bluuebunny/crossref_metadata_2025 huggingface dataset:
Daily exercise and gender influence arterial baroreflex regulation of heart rate and nerve activity
Authors: Chen C. Y. , DiCarlo S. E.
Published: December 2017

The influence of daily spontaneous running (DSR) and gender on the arterial baroreflex regulation of heart rate (HR) and lumbar sympathetic nerve activity (LSNA) was examined in 13 male [7 sedentary (SED) and 6 DSR] and 12 female (6 SED and 6 DSR) Sprague-Dawley rats. After 8-9 wk of DSR or SED control, all animals were chronically instrumented with right femoral venous and left carotid arterial catheters and electrodes around the lumbar sympathetic trunk. DSR resulted in an increase in heart weight-to-body weight ratio (P = 0.001) in male and female rats and resting bradycardia in male rats (P = 0.001). Arterial baroreflex function was examined by ramp increases (1.25 +/- 0.07 mmHg/s) and decreases (1.47 mmHg/s) in arterial pressure. DSR attenuated the arterial baroreflex regulation of LSNA in a similar manner in female and male rats. DSR reduced the range (32 and 29% for female and male rats, respectively), maximum (26 and 21% for female and male rats, respectively), and maximum gain (Gmax; 46 and 17% for female and male rats, respectively). In contrast, there was a gender influence on the arterial baroreflex regulation of HR. For example, SED female rats had a higher Gmax (40%) than SED male rats. Furthermore, DSR altered the arterial baroreflex regulation of HR differently in male and female rats. DSR female rats had a reduced Gmax (38%), range (25%), and maximum (12%), whereas DSR male rats had a reduced maximum (17%) and minimum (23%). These results demonstrate that DSR attenuated the arterial baroreflex regulation of LSNA in a similar manner in female and male rats. In contrast, DSR altered the arterial baroreflex regulation of HR differently in female and male rats.
Compressibility of perfused passive myocardium
Authors: Yin F. C. , Chan C. C. , Judd R. M.
Published: December 2017

In most theoretical analyses of the heart, the tissue has been assumed to be incompressible. Because the myocardium is extensively perfused with distensible vessels, increasing the stiffness of the surrounding tissue, as with contraction or passive stretching, should decrease the volume of fluid in these vessels. Using a digital subtraction angiographic method, we quantified the amount of vascular volume extruded from six passive, perfused canine interventricular septa during cyclic biaxial loading from 300 to 900 g force. At pressures from 0 to 120 mmHg the amount of fluid extruded during a loading cycle varied from 2 to 4 ml/100 g tissue at 0 and 120 mmHg, respectively. This volume change increased with perfusion pressure and was significantly greater at 120 than at 0, 30, or 60 mmHg. The amount of fluid extruded was on the same order as that estimated during active contraction or with a 60-mmHg change in perfusion pressure. The finding that perfused myocardium is compressible implies that results from existing analyses of the heart assuming incompressibility are not realistic. Such analyses must account for compressibility with, e.g., mixture theory or other similar approaches.
Modulation of mitochondrion-mediated oxidative stress by nitric oxide in human placental trophoblastic cells
Authors: Goda N. , Suematsu M. , Mukai M. , Kiyokawa K. , Natori M. , Nozawa S. , Ishimura Y.
Published: December 2017

Intracellular hydroperoxide generation in cultured human placental trophoblastic cells (HPTCs) was quantitatively monitored in the presence or absence of an NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 1 mM), by digital microfluorography with use of carboxydichlorofluorescein, a hydroperoxide-sensitive fluorogenic probe. In the absence of L-NAME, HPTCs displayed a time-dependent gradual elevation of the fluorescence, suggesting the ability to produce oxidants spontaneously. In the presence of L-NAME, however, the fluorescent response in these cells increased further; the oxidative impact elicited by L-NAME treatment for 30 min was equivalent to that induced by application of 230 microM tert-butyl hydroperoxide for 5 min. This oxidative process was completely blocked by rotenone, a reagent that interferes with electron entry into complex I of the mitochondrial respiratory chain. On the other hand, antimycin A, which blocks mitochondria at the distal site of the ubiquinone pool, potentiated the L-NAME-induced oxidative change. These findings suggest that constitutive levels of nitric oxide production contribute to regulation of mitochondrion-derived intracellular oxidant generation in HPTCs.
Nitric oxide inhibits pulmonary artery catalase and H2O2-associated relaxation
Authors: Mohazzab-H K. M. , Fayngersh R. P. , Wolin M. S.
Published: December 2017

