary 5-HT3-sensitive vagal afferent fibers participate in the control of renal nerve activity. Two sets of experiments were performed. First, the responses of multifiber RSNA, heart rate (HR), and blood pressure (BP) to the 5-HT3-receptor agonist phenylbiguanide (PBG; 10 microg iv) were recorded in the presence of intact pulmonary afferents. Abdominal afferents were removed by subdiaphragmatic vagotomy. Cardiac afferents were blocked by intrapericardial injection of 10% procaine. Second, the responses of 25 single vagal pulmonary afferent C fibers to PBG were assessed. PBG decreased BP, HR, and RSNA (-90 +/- 8%). When cardiac afferents were blocked by procaine, BP and HR failed to decrease in response to PBG; however, the RSNA decrease was still -48 +/- 8%. Single fibers generally responded to PBG by a slight increase in firing rate. A distinct subset of fibers (5 of 25) showed an activity increase of >15 Hz that preceded changes in BP and HR. The decreased RSNA in the absence of cardiac and abdominal vagal afferents and the strong response of 20% of pulmonary single fibers to intravenous PBG suggest that pulmonary fibers play a role in a 5-HT3 serotenergic reflex. Thus pulmonary serotonin could influence the neural control of renal function.
Effect of reperfusion on ventricular mass, topography, and function during healing of anterior infarction
Authors: Jugdutt B. I.
Published: December 2017

The effect of reperfusion performed 2 h after left anterior descending coronary artery occlusion on in vivo changes (echocardiograms) in ventricular mass, topography, and function during postinfarction healing over 6 wk and postmortem topography (planimetry) and collagen (hydroxyproline) content at 6 wk were measured in dogs randomized to reperfusion (n = 12) and no reperfusion (n = 12). Compared with no reperfusion over the 6 wk, reperfusion resulted in less increase in systolic and diastolic volumes, less increase in ventricular mass, less infarct wall thinning, and mild improvement in global ejection fraction without any change in regional asynergy. Although reperfusion decreased the infarct collagen content at 6 wk, it reduced the in vivo expansion of the endocardial surface area; the elongation, diastolic bulge, echogenicity, and systolic thinning of the infarct zone; and the global shape index and aneurysm frequency. Thus reperfusion after 2 h attenuates regional and global dilation and produces less increase in mass during postinfarct healing than no reperfusion, so that the improvement in global systolic function cannot be attributed to global hypertrophy.
Correlation between myocardial contractile force and cytosolic inorganic phosphate during early ischemia
Authors: He M. X. , Wang S. , Downey H. F.
Published: December 2017

To test the role of inorganic phosphate (Pi) in downregulation of myocardial contractile force at the onset of ischemia, Pi of rat hearts was determined with 31P nuclear magnetic resonance spectroscopy. Forty cycles of brief hypoperfusion (30% of baseline flow for 33 s) were used to achieve a time resolution of 0.512 s for comparing dynamic changes in Pi and contractile force. Initial control values of left ventricular developed pressure (LVP), heart rate, and oxygen consumption were 136 +/- 11 mmHg, 236 +/- 4 beats/min, and 95 +/- 3 microl O2 x min(-1) x g(-1); these values were unchanged at the end of the experiment. During the first 10 s of hypoperfusion, Pi increased at a rate (percentage of the total observed change) faster than the decrease in LVP; Pi and LVP then changed at the same rate during the remainder of the hypoperfusion. ADP did not change in advance of LVP. Intracellular pH did not change. The results indicate that Pi plays an important role in initiating the downregulation of myocardial contractile force at the onset of ischemia. Perfusion pressure also declined faster than LVP at the onset of ischemia, indicating potential importance of vascular collapse in contractile downregulation during early ischemia.
T-kinin has endothelium-dependent vasodilator activity in the cat
Authors: Santiago J. A. , Champion H. C. , Kadowitz P. J.
Published: December 2017

