bluuebunny/crossref_metadata_2025 huggingface dataset:
Time-dependent changes in kinetics of Na+ current in single canine cardiac Purkinje cells
Authors: Hanck D. A. , Sheets M. F.
Published: December 2017

The spontaneous hyperpolarizing shift in Na+ channel kinetics that occurs during a series of voltage-clamp recordings was characterized in single canine cardiac Purkinje cells at 10-13.5 degrees C. The change in the half-point of voltage-dependent availability, in the half-point of peak conductance, in the voltage dependence of deactivation and time to peak Na+ channel current (INa), and in the time constants of INa decay in response to step depolarizations were examined. The half points of availability and conductance shifted similarly, -0.41 +/- 0.13 and -0.47 +/- 0.19 mV/min, respectively (n = 14). These were directly correlated (slope 1.14 +/- 0.06, R2 = 0.81) with conductance shifting on average only -0.05 mV/min faster than availability. The deactivation time constant-voltage relationship shifted similarly to availability and conductance. Tail current decay time constants predicted the voltage dependence of the open to closed transition to be 0.9e-. Time to peak INa in response to step depolarizations changed e-fold for 25 mV but plateaued at positive potentials (531 microseconds, n = 22). INa decay was multiexponential between -40 and 80 mV. Decay time constants changed little as a function of voltage at positive potentials. The contribution of the second time constant to decay amplitude was 15-20% over the entire voltage range. Time to peak INa shifted in a curvilinear fashion, changing less late in an experiment. We conclude that the channel-voltage sensor responds to a changing fraction of the applied voltage during an experiment, producing similar rates of shift of voltage-dependent availability, conductance, and deactivation time constants.
Three ways of abolishing automaticity in sinoatrial node: ionic modeling and nonlinear dynamics
Authors: Guevara M. R. , Jongsma H. J.
Published: December 2017

A review of the experimental literature reveals that there are essentially three qualitatively different ways in which spontaneous activity in the sinoatrial node can be abolished. We show that these three ways also occur in an ionic model of space-clamped nodal membrane. In one of these three ways, injection of a current pulse abolishes (“annihilates”) spontaneous action potential generation. In the other two ways, as some parameter is changed, one sees a sequence of qualitative changes in the behavior of the membrane as it is brought to quiescence. In one of these two ways there are incrementing prepotentials intermixed with action potentials, with a maintained small-amplitude subthreshold oscillation being the limiting case of such behavior. Thus both experimental and modeling work indicate that the number of ways in which spontaneous activity can be abolished, or initiated, in the sinoatrial node is limited. The classification into three ways is based on ideas drawn from the qualitative theory of differential equations, which are introduced. The classification scheme can be extended to encompass behaviors seen in other cardiac oscillators.
Bradykinin-activated calcium influx pathway in bovine aortic endothelial cells
Authors: Mendelowitz D. , Bacal K. , Kunze D. L.
Published: December 2017

Clusters of electrically coupled endothelial cells were used to characterize a bradykinin (BK)-activated Ca2+ influx pathway. Spatial voltage control of clusters containing three to eight cells, evaluated as the ratio of the voltage response in one cell to a voltage pulse in the most distant cell of the cluster, was 0.96 at a holding potential of 0 mV in normal saline bath and 0.88 in the presence of BK. BK activated an inward current that was carried by either Na+ or Ca2+ when the membrane potential was held at -60 mV. Current was activated within 3 s of application of BK and peaked within 1 min. With Ca2+ as the permeable extracellular ion the current was stable for 1-3 min and then declined over a period of 5-8 min in the continued presence of BK. However, when Na+ carried the current it was sustained over a 10-min test period. The reversal potential of the BK-activated current was near 0 mV, suggesting activation of a nonspecific cation channel(s). The inward current at -60 mV averaged 13 +/- 4.5 pA (n = 9)/cell in Ca2+ and 12.2 +/- 9.3 pA (n = 5)/cell in Na+. Both Na+ and Ca2+ currents were blocked by 200 microM lanthanum.
Electrical field stimulation causes endothelium-dependent and nitric oxide-mediated relaxation of pulmonary artery
Authors: Buga G. M. , Ignarro L. J.
Published: December 2017

The objective of this study was to ascertain the mechanism by which electrical field stimulation (EFS) of bovine pulmonary arterial rings causes endothelium-dependent smooth muscle relaxation. Like acetylcholine-elicited relaxation, EFS-elicited relaxation was endothelium-dependent and accompanied by accumulation of guanosine 3',5'-cyclic monophosphate (cGMP) in the vascular smooth muscle. Relaxation in response to EFS was unaltered by tetrodotoxin, guanethidine, atropine, propranolol, chlorpheniramine, cimetidine, indomethacin, aminophylline, alpha, beta-methylene ATP, nifedipine, capsaicin, and certain antioxidants and free radical scavengers. Thus the relaxation was not neurogenically mediated and was not attributed to free radical formation during EFS. Like nitric oxide-elicited relaxation, EFS-elicited relaxation was antagonized by oxyhemoglobin and methylene blue. Relaxation was also antagonized by the three NG-substituted L-arginine analogues: NG-methyl-L-arginine, NG-nitro-L-arginine, and NG-amino-L-arginine. NG-amino-L-arginine also inhibited the tissue cGMP accumulation in response to EFS. The inhibitory effect of the NG-substituted L-arginine analogues was reversed by addition of excess L-arginine but not D-arginine. Relaxation in response to EFS was dependent on the presence of extracellular calcium and intracellular calmodulin, as removal of extracellular calcium or addition of trifluoperazine nearly abolished relaxation. EFS-elicited relaxation was inhibited also by tetraethylammonium chloride and elevated extracellular potassium concentration. These observations indicate that EFS-elicited relaxation of bovine pulmonary artery is mediated by neuronally independent, but endothelium- and calcium-dependent, stimulation of nitric oxide and cGMP formation.
L-NMMA in brain microcirculation of mice is inhibited by blockade of cyclooxygenase and by superoxide dismutase
Authors: Rosenblum W. I. , Nishimura H. , Nelson G. H.
Published: December 2017

As previously reported, NG-monomethyl-L-arginine (L-NMMA) constricted pial arterioles, inhibited dilation of pial arterioles by acetylcholine (ACh) or L-arginine (L-Arg), