bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction of hypokalemia and ventricular dilatation in isolated rabbit hearts
Authors: Reiter M. J. , Mann D. E. , Williams G. R.
Published: December 2017

Potassium depletion has been implicated in the genesis of ventricular arrhythmias, especially in patients with congestive heart failure, but the nature of this interaction is unknown. We studied the electrophysiological effects of varying concentrations of extracellular K+ in 24 isolated, retrogradely perfused rabbit hearts. The left ventricular cavity was dilated with a fluid-filled balloon. Left ventricular effective refractory period decreased significantly (from 119 +/- 3 to 105 +/- 3 ms) with ventricular dilatation but was not influenced by K+ concentration. Conduction velocity was not changed by dilatation but was decreased by hypokalemia (81 +/- 2 cm/s, K+ = 4.9 mM; 75 +/- 2 cm/s, K+ = 3.5 mM; 70 +/- 2 cm/s, K+ = 2.5 mM; P < 0.05). No ventricular arrhythmias were induced in undilated hearts at a K+ concentration of 4.9 mM. Induced ventricular fibrillation was more frequent (38%; P < 0.01) in the dilated heart and increased markedly (92%; P < 0.01) with coexisting hypokalemia. The incidence of induced fibrillation was highly correlated with the wavelength of the ventricular impulse (wavelength = refractory period x conduction velocity). Thus dilatation and hypokalemia have very different electrophysiological effects that can interact synergistically to predispose the heart to reentrant arrhythmias in this model.
Two-port analysis of systemic venous and arterial impedances
Authors: Rose W. C. , Shoukas A. A.
Published: December 2017

Hemodynamic properties of the systemic vasculature were measured in eight anesthetized dogs using two-port impedance analysis. Blood pressures and flows were measured at the aortic root and the caval-atrial junction. Impedances were computed from 0.05 to 20 Hz to characterize the systemic vasculature. Pseudorandom variations in flow were produced with an extracorporeal perfusion system. Impedance measurements were made at carotid baroreceptor pressures of 50, 125, and 200 mmHg. A six-parameter lumped-element model best fitted the measured impedance spectra. At 125 mmHg, the mean parameter values were venous inertance, 13.5 g.kg.cm-4; venous and arterial compliances, 0.769 and 0.0214 ml.mmHg-1.kg-1; venous and arterial characteristic impedances, 0.028 and 0.084 mmHg.kg.min.ml-1; and arterial-to-venous small-vessel resistance, 0.706 mmHg.kg.min.ml-1. Regression analysis showed significant dependence of small-vessel resistance on baroreceptor pressure. The other parameters were not dependent on carotid sinus pressure, which is consistent with baroreflex control of venous unstressed volume but not compliance. We conclude that two-port impedance analysis is a useful tool for studying venous hemodynamics and the dynamic coupling between the veins and the right heart.
Capillary filtration during acute inflammation: role of adherent neutrophils
Authors: Harris N. R. , Benoit J. N. , Granger D. N.
Published: December 2017

Fluid filtration rate with respect to surface area (Jv/S) was measured in capillaries of rat mesentery by a micro-occlusion technique. Superfusion of the mesentery with 100 nM platelet-activating factor (PAF) caused a fivefold increase in Jv/S (control, mean +/- SE = 0.016 +/- 0.002 micron/s, n = 44 rats; PAF, 0.078 +/- 0.010, n = 10), whereas 20 nM leukotriene B4 (LTB4) had no effect (0.010 +/- 0.003, n = 8). These doses of PAF and LTB4 induced a similar level of leukocyte adherence to venular endothelium. Neutrophils play a role in PAF-mediated increases in Jv/S, since a significantly lower Jv/S was elicited by PAF superfusion in neutropenic rats (0.024 +/- 0.006, n = 7). Monoclonal antibodies (MAb) directed against either the leukocyte adhesion glycoprotein CD11/CD18 (0.037 +/- 0.006, n = 8) or the endothelial cell adhesion molecule P-selectin (0.025 +/- 0.004, n = 8) also attenuated PAF-induced capillary filtration, whereas a nonbinding form of the P-selection MAb had no inhibitory effect (0.066 +/- 0.024, n = 3). These results indicate that PAF, but not LTB4, enhances capillary fluid filtration rate. While neutrophils do not adhere to endothelium in capillaries exposed to PAF, they do appear to contribute significantly to the PAF-induced capillary fluid filtration.
Resetting of regional preload due to ventricular shape change alters diastolic and systolic performance
Authors: Yamaguchi S. , Tamada Y. , Miyawaki H. , Niida Y. , Fukui A. , Shirakabe M. , Ohta I. , Tsuiki K. , Tomoike H.
Published: December 2017

The diastolic and systolic pressure of one ventricle is increased by an increase in volume and/or pressure of the opposite ventricle; however, a mechanism for the ventricular interaction remains unclear. We hypothesized that the shape change of one ventricle elicited by the opposite ventricle would lead to resetting of the regional length, which may explain the ventricular interaction. We used 15 cross-circulated isovolumically contracting canine hearts in which both ventricular volumes were independently controlled. Diastolic regional segment area was calculated by multiplying circumferential and longitudinal lengths on right ventricular free wall (RVFW; n = 6), interventricular septum (IVS; n = 11), and left ventricular (LV) FW (n = 12). The regional area at relatively small volumes of both ventricles were expressed as 100%. With constant RV volume, increasing LV from 7 to 19 ml increased RV diastolic and systolic pressures by 2.7 and 5.5 mmHg, respectively. Conversely, increasing RV volume increased LV diastolic and systolic pressures by 2.3 and 7.5 mmHg, respectively. Increasing LV volume increased RVFW regional area from 121.0 to 124.6% (P < 0.01) and increased IVS regional area from 103.3 to 108.7% (P < 0.01), whereas the RV volume was held constant. Increasing RV volume also increased LVFW and IVS regional areas from 109.9 to 111.6% (P < 0.01) and from 106.8 to 108.9% (P < 0.05), respectively. Ventricular shape change elicited by ventricular interaction will increase the regional wall area, even though the volume of the chamber is unchanged. The increase in the regional area alters the position of the tissue on its resting and active length-tension relations and, thus, leads to enhancement of the chamber pressure.
Endothelium-dependent and -independent responses to severe hypoxia in rat pulmonary artery
Authors: Greenberg B. , Kishiyama S.
Published: December 2017