Our previous studies on the mechanism of relaxation of calf pulmonary arteries to H2O2 detected a role for increased formation of guanosine-3',5'-cyclic monophosphate as a result of a catalase-elicited activation of soluble guanylate cyclase. We have also shown that lactate elicits relaxation through increasing H2O2 produced from NADH oxidase-derived superoxide anion (O2-.). Because nitric oxide (NO) is a potential inhibitor of catalase, we examined the effects of exposure of endothelium-denuded bovine calf pulmonary arteries to an elevated physiological level of NO on relaxation to H2O2 and lactate. Treatment of pulmonary arteries with approximately 50 nM of NO gas for 2 min caused a subsequent inhibition of relaxation to H2O2 (10(-6) to 10(-3)M) and lactate (1-10 mM), without markedly altering relaxation responses to S-nitroso-N-acetylpenicillamine (10(-9) to 10(-6) M) or isoproterenol (10(-9) to 10(-6) M). This NO exposure caused a 63 and 70% inhibition of the metabolism by smooth muscle catalase of both endogenously produced and exogenous (100 microM) H2O2, respectively, as measured by the H2O2-dependent cooxidation of methanol to formaldehyde. A similar treatment of purified catalase with NO caused subsequent inhibition of its ability to metabolize H2O2, associated with changes in the spectra of catalase (increases in the absorbance at 535 and 570 nm) to a species that resembled compound II, an inactive form of catalase. The exposure of pulmonary arteries to NO also resulted in the detection of H2O2 release (by catalase-inhibitable luminol/ peroxidase-chemiluminescence). Thus exposure of pulmonary arteries to increased physiological levels of NO may promote altered vasoactive responses involving H2O2 as a result of the inhibition of catalase.
Dynamics of muscle sympathetic nerve activity in advanced heart failure patients
Authors: Nguyen A. H. , Garfinkel A. , Walter D. O. , Hamilton M. A. , Fonarow G. C. , Moriguchi J. D. , Hage A. , Weiss J. N. , Middlekauff H. R.
Published: December 2017

Muscle sympathetic nerve activity (MSNA) is increased in patients with heart failure compared with healthy subjects. We applied spectral and correlation techniques to determine if qualitative as well as quantitative differences in MSNA differentiate heart failure patients from healthy subjects. We recorded MSNA, heart rate, and respiration in 11 heart failure patients and 10 healthy humans. Our results are as follows. 1) Statistically significant low-frequency modulation of MSNA at 0.029 +/- 0.002 Hz (mean +/- SE; range 0.026-0.038 Hz) was found in 10 of 11 heart failure patients but in only 2 of 10 healthy controls (differences between groups, P < 0.01; chi 2 test). 2) Heart rate and respiration also demonstrated significant low-frequency modulation in a similar range. 3) Spectral and correlation techniques revealed that low-frequency modulation of MSNA was highly correlated with low-frequency modulation of respiration in heart failure patients, but not in healthy subjects. In contrast, low-frequency modulation of MSNA did not correlate well with low-frequency modulation of heart rate. In summary, low-frequency modulation of respiration is coupled to low-frequency modulation of MSNA in heart failure patients, but not in normal subjects. We speculate that this low-frequency modulation of respiration may represent subclinical Cheyne-Stokes breathing, which has marked qualitative effects on MSNA in patients with heart failure.
Exogenous NO inhibits basal NO release from vascular endothelium in vitro and in vivo
Authors: Ma X. L. , Lopez B. L. , Christopher T. A. , Birenbaum D. S. , Vinten-Johansen J.
Published: December 2017

This study tested the hypothesis that exogenous nitric oxide (NO) inhibits basal release of NO in isolated rat aortic rings and in vivo. Thoracic aortic rings were suspended in organ chambers with Krebs-Henseleit solution. In untreated rings, the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) markedly increased basal vascular tone by 34.6 +/- 5.2% of maximal force produced by 100 nM thromboxane A2 mimetic U-46619, indicating a basal release of NO. Other rings were pretreated with the exogenous NO donor S-nitroso-N-acetylpenicillamine (SNAP) for 20 min and then washed free of drug. In these rings, L-NAME-induced vasoconstriction was significantly attenuated in a concentration-dependent manner (from 34.6 +/- 5.2 to 25.7 +/- 2.9% at SNAP = 0.5 microM, 15.2 +/- 3.1% at 1 microM, and 11.9 +/- 2.5% at 5 microM), while having no effect on NO-independent phenylephrine-induced vasoconstriction (35.4 +/- 4.7 untreated vs. 41.3 +/- 4.3% SNAP pretreated, not significant). In addition, the nonnitrosylated parent molecule of SNAP, acetylpenicillamine, had no effect on the vasoconstriction induced by L-NAME. In the in vivo studies in anesthetized rats, L-NAME caused significant hypertensive responses (34 +/- 4-mmHg increase in mean arterial blood pressure). Subvasoactive doses of SNAP attenuated these hypertensive responses in a dose-dependent manner (20 +/- 3-mmHg increase with 10 micrograms/kg SNAP pretreatment and 16 +/- 4-mmHg increase with 20 micrograms/kg SNAP pretreatment), but any dose of acetylpenicillamine studied had no effect. Coadministration of superoxide dismutase and SNAP significantly potentiated the inhibitory effect of the NO donor on vasocontraction responses to L-NAME. Furthermore, SNAP did not attenuate the hypertensive responses to phenylephrine. These results indicate that exogenous NO significantly inhibits basal NO release both in vitro and in vivo, suggesting that NO plays an important negative-feedback regulatory role under physiological conditions.
Antecedent ischemia reverses effects of adenosine on glycolysis and mechanical function of working hearts
Authors: Finegan B. A. , Gandhi M. , Lopaschuk G. D. , Clanachan A. S.
Published: December 2017

