bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of adenosine-induced coronary vasodilation by block of large-conductance Ca(2+)-activated K+ channels
Authors: Cabell F. , Weiss D. S. , Price J. M.
Published: December 2017

The aim of the present study was to investigate the contribution of large-conductance calcium-activated potassium (large-conductance KCa) channels to adenosine (Ado)- and nitroprusside-mediated relaxation in small coronary arteries. Canine subepicardial arteries (170 +/- 23 microns at 120 mmHg) were studied as in vitro pressurized vessels. Pressure-diameter experiments showed myogenic tone over a physiological range of pressures. Tone was increased with the thromboxane A2 analogue 9,11-dideoxy-11 alpha,9 alpha-epoxy-methanoprostaglandin F2 alpha (U-46619). Tetraethylammonium (TEA+; 1 mM) significantly inhibited Ado-induced [and by implication, adenosine 3',5'-cyclic monophosphate (cAMP)-induced] relaxations at Ado concentrations ranging from 0.1 to 10 microM with maximal inhibition (61 +/- 8%) at 1 microM Ado. The large-conductance KCa-channel blocker iberiotoxin (IbTX; 0.01-0.1 microM) inhibited Ado-mediated relaxation in a concentration-dependent manner. Inhibition by IbTX increased with increasing vessel pressure (i.e., 45 +/- 12% at 40 mmHg and 83 +/- 20% at 120 mmHg). TEA+ had a minimal effect (8 +/- 3%) on relaxation induced by nitroprusside. Similar results were found with acetylcholine and bradykinin. These results suggest that (in dog coronary arteries with diameter < 200 microns) large-conductance KCa-channel modulation may play a major role in cAMP-mediated relaxation but is not significant in guanosine 3',5'-cyclic monophosphate-mediated relaxation.
NO donor SIN-1 protects against reoxygenation-induced cardiomyocyte injury by a dual action
Authors: Schluter K. D. , Weber M. , Schraven E. , Piper H. M.
Published: December 2017

It was investigated whether morpholinosydnonimine (SIN-1), which spontaneously decomposes into NO and 3-morpholinoiminoacetonitrile (SIN-1C), can be used for protection of cardiomyocytes against reoxygenation-induced hypercontracture. Isolated ventricular cardiomyocytes (from adult rats) were used as the experimental model. SIN-1 [concentration with half-maximal effect (EC50) 2.5 x 10(-4) M] and SIN-1C (EC50 8.3 x 10(-3) M) inhibited the contractile response of electrically paced cardiomyocytes. When the cells were submitted to substrate-free anoxia (135 min) and subsequent reoxygenation (30 min), the onset of reoxygenation provoked their hypercontracture. It was studied whether the temporary presence of the test agents during the last 15 min of anoxia and the first 15 min of reoxygenation prevented hypercontracture. At 10 nM, SIN-1 prevented hypercontracture in 96% of the cells and SIN-1C in 72% of the cells. The protective effect of SIN-1 was reduced to that of SIN-1C by simultaneous presence of methylene blue (50 microM). Methylene blue had no influence on the protective action of SIN-1C. SIN-1C (10 mM) plus sodium nitroprusside (another NO donor, 250 microM) provided the same degree of protection as SIN-1 (10 mM). The results show that reoxygenation-induced hypercontracture can be prevented or attenuated by the temporary presence of high concentrations of SIN-1 or SIN-1C. SIN-1 acts through a dual mechanism, protecting through the generation of NO and SIN-1C.
Ischemic preconditioning elevates cardiac stress protein but does not limit infarct size 24 or 48 h later in rabbits
Authors: Tanaka M. , Fujiwara H. , Yamasaki K. , Miyamae M. , Yokota R. , Hasegawa K. , Fujiwara T. , Sasayama S.
Published: December 2017

We investigated whether ischemic preconditioning (PC) produced a second window of protection by delayed synthesis of cardioprotective proteins. Anesthetized open-chest rabbits were subjected to 30 min of coronary occlusion and 3 h of reperfusion. PC was elicited by 5 min of ischemia and was separated from sustained ischemia by 5 min, 2 h, or 24 h of reperfusion. Infarct size (% area at risk) was markedly limited by PC with 5 min of reperfusion when compared with controls (13.3 +/- 2.5 vs. 46.8 +/- 7.0%; P < 0.05). This protective effect was lost when the interval between PC and sustained ischemia was extended to 2 h (47.8 +/- 4.8%; P = NS vs. control) and did not reoccur even when it was extended to 24 h (44.2 +/- 6.5%; P = NS vs. sham-operated control). To potentiate induction of heat shock proteins (HSPs), a PC protocol involving four 5-min episodes of ischemia and reperfusion was also used and was separated from sustained ischemia by 24 or 48 h of reperfusion. However, neither of these protocols was protective, and limitation of infarct size was not observed (55.5 +/- 5.9 and 53.4 +/- 6.5% in 24 and 48 h of reperfusion, respectively; P = NS vs. corresponding sham-operated control). Myocardial expression of HSPs was examined using a monoclonal antibody against 72- to 73-kDa HSP in additional rabbits. Immunoreactivity was observed in the myocardium at 24 and 48 h after PC, but not immediately after PC.(ABSTRACT TRUNCATED AT 250 WORDS)
Lactate enhances sodium channel conductance in isolated guinea pig ventricular myocytes
Authors: Guo H. , Wasserstrom J. A. , Rosenthal J. E.
Published: December 2017