The changes in pulmonary artery (PA) tone that develop during hypoxia are complex and appear to involve multiple vasoregulatory pathways. This study was designed to identify the phases of the response to severe hypoxia in isolated segments of rat PA and to evaluate the mechanisms involved. Exposure of preconstricted PA segments to severe hypoxia (i.e., PO2 < 3 Torr) resulted in transient relaxation followed by vigorous hypoxic vasoconstriction (HVC), which averaged 0.26 +/- 0.02 g (or 43.9 +/- 3.7% of the maximal force developed in response to phenylephrine). HVC was followed by sustained and nearly complete inhibition of existing tone. The first two phases of the response were endothelium dependent and could be blocked by nonspecific inhibitors of endothelium-derived relaxing factor (EDRF) activity and by 500 microM N omega-nitro-L-arginine, a specific inhibitor of nitric oxide (NO) formation. The transient early relaxation could also be inhibited by superoxide dismutase (50 U/ml). In contrast, the late relaxation phase was neither endothelium dependent nor could it be blocked by inhibitors of EDRF/NO activity. Rat PA segments were relaxed by pinacidil and lemakalim, both of which activate ATP-sensitive potassium channels. Preincubation with glibenclamide, a selective inhibitor of these channels, blocked this response and also reduced late hypoxic vasodilation by nearly 40% (P < 0.001). These findings demonstrate that the response of rat PA to hypoxia involves both endothelium-dependent and endothelium-independent components. The initial relaxation results from enhanced EDRF/NO activity, which is likely due to diminished breakdown by superoxide radicals.(ABSTRACT TRUNCATED AT 250 WORDS)
ANG II reverses selective inhibition of alpha 2-adrenoceptor sensitivity after in vitro isolation of arterioles
Authors: Ikeoka K. , Faber J. E.
Published: December 2017

To determine whether in vitro isolation attenuates alpha 2-reactivity, we examined postjunctional alpha-adrenoceptor sensitivity of isolated rat skeletal muscle first-order arterioles that we have previously characterized in vivo. Microdissected, pressurized arterioles (mean lumen diam +/- SE, 115 +/- 7 microns) were studied after cannulation with micropipettes. As expected, the alpha 1-antagonist, prazosin (10(-8) M), produced a parallel, 10-fold dextral displacement of the phenylephrine (alpha 1-agonist) concentration-response curve, whereas the alpha 2-antagonist, rauwolscine (10(-7) M) had no effect. However, prazosin inhibited UK-14,304 (full alpha 2- but partial alpha 1-agonist), which was opposite to our previous in vivo studies of these vessels; namely, prazosin shifted the UK-14,304 response curve by 21-fold, whereas rauwolscine induced only a twofold shift. These data suggest a loss of alpha 2-adrenoceptor responsiveness after in vitro isolation. In a second experiment, the presence of 10 pM angiotensin II, which was subthreshold for constriction, increased phenylephrine sensitivity 10-fold, UK-14,304 sensitivity 16-fold, and the UK-14,304 maximal response by 63%; the half maximum effective concentration response to UK-14,304 was now abolished by rauwolscine at a concentration that did not inhibit phenylephrine constriction. These data suggest that in vitro conditions selectively attenuate alpha 2-adrenoceptor sensitivity, and that subthreshold angiotensin II restores alpha 2-sensitivity to in vivo values.
Role of endothelium in sexual dimorphism in vasopressin-induced contraction of rat aorta
Authors: Stallone J. N.
Published: December 2017

In rat thoracic aorta, contractile responses to arginine vasopressin (AVP) are twofold higher in females than in males. To determine the role of the endothelium in this phenomenon, the effects of endothelium removal and inhibition of nitric oxide (NO) synthase and cyclooxygenase were examined in thoracic aortas prepared from male and female Sprague-Dawley rats and mounted for isometric tension recording. Maximal contractile response to AVP was substantially higher in female (4,232 +/- 316 mg/mg ring dry wt) than in male aortas (1,365 +/- 239; P < 0.01). Removal of the endothelium markedly potentiated maximal response to AVP in male aortas (4,100 +/- 422 mg/mg ring wt; P < 0.01); endothelium removal increased sensitivity but not maximal response in female aortas. Inhibition of NO synthase with NG-monomethyl-L-arginine (L-NMMA, 250 microM) doubled maximal contraction to AVP in male aortas (3,175 +/- 193 mg/mg ring wt; P < 0.01); L-NMMA increased sensitivity but not maximal response in female aortas. Inhibition of cyclooxygenase with indomethacin (10 microM) did not alter maximal response to AVP in male aortas but significantly attenuated responses of female aortas (2,816 +/- 306 mg/mg ring wt; P < 0.01). In contrast, maximal contractile response to phenylephrine hydrochloride (PE) was 40% higher in males than in females (P < 0.01); L-NMMA increased both the sensitivity and maximal response to PE to a greater extent in female (3,061 +/- 121 vs. 4,971 +/- 135 mg/mg ring wt; P < 0.01) than in male aortas (4,317 +/- 227 vs. 4,899 +/- 104 mg/mg ring wt; P < 0.01). (ABSTRACT TRUNCATED AT 250 WORDS)
Nitric oxide contributes to dilatation of cerebral arterioles during seizures
Authors: Faraci F. M. , Breese K. R. , Heistad D. D.
Published: December 2017