This study compared the effects of adenosine (Ado) on the coupling of glycolysis and glucose oxidation and on mechanical function in normal hearts and in hearts subjected to transient ischemia. Isolated working rat hearts were perfused with Krebs containing 1.2 mM palmitate and 100 microU/ml insulin. After 15 min of aerobic perfusion, hearts underwent either two cycles of 10 min of ischemia and 5 min of reperfusion (stressed) or 30 min of aerobic perfusion (control). After 45 min, hearts underwent either aerobic perfusion for 35 min (series A) or 30 min of ischemia and 30 min of reperfusion (series B). In series A, left ventricular minute work (LV work) was similar in control and stressed hearts and was not affected by Ado (500 microM) or N6-cyclohexyladenosine (CHA 0.5 microM). Ado reduced glycolysis by 49% in control hearts but increased glycolysis by 74% in stressed hearts. CHA inhibited glycolysis in both groups by 50 and 62%, respectively. In series B, LV work during reperfusion recovered to a similar extent in untreated control and stressed hearts. In control hearts, Ado reduced glycolysis by 50% while enhancing LV work to 81% of preischemic values. In stressed hearts, Ado increased glycolysis by 34% and depressed LV work to 9%, whereas CHA inhibited glycolysis by 53% and LV work to 91%. These data indicate that coupling of glycolysis to glucose oxidation is a key determinant of mechanical function of the postischemic myocardium. They also show that the metabolic and protective effects of Ado depend on the status of the heart before sustained ischemia.
Model clamp and its application to synchronization of rabbit sinoatrial node cells
Authors: Wilders R. , Verheijck E. E. , Kumar R. , Goolsby W. N. , van Ginneken A. C. , Joyner R. W. , Jongsma H. J.
Published: December 2017

A method for coupling an isolated cardiac cell to a simulated cardiac cell, i.e., the real-time solution of a mathematical model of such cell, has been developed. With this "model clamp" technique, the real cell and the model cell are coupled by any desired value of intercellular coupling conductance, producing the effect of mutual interaction by electrical coupling through gap junctional channels. We implemented the model clamp technique with our previously published model of an isolated rabbit sinoatrial node cell. We used this model clamp system to study synchronization of sinoatrial node cells with regard to the critical value of intercellular coupling conductance required for frequency entrainment and the common interbeat interval during frequency entrainment. This common interbeat interval lay between the intrinsic intervals of the real cell and the model cell, but was closer to that of the intrinsically faster beating cell. Critical coupling conductance increased with increasing difference in intrinsic interbeat interval of the real cell and the model cell and ranged between 50 and 300 pS in 11 hybrid cell pairs.
Prostaglandin F2 alpha induces cardiac myocyte hypertrophy in vitro and cardiac growth in vivo
Authors: Lai J. , Jin H. , Yang R. , Winer J. , Li W. , Yen R. , King K. L. , Zeigler F. , Ko A. , Cheng J. , Bunting S. , Paoni N. F.
Published: December 2017

Several prostaglandins [prostaglandin (PG) A2, -B2, -D2, -E2, -F2 alpha, and -I2 and carbaprostacyclin] and the thromboxane analogue U-46619 were analyzed for the ability to induce hypertrophy of rat neonatal cardiac ventricular myocytes. Myocyte hypertrophy was induced specifically by PGF2 alpha. Myocytes exposed to this prostanoid in culture increased in size and protein content. The contractile fibrils within the cells became organized into parallel arrays, and the cells tended to cluster and beat spontaneously. PGF2 alpha also induced the expression of c-fos, atrial natriuretic factor (ANF), and alpha-skeletal actin in these cells. The effects of PGF2 alpha were compared with several known cardiac myocyte hypertrophy factors (phenylephrine, endothelin-1, leukemia inhibitory factor, cardiotrophin-1, and angiotensin II). PGF2 alpha was found to be intermediate in potency among the factors but induced a level of ANF production that was approximately 10-fold higher than any of the other effectors. Responsiveness to PGF2 alpha was not limited to neonatal cardiocytes. Ventricular myocytes isolated from adult rats also responded specifically to PGF2 alpha with a morphological change similar to that observed with phenylephrine and by producing ANF. In rats, chronic administration of fluprostenol, a potent agonist analogue of PGF2 alpha, resulted in a dose-dependent increase in heart weight- and ventricular weight-to-body weight ratios. The amount of PGF2 alpha extractable from the hearts of rats with cardiac hypertrophy induced by myocardial infarction was also found to be greater than that in sham-operated control rats. These results indicate that PGF2 alpha may play an important role in inducing cardiac hypertrophy.
Glycogen depletion contributes to ischemic preconditioning in the rat heart in vivo
Authors: McNulty P. H. , Darling A. , Whiting J. M.
Published: December 2017

Ischemic preconditioning depletes the myocardium of glycogen, thus blunting lactic acidosis during subsequent episodes of ischemia. Preconditioning also protects against reperfusion arrhythmias and infarction. To test whether glycogen depletion is necessary for this ischemic tolerance, we preconditioned two groups of intact rats with a series of 3-min coronary artery occlusions. In one group, preconditioning lowered the glycogen concentration of the ischemic region by approximately 50% (24.9 +/- 2.5 to 12.5 +/- 1.8 mumol/g; P < 0.01). In the other, the heart was first loaded with glycogen via glucose-insulin infusion so that preconditioning merely reduced its glycogen concentration back to normal physiological levels. Compared with nonpreconditioned control rats, preconditioned rats with both normal and subnormal glycogen concentrations were protected from reperfusion arrhythmias after a 6-min coronary occlusion (incidence: control rats, 100%; normal glycogen rats, 11%; reduced glycogen rats, 11%). In contrast, only rats with subnormal glycogen concentration after preconditioning exhibited reduced lactate formation and infarct size after a 45-min coronary occlusion [infarct size (percentage of risk area): control rats, 53 +/- 10%; normal glycogen rats, 50 +/- 16%, P = not significant; subnormal glycogen rats, 18 +/- 10%, P < 0.01]. Thus, in the intact rat, myocardial glycogen depletion appears to be necessary for the infarct-limiting, but not for the antiarrhythmic, effects of ischemic preconditioning.
Rapid mast cell activation causes leukocyte-dependent and -independent permeability alterations
Authors: Kubes P. , Gaboury J. P.
Published: December 2017