Myocardial hypoxia and ischemia result in the production of lactate. To study the effect of lactate on the rapid Na+ current (INa), we used the whole cell voltage-clamp technique in enzymatically isolated guinea pig ventricular myocytes. Experiments were conducted at 16 degrees C. Extracellular Na+ concentration ([Na+]o) was maintained in control and test solutions and extracellular pH was 7.4. Lactate (4-10 mM, either sodium lactate or lactic acid) augmented INa in each of eight experiments, increasing the peak Na+ conductance from 75.4 to 84.7 nS (13-16% at all test voltages in the linear portion of the conductance curve). The voltage dependence of steady-state availability and the time course of inactivation remained unchanged. The increase in peak Na+ conductance was concentration dependent, with an apparent dissociation constant of 1.8 mM and Hill coefficient of 1.8. Lactate in the range of 1-10 mM did not significantly reduce the Ca2+ activity of test solutions. These effects of lactate were still observed in Mg(2+)-free test solutions and when the buffering capacity of internal solution was reinforced by increasing N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid concentration from 5 to 20 mM. In conclusion, lactate enhances INa via a mechanism that does not involve chelation of Ca2+ or Mg2+ or changes in intracellular pH. These effects of lactate on the Na+ channel might alter electrophysiological properties during myocardial ischemia and could protect the heart from ischemia-induced conduction abnormalities or, alternatively, could lead to arrhythmias.
Modulation of phorbol ester-induced contraction by endogenously released cyclooxygenase products in rat aorta
Authors: Williams S. P. , Campbell A. K. , Roszell N. , Myatt L. , Leikauf G. D. , Rapoport R. M.
Published: December 2017

This study tests the hypothesis that prostaglandins (PGs) released in response to phorbol esters act as modulators of the phorbol ester-induced smooth muscle contraction. The rate and magnitude of the phorbol 12-myristate 13-acetate (PMA)-induced contraction of deendothelialized rat aorta were decreased by the cyclooxygenase inhibitor, indomethacin. The thromboxane (Tx) A2/PGH2 receptor antagonist, SQ-29548, also inhibited PMA-induced contraction, and the magnitude of inhibition was greater than that due to indomethacin. PMA induced the release of PGI2, PGE2, PGF2 alpha, and arachidonic acid, but not TxA2. The amount of PGI2 released was greater than that of PGE2 and PGF2 alpha. Indomethacin blocked the PMA-induced release of PG, but not of arachidonic acid. In PMA-contracted tissues, PGF2 alpha, PGE2, and the stable PGI2 and PGH2 analogues, carbacyclin and U-46619, respectively, induced further contraction. Pretreatment of PMA-contracted tissues with SQ-29548 partially inhibited the PGF2 alpha- and PGE2-induced contractions, completely inhibited contraction to U-46619, and reversed the carbacyclin-induced contraction to relaxation. These results demonstrate that, in rat aorta, PMA induces the release of PGs that exert both contractile and relaxant effects but whose net effect is to accelerate and augment the contraction induced by PMA. The PG-induced increase in PMA contraction is mediated, in large part, through TxA2/PGH2 receptor activation. The ability of various PGs, including carbacyclin, to activate the TxA2/PGH2 receptor suggests that one or more of these PGs, in addition to, presumably, PGH2, may be responsible for the increase in PMA contraction. PGI2 is the only endogenously released PG that can account for the relaxant effect.
Thrombin receptor-mediated vascular relaxation differentiated by a receptor antagonist and desensitization
Authors: Tesfamariam B.
Published: December 2017

The vasorelaxant actions of the serine protease, alpha-thrombin, are selectively blocked by the thrombin active site inhibitors, suggesting that proteolytic cleavage is required for alpha-thrombin-induced release of nitric oxide. Whether these relaxations are caused by interaction with a thrombin receptor was evaluated using a prototype thrombin receptor antagonist, a decapeptide analogue of the tethered ligand thrombin receptor [3-mercapto-propionyl-Phe-Cha-Cha-Arg-Lys-Pro-Asn-Asp-Lys-amide (c186–65)]. In rings of pig coronary arteries with endothelium contracted submaximally with U-46619, the relaxation caused by extremely low concentrations of alpha-thrombin were mimicked by the synthetic thrombin receptor-activating peptide (TRAP-7: SFLLRNP). These relaxations were inhibited by C186–65. In contrast, C186–65 had no effect on the relaxations caused by bradykinin and serotonin. Exposure of arteries to alpha-thrombin or TRAP-7 caused heterologous desensitization to subsequent stimulation by alpha-thrombin or TRAP-7 but not by bradykinin. These studies support the hypothesis that alpha-thrombin-induced endothelium-dependent relaxations occur by activation of the cloned “tethered-ligand” thrombin receptor in vascular endothelium.
Fractals describe blood flow heterogeneity within skeletal muscle and within myocardium
Authors: Iversen P. O. , Nicolaysen G.
Published: December 2017

A marked perfusion heterogeneity exists within single skeletal muscles and within the left ventricular (LV) myocardium. The relative dispersion (RD) of blood flows to regions < 1 g amounts to approximately 0.35 in both organs in rabbits. RD is changed with refinement of spatial resolution because the observed variance in regional flows increases. It has been shown with fractal analyses that the fractal dimension (D) can describe the relationship between the measured RD and size of the region studied within both the myocardium and the lung. A similar study has not been done with skeletal muscle. Barbital-anesthetized rabbits, cats, and sheep were used. Regional blood flow distribution was assessed with the microsphere method. Microsphere deposition in organ regions was determined after successive regrouping of either the LV or one skeletal muscle into various sized regions. We found that the perfusion patterns could be described with fractals for both organs, with the corresponding D values of 1.22-1.37 for the myocardium and 1.30-1.46 for muscle. It appears that fractals also yield a good description of blood flow distribution within skeletal muscle. In rabbits, D for myocardium was strongly correlated to the D for muscle (correlation coefficient = 0.98). This surprising finding of the strong correlation in D sampled from two organs originating from the same rabbit has hitherto not been reported.
Effect of erythrocyte deformability on myocardial hematocrit gradient
Authors: Baskurt O. K. , Edremitlioglu M. , Temiz A.
Published: December 2017

Myocardial hematocrit gradient was determined between epicardium and endocardium of the left ventricular wall in rat heart under the influence of erythrocyte deformability alterations. Hematocrit determinations were performed by measuring two different radionuclides labeling plasma (125I-labeled albumin) and erythrocytes (99mTc) in 100-microns-thick left ventricular myocardium slices. Myocardial hematocrit gradient calculated after exchange transfusions with partially hardened red blood cell suspensions was compared with the results of the control group, in which the exchange transfusions were done using normal, hematocrit-matched blood. In the control group, the hematocrit value in the myocardium adjacent to epicardium was 0.331 +/- 0.076 l/l and decreased to 0.232 +/- 0.054 l/l near the endocardium. Myocardial hematocrit between these two was represented by a linear gradient. In the group with impaired erythrocyte deformability, the hematocrit value was 0.359 +/- 0.074 l/l in the epicardial myocardium and remained at 0.341 +/- 0.082 l/l in the endocardial layer. These results indicate that tissue hematocrit gradient in the left ventricular myocardium may be disturbed if erythrocyte deformability is altered.
Activation of ANP synthesis during congestive heart failure in rats treated with monocrotaline
Authors: Comini L. , Agnoletti G. , Panzali A. , Mantero G. , Pasini E. , Gaia G. , Albertini A. , Ferrari R.
Published: December 2017

We studied plasma concentration, content, and mRNA for atrial natriuretic peptide (ANP-mRNA) in heart chambers of monocrotaline-treated rats. Three distinct groups emerged: group 1, with moderate congestive heart failure (CHF; pleural effusion < 1 ml; no peritoneal effusion); group 2, with severe CHF (pleural and peritoneal effusion > 1 ml); and group 3, with right hypertrophy and no CHF. Group 1 and 2 rats had right atrial and ventricular hypertrophy, raised plasma ANP (from 16.31 +/- 11.32 to 98.50 +/- 22.50 and 124.09 +/- 57.29 pg/ml, respectively; P < 0.001), and depletion of right atrial ANP (from 143.23 +/- 29.79 to 21.70 +/- 17.70 and 18.12 +/- 14.64 nmol/g, respectively; P < 0.001). Ventricular ANP concentration was unchanged. ANP-mRNA rose in the right atrium [10.6 (P < 0.02) and 7.9 (P < 0.01) times] and right ventricle (53.0 and 46.6 times; P < 0.01). In left unhypertrophied chambers it also increased, although to a smaller extent. Group 3 rats had isolated right ventricular hypertrophy, normal ANP levels in plasma and tissues, and no activation of synthesis. These data suggest that 1) plasma concentration and ANP synthesis are increased only in animals with CHF, 2) activation of ANP synthesis is maximal in early stages of CHF and is not related to the degree of hypertrophy, and 3) ANP-mRNA is also expressed in unhypertrophied heart chambers of rats with CHF but is not expressed in hypertrophied chambers of animals without CHF.
An integrated model of LV muscle mechanics, coronary flow, and fluid and mass transport
Authors: Zinemanas D. , Beyar R. , Sideman S.
Published: December 2017

An integrated left ventricular (LV) model that accounts for the three-phase (fiber-blood-interstitium) myocardial structure and composition is used to study the interactions among myocardial mechanics, coronary flow, and fluid and mass transport. Effects of ventricular load, coronary perfusion pressure, and fluid and mass transport on ventricular performance and coronary dynamics are studied here. In agreement with experimental observations, the analysis shows that 1) coronary flow impediment is not significantly affected by changes in the afterload and preload at constant coronary perfusion pressures, 2) an increase in coronary perfusion pressure increases the intramyocardial pressure (IMP) as well as the mean flow and oscillatory flow amplitude, 3) contractility has a direct effect on IMP and coronary flow impediment, and 4) changes in blood osmolarity and lymphatic outflow, which may cause myocardial edema, affect both ventricular mechanics and coronary flow. Clearly, accounting for fluid and mass transport allows to study the interactions among coronary flow, ventricular and myocardial mechanics, and intramyocardial fluid shifts.
Miniaturized electrical stimulator with controllable duty cycles
Authors: Hang J. , Fleming J. B. , Wells M. L. , Adair T. H.
Published: December 2017

A stimulator with adjustable duty cycles is described for chronic electrical stimulation of skeletal muscles by way of a motor nerve. The stimulator is unique in that it can stimulate a muscle or group of muscles for 2-h intervals that alternate with variable periods of rest (2, 4, 6, 8, or 10 h). A given duty cycle is selected with a rotary switch at the beginning of an experiment and will continue automatically, without human intervention, for the duration of the experiment. Other features include an adjustable voltage output, a stimulation indicator light-emitting diode (LED), and a low-battery indicator LED. The stimulator is powered by two 9-V batteries or can be used with a bench-top power supply. The stimulation frequency (10 Hz) and pulse width (300 microseconds) are fixed in our design but can be changed to other values by substituting two of the resistors and one capacitor in accordance with simple formulas. We have used the stimulator in rat and rabbit experiments to stimulate the anterior tibialis and extensor digitorum longus muscles for up to 60 days. The timing and output of the stimulator were found to be stable and accurate over the entire 60-day period. The stimulator and batteries were carried in a jacket worn by the rabbits. In the rat experiments, the stimulator was used in a remote fashion with the electrical leads connected to the animals by way of a tethering system. In both animals, the electrodes were implanted adjacent to the common peroneal nerve.(ABSTRACT TRUNCATED AT 250 WORDS)
Release of EDRF and NO in ex vivo perfused aorta: inhibition by in vivo E. coli endotoxemia
Authors: Myers P. R. , Zhong Q. , Jones J. J. , Tanner M. A. , Adams H. R. , Parker J. L.
Published: December 2017