Endogenous release of excitatory amino acids during seizures produces marked increases in neuronal activity and guanosine 3',5'-cyclic monophosphate levels in brain tissue, which are mediated by nitric oxide (NO). We tested the hypothesis that dilatation of the cerebral microcirculation during seizures is mediated by NO. Diameters of cerebral arterioles were measured using a closed cranial window in anesthetized rabbits. Three, five, nine, and eleven minutes after the onset of pentylenetetrazole-induced seizure (which releases endogenous excitatory amino acids), arteriolar diameter increased by 42 +/- 6, 30 +/- 3, 20 +/- 2, and 16 +/- 2% (means +/- SE), respectively, from a control diameter of 86 +/- 6 microns. Arterial pressure was maintained at control levels during seizures. In the presence of NG-nitro-L-arginine (L-NNA, 300 microM), an inhibitor of NO synthase, vasodilatation during seizures was not affected at 3 min (40 +/- 8%) but was significantly reduced at 5, 9, and 11 min (17 +/- 5, 6 +/- 3, and 1 +/- 3%, respectively, P < 0.05 vs. control). Vasodilatation in response to topical application of acetylcholine (1 microM) was also inhibited by L-NNA (33 +/- 5 vs. 3 +/- 2%, P < 0.05). Dilatation of cerebral arterioles in response to nitroprusside (1 and 10 microM) was not inhibited by L-NNA. Thus sustained, but not initial, dilatation of cerebral arterioles during seizures appears to be mediated in part by NO.
Stretch preconditions canine myocardium
Authors: Ovize M. , Kloner R. A. , Przyklenk K.
Published: December 2017

Preconditioning is believed to be directly triggered by brief ischemia-reperfusion. However, brief ischemia results in transient dilation (or stretching) of the heart. We therefore sought to determine whether stretch per se, induced by rapid volume overload instead of brief coronary occlusion, could precondition the heart via stretch-activated ion channels. Forty-two anesthetized dogs underwent 1 h of coronary artery occlusion followed by 4.5 h of reperfusion. Before this, each dog underwent either no intervention (control) or acute volume overload. In three additional groups, Gd3+, a potent blocker of stretch-activated channels was injected as a bolus into the left atrium of each dog at the onset of the treatment period. Then the dogs underwent either acute volume overload, a 5-min episode of coronary occlusion followed by 10 min of reperfusion, or no intervention. Myocardial stretch significantly reduced infarct size after a subsequent 60-min ischemic insult. Protection afforded by stretch was completely prevented by Gd3+. Reduction in infarct size afforded by ischemic preconditioning was partially reversed by Gd3+. Gd3+ per se did not, however, alter the extent of necrosis. The present study suggests that myocardial stretch per se can precondition the canine heart, probably by activation of stretch-activated ion channels.
Effect of bacterial lipopolysaccharide on function of rat small femoral arteries
Authors: Schneider F. , Bucher B. , Schott C. , Andre A. , Julou-Schaeffer G. , Stoclet J. C.
Published: December 2017

The effects of endotoxin on endothelial and smooth muscle function were investigated in small femoral arteries removed from rats 4 h after intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS; 20 mg/kg) or solvent. In the absence of L-arginine in the organ bath, the sensitivity of the arteries to norepinephrine (NE) was decreased only slightly, and the relaxing effects of neither 3-morpholinosydonimine-N-ethyl-carbamide (SIN-1), a nitric oxide (NO) donor, nor acetylcholine (ACh) were modified by LPS treatment despite morphological damage to the endothelium seen with scanning electron microscopy. However, L-arginine (30 microM to 1 mM), which had no effect on control vessels, caused a rapid and stereospecific relaxation of arteries from LPS-treated rats that was abolished by both NG-nitro-L-arginine methyl ester (1 mM), a NO synthase inhibitor, and methylene blue, an inhibitor of the activation of guanylyl cyclase by NO. The relaxing effect of L-arginine was observed in the absence of endothelium, although it was significantly greater in its presence. In addition, a 30-min exposure to extracellular L-arginine (100 microM) moderately but significantly decreased the sensitivity to ACh and SIN-1 of vessels from LPS-treated but not from control rats. These results indicate that LPS treatment induced a NO synthase activity in smooth muscle cells of rat small femoral arteries and that the resulting relaxation was dependent on extracellular L-arginine in these resistance vessels.(ABSTRACT TRUNCATED AT 250 WORDS)
Baroreflex dysfunction in diabetes mellitus. II. Site of baroreflex impairment in diabetic rabbits
Authors: McDowell T. S. , Hajduczok G. , Abboud F. M. , Chapleau M. W.
Published: December 2017

In our companion paper [T. S. McDowell, M. W. Chapleau, G. Hajduczok, and F. M. Abboud, Am. J. Physiol. 266 (Heart Circ. Physiol. 35): H235-H243, 1994] we report that baroreflex-mediated bradycardia is impaired in diabetic rabbits. The purpose of the present study was to identify the site of impairment. Diabetes was induced in rabbits by alloxan (90–100 mg/kg iv; n = 7). Alloxan-treated rabbits that remained normoglycemic (n = 8) and rabbits given saline instead of alloxan (n = 4) served as controls. Twenty-four weeks after administration of alloxan or saline, rabbits were anesthetized with alpha-chloralose. Aortic baroreceptor and renal sympathetic nerve activity (RSNA) were recorded during phenylephrine- and nitroglycerin-induced changes in arterial pressure. The slope of the baroreceptor pressure-activity relation was not significantly different in diabetic rabbits (1.3 +/- 0.3%/mmHg, n = 7) compared with either alloxan-treated (1.3 +/- 0.1%/mmHg) or saline-treated normoglycemic rabbits (1.2 +/- 0.2%/mmHg). The slope of the arterial pressure-RSNA relation was not significantly different in diabetic rabbits (-3.5 +/- 0.3%/mmHg, n = 7) compared with the alloxan-treated normoglycemic rabbits (-3.0 +/- 0.4%/mmHg, n = 8) and was greater than that in saline-treated normoglycemic rabbits (-1.9 +/- 0.3%/mmHg, n = 4; P < 0.05). The decreases in heart rate in response to electrical stimulation (10 V, 2 ms, 0.5–16 Hz) of the cut peripheral end of the right cervical vagus were similar in diabetic and alloxan-treated normoglycemic rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)
Moderate hyperglycemia affects ischemic brain ATP levels but not intracellular pH
Authors: Hsu S. S. , Meno J. R. , Gronka R. , Kushmerick M. , Winn H. R.
Published: December 2017

We used 31P nuclear magnetic resonance (NMR) spectroscopy to study the effect of moderate hyperglycemia on brain ATP and intracellular pH in a model of severe incomplete forebrain ischemia. Plasma glucose in the hyperglycemic rats was 277 +/- 9 mg/100 ml compared with 115 +/- 10 mg/100 ml in the normoglycemic rats at the onset of ischemia. After 15 min of ischemia, brain ATP levels decreased to 31 +/- 8% in normoglycemic rats vs. 63 +/- 11% in hyperglycemic rats (P < 0.05). Phosphocreatine levels were 31 +/- 9 and 55 +/- 8% for normoglycemic and hyperglycemic rats, respectively. Intracellular pH decreased to the same level (approximately 6.5) in both normoglycemic and hyperglycemic animals after 15 min of ischemia. In summary, we found that moderate hyperglycemia during severe incomplete forebrain ischemia significantly increases ischemic brain ATP levels but does not have a significant effect on intracellular pH. These results support the hypothesis that alterations in brain ATP and adenosine concentrations may be important in the pathogenesis of ischemic tissue injury under moderate hyperglycemic conditions, whereas alterations in tissue pH may be less important.
Dysfunction and safety factor strength-duration curves for biphasic defibrillator waveforms
Authors: Jones J. L. , Milne K. B.
Published: December 2017

Newly developed biphasic waveforms significantly lower defibrillation threshold in animal and clinical models. However, underlying mechanisms and optimum waveform shape are unknown. Defibrillation shocks produce dysfunction; safety factor, the ratio of shock intensity inducing dysfunction to that producing stimulation of partially refractory cells, is an important parameter for defibrillator waveforms. We determined dysfunction and safety factor strength-duration curves for symmetric and asymmetric (50% undershoot) monophasic and biphasic rectangular (0%-tilt) waveforms. Dysfunction threshold, defined as the voltage producing a 4-s postshock contractile arrest, was determined for waveforms with total durations from 1 to 40 ms. For all waveforms, dysfunction threshold decreased with waveform duration. At all durations, dysfunction threshold was similar for symmetric monophasic and biphasic waveforms with the same total duration. In contrast, asymmetric biphasic waveforms increased dysfunction threshold 14 +/- 3% (P < 0.005) compared with monophasic control waveforms. Because long-duration, low-tilt, biphasic waveforms improve excitation threshold for refractory cells, they should improve defibrillation threshold. Asymmetric waveforms have the additional advantage of improving safety factor by reducing postshock dysfunction.
Interactions of nitroglycerin and sulfhydryl-donating compounds in coronary microvessels
Authors: Wheatley R. M. , Dockery S. P. , Kurz M. A. , Sayegh H. S. , Harrison D. G.
Published: December 2017

Previous studies have shown the effect of nitroglycerin on coronary microvessels < 100 microns in diameter is markedly enhanced by L-cysteine. These studies were performed to examine the mechanisms responsible for this effect. Under control conditions, nitroglycerin caused potent dilations of large (> 200 microns diam) coronary microvessels while having minimal effects on small (< 100 microns diam) coronary microvessels [peak relaxations 85 +/- 4 vs. 23 +/- 3% (mean +/- SE) of endothelin-1-constricted vessels, respectively]. L-Cysteine (100 microM) and N-acetylcysteine (100 microM) markedly enhanced nitroglycerin-induced relaxations of small coronary microvessels (peak relaxation 84 +/- 6 and 87 +/- 12%, respectively) while having no effect on relaxations of vessels > 100 microns. In contrast, neither L-methionine (100 microM) nor glutathione (100 microM) enhanced nitroglycerin's vasodilation of small coronary microvessels. The effects of L-cysteine and N-acetylcysteine on the augmentation of nitroglycerin vasodilatation in smaller coronary microvessels was abolished in the presence of buthionine sulfoximine (100 microM), a potent inhibitor of intracellular glutathione synthesis. Buthionine sulfoximine had no effect on the vasodilatation produced by nitroprusside. These data demonstrate that, in smaller coronary microvessels, L-cysteine and N-acetylcysteine enhance nitroglycerin-induced vasodilatation by increasing intracellular glutathione concentrations. Intracellular glutathione, formed from either L-cysteine or N-acetylcysteine, may participate in the formation of an intermediate of nitroglycerin biotransformation or may maintain a redox potential within coronary microvessels that favors enzymatic bioconversion of nitroglycerin.
Effects of potassium channel blockers on basal vascular tone and reactive hyperemia of canine diaphragm
Authors: Vanelli G. , Hussain S. N.
Published: December 2017