The major objective of this study was to systematically elucidate the mechanisms underlying microvascular permeability in rat mesenteric venules after the activation of perivascular mast cells. Intravital microscopy was used to assess polymorphonuclear leukocyte (PMN) infiltration and microvascular permeability alterations in single 25- to 40-micron diameter venules. Ruthenium red was used to detect mast cell activation on-line. Exposure of mast cells to compound 48/80 (CMP 48/80) caused a rapid mast cell activation and increase in microvascular permeability (within 15 min) that was maintained for the duration of the experiment. CMP 48/80 also increased PMN adhesion to the microvascular endothelium. Anti-PMN serum, as well as various antiadhesion therapies, including CL26 (anti-CD18 antibody) and fucoidan (selectin-immunoneutralizing carbohydrate), revealed that the early microvascular permeability was PMN independent. However, these regimens significantly reduced plasma protein leakage out of venules between 30 and 60 min. Methysergide (serotonin receptor antagonist), but not diphenhydramine (histamine receptor antagonist), inhibited the early PMN-independent microvascular permeability. Finally, a platelet-activating factor (PAF)-receptor antagonist did not affect the early phase of microvascular permeability but reversed the later phase, consistent with PAF's role as a proadhesive molecule for PMN during mast cell activation. These data demonstrate that, within the first hour of mast cell activation, a biphasic PMN-independent and -dependent response in microvascular permeability is observed. The data also raise the possibility that histamine's physiological role in this model may be unrelated to alterations in microvascular permeability.
Alpha-adrenoceptor activation of a chloride conductance in rat iris arterioles
Authors: Gould D. J. , Hill C. E.
Published: December 2017

Changes in membrane potential associated with alpha-adrenoceptor-mediated contraction of rat iris arterioles after nerve stimulation (10 Hz, 1 s) have been measured with conventional intracellular recording techniques. Two different types of intracellular responses were recorded. Cells that show a depolarization are proposed to represent the arteriolar smooth muscle cells because the characteristics of the depolarization are correlated with those of the contraction. Cells that show no response or a small hyperpolarization in response to nerve stimulation are proposed to represent the endothelial cells of the arteriole. Both the depolarization and the contraction were abolished by tetrodotoxin (1 microM), benextramine (10 microM), and prazosin (0.1 mM), indicating that they result from nerve-mediated activation of alpha-adrenoceptors. A small but significant part of the contraction (30%) and the depolarization (11%) was nifedipine sensitive (10 microM). Caffeine (1 mM) abolished the contraction and reduced the depolarization by one-half. Reducing the external chloride concentration also abolished the contraction and reduced the depolarization by 90%. Flufenamic acid (250 mM) abolished both the contraction and the depolarization. It is suggested that, in iris arterioles, the activation of synaptic alpha-adrenoceptors leads to the release of intracellular calcium that activates both the chloride channels in the cell membrane leading to depolarization and the intracellular contractile apparatus leading to vasoconstriction.
Function and bioenergetics in isolated perfused trained rat hearts
Authors: Spencer R. G. , Buttrick P. M. , Ingwall J. S.
Published: December 2017

To evaluate the resistance of physiologically hypertrophied hearts to hypoxic insult, we quantified the development of functional deficits during hypoxia and reoxygenation in hypertrophied hearts from swim-trained female rats and we correlated this with assessment of high-energy phosphate (HEP) metabolites from simultaneous 31P nuclear magnetic resonance (NMR) measurements. Furthermore, in vivo enzymatic studies were carried out with saturation transfer NMR under well-oxygenated perfusion conditions for both beating and KCl-arrested hearts. Finally, in vitro enzymatic assays were performed. During hypoxia, the trained hearts exhibited improved systolic and diastolic function compared with hearts from sedentary animals. After 16 min of hypoxia, left ventricular (LV) developed pressure fell to 9% of baseline in control hearts but to only 21% of baseline in trained hearts (P < 0.01). LV diastolic function was also improved by training, increasing during hypoxia from a baseline of 10 to 71.0 +/- 3.3 mmHg in control hearts and to 55.3 +/- 4.8 mmHg in trained hearts (P < 0.05). Trained hearts also showed more rapid and complete recovery of function during reoxygenation and greater coronary flow per gram of heart throughout the entire protocol. Functional differences were not accompanied by differences in HEP at baseline; moreover, ATP and phosphocreatine (PCr) loss during hypoxia was similar between control and trained hearts, as was the recovery of PCr during reoxygenation. Saturation transfer experiments showed an increase in the forward creatine kinase (CrK) rate constant in trained hearts of 18% while beating, whereas in vitro enzymatic analysis revealed a 16% increase in the ratio of mitochondrial CrK to citrate synthase activity in LV tissue. Thus the relative preservation of function in hearts from trained rats could not be accounted for by overall HEP levels but may reflect adaptations in the CrK system.
Capacitive function of the heart: influence of acute changes in heart volume on mean right atrial pressure
Authors: Sheriff D. D. , Luo Z.
Published: December 2017