Responses to T-kinin, a peptide formed from the acute-phase substrate T-kininogen, were investigated in the hindlimb vascular bed of the cat. Under constant-flow conditions, injections of T-kinin into the perfusion circuit in doses of 0.03-1 nmol induced rapid dose-related decreases in perfusion pressure. Responses to T-kinin were similar in time course and magnitude to responses to bradykinin and kallidin and were inhibited by the kinin B2-receptor antagonist, Hoe-140. Responses to T-kinin were attenuated by an inhibitor of nitric oxide synthase and by tetraethylammonium chloride and were enhanced in duration by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor zaprinast. Responses to T-kinin were not altered by inhibitors of K+(ATP) channels, by the cyclooxygenase pathway, or by muscarinic or beta-adrenergic-receptor antagonists. These data suggest that vasodilator responses to T-kinin are mediated by kinin B2-receptor-stimulated release of nitric oxide from the endothelium and increased smooth muscle cGMP levels. These results indicate that activation of K+(ATP) channels and muscarinic or beta-adrenergic receptors and the release of vasodilator prostaglandins are not involved in mediating the response to T-kinin in the hindlimb circulation of the cat.
Facilitation of postischemic reperfusion with alpha-PBN: assessment using NMR and Doppler flow techniques
Authors: Schulz J. B. , Panahian N. , Chen Y. I. , Beal M. F. , Moskowitz M. A. , Rosen B. R. , Jenkins B. G.
Published: December 2017

We examined the effects of the free radical spin trap N-tert-butyl-alpha-phenylnitrone (PBN) on focal cerebral ischemia/reperfusion injury in halothane-anesthetized rats. Ninety minutes after middle cerebral artery occlusion by an intraluminal filament, the artery was reperfused. Intravenous injections of 25 mg/kg PBN 5 min before and 30 min after insertion of the filament significantly attenuated the lesion volume measured 24 h after ischemia. During ischemia and during the first 30 min after reperfusion, cerebral blood volume and blood flow were measured by volume-sensitive and newly developed flow-sensitive magnetic resonance imaging (MRI) techniques and by laser-Doppler flowmetry. In all animals the area of decreased blood flow was larger than the area of decreased volume by a factor of 2.2. The area of the postreperfusion flow deficits matched the final lesion volumes at 24 h measured histologically much better than did the blood volume deficits in both saline and PBN-treated animals. Reperfusion led to a return of blood flow and volume to values close to the contralateral side in the PBN-treated animals, in contrast to the saline-treated control group. We conclude that in focal ischemia/reperfusion PBN provides protection of the vascular endothelium, leading to enhanced postischemic reperfusion. The implication of this is that the vascular endothelium may be a primary target for the damaging action of free radicals given the protection afforded by putative spin traps.
Stage-dependent changes in membrane currents in rats with monocrotaline-induced right ventricular hypertrophy
Authors: Lee J. K. , Kodama I. , Honjo H. , Anno T. , Kamiya K. , Toyama J.
Published: December 2017