Previous studies have yielded contradictory results about interrelations between endotoxin and endothelium-derived relaxing factor (EDRF). We tested the hypothesis that in vivo endotoxemia inhibits basal and/or agonist-mediated release of EDRF and nitric oxide (NO). EDRF bioactivity, NO production, and NO synthase (NOS) activity were measured in aorta from guinea pigs following 16 h of Escherichia coli endotoxemia (4 mg/kg endotoxin i.p.). Endothelium-dependent relaxation of aortic rings was studied under standard isometric conditions. Endotoxemia resulted in an 89% reduction in basal EDRF bioactivity and a 62% reduction in basal NO production in perfused aorta. EDRF bioactivity and NO production in response to the receptor-dependent agonists acetylcholine and ADP were significantly reduced in perfused aorta from endotoxemic animals. In contrast, endotoxin did not significantly inhibit EDRF bioactivity and NO production by the receptor-independent agonist A-23187. Aortic rings from endotoxemic animals likewise showed decreased vasodilator responses to acetylcholine and ADP but not to A-23187. Inducible (Ca2+ independent) NOS activity was not significantly different in control and endotoxin-treated animals. These findings indicate that prolonged endotoxemia resulted in diminution of release of EDRF, consistent with the interpretation that endotoxemia decreases basal and agonist-stimulated EDRF bioactivity and NO production with loss of endothelium-dependent vasodilator reserves during gram-negative sepsis.
Cardiovascular adjustments to acute hypoxemia superimposed on chronic hypoxemia in lambs
Authors: Dalinghaus M. , Gratama J. W. , Zijlstra W. G. , Kuipers J. R.
Published: December 2017

Cardiovascular responses to acute hypoxemia are in part mediated through adrenergic and chemoreceptor stimulation. In chronic hypoxemia the response to these stimuli may be blunted. Therefore, we determined whether the cardiovascular responses to acute hypoxemia superimposed on 3–4 wk of chronic hypoxemia were blunted in lambs with an experimental cardiac right-to-left shunt (combination of atrial septal defect and variable pulmonary stenosis). Cardiovascular variables and regional blood flows were determined during chronic hypoxemia and after acutely reducing the arterial oxygen saturation by increasing the cardiac right-to-left shunt. Arterial oxygen saturation decreased (65 +/- 7 to 40 +/- 7%, P < 0.001) and systemic blood flow increased (164 +/- 63 to 233 +/- 100 ml.min-1.kg-1, P < 0.01), maintaining systemic oxygen supply and oxygen uptake. Blood flow to the myocardium (P < 0.01), the adrenals (P < 0.05), and the brain (0.05 < P < 0.10) increased, and oxygen supply to these organs was maintained. Conversely, blood flow to the kidneys and the gastrointestinal tract was unaltered, so that oxygen supply to these organs was decreased. The responses to acute hypoxemia in chronically hypoxemic lambs were similar to those previously reported in normoxemic lambs. We conclude that the cardiovascular responses to acute hypoxemia in chronically hypoxemic lambs are not blunted.
A novel 5-HT1-like receptor subtype mediates cAMP synthesis in porcine pial vein
Authors: Ueno M. , Ishine T. , Lee T. J.
Published: December 2017

The 5-hydroxytryptamine (5-HT) receptor subtype mediating 5-HT inhibition of spontaneous rhythmic contractions (SRC) in the porcine pial vein was characterized. Results from pharmacological studies using in vitro tissue bath techniques indicated that the inhibitory effects of 5-HT on SRC were qualitatively and quantitatively mimicked by 5-HT1-like agonists 5-methoxytryptamine (5-MT) and 5-carboxamidotryptamine (5-CT). 5-HT-, 5-MT-, and 5-CT-induced inhibitions of SRC were attenuated in a concentration-dependent manner by methysergide, which yielded similar pA2 values against these three agonists, suggesting that 5-HT, 5-MT, and 5-CT act on the same 5-HT1-like receptors. 5-MT inhibition of SRC was not affected by blocking 5-HT2 (with ketanserin and spiperone), 5-HT3 (with MDL-72222 and ICS-205-930), or 5-HT4 (with ICS-205-930) receptors. Neither was 5-MT inhibition of SRC affected by blocking 5-HT1A (with propranolol and spiperone), 5-HT1B (with propranolol), or 5-HT1C (with ketanserin) receptors. Furthermore, 5-HT and 5-MT inhibitions of SRC were enhanced by cilostazol [a selective adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitor] and were diminished by KT-5720 (a cAMP-dependent protein kinase inhibitor) but were not affected by M&B-22948 [a selective guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor] or KT-5823 (a cGMP-dependent protein kinase inhibitor). Biochemical studies further demonstrated that 5-HT inhibition of SRC in porcine pial veins was accompanied by an increase in cAMP, but not cGMP, synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Tumor necrosis factor induces E-selectin production in splanchnic artery occlusion shock
Authors: Altavilla D. , Squadrito F. , Canale P. , Ioculano M. , Campo G. M. , Squadrito G. , Saitta A. , Caputi A. P.
Published: December 2017

Splanchnic arteries were clamped for 45 min to induce splanchnic artery occlusion (SAO) shock in anesthetized rats. Sham-operated animals were used as controls. Survival time, serum tumor necrosis factor-alpha (TNF-alpha), white blood cell (WBC) count, mean arterial blood pressure, myeloperoxidase (MPO) activity, and serum levels of soluble E-selectin (sE-selectin) were investigated. SAO-shocked rats exhibited decreased survival time (95 +/- 11 min, whereas sham-shocked rats survived for > 5 h), reduced mean arterial blood pressure, increased serum levels of TNF-alpha (185 +/- 8 U/ml) and MPO activity in the ileum (0.11 +/- 0.03 U x 10(-3)/g tissue) and lung (1.5 +/- 0.4 U x 10(-3)/g tissue), leukopenia, and enhanced serum levels of sE-selectin. Furthermore SAO-shocked rats showed histological alterations in the ileum and lung. Administration of cloricromene (2 mg/kg i.v.), an inhibitor of TNF-alpha, significantly increased survival time (225 +/- 10 min), decreased serum levels of TNF-alpha and sE-selectin, reduced leukopenia and MPO activity in the ileum (0.035 +/- 0.003 U x 10(-3)/g tissue) and lung (0.3 +/- 0.005 U x 10(-3)/g tissue), improved the cardiovascular changes, and reduced the histological changes in the ileum and lung. Finally, an anti-E-selectin antibody protected rats against SAO shock. Our findings are consistent with an involvement of E-selectin, “in vivo,” in the pathogenesis of SAO shock.
Role of cyclooxygenase inhibition and hyperoxia in regulating pulmonary perfusion in dogs
Authors: Schulman L. L. , Enson Y.
Published: December 2017

To assess the roles of cyclooxygenase inhibition and hyperoxia in regulating pulmonary perfusion, we studied 13 dogs with diffuse granulomatous lung disease (DGLD) and 13 normal dogs. Baseline observations were obtained at fractional inspired O2 (FIO2) 0.21 and 1.0 and repeated after infusion of meclofenamate (Mec; n = 8) or saline (n = 5). Resistance to flow was evaluated from the pulmonary end-diastolic gradient (PDG) and by ohmic pulmonary vascular resistance (PVR). Distribution of blood flow was evaluated with sulfur hexafluoride in DGLD and with multiple inert gas alveolar ventilation-perfusion (VA/Q) plots in normal dogs. Before infusion, there were no differences between the saline and Mec groups at either FIO2. Saline induced no significant changes at either FIO2. After Mec in DGLD, PDG at FIO2 0.21 rose from 4 +/- 2 to 6 +/- 4 mmHg (P < 0.04), PVR increased from 297 +/- 98 to 484 +/- 181 dyn.s.cm-5.m-2 (P < 0.01), whereas shunt flow (Qs/Qt) fell form 13.6 +/- 12.0 to 6.2 +/- 5.3% (P < 0.03). At FIO2 1.0 PDG rose from 3 +/- 2 to 4 +/- 3 mmHg (P < 0.02), PVR increased from 262 +/- 78 to 374 +/- 139 dyn.s.cm-5.m-2 (P < 0.01), whereas Qs/Qt fell from 14.5 +/- 13.3 to 6.4 +/- 5.2% (P < 0.02). After Mec in normal dogs, PDG at FIO2 0.21 rose from 3 +/- 1 to 4 +/- 1 mmHg (P < 0.015) and PVR increased from 256 +/- 92 to 340 +/- 101 dyn.s.cm-5.m-2 (P < 0.05); at FIO2 1.0 PDG and PVR were unchanged from preinfusion levels. In normal dogs, no parameters of VA/Q changed significantly with hyperoxia or Mec. These data suggest that perivascular inflammation enhances perfusion in DGLD by elaboration of vasodilator prostaglandins (PG). By inhibiting PG synthesis, Mec selectively increases resistance in diseased lung at FIO2 0.21 and lowers Qs/Qt. In contrast, there was vasoconstriction without flow redistribution in normal dogs, suggesting that vasodilator PGs contribute to the low tone in the normal pulmonary bed. The vasodilation without flow redistribution in both models during hyperoxia after Mec suggests an effect of O2 that is related neither to PG synthesis nor to hypoxic vasoconstriction.
Oxidative injury of coronary venular endothelial cells depletes intracellular glutathione and induces HSP 70 mRNA
Authors: Aucoin M. M. , Barhoumi R. , Kochevar D. T. , Granger H. J. , Burghardt R. C.
Published: December 2017

Vascular endothelium is one of the first tissues exposed to reactive oxygen species produced during myocardial ischemia-reperfusion. Bovine coronary venular endothelial cells (CVEC) were evaluated for intracellular glutathione (GSH) levels and heat shock protein 70 (HSP 70) mRNA and protein during in vitro oxidative stress. CVEC were incubated with 0.01875 U/ml xanthine oxidase (XO) and 0.5 mM hypoxanthine (HX) for 30 min and then allowed to recover for 0, 1, 2, or 3 h. Relative GSH levels were determined by evaluation of monochlorobimane fluorescence. GSH fluorescence was significantly lower in CVEC treated with XO+HX for 30 min than in controls. GSH fluorescence was also decreased in heat-shocked CVEC. After oxidative stress, GSH levels were higher than in controls at 1 h, but by 2 or 3 h after treatment, GSH fluorescence fell below control values. HSP 70 mRNA was induced in CVEC by a 30-min treatment with XO+HX exposure. These data suggest that CVEC respond to oxidative stress by reducing intracellular GSH levels and inducing HSP 70 mRNA, although significant increases in HSP 70 protein were not detected at the time points tested.
Ischemic preconditioning attenuates capillary no-reflow induced by prolonged ischemia and reperfusion
Authors: Jerome S. N. , Akimitsu T. , Gute D. C. , Korthuis R. J.
Published: December 2017

Ischemic preconditioning (IPC) refers to a phenomenon in which a tissue is rendered resistant to the deleterious effects of prolonged ischemia and reperfusion by prior exposure to brief, repeated periods of vascular occlusion. The purposes of this study were to determine whether IPC would reduce the extent of capillary no-reflow in postischemic skeletal muscle and whether the protective effect of IPC was due to activation of ATP-sensitive potassium (KATP) channels. To address the first aim, capillary perfusion was assessed in vascularly isolated canine gracilis muscles subjected to 4.5 h of continuous perfusion, 4 h of ischemia followed by 30 min of reperfusion (I-R), and IPC (4 periods of 5 min ischemia followed by 5 min reperfusion) before I-R. I-R was associated with a reduction in the number of patent capillaries per fiber (0.6 +/- 0.1) relative to nonischemic control muscles (2.5 +/- 0.1), an effect that was attenuated by IPC (1.3 +/- 0.1 patent capillaries fiber). A role for KATP channels in the protective effect of IPC is supported by the observation that administration of a KATP channel antagonist (glibenclamide) 10 min before induction of IPC abolished the protective effect of preconditioning (0.6 +/- 0.1 patent capillaries/fiber). On the other hand, treatment of nonpreconditioned muscles with a KATP channel agonist (pinacidil) mimicked the protection afforded by IPC (1.2 +/- 0.1 patent capillaries/fiber). Moreover, the protective effect of pinacidil treatment was reversed by prior administration of glibenclamide (0.5 +/- 0.1 patient capillaries/fiber). These data indicate that IPC improves postischemic capillary perfusion by a mechanism that involves activation of KATP channels.
Inhibition of arteriole alpha 2- but not alpha 1-adrenoceptor constriction by acidosis and hypoxia in vitro
Authors: Tateishi J. , Faber J. E.
Published: December 2017