Net transfer of blood volume into or out of the cardiac chambers should have the same effect on central venous pressure as does transfer of an equal volume of blood to or from peripheral organs (e.g., spleen, or liver). We studied five pentobarbital sodium-anesthetized open-chest pigs (20-23 kg) to determine whether a reduction in the time-averaged volume of blood contained in the heart, induced by rapid atrial pacing, can raise right atrial pressure. A central premise of our study is that the mean value of right atrial pressure is acutely governed by the volume of blood that distends the central veins, and that atrial contractions primarily determine how atrial pressure varies about its mean value. To prevent changes in cardiac output from altering central blood volume and pressure, cardiac output during rapid pacing (2.36 +/- 0.18 l/min) was made to equal the resting output (2.35 +/- 0.16 l/min). This was achieved by selecting a rate of pacing at which the tendency for more frequent cardiac contractions to raise cardiac output was counterbalanced by the decrease in stroke volume induced by rapid pacing. Autonomic reflex mechanisms were attenuated by pharmacological blockade. Mean arterial pressure was minimally affected in the transition from a normal sinus rhythm (89 +/- 6 beats/min) to rapid atrial pacing (165 +/- 7 beats/min) in four pigs. Mean right atrial pressure rose abruptly from 2.8 +/- 0.5 mmHg during normal sinus rhythm to 3.5 +/- 0.5 mmHg (P = 0.015) at the onset of rapid pacing in these four pigs, presumably owing to decreased cardiac blood volume and a reciprocal expansion of central venous volume. In the fifth pig, a reduction in cardiac output induced by tachycardia led to a larger rise in mean right atrial pressure than did a reduction in cardiac output induced by bradycardia, presumably because tachycardia reduces cardiac blood volume whereas bradycardia raises cardiac volume. We conclude that the heart may play an important role in maintaining or raising its own filling pressure when heart rate rises.
Regional myocardial effects of intracoronary bradykinin in conscious dogs
Authors: Houel R. , Su J. , Barbe F. , Choussat R. , Crozatier B. , Hittinger L.
Published: December 2017

This study examined in conscious dogs, the coronary and regional myocardial effects of bradykinin (BK) administered by intracoronary route and their modulation by an angiotensin-converting enzyme inhibitor. Eleven dogs were chronically instrumented with a left ventricular (LV) micromanometer, a circumflex coronary catheter, a flow probe, and ultrasonic crystals in the LV posterior wall. In the absence of systemic hemodynamic changes, BK (0.1-10 ng/kg i.c.) produced dose-dependent increases in coronary blood flow velocity (CBFV) and in LV posterior end-diastolic wall thickness (EDWT) but produced no change in LV regional myocardial function as assessed by LV posterior systolic wall thickening. The increases in LV EDWT and CBFV were linearly correlated. The BK B2 antagonist (HOE 140) abolished the effects of BK. Intracoronary enalaprilat (0.75 mg) extended the duration of the effect of BK on CBFV without modification of peak responses and induced a further increase in LV posterior EDWT but no change in LV regional myocardial function. Thus, in conscious dogs, the vasodilator effect of intracoronary BK alone or modulated by enalaprilat is not associated with changes in LV regional myocardial function.
Single HERG delayed rectifier K+ channels expressed in Xenopus oocytes
Authors: Zou A. , Curran M. E. , Keating M. T. , Sanguinetti M. C.
Published: December 2017

HERG is a K+ channel with properties similar to the rapidly activating component (I(Kr)) of delayed rectifier K+ current, which is important for repolarization of human cardiac myocytes. In this study, we have characterized the single-channel properties of HERG expressed in Xenopus oocytes. Currents were measured in cell-attached patches with an extracellular K concentration of 120 mM. The single HERG channel conductance, determined at test potentials between -50 and -110 mV, was 12.1 +/- 0.6 pS. At positive test potentials (+40 to +80 mV), the probability of channel opening was low and slope conductance was 5.1 +/- 0.6 pS. The mean channel open times at -90 mV were 2.9 +/- 0.5 and 11.8 +/- 1.0 ms, and the mean channel closed times were 0.54 +/- 0.02 and 14.5 +/- 5.3 ms. Single HERG channels were blocked by MK-499, a class III antiarrhythmic agent that blocks I(Kr) in cardiac myocytes. The development of block was more rapid in inside-out patches than in cell-attached patches or in whole cell recordings, indicating that block occurs from the cytoplasmic side of the membrane. The single-channel properties of HERG are similar to I(Kr) channels of isolated cardiac myocytes, which provides further evidence that HERG proteins coassemble to form I(Kr) channels.
Acetylcholine induces conducted vasodilation by nitric oxide-dependent and -independent mechanisms
Authors: Doyle M. P. , Duling B. R.
Published: December 2017

Conducted vasodilation has been proposed as an important component of local vascular control. Because conducted vasomotor responses have previously been studied only in response to short pulses (<500 ms) of agonist, this study examined conducted vasodilation in response to sustained stimuli. In addition, we examined the contribution of nitric oxide (NO) to initiation and maintenance of conducted responses induced by acetylcholine (ACh). Responses to 2-min applications of ACh, sodium nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate were obtained in cannulated, perfused hamster cheek pouch arterioles (approximately 60 microm in diameter). Changes of luminal diameter in response to pressure ejection of agonists from a micropipette placed close to the downstream end of the vessel were observed at the site of stimulation ("local") as well as 570 and 1,140 microm upstream. At the local site, ACh stimuli produced large changes in diameter (approximately 70% of the maximum response) that peaked within 45 s before declining slowly to levels of approximately 50% of the maximum response. A similar response pattern was observed at both upstream sites, with the conducted responses being maintained for the duration of the stimulus. Local responses of similar magnitude were found with sodium nitroprusside and 8-bromoguanosine 3',5'-cyclic monophosphate, but only minimal responses were observed at the conducted sites. In a separate set of arterioles, ACh responses were obtained before and during perfusion with 10 microM N(omega)-nitro-L-arginine. Inhibition of NO synthesis diminished the local response to ACh, but the initial phase of the conducted response was unaffected. Furthermore, the conducted responses faded more rapidly in the presence of N(omega)-nitro-L-arginine. We conclude from these results that local NO synthesis alone is insufficient to initiate conducted responses but that NO synthesis contributes to maintenance of sustained conducted responses.
Regional perfusion parameters from pulmonary microfocal angiograms
Authors: Clough A. V. , Linehan J. H. , Dawson C. A.
Published: December 2017