Sequential changes in action potential configuration, 4-amino-pyridine-sensitive transient outward current (Ito), and L-type calcium current (ICa) in association with hypertrophy were investigated in ventricular myocytes from rats with monocrotaline (MCT)-induced pulmonary hypertension. The tissue weight ratio of right ventricle (RV) to left ventricle plus septum 14 and 28 days after a subcutaneous injection of MCT increased by 29.7 and 77.2%, respectively. Action potential duration (APD) of RV cells from MCT rats increased progressively, prolonged by 73.2 and 92.2% on days 14 and 28, respectively. The current density of Ito in RV cells from MCT rats on day 14 (32.5 +/- 4.5 pA/pF, n = 13) was significantly larger than in controls (26.8 +/- 4.5 pA/pF, n = 8; P < 0.05). On day 28, however, Ito density in MCT rats (15.3 +/- 4.6 pA/pF, n = 9) was significantly less than in controls (27.3 +/- 4.2 pA/pF, n = 10; P < 0.05). There were no differences in the voltage dependence of steady-state activation and inactivation of Ito between MCT and control rats. ICa density in MCT rats on day 14 (15.7 +/- 2.6 pA/pF, n = 10) was significantly larger than in controls (10.0 +/- 2.3 pA/pF, n = 10; P < 0.05), but there was no significant difference in Ito density between MCT rats (8.3 +/- 3.7 pA/pF, n = 10) and controls (11.6 +/- 3.0 pA/pF, n = 10) on day 28. These findings suggest that hypertrophy of mammalian hearts may cause stage-dependent changes in Ito and ICa density of ventricular myocytes. The APD prolongation in the early stage of hypertrophy may be caused mainly by an increase in ICa density, whereas the APD prolongation in the late stage may be ascribed to a reduction in Ito density.
Transient outward current contributes to Wenckebach-like rhythms in isolated rabbit ventricular cells
Authors: Yehia A. R. , Shrier A. , Lo K. C. , Guevara M. R.
Published: December 2017

Wenckebach-like rhythms in isolated rabbit ventricular cells are characterized by beat-to-beat increments in action potential duration (APD) and latency, giving rise to a beat-to-beat decrease in the recovery interval and culminating in a skipped beat. These systematic APD changes are associated with a beat-to-beat decrease in the slope of the early repolarizing phase (phase 1) of the action potential, which is partially controlled by the transient outward potassium current (Ito). When Ito is blocked with 4-aminopyridine, periodic Wenckebach rhythms are replaced by aperiodic Wenckebach rhythms, in which the beat-to-beat changes in the slope of phase 1 and in APD disappear but the beat-to-beat increase in latency remains. A beat-to-beat decrease in Ito, paralleling the beat-to-beat changes in the slope of phase 1 and in APD, is seen in action-potential clamp experiments with Wenckebach rhythms previously recorded in the same cell. Simulations with an ionic model of Ito show cyclical changes in Ito consistent with the experimental data. These results demonstrate a key role for Ito in the generation of maintained periodic Wenckebach rhythms in isolated rabbit ventricular cells.
Constitutive expression of ICAM-1 in rat microvascular systems analyzed by laser confocal microscopy
Authors: Iigo Y. , Suematsu M. , Higashida T. , Oheda J. , Matsumoto K. , Wakabayashi Y. , Ishimura Y. , Miyasaka M. , Takashi T.
Published: December 2017

The present study aimed to demonstrate constitutive expression of the intercellular adhesion molecule (ICAM)-1 among arterioles, capillaries, and venules in the mesentery and liver and to examine the interaction between cultured endothelial cells and leukocytes in rats. ICAM-1 expression in the microvessels in vivo was visually demonstrated by laser confocal fluorescence microscopy. A monoclonal antibody against rat ICAM-1 (1A29) was labeled with fluorescein isothiocyanate, and the binding ratio between the fluorescence and immunoglobulin was determined for data calibration. Intravascularly administered fluorescein isothiocyanate-labeled 1A29 was distributed heterogeneously among the hierarchy of microvessels in the mesentery: postcapillary venules were the major portion expressing ICAM-1 constitutively, and the density of 1A29 bound to their endothelium was at least 10 times higher than that in true capillaries and arterioles in the same mesentery. On the other hand, the liver expressed ICAM-1 abundantly in sinusoids to the extent similar to that in central venules. These results suggest that postcapillary venules serve as an active gateway with the readiness to help adhere circulating leukocytes exposed to proinflammatory stimuli in acute inflammation.
Myocardial temperature in acute myocardial infarction: protection with mild regional hypothermia
Authors: Hale S. L. , Kloner R. A.
Published: December 2017