We have found that hypoxia and acidosis inhibit constriction by alpha 2D-adrenoceptors but not by alpha 1D-adrenoceptors on arterioles of rat skeletal muscle, facilitating local metabolic control of blood flow. When activated by full agonists like norepinephrine, this alpha 2D-constriction relies on Ca2+ influx through dihydropyridine-sensitive, voltage-operated Ca2+ channels (VOC), while alpha 1D-constriction does not. The purpose of the present study was to examine the dose sensitivity of this selective metabolic inhibition of alpha 2D-constriction and determine whether inhibition of VOCs is involved. Changes in lumen diameter of microcannulated arterioles isolated from rat skeletal muscle (107 +/- 3 microns control diam) were measured by videomicroscopy for bath-added agents. Decreases in pH (7.4-7.0) or PO2 (70 to 10 mmHg) caused graded inhibition of alpha 2D-adrenoceptor constriction (UK-14304 plus prazosin); the half-maximum inhibitory concentration for acidosis was 7.1 and for PO2 was 24 mmHg. alpha 1D-Adrenoceptor constriction by the respective full and partial alpha 1-agonists, phenylephrine (PE) and St-587 (both plus rauwolscine), was unaffected. Because St-587 but not PE constriction was dependent on VOC activation, the sensitivity of alpha 2D- but not alpha 1D-constriction to acidosis and hypoxia appeared to be independent of reliance on VOCs. This was examined directly; contractile sensitivity to KCl and the VOC agonist, SDZ-202-791, was unaffected by pH 7.0 or PO2 10 mmHg. These data suggest that alpha 2D-constriction is sensitive to inhibition by hypoxia and acidosis through a mechanism that does not involve direct blockade of dihydropyridine-sensitive Ca2+ channels.
Reperfusion at reduced flow rates enhances postischemic contractile recovery of perfused heart
Authors: Takeo S. , Liu J. X. , Tanonaka K. , Nasa Y. , Yabe K. , Tanahashi H. , Sudo H.
Published: December 2017

The effects of reperfusion at reduced flow rates on postischemic cardiac contractile function were examined in perfused rat hearts. Isolated hearts were subjected to 35-min ischemia followed by reperfusion at the preischemic flow rate (9.0 ml.g-1.min-1; ordinary flow rate) or at reduced flow rates (0.9-8.1 ml.g-1.min-1). Reperfusion at ordinary flow rate did not generate any left ventricular developed pressure (LVDP), whereas reperfusion at reduced flow rates (0.9-7.2 ml.g-1.min-1) elicited 13-57% of initial contractile force at reperfusion's end; optimal recovery occurred at 3.6 ml.g-1.min-1 (reduced flow rate). Reduced flow rate reperfusion attenuated ischemia-reperfusion-induced increase in left ventricular end-diastolic pressure (LVEDP) and perfusion pressure (PP), alteration in tissue Na+, K+, Ca2+, and Mg2+, release of creatine kinase and ATP metabolites, and development of triphenyltetrazolium chloride-unstained areas. Enhanced postischemic LVDP recovery was inversely related to higher coronary PP at the initial stage (4 min) of reperfusion (r = -0.763). The benefit of reduced flow rate reperfusion could not be attributed to rate of calcium delivery to the heart, formation of oxygen free radicals in myocardium, endothelium-dependent coronary artery dilation, or LVDEP reduction. Enhancement of postischemic LVDP recovery was associated with attenuation of ischemia-reperfusion-induced increases in myocardial sodium and calcium; failure of postischemic LVDP recovery was accompanied by an increase. Reduction in sodium and calcium overload may underlie the beneficial effects of reduced flow rate reperfusion in ischemic-reperfused heart.
Cardiovascular actions of adrenomedullin in conscious sheep
Authors: Parkes D. G.
Published: December 2017

Adrenomedullin (Adm) is a 52-amino acid peptide that promotes a potent vasodilator action in rats and elevates adenosine 3',5'-cyclic monophosphate levels in isolated vascular tissue preparations. To date, the cardiovascular activity of Adm has been examined only in anesthetized animals, hence the present study examines in detail the hemodynamic actions of human Adm-(1-52) in conscious, chronically instrumented sheep. Five sheep were injected intravenously with 0.1, 1, 10, 50, or 100 micrograms Adm, and mean arterial pressure, heart rate (HR), cardiac output (CO), stroke volume (SV), total peripheral conductance (TPC), coronary blood flow (CF), coronary conductance (CC), peak aortic flow (Fmax), and left ventricular dF/dt were monitored by a computer-based data collection system. Adm produced dose-dependent changes in all parameters measured, with the threshold dose being 10 micrograms. Adm injected at 100 micrograms rapidly and significantly decreased blood pressure by 10 +/- 1 mmHg, accompanied by an increase in HR of 35 +/- 4 beats/min. CO increased by 1.6 +/- 0.3 l/min, whereas SV exhibited a small reduction of 11 +/- 4 ml/beat. TPC was markedly increased by 35 +/- 7 ml.min-1.mmHg-1. CF showed an increase of 27 +/- 4 ml/min, and CC increased in parallel by 0.45 +/- 0.06 ml.min-1. mmHg-1. Fmax and dF/dt showed small increases of 3.8 +/- 0.8 l/min and 104 +/- 12 l.min-1.s-1, respectively. All hemodynamic parameters had returned to control values by 40 min postinjection.(ABSTRACT TRUNCATED AT 250 WORDS)
Downward shift of coronary pressure-flow relationship following a brief period of ischemia in dogs
Authors: Morioka T. , Kitakaze M. , Minamino T. , Takashima S. , Node K. , Okazaki Y. , Sato H. , Shinozaki Y. , Chujo M. , Mori H. , et al.
Published: December 2017