An indicator-dilution model was developed to describe transport of vascular contrast medium through an organ during acquisition of vascular dynamic contrast images. The model provides the theoretical basis for methods of determining regional blood flow, blood volume, and mean transit time from time-absorbance curves acquired from the images of tissue regions of interest (ROI) distal from the inlet site. The robustness of these methods was evaluated using a computer-simulated vessel network, which simulated the passage of a bolus of contrast medium through arterioles, networks of capillaries, and venules. The network was used to evaluate the reliability of ROI parameter estimation methods when the underlying model assumptions are violated. The shape of the ROI inlet concentration curve and moderate amounts of random noise did not affect the ability of the method to recover accurate parameter estimates. The estimates of ROI flow and transit time were degraded in the presence of significant dispersion of the inlet concentration curve as it traveled through arteries upstream from the microvascular ROI or when the flow was redistributed within the ROI. The estimates of ROI volume were relatively robust. The method was applied to image data of the dog pulmonary vasculature obtained using microfocal X-ray angiography to show that the results obtained from the simulations are consistent with actual data.
Nitric oxide-mediated neurogenic vasodilatation in isolated monkey lingual arteries
Authors: Toda N. , Ayajiki K. , Uchiyama M. , Okamura T.
Published: December 2017

In isolated monkey lingual arteries denuded of the endothelium and contracted with prostaglandin F2alpha, transmural electrical stimulation produced a contraction that was reduced by prazosin and reversed to a relaxation by additional treatment with alpha,beta-methylene ATP. The relaxation thus induced was abolished by tetrodotoxin and N(G)-nitro-L-arginine (L-NNA), a nitric oxide (NO) synthase inhibitor, and L- but not D-arginine restored the response in the L-NNA-treated arteries. Under treatment with prazosin and alpha,beta-methylene ATP, the arterial strips responded to nicotine with a relaxation that was not influenced by atropine and timolol but was abolished by hexamethonium, oxyhemoglobin, and methylene blue. The nicotine-induced relaxation was abolished by L-NNA but not by N(G)-nitro-D-arginine and was reversed by L-arginine. Relaxations to exogenously applied NO (acidified NaNO2 solution) were not influenced by L-NNA but were abolished by oxyhemoglobin and methylene blue. The response was not affected in the strips made unresponsive to vasoactive intestinal polypeptide and calcitonin gene-related peptide by desensitization. Histochemical study demonstrated the presence of perivascular neurons containing neuronal NO synthase. It is concluded that monkey lingual arteries are innervated by vasoconstrictor nerves liberating norepinephrine and possibly ATP and also by nonadrenergic noncholinergic vasodilator nerves liberating NO as a neurotransmitter to activate soluble guanylate cyclase. Vasoactive intestinal polypeptide and calcitonin gene-related peptide do not appear to be involved in the neurogenic vasodilatation.
Effects of elevated plasma epinephrine on glucose utilization and blood flow in conscious rat brain
Authors: Horinaka N. , Artz N. , Cook M. , Holmes C. , Goldstein D. S. , Kennedy C. , Sokoloff L.
Published: December 2017

Acute glucoprivation increases cerebral blood flow (CBF), which is often attributed to the associated rise in plasma epinephrine levels. This study examined directly the effects of comparable increases in plasma epinephrine levels achieved by continuous intravenous infusions of epinephrine in normoglycemic, unanesthetized rats on local and overall CBF and cerebral glucose utilization (1CMRglc). CBF was determined by the autoradiographic [14C]iodoantipyrine method in six unanesthetized rats in which epinephrine dissolved in 1% ascorbic acid-1 mM EDTA was infused at a rate of 1 microg/min and in five normal controls infused with the vehicle alone. 1CMRglc was determined by the autoradiographic [14C]deoxyglucose method in six conscious rats infused similarly with the epinephrine solution and in six normal controls treated with the vehicle alone. The epinephrine infusions raised arterial plasma epinephrine levels 10- to 20-fold and increased arterial blood pressure and plasma glucose levels. Local CBF, however, was significantly changed (P < 0.05, Student's t-test) in only 2 of 25 structures examined, and the changes were decreases not increases. 1CMRglc was not changed significantly in any of 42 brain structures examined, and average blood flow and glucose utilization in the brain as a whole were unaffected. These results show that high circulating levels of epinephrine similar to those accompanying glucoprivation alter neither local nor overall CBF and glucose utilization and cannot explain the increases in CBF associated with glucoprivation.
Effects of relaxin on rat atrial myocytes. II. Increased calcium influx derived from action potential prolongation
Authors: Piedras-Renteria E. S. , Sherwood O. D. , Best P. M.
Published: December 2017