This study tests the hypothesis that a 2-4 degrees C reduction in myocardial temperature, obtained by using topical regional hypothermia (TRH), reduces infarct size. Anesthetized rabbits received coronary artery occlusion and reperfusion. We cooled hearts in the TRH group by applying an ice bag directly over the risk zone; the control group received no intervention. Risk zone myocardial temperature (MT) in the TRH group was reduced at occlusion by 2 degrees C from baseline and after 5 min of occlusion by 3.6 degrees C. In the control group, MT in the risk region remained within 0.3 degree C of baseline. The ischemic area was similar in both groups, yet infarct size in the TRH group was reduced by an average of 65% compared with the control group. Infarct size closely correlated with MT in the risk region at the time of occlusion. In a second protocol in which all hearts were paced, infarct size was 21% of the risk region in TRH hearts compared with 44% in controls. These results strongly support the important role of MT in the progression of necrosis and demonstrate that the application of local cooling to the risk region profoundly reduces myocardial infarct size.
cAMP induces heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle
Authors: Durante W. , Christodoulides N. , Cheng K. , Peyton K. J. , Sunahara R. K. , Schafer A. I.
Published: December 2017

Recent studies indicate that vascular smooth muscle cells generate carbon monoxide (CO) via the action of heme oxygenase (HO). Because adenosine 3',5'-cyclic monophosphate (cAMP) is an important intracellular signaling molecule in the regulation of vascular cell function, we examined whether this second messenger modulates the expression of HO and the production of CO by rat aortic smooth muscle cells. Treatment of smooth muscle cells with the membrane-permeable cAMP derivative dibutyryl cAMP or with compounds that increase intracellular cAMP levels (isoproterenol and forskolin) resulted in a concentration- and time-dependent increase in the levels of HO-1 mRNA and protein, whereas the expression of HO-2 remained unchanged. Both actinomycin D and cycloheximide blocked the basal expression of HO-1 mRNA and protein and prevented the cAMP-mediated induction of HO-1. Incubation of platelets with cAMP-treated smooth muscle cells resulted in a significant increase in platelet cGMP concentration that was partially reversed by treatment of smooth muscle cells with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine or the HO blocker zinc protoporphyrin-IX. However, the combined addition of these two inhibitors to cAMP-treated smooth muscle cells or the addition of the CO and NO scavenger hemoglobin to platelets completely blocked the stimulatory effect on platelet cGMP levels. These results demonstrate that cAMP induces the expression of the HO-1 gene and stimulates the formation of CO and NO in vascular smooth muscle cells. The capacity of cAMP to induce the synthesis of guanylate cyclase-stimulatory CO from smooth muscle cells may represent a novel mechanism by which this nucleotide regulates vascular tone.
Adenosine stimulates nitric oxide synthesis in rat cardiac myocytes
Authors: Ikeda U. , Kurosaki K. , Shimpo M. , Okada K. , Saito T. , Shimada K.
Published: December 2017

We investigated the effects of adenosine on nitric oxide (NO) synthesis by measuring the production of nitrite, a stable metabolite of NO, in cultured neonatal rat cardiac myocytes. Incubation of cultures with interleukin-1 beta (10 ng/ml) for 24 h caused a significant increase in nitrite production. The interleukin-1 beta-induced nitrite production by cardiac myocytes was significantly increased by adenosine or its stable analog 2-chloroadenosine in a dose-dependent manner (10(-7)-10(-4) M). The adenosine A2-receptor antagonist KF-17837 (10(-6) M), but not the A1-receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (10(-6) M), significantly inhibited 2-chloroadenosine-mediated nitrite production. The 2-chloroadenosine-induced nitrite production by interleukin-1 beta-stimulated cells was accompanied by inducible NO synthase mRNA and protein accumulation. In the presence of N6, 2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (cAMP) (10(-3) M) or isoproterenol (10(-5) M), interleukin-1 beta-induced nitrite accumulation was further increased, but the effect of 2-chloroadenosine was not additive or synergistic. The protein kinase C inhibitor calphostin C did not inhibit the effect of 2-chloroadenosine. These results indicate that adenosine acts on A2 receptors and augments NO synthesis in interleukin-1 beta-stimulated cardiac myocytes, at least partially through a cAMP-dependent pathway.
In vivo hydraulic conductivity of muscle: effects of hydrostatic pressure
Authors: Zakaria El Rasheid , Lofthouse Joanne , Flessner Michael F.
Published: December 2017

We and others have shown that the loss of fluid and macromolecules from the peritoneal cavity is directly dependent on intraperitoneal hydrostatic pressure (Pip). Measurements of the interstitial pressure gradient in the abdominal wall demonstrated minimal change when Pipwas increased from 0 to 8 mmHg. Because flow through tissue is governed by both interstitial pressure gradient and hydraulic conductivity ( K), we hypothesized that K of these tissues varies with Pip. To test this hypothesis, we dialyzed rats with Krebs-Ringer solution at constant Pipof 0.7, 1.5, 2.2, 3, 4.4, 6, or 8 mmHg. Tracer amounts of125I-labeled immunoglobulin G were added to the dialysis fluid as a marker of fluid movement into the abdominal wall. Tracer deposition was corrected for adsorption to the tissue surface and for local loss into lymphatics. The hydrostatic pressure gradient in the wall was measured using a micropipette and a servo-null system. The technique requires immobilization of the tissue by a porous Plexiglas plate, and therefore a portion of the tissue is supported. In agreement with previous results, fluid flux into the unrestrained abdominal wall was directly related to the overall hydrostatic pressure difference across the abdominal wall (Pip= 0), but the interstitial pressure gradient near the peritoneum increased only ∼40% over the range of Pip= 1.5–8 mmHg (20–28 mmHg/cm). K of the abdominal wall varied from 0.90 ± 0.1 × 10−5cm2⋅ min−1⋅ mmHg−1at Pip= 1.5 mmHg to 4.7 ± 0.43 ×10−5cm2⋅ min−1⋅ mmHg−1on elevation of Pipto 8 mmHg. In contrast, for the same change in Pip, abdominal muscle supported on the skin side had a significantly lower range of fluid flux (0.89–1.7 × 10−4vs. 1.9–10.1 × 10−4ml ⋅ min−1⋅ cm−2in unsupported tissue). The differences between supported and unsupported tissues are likely explained in part by a reduced pressure gradient across the supported tissue. In conclusion, the in vivo hydraulic conductivity of the unsupported abdominal wall muscle in anesthetized rats varies with the superimposed hydrostatic pressure within the peritoneal cavity.
Conduction between isolated rabbit Purkinje and ventricular myocytes coupled by a variable resistance
Authors: Huelsing Delilah J. , Spitzer Kenneth W. , Cordeiro Jonathan M. , Pollard Andrew E.
Published: December 2017

Conduction at the Purkinje-ventricular junction (PVJ) demonstrates unidirectional block under both physiological and pathophysiological conditions. Although this block is typically attributed to multidimensional electrotonic interactions, we examined possible membrane-level contributions using single, isolated rabbit Purkinje (P) and ventricular (V) myocytes coupled by an electronic circuit. When we varied the junctional resistance ( R j) between paired V myocytes, conduction block occurred at lower R j values during conduction from the smaller to larger myocyte (115 ± 59 MΩ) than from the larger to smaller myocyte (201 ± 51 MΩ). In Purkinje-ventricular myocyte pairs, however, block occurred at lower R j values during P-to-V conduction (85 ± 39 MΩ) than during V-to-P conduction (912 ± 175 MΩ), although there was little difference in the mean cell size. Companion computer simulations, performed to examine how the early plateau currents affected conduction, showed that P-to-V block occurred at lower R j values when the transient outward current was increased or the calcium current was decreased in the model P cell. These results suggest that intrinsic differences in phase 1 repolarization can contribute to unidirectional block at the PVJ.