Glibenclamide, iberiotoxin, and apamin (blockers of ATP-sensitive, large-conductance, and small-conductance Ca(2+)-activated potassium channels, respectively) were infused into the diaphragmatic vasculature of anesthetized dogs to assess the contribution of these channels in the regulation of basal tone and the response to brief occlusions of the left phrenic artery (reactive hyperemia). Baseline phrenic flow (Qphr), peak postocclusive flow, and reactive hyperemia duration in response to 10-, 30-, 60-, and 120-s arterial occlusions were measured before (control) and after the infusion of K+ channel blockers in three groups of animals. Glibenclamide at 5 x 10(-6), 1 x 10(-5), and 8 x 10(-5) M increased baseline phrenic resistance to 140, 204, and 192% of control values, respectively. Peak postocclusive Qphr and duration of hyperemia in response to all occlusion durations were significantly attenuated after glibenclamide infusion. Iberiotoxin infusion at 1 x 10(-8), 3 x 10(-8), and 1 x 10(-7) M increased phrenic resistance to 141, 133, and 146% of control values, respectively. By comparison, baseline phrenic resistance rose to 159 and 145% of control in response to 1 x 10(-7) and 1 x 10(-6) M apamin, respectively. Iberiotoxin and apamin reduced peak postocclusive flow and duration of hyperemia only in response to 10- and 30-s occlusions. We infused K+ channel blockers along with lemakalim into the diaphragm during constant flow perfusion in separate groups of animals. When infused alone, lemakalim reduced phrenic resistance by 60–70%.(ABSTRACT TRUNCATED AT 250 WORDS)
Exogenous intracellular, but not extracellular, iron augments myocardial reperfusion injury
Authors: Lesnefsky E. J. , Ye J.
Published: December 2017

Although previous studies using iron chelators suggest that iron-catalyzed reactions exacerbate myocardial injury, a direct demonstration of the timing, sites, and mechanisms of iron-mediated damage during reperfusion has been lacking. Catalytic doses of redox-active iron react with exogenously administered oxygen radical-generating systems to exacerbate myocardial injury. In an analogous manner, catalytic doses (5 microM) of excess iron present during early reperfusion should augment oxidative injury, if the redox-active iron is present in the same compartment as both the oxygen radicals generated during reperfusion as well as the critical biochemical targets of oxidative injury. We determined whether catalytic doses of iron given during early reperfusion could exacerbate myocardial injury and whether iron-catalyzed injury required intra- or extracellular iron. Buffer-perfused rabbit hearts underwent 30 min of 37 degrees C global ischemia and 30 min of reperfusion. Iron (5 microM), attached to ligands that either restrict iron to the extracellular space (ADP) or facilitate the entry of iron into myocytes (omadine, tropolone), was infused during the last 3 min of ischemia and the first 4 min of reperfusion. Recovery of developed pressure was decreased (P < 0.05) in omadine-iron and tropolone-iron compared with ADP-iron and noniron hearts treated with ligands alone. Tissue lipid peroxide levels, an index of oxidative injury, were increased (P < 0.05) by omadine-iron and tropolone-iron, but not ADP-iron. The oxidative damage caused by omadine-iron was blocked by pretreatment with dimethylthiourea, a cell-permeable scavenger of the hydroxyl radical.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of vasoactive intestinal peptide on myocardial performance
Authors: Xenopoulos N. P. , Applegate R. J.
Published: December 2017

It is now recognized that stimulation of the vagus releases both acetylcholine (ACh) and vasoactive intestinal peptide (VIP). Whereas ACh depresses cardiac function, recent data indicate that VIP may have a cardiostimulatory effect. Exogenously administered VIP appears to enhance left ventricular (LV) contractile function; however, whether endogenously released VIP alters LV performance is not known. Accordingly, we evaluated the effects of exogenous VIP and endogenously released VIP during vagal stimulation after muscarinic and beta-adrenergic blockade (VS-B) on LV performance using pressure-volume analysis. Eight anesthetized open-chest dogs instrumented to measure LV pressure and volume (conductance catheter) were pretreated with atropine (0.1 mg/kg) and propranolol (1 mg/kg). The cervical vagi were transected. Hemodynamic data were obtained at steady state and during transient vena caval occlusion. Exogenous intravenous VIP (0.05 microgram/kg-1 x min-1) increased HR minimally [2.1 +/- 0.9% increase; P = not significant (NS)] but significantly increased maximum first time derivative of left ventricular pressure (dP/dtmax; 29.4 +/- 19.9% increase; P < 0.05) and the slope of the end-systolic pressure-volume relation (Ees; 3.1 +/- 1.3 to 8.9 +/- 4.2 mmHg/ml; P < 0.05). Minimum first time derivative of left ventricular pressure (dP/dtmin) decreased 22 +/- 16.2% (P < 0.05), and the time constant of isovolumic relaxation (tau) decreased 38 +/- 18% (P < 0.05). During VS-B (20 Hz, 15 v, 5 min), HR increased significantly (98 +/- 11 to 130 +/- 26 beats/min; P < 0.05). Ees also increased significantly (3.3 +/- 1.6 vs. 5.2 +/- 2.8 mmHg/ml; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Mechanisms of myogenic enhancement by norepinephrine
Authors: Liu J. , Hill M. A. , Meininger G. A.
Published: December 2017

Mechanisms contributing to the ability of norepinephrine (NE) to enhance arteriolar myogenic responsiveness were studied in the rat cremaster muscle. Anesthetized rats were enclosed in an airtight box that could be pressurized to increase intravascular pressure in the cremaster, which was exteriorized into a tissue bath. Vessel diameter, intravascular pressure, and red cell velocity were measured in the first-order (1A) arteriole during box pressure increases of 10, 20, and 30 mmHg. Control arterioles [diameter = 113 +/- 3 (SE) microns] did not exhibit myogenic constriction in response to step increases in intravascular pressure (e.g., + 30 mmHg, diameter = 122 +/- 5 microns), whereas after 25% constriction with NE (diameter = 85 +/- 2 microns) arterioles exhibited significant myogenic constriction (e.g., +30 mmHg, diameter = 70 +/- 4 microns). The NE effect on myogenic reactivity was augmented by Ca2+ channel agonists and inhibited by antagonists, suggesting a role for voltage-operated Ca2+ channels. In contrast to NE, exposure to KCl (30 mM) did not enhance myogenic responsiveness, suggesting that factors in addition to voltage-operated channels were involved in the NE effect. The protein kinase C (PKC) activator indolactam (1 microM) was found to increase vascular tone in the 1A arterioles (diameter = 109 +/- 6 to 89 +/- 7 microns) and to induce significant myogenic responsiveness similar to that produced by NE (e.g., +30 mmHg, diameter = 65 +/- 9 microns). Staurosporine (0.1 microM) and calphostin C (1 microM), inhibitors of PKC, significantly attenuated the NE-induced myogenic response.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypoxia, alpha 2-adrenergic, and nitric oxide-dependent interactions on canine cerebral blood flow
Authors: McPherson R. W. , Koehler R. C. , Traystman R. J.
Published: December 2017