Relaxin produces positive inotropic and chronotropic effects in rat hearts. The effect of relaxin on the action potential duration (APD) of single quiescent rat atrial cells was investigated with a whole cell patch clamp. Relaxin induced a significant, dose-dependent prolongation of the APD. This effect was maximal at 200 ng/ml (nominal concentration of 33.6 nM), which caused, on average, a 57% increase in the time taken to reach 90% repolarization. The effect of relaxin was blocked by the protein kinase A inhibitor 5-24 amide, indicating that its effect is mediated by an adenosine 3',5'-cyclic monophosphate-dependent mechanism. The increased APD induced by relaxin caused an enhanced entrance of calcium, with the charge carried through voltage-activated calcium channels increased by approximately 25%. This increase was not due to a direct modulation of calcium currents (20); rather, it was a consequence of the longer period of cellular depolarization. Our findings that relaxin increased the APD and therefore increased the calcium influx in atrial myocytes could explain the positive inotropic effects induced by relaxin in atrial preparations.
Gender difference in myogenic tone of rat arterioles is due to estrogen-induced, enhanced release of NO
Authors: Huang A. , Sun D. , Koller A. , Kaley G.
Published: December 2017

The characteristics of arteriolar myogenic responses of female rats have not been investigated. Thus experiments were conducted on isolated gracilis muscle arterioles (approximately 55 microm diameter) of four groups of 12-wk-old rats: male rats, female rats, ovariectomized female rats with no estrogen replacement (OV), and ovariectomized female rats with estrogen replacement (OV + E2, 50 microg/kg s.c. injection of 17beta-estradiol benzoate every 48 h). Diameter changes in response to increases in perfusion pressure from 20 to 140 mmHg and to various concentrations of substance P (SP, 10(-9)-5 x 10(-8) M) and sodium nitroprusside (SNP, 10(-8)-10(-6) M) were measured before and after administration of N(omega)-nitro-L-arginine (L-NNA, 10(-4) M), an inhibitor of NO synthase. Arteriolar diameters of male and OV female rats were significantly less at 60-140 mmHg pressure than those of normal female and OV + E2 female rats (at 80 mmHg, 45.4 +/- 1.8 and 43.1 +/- 2.2 vs. 58.4 +/- 1.6 and 57.3 +/- 1.3%). L-NNA elicited a significantly greater downward shift of pressure-diameter curves in arterioles of normal female and OV + E2 female rats than in arterioles of male and OV female rats (28.6 +/- 4.6 and 30.6 +/- 4.7 vs. 13.2 +/- 0.9 and 10.4 +/- 2.6%). Dilations of arterioles from normal female and OV +/- E2 female rats to SP were significantly greater (by 50-60%) than those from male and OV female rats (20.8 +/- 1.8 and 22.3 +/- 1.9 vs. 13.8 +/- 1.4 and 13.8 +/- 0.6% at 10(-8) M). L-NNA did not affect dilations to SNP but significantly reduced the dilation of arterioles in all groups to SP, more so in arterioles of male and OV female rats than in arterioles of the other two groups. We conclude that pressure-induced myogenic constriction of arterioles of female rats is less pronounced than that of male rats; this is, most likely, due to the enhanced release and/or activity of NO related to the presence of estrogen.
Flow-independent heterogeneity of brain capillary plasma perfusion after blood exchange with a Newtonian fluid
Authors: Vogel J. , Waschke K. F. , Kuschinsky W.
Published: December 2017

Previous studies from our group have indicated a heterogeneity of plasma transit times in brain capillaries. The heterogeneity was decreased with increasing cerebral blood flow during hypercapnia. In the present study, the hypothesis was tested that these apparent changes in microvascular plasma perfusion heterogeneity depend on the existence of red blood cells (RBC). To this end, the blood of anesthetized and paralyzed rats was replaced by a shear rate-independent oxygen-carrying substitute, ultrapurified polymerized bovine hemoglobin (UPBHB). Cerebral blood flow ([14C]iodoantipyrine technique) or microvascular perfusion pattern (intravenous bolus injection of Evans blue and decapitation 3-4 s later) was measured. After exchange transfusion with UPBHB, cerebral blood flow still varied with arterial PCO2, whereas in contrast to the unexchanged condition, the heterogeneity of the intracapillary Evans blue concentration remained unchanged. Compared with the unexchanged normocapnic condition, the heterogeneity of intracapillary dye concentration was decreased by one-quarter. It is concluded that RBC contribute to the microvascular perfusion heterogeneity in the brain.
Computer model of electrophysiological instability in very small heterogeneous ventricular syncytia
Authors: Nordin C.
Published: December 2017