This study was undertaken to test whether a brief period of ischemia affects the coronary pressure-flow relationship during reduction of coronary perfusion pressure (CPP). The left anterior descending coronary artery was cannulated and perfused with blood from the left carotid artery in 40 open-chest dogs. Coronary blood flow (CBF) was measured during intracoronary administrations of papaverine and adenosine. The coronary pressure-flow relationship was assessed during transient reduction of CPP from 100 to 30 mmHg. Coronary hyperemic flow due to adenosine and papaverine was attenuated 30 min after transient 10- and 15-min periods of ischemia. In the group of transient 10-min ischemia, both fractional shortening (FS) and CBF returned to the preischemic values at 30 and 60 min of reperfusion; however, marked decreases in CBF (35 +/- 5 vs. 56 +/- 4 ml.100 g-1.min-1 at CPP = 60 mmHg, P < 0.01) during graded reductions in CPP were observed. The endomyocardial blood flow was reduced relative to the control condition. Furthermore, both FS (6 +/- 1 vs. 14 +/- 1% at CPP = 60 mmHg, P < 0.01) and lactate extraction ratio (-41 +/- 15 vs. 1 +/- 6% at CPP = 60 mmHg, P < 0.05) were decreased. The downward shift of the CPP-CBF relationship and the deterioration of myocardial contractile and metabolic function during reduction of CPP were restored 60 min after the onset of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Reflex control of vasopressin during hemorrhage in hypertensive rabbits
Authors: Courneya C. A. , Weichert G.
Published: December 2017

Hypertensive (HT) rabbits have impaired reflex control of heart rate and vascular tone, which is, at least in part, related to dysfunctional baroreceptors. We hypothesized that reflex control of vasopressin (AVP) would also be impaired in the HT rabbit. To test this, we compared hemorrhage-induced increases in AVP between conscious normotensive (NT) and HT rabbits. The hemorrhage-induced rise in AVP was found to be significantly (P < 0.05) attenuated in the HT rabbits. We tested a second hypothesis, that the observed impairment was related to arterial baroreceptor function, by hemorrhaging the same rabbits after reversible cardiac denervation. Under these conditions, only the arterial baroreceptors would be expected to contribute to reflex control of AVP. Impairment was still evident after cardiac denervation; that is, the hemorrhage-induced rise in AVP was significantly (P < 0.01) attenuated in the cardiac-denervated HT rabbits compared with NT rabbits. Thus impairment was, at least in part, related to arterial baroreceptors. Previously, we showed in NT rabbits that AVP only contributed to maintenance of arterial pressure (during hemorrhage), after the autonomic nervous system (ANS) had been blocked. Thus, in the present study, we compared the maintenance of arterial pressure during hemorrhage between NT and HT rabbits after ANS blockade. Blood pressure maintenance was significantly attenuated in the HT rabbits (P < 0.05). In addition, for a given fall in pressure, significantly less AVP (P < 0.05) was released in the ANS-blocked HT rabbits as compared with NT rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of responses to angiotensin I-(3-10) in the hindlimb vascular bed of the cat
Authors: Garrison E. A. , Kadowitz P. J.
Published: December 2017

Responses to angiotensin I-(3-10), the precursor for angiotensin IV, were investigated in the anesthetized cat. Intravenous injections of the precursor caused dose-related increases in systemic arterial pressure that were similar to responses elicited by angiotensin i.v. and that were inhibited by captopril. in the hindlimb vascular bed of the cat under constant-flow conditions, injections of the substrate into the perfusion circuit in doses of 3-100 micrograms caused dose-related increases in hindlimb perfusion pressure that were rapid in onset and were not altered by the presence of a time-delay coil in the perfusion circuit. Dose-response curves for the precursor and angiotensin i.v. were parallel, and the precursor was approximately twofold less potent than angiotensin i.v. in its ability to increase hindlimb perfusion pressure. Responses to the precursor were inhibited by captopril in a dose that attenuated hindlimb vasoconstrictor responses to angiotensin I. Increases in hindlimb perfusion pressure in response to angiotensin I-(3-10) were inhibited by DuP-532 in a dose that attenuated the response to angiotensin i.v. PD-123,319, an AT2 receptor antagonist, had no significant effect on responses to angiotensin I-(3-10). The present results suggest that angiotensin I-(3-10) is rapidly and efficiently converted by an angiotensin converting enzyme-dependent pathway into an active peptide, which induces vasoconstriction by activating AT1 receptors in the peripheral vascular bed of the cat.
Nitric oxide synthase inhibition reduces venous return in porcine endotoxemia
Authors: Saetre T. , Smiseth O. A. , Scholz T. , Carlsen H. , Nordsletten L. , Fahlstrom E. , Aasen A. O.
Published: December 2017