We tested the hypothesis that NO synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME) and alpha 2-adrenoreceptor stimulation with dexmedetomidine (Dex) decreases the cerebral blood flow (CBF) response to hypoxia. In isoflurane-anesthetized dogs, CBF was measured during two episodes of hypoxic hypoxia. In a control group (n = 6), CBF increased similarly from 83 +/- 4 to 210 +/- 30 ml.min-1 x 100 g-1 and from 88 +/- 7 to 205 +/- 27 (+/- SE) ml.min-1 x 100 g-1 during two hypoxic episodes. In a second group (n = 6), hypoxia increased CBF from 88 +/- 15 to 204 +/- 38 ml.min-1 x 100 g-1. Dex (10 micrograms/kg i.v.) reduced normoxic CBF to 54 +/- 8 ml.min-1 x 100 g-1, and subsequent hypoxia increased CBF to 97 +/- 14 ml.min-1 x 100 g-1. In a third group pretreated with L-NAME (40 mg/kg i.v.) 1 h before anesthesia (n = 6), normoxic CBF was less than in the control group (52 +/- 2 vs. 83 +/- 4 ml.min-1 x 100 g-1). Hypoxia increased CBF to 177 +/- 13 ml.min-1 x 100 g-1. Dex after L-NAME further decreased normoxic CBF to 37 +/- 3 ml.min-1 x 100 g-1, and subsequent hypoxia increased CBF to 106 +/- 18 ml.min-1 x 100 g-1. Dex, L-NAME, and Dex + L-NAME each reduced cerebral O2 transport (CBF x arterial O2 content) during normoxia, but the increase in CBF during hypoxia was sufficient to prevent further decreases in O2 transport. Thus the response to hypoxia remained proportional to normoxic levels of CBF.(ABSTRACT TRUNCATED AT 250 WORDS)
Endothelium-dependent phosphorylation of vasodilator-stimulated protein in platelets during coronary passage
Authors: Pohl U. , Nolte C. , Bunse A. , Eigenthaler M. , Walter U.
Published: December 2017

Compounds that elevate intraplatelet guanosine 3',5'-cyclic monophosphate (cGMP) or adenosine 3',5'-cyclic monophosphate (cAMP) stimulate the phosphorylation of a 46- to 56-kDa thrombocyte protein designated “vasodilator-stimulated protein” (VASP), which is most likely involved in the regulation of adhesion/aggregation. We investigated whether endothelium-derived relaxing factor (EDRF)/nitric oxide (NO) and prostaglandin I2 (PGI2) affected VASP phosphorylation in washed human platelets that were injected into the coronaries of saline-perfused rabbit hearts (n = 22) and collected immediately after passage. The endothelial stimulator acetylcholine (ACh; 1 microM) significantly increased the concentration of cGMP (indicating release of EDRF) and PGI2 in the coronary venous effluent, as well as the concentration of cGMP and cAMP in platelets. Phosphorylation state of VASP increased from 32.1 +/- 2.9 to 64.8 +/- 2.7%. Inhibition of EDRF/NO synthesis by NG-nitro-L-arginine (30 microM) completely abolished the ACh-induced cGMP increase, attenuated the cAMP-elevation without affecting PGI2, and caused a 20.5 +/- 5.8% decrease of the phosphorylation state of VASP. Indomethacin (30 microM) virtually abolished ACh-induced increases of PGI2, cAMP (but not cGMP), and phosphorylated VASP. These results indicate that both EDRF/NO and PGI2 contribute to the regulation of VASP phosphorylation in platelets collected after a single coronary passage. Their synergistic inhibitory effects on platelet function may thus be mediated by a common effect on target proteins like VASP as well as by a secondary increase in cAMP in response to cGMP-elevating compounds such as EDRF.
Regional differences in rabbit atrial repolarization: importance of transient outward current
Authors: Qi A. , Yeung-Lai-Wah J. A. , Xiao J. , Kerr C. R.
Published: December 2017

Regional differences in rabbit atrial repolarization were investigated using a conventional microelectrode technique. A more rapid phase 1 repolarization (lower phase 1 amplitude) was seen in the left atrial (LA) roof area compared with the right atrial (RA) roof area: 54 +/- 10 vs. 82 +/- 6 mV at 1,000 ms (P < 0.001). In addition, action potential duration at 40 mV above the resting potential (APD40) was shorter in LA and was associated with a slower phase 3 repolarization rate. Furthermore, the recovery time constant of phase 1 amplitude at 500 ms was 0.9 +/- 0.2 s in LA and 3.5 +/- 1.5 s in RA (P < 0.001). Pacing cycle lengths (2,000, 1,500, 1,000, 800, and 500 ms) modulated phase 1 amplitude, APD40, and phase 3 rate in both regions. 4-Aminopyridine (4-AP; 1 mM), a selective transient outward current (I(to)) blocker, abolished cycle length dependence of the above action potential parameters and diminished the differences in electrophysiological properties between the two regions. 4-AP also flattened the restitution curve of phase 1 amplitude in both regions. In conclusion, the findings suggest that the different kinetics of I(to) play an important role in regional differences of atrial repolarization.
Role of carotid sinus baroreflex in attenuating systemic arterial pressure variability studied in anesthetized dogs
Authors: Yoshida T. , Harasawa Y. , Kubota T. , Chishaki H. , Kubo T. , Sunagawa K. , Takeshita A.
Published: December 2017

Attenuation of systemic arterial pressure (SAP) variability by the carotid sinus baroreflex (CSBR) was quantified in nine anesthetized, vagotomized dogs. SAP amplitude spectrum was compared between open-loop [SAPo(f)] and closed-loop [SAPc(f)] operation of the CSBR. At 0.002 Hz, SAPc amplitude was 3.5 +/- 2.2 (SD) mmHg, and SAPo was 9.6 +/- 3.5 mmHg (P < 0.01). At 0.02 Hz, SAP(c) amplitude was 2.8 +/- 1.2 mmHg, and SAPo was 4.3 +/- 1.2 mmHg (P < 0.05). At higher frequencies, SAPo(f) was indistinguishable from SAPc(f). With the opened CSBR, intracarotid sinus pressure (CSP) was pseudorandomly varied, and the resulting SAP responses were recorded to determine the transfer function from CSP to SAP [HCSP.SAP(f)]. From SAPo(f) and the determined HCSP.SAP(f), we estimated SAP(f) if the CSBR was closed [SAPc,est(f)] and compared it with SAPc(f). These two spectra were similar in each dog over a frequency range of 0.002–0.15 Hz, the differences between SAPo(f) and SAPc(f) being reconcilable with HCSP.SAP(f). Although the anesthetized state and vagotomy may have distorted the transfer characteristics of the CSBR from those in conscious (with the intact vagi) states, the results of the present study indicate that the CSBR attenuated SAP variability mainly in a low-frequency range below 0.02 Hz and that this attenuation was attributable to the transfer properties of the CSBR.
Regulation of native collateral vessel dilation after coronary occlusion in the dog
Authors: Lamping K. G. , Bloom E. N. , Harrison D. G.
Published: December 2017

The purpose of this study was to examine mechanisms involved in the response of native collaterals to coronary occlusion. In anesthetized dogs native collaterals were identified as vessels coursing between the left anterior descending and left circumflex arteries using fluorescence angiography. After a left anterior descending occlusion in 12 dogs, collaterals < 100 microns in diameter progressively dilated by 21 +/- 4% (n = 12) 1 min after occlusion and by 39 +/- 6% 15 min after occlusion. Collaterals > 100 microns in diameter did not dilate after coronary occlusion. NG-nitro-L-arginine (1 mg/min intracoronary) caused constriction under basal conditions in collaterals < 100 microns but did not prevent the dilation of collaterals after occlusion. In contrast, glibenclamide (10(-5) M), an inhibitor of ATP-sensitive potassium channels, had no effect on baseline diameter of collaterals < 100 microns diameter but completely prevented dilation of collaterals after occlusion. We conclude that collaterals are not maximally dilated immediately after a coronary occlusion but rather progressively dilate for at least 15 min after an occlusion. This dilation of native collaterals after an occlusion is not mediated by release of an endothelium-derived relaxing factor derived from L-arginine but is mediated by activation of ATP-sensitive K+ channels.
Measurement of coronary blood flow velocity in conscious rats
Authors: Jones L. F. , Landas S. K. , Johnson A. K.
Published: December 2017

This study describes a technique for the continuous recording of coronary blood flow velocity (CBV) in conscious unrestrained rats. A pulsed Doppler flow probe consisting of a 1-mm2 crystal mounted in a 4-mm suction cup was positioned over the left coronary artery of pentobarbital sodium-anesthetized rats. The probe was held in place with mild suction and sutured to the surface of the myocardium. Probes were connected to a pulsed Doppler flowmeter, which measures Doppler shift and provides an index of blood flow velocity. While rats were still anesthetized, the measurement of CBV was validated by determining that CBV peaked during diastole and increased in parallel with arterial pressure. Phasic CBV signals obtained in conscious rats were similar to those observed in anesthetized animals. Intravenous infusion of dipyridamole (0.5–3 mg.kg-1 x mg-1) produced a dose-dependent increase in CBV and decrease in coronary vascular resistance in conscious unrestrained rats 7 days after placement of the probe. Light microscopic review of cardiac tissue from instrumented rats revealed minimal epicardial reaction (fibrin deposition) restricted to the immediate area of the probe without distortion of the coronary architecture, edema, inflammation, or necrosis compared with controls. Heart weight-to-body weight ratios of instrumented rats were also not different from those of control rats. This study describes the first technique by which CBV can be measured continuously in chronically instrumented rats.
Nitric oxide synthase inhibition attenuates hypoglycemic cerebral hyperemia in piglets
Authors: Ichord R. N. , Helfaer M. A. , Kirsch J. R. , Wilson D. , Traystman R. J.
Published: December 2017

We tested the hypothesis that nitric oxide (NO) mediates hypoglycemia-induced cerebral vasodilation in piglets. Piglets (1-2 wk old) were made hypoglycemic with insulin (200 U/kg i.v.) with and without an NO synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 40 mg/kg i.v.). Electroencephalogram (EEG), cerebral O2 consumption (CMRO2), and cerebral blood flow (CBF) were measured before L-NAME and insulin and for 180 min after insulin. Hypoglycemia led to isoelectric EEG earlier after L-NAME (87 +/- 8 min) than without L-NAME pretreatment (132 +/- 13 min). CBF increased in all brain regions during hypoglycemia at the onset of isoelectric EEG and was associated with increased CMRO2.L-NAME prevented the increase in CMRO2 and attenuated vasodilation in forebrain (154 +/- 37 vs. 400 +/- 60%), cerebellum (251 +/- 52 vs. 386 +/- 52%), and cortical gray matter (183 +/- 47 vs. 524 +/- 93%) but had no effect on CBF responses in brain stem, thalamus, caudate, or hippocampus. We conclude that NO or a NO-containing compound mediates cerebral vasodilation induced by profound insulin-hypoglycemia in piglets and that this vasodilation plays an important role in the adaptation of immature brain to hypoglycemia.
Vasodilation induced by substance P in guinea pig carotid arteries
Authors: Zhang G. , Yamamoto Y. , Miwa K. , Suzuki H.
Published: December 2017

In the guinea pig carotid artery with an intact endothelium, substance P (SP, 10(-10)-10(-7) M) relaxed the norepinephrine- (NE) contracted smooth muscles transiently, in a concentration-dependent manner. Acetylcholine (ACh, 10(-6) M) produced a sustained relaxation. SP and ACh also relaxed muscles contracted with high-K (29.6 mM) solution, with a similar form but with a reduced amplitude compared with findings in NE-contracted muscles. In the presence of nitroarginine (10(-5) M) and NE, the ACh-induced relaxation was transient, with a reduced amplitude, whereas the SP-induced relaxation was not significantly changed. In muscles contracted with high-K solution containing nitroarginine, neither SP nor ACh produced relaxation. SP (> 10(-11) M) transiently hyperpolarized the membrane, but only when this peptide was applied from the intimal side of the intact vessel, and the peak amplitude reached approximately 20 mV from the resting potential at 10(-8) M. ACh transiently hyperpolarized the membrane (the peak amplitude being approximately 10 mV), in both the adventitial and intimal applications. In high-K solution, neither SP nor ACh produced hyperpolarization. The amplitude of hyperpolarizations produced by SP did not significantly change in the presence of nitroarginine, oxyhemoglobin, or indomethacin. Thus, SP-induced relaxation seems to be produced mainly by endothelium-derived hyperpolarizing factor-induced hyperpolarization.
Role of cyclic nucleotides in the regulation of endothelin-1 production by human endothelial cells
Authors: Stewart D. J. , Cernacek P. , Mohamed F. , Blais D. , Cianflone K. , Monge J. C.
Published: December 2017

The regulation of endothelin-1 (ET-1) production by endothelial cells is likely of crucial physiological importance in the maintenance of vascular homeostasis. The aim of the present study was to explore the possible role of cyclic nucleotides in the control of ET-1 production in human umbilical vein endothelial cells (HUVEC). ET-1 release was determined by measuring levels of immunoreactive ET-1 in HUVEC-conditioned media after 6-h incubations. In the presence of 10% fetal calf serum (FCS) there was a threefold increase in ET-1 release compared with serum-free conditions (1.96 +/- 0.17 vs. 0.56 +/- 0.06 pg/micrograms protein), respectively. Inhibition of protein kinase (PK) C using staurosporine (10 nM) reduced basal ET-1 release by approximately 50% and completely prevented the response to FCS. In contrast, the addition of other PK inhibitors had little effect on basal or serum-stimulated ET-1 release at the concentrations used. N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (DBcAMP) produced significant alterations in ET-1 release depending on the basal level of production. Under serum-free conditions of low basal ET-1 production, DBcAMP increased ET-1 release by 68 +/- 22% but only at the highest concentration studied (1 mM). The dose-response relationship for DBcAMP was potentiated by KT-5720 (0.1 microM), an inhibitor of PKA, with a significant shift to 10-fold lower concentrations, whereas it was blocked by KT-5823 (4 microM), which can inhibit PKG.(ABSTRACT TRUNCATED AT 250 WORDS)
Influence of filling on left ventricular diastolic pressure-volume curve during pacing ischemia in dogs
Authors: Shintani H. , Glantz S. A.
Published: December 2017

The reversible upward shift of the diastolic pressure-volume curve that occurs during pacing-induced ischemia has not been fully explained by increases in passive chamber stiffness or reductions in relaxation rate. We measured the fully relaxed pressure-volume relation defined by both filling and nonfilling beats and the isovolumic relaxation time constant in nonfilling beats before and during demand ischemia using our in situ left ventricular volume clamping technique in 10 dogs. Pacing-induced ischemia shifted the diastolic pressure-volume curves in filling beats upward compared with the end-diastolic pressure-volume relation of the normally perfused heart. In contrast, the end-diastolic points for nonfilling beats during pacing-induced ischemia fell on the fully relaxed pressure-volume relation defined by the normally perfused heart. Left ventricular filling per se was necessary for the upward shift of the diastolic pressure-volume curve observed during pacing-induced ischemia. We speculate that active force developed during diastole induced by stretch activation or, perhaps, length-dependent changes in calcium sensitivity of the myofilaments in the ischemic myocardium due to stretch of the myocardium during rapid diastolic filling may contribute to the upward shift of the diastolic pressure-volume curve observed during pacing-induced ischemia.
Constitutive nonexocytotic norepinephrine release in sympathetic curves of in situ canine heart
Authors: Rose C. P. , Cousineau D. , Goresky C. A. , De Champlain J.
Published: December 2017

Nonexocytotic norepinephrine bulk overflow from sympathetic nerves has been previously demonstrated in the perfused isolated heart only after inhibition of sympathetic nerve metabolism by hypoxia, ischemia, or metabolic inhibitors. The measurement, however, ignores simultaneous uptake of norepinephrine by sympathetic nerves. We quantitated simultaneous norepinephrine uptake and release in pentobarbital-anesthetized dogs by the use of a transient tracer approach, the multiple indicator dilution technique, combined with measurement of endogenous arterial and venous plasma norepinephrine levels. Sympathetic vesicles were previously depleted by reserpine, and desipramine was used to inhibit the neuronal membrane pump. Labeled albumin, sucrose, and norepinephrine were injected into the coronary artery, and sequential samples were collected from the coronary sinus. Reserpine pretreatment significantly depleted tissue and decreased plasma norepinephrine levels; tracer norepinephrine uptake increased slightly, and there was a substantial decrease in the rate of release of unlabeled norepinephrine. Desipramine then decreased tracer uptake and virtually eliminated norepinephrine release. We conclude that desipramine-suppressible, constitutive nonexocytotic norepinephrine release is present in cardiac sympathetic nerves.