Computer simulations based on a model of transmembrane currents and intracellular Ca2+ flux of an isolated guinea pig myocyte [Nordin, C. Am. J. Physiol. 265 (Heart Circ. Physiol. 34): H2117-H2136, 1993] have previously shown that very small heterogeneous ventricular myocardial syncytia can be constructed in which trains of sustained, nondriven action potentials are initiated and terminated with critically timed premature stimulations by a nonreentrant mechanism. A more detailed examination of the characteristics of such syncytia and the nature of the responses is explored. When cells with the normal configuration of equations were connected by high-resistance gap junctions to other cells in which their configuration was modified to reproduce a myocyte with mild Ca2+ overload and two regenerative levels of diastolic potential, critically timed stimulations shifted the electrical response of the syncytium between a stable phase, in which all myocytes were quiescent until stimulated and generated full action potentials from resting potentials between -90 and -65 mV, and an oscillatory phase, in which all cells generated sustained trains of nondriven action potentials from takeoff potentials between -70 and -30 mV. The following predominant responses were observed in such syncytia: 1) a range of 40-60 ms starting at the refractory period with an inverse relationship between prematurity of the stimulation and time to the first upstroke of nondriven activity, followed by a much shorter period with a direct relationship; 2) a delay shorter than a full compensatory pause following single premature stimulations that do not terminate spontaneous action potentials; and 3) entrainment of nondriven action potentials with short bursts of stimulations at rates just above the intrinsic rate of spontaneous activity and termination at faster rates. The propensity to develop nondriven action potentials was enhanced by Ca2+ loading. Other simulations demonstrated that activity can propagate in syncytia of >100 myocytes from small foci to generate full action potentials in larger regions of normal cells. Analysis of the model shows that these patterns arise primarily from crucial, dynamic relationships among membrane potential, intracellular Ca2+ cycling, and gap junction currents. The results suggest that highly localized interactions between normal and depolarized myocytes in uncoupled heterogeneous syncytia may reproduce many of the characteristic responses of ventricular tachycardia.
Infarct size reduction with the nucleoside transport inhibitor R-75231 in swine
Authors: Martin B. J. , Lasley R. D. , Mentzer R. M.
Published: December 2017

Adenosine (Ado) has been reported to be cardioprotective in several models of myocardial ischemia. The nucleoside transport inhibitor R-75231 (R-75) has been reported to enhance local Ado concentrations and postischemic recovery of function, but little is known regarding its effects on myocardial infarct size. The purpose of the present study was to determine the effects of R-75 on infarct size and to measure myocardial regional Ado concentrations. Studies were conducted in pentobarbital-anesthetized swine undergoing 60 min of coronary artery occlusion and 2 h of reperfusion. Control pigs (n = 8) were compared with those receiving R-75 (0.1 mg/kg i.v.) 15 min before either occlusion (Pre R-75, n = 8) or reperfusion (Rep R-75, n = 8). Interstitial fluid (ISF) Ado, coronary venous Ado, and infarct size (% of the region at risk) were measured. In the Pre R-75 group, ISF Ado concentrations were significantly increased before and during ischemia, reaching a peak value of 71.8 +/- 8.6 microM (vs. 16.8 +/- 0.8 microM in control). ISF inosine and hypoxanthine concentrations were significantly reduced during ischemia in Pre R-75 animals. Infarct size was smaller in Pre R-75 compared with control (21.6 +/- 1.9 vs. 38.4 +/- 2.6%, P < 0.05). The Rep R-75 group had significantly elevated coronary venous Ado concentrations but no increases in ISF Ado or reduction in infarct size (33.5 +/- 3.5%). These data indicate that R-75 increases myocardial Ado and reduces infarct size when administered before coronary occlusion. The R-75-induced reduction in infarct size appears to be related to the augmentation of ISF Ado before ischemia rather than to increased plasma Ado during reperfusion.
Impulse response analysis of baroreceptor sensitivity
Authors: Panerai R. B. , James M. A. , Potter J. F.
Published: December 2017

The impulse response function (IRF) can express the dynamic relationship between systolic arterial pressure (SAP) and pulse interval (PI) and, consequently, represents an alternative method to assess baroreceptor sensitivity (BRS) in humans. Five normotensive and 13 hypertensive subjects (age 68 +/- 5 yr, range 60-74 yr) were studied at rest in the supine position during baseline conditions and after injections of phenylephrine and sodium nitroprusside. SAP and PI signals were derived from multiple 5-min noninvasive recordings of arterial blood pressure (Finapres) and electrocardiogram. Standard estimates of BRS were obtained by the slopes of transient changes in SAP and PI after the injection of phenylephrine and sodium nitroprusside (BRS(PE) and BRS(SNP)) and by spectral analysis (alpha-index). Impulse responses were obtained by the inverse Fourier transform of the transfer function between PI and SAP. The temporal pattern of the IRF was characterized by a main peak at t = 0, preceded by a "trough" at t = -1 s. A mathematical model of the baroreflex suggests that the peak value of IRF is linearly related to the BRS. The peak value and its smoothed version were shown to be significantly correlated to alpha, BRS(PE), and BRS(SNP) and significantly reduced in the hypertensive group during the three stages of the protocol. We suggest that IRF might be the ideal method to assess BRS because it does not require any subjective preselection of data segments or spectral bands.
Indicator-dilution dispersion models and cardiac output computing methods
Authors: Millard R. K.
Published: December 2017

The general theory of indicator-dilution methods provides a basis for computing improved cardiac output estimates. Interpretation is via indicator-dispersion modeling with Brownian motion of drifting particles. Detected curves indicate the distribution of passage times from the injection site: the local density random walk (LDRW) function of a Wiener process. Fitting the LDRW to 70 dye curves by nonlinear regression for examples, I show how all possible undistorted curves can, in principle, be simulated. I show via semilogarithmic plots that conventional exponential decay constructs systematically underestimate cardiac output by up to 8%. To help reconcile the predictions of LDRW-fitted dilution curves and contemporary practice, I show how curve-shape asymmetry (skewness) dramatically affects the enclosed areas. Mean transit times may overestimate blood volumes by 15-100% in very skewed thermodilution curves if the dispersion effects are overlooked. Triangle constructions, which accounted for hundreds of experimental findings, also have theoretical explanations. Curve-fitting methods reduce the extrapolation biases inherent in many computers and in any respiration-induced artifacts. Compatibility of cardiac output predictions from various dilution methods and modules becomes feasible.