Mechanisms of circulatory effects induced by nitric oxide synthase inhibition in endotoxemia were investigated in 36 pigs randomized to 1) endotoxin infusion (1.7 micrograms.kg-1.h-1 iv) for 7 h and bolus NG-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg iv) after 3 h; 2) endotoxin infusion for 7 h; 3) saline infusion for 7 h and L-NAME after 3 h; and 4) saline infusion for 7 h. Fifteen minutes after L-NAME injection during endotoxemia, reductions in cardiac output (41%, P < 0.05), portal venous flow (51%, P < 0.05), and hepatic artery flow (50%, P < 0.05) were observed. Systemic vascular resistance increased by 82% (P < 0.05), and the portocaval vascular resistance increased by 101% (P < 0.05). Despite marked vasoconstriction after L-NAME, left ventricular intracavitary filling pressure, central venous pressure, and arterial pressure remained unchanged. During endotoxemia, hematocrit increased from 38.4 +/- 1.4 to 41.9 +/- 1.2 after L-NAME, and blood volume (n = 3) was reduced by an average of 8.3 ml/kg body wt. These changes probably reflect transcapillary fluid loss as urine output was unchanged. In conclusion, L-NAME decreased intravascular blood volume and increased splanchnic venous resistance. These effects will tend to reduce venous return. Combined with a marked increase in left ventricular after-load, L-NAME may thus compromise cardiovascular function in endotoxemia.
Alpha 1-adrenergic stimulation induces cardiac tolerance to hypoxia via induction and activation of Mn-SOD
Authors: Yamashita N. , Nishida M. , Hoshida S. , Igarashi J. , Hori M. , Kuzuya T. , Tada M.
Published: December 2017

We examined whether or not alpha 1-adrenergic stimulation increases the tolerance of the heart to ischemia using a hypoxia-reoxygenation model of cardiac myocytes. After exposure to norepinephrine (NE; 0.2 microM) for 24 h, the manganese superoxide dismutase (Mn-SOD) content and activity in the cells were increased from 0.61 +/- 0.03 to 0.87 +/- 0.04 microgram/dish and 22 +/- 1 to 55 +/- 4 U/dish, respectively. The specific activity of Mn-SOD was also increased from 36 to 63 U/microgram Mn-SOD protein after the stimulation with NE. Prazosin (2 microM) abolished the increase in Mn-SOD activity (U/mg total protein). Creatine kinase (CK) release after hypoxia (PO2 7 mmHg; 3 h)-reoxygenation (1 h) from cells pretreated with NE in the presence of propranolol and yohimbine for 24 h was attenuated by 48% compared with that from cells without NE stimulation. When antisense oligodeoxyribonucleotides to Mn-SOD were added to myocyte cultures, the increase in Mn-SOD activity (U/mg total protein) and the attenuation of CK release after the addition of NE in the presence of propranolol and yohimbine were not observed. These results suggest that alpha 1-adrenergic stimulation increases the tolerance of myocytes to hypoxia through induction and activation of Mn-SOD.
Chronic exercise enhances cardiac alpha 1-adrenergic inotropic responsiveness in rats with mild hypertension
Authors: Korzick D. H. , Moore R. L.
Published: December 2017

The singular and combined effects of mild renovascular hypertension (HTN) and chronic exercise on the contractile responsiveness of the heart to alpha 1-adrenergic receptor (alpha 1-AR) stimulation were determined. Age-matched normotensive and HTN male Fischer-344 rats were assigned to sedentary control or treadmill training groups. Left ventricular (LV) contractile performance was assessed by utilizing a modified isovolumic heart preparation at varying concentrations of phenylephrine (PE). Groups studied were normotensive sedentary (NSD), hypertensive sedentary (HSD), normotensive trained (NTR), and hypertensive trained (HTR). PE elicited increases in LV developed pressure (delta P), LV maximal rate of pressure development (dP/dt(max)), and LV dP/dt(max)/delta P in all experimental groups in a dose-dependent fashion. These PE-induced effects were representative of alpha 1-AR-mediated responses because they were observed in the presence of beta-adrenoceptor blockade with propranolol. Relative to NSD, the effects of PE on contractile function were attenuated in HSD and augmented in NTR and HTR hearts. The strength of extrasystolic contractions elicited by the delivery of a 300-ms extrasystolic interval at each of three different pacing frequencies (240, 270, and 300 beats/min) was greater in NTR and HTR and significantly reduced in HSD compared with NSD. Scatchard analysis of [3H]prazosin binding was used to assess alpha 1-AR number in myocardium isolated from each experimental group. Across all groups, a significant correlation was found between alpha 1-AR number and the inotropic responsiveness of the heart to PE stimulation. Collectively, these data provide evidence that mild HTN diminishes while training augments the inotropic responsiveness of the heart to alpha 1-AR stimulation. In addition, training appears to attenuate the adverse effects of mild HTN on the alpha 1-AR contractile responsiveness of the myocardium.
Anisotropic repolarization in ventricular tissue
Authors: Gotoh M. , Uchida T. , Fan W. , Fishbein M. C. , Karagueuzian H. S. , Chen P. S.
Published: December 2017

Extracellular recording and stimulation techniques have been used to demonstrate that the effective refractory period of epicardial ventricular cells is significantly influenced by the sequence of activation. Whether myocardial fiber orientation is also important in determining the repolarization process is unclear. To determine the importance of fiber orientation on the repolarization process, we studied 12 blocks of pig right ventricular tissue in vitro. The size of each tissue block was 30 x 30 x 2 mm. Transmembrane action potentials were recorded, and effective refractory periods were measured from the preparation's epicardial surface, which showed nearly uniform fiber orientation. Tissues were paced at 500- and 1,000-ms cycle lengths. Sequential recordings were made at 1, 4, 7, 10, 13, and 16 mm from the stimulation site along and across the fibers. The results show that propagation of depolarization was much slower in the transverse direction than in the longitudinal direction. In the transverse direction, action potential duration was longest at the closest observation point, i.e., 1 mm from the stimulation, site (188 +/- 14 and 267 +/- 18 ms for 500- and 1,000-ms pacing cycle lengths, respectively). Action potential duration progressively shortened as the recording site was moved farther from the stimulation site (P < 0.001). The action potential duration 16 mm from the stimulation site was 165 +/- 11 and 247 +/- 12 ms for 500- and 1,000-ms pacing cycle lengths, respectively. In contrast, the action potential duration in the longitudinal direction did not change as the distance between the recording site and stimulation site increased. We conclude that, at physiological temperature and pacing cycle lengths, sequence of activation significantly influenced action potential duration when the propagation of activation was transverse to myocardial fiber orientation. When activation propagated parallel to fiber orientation, there was little or no change of action potential duration as distance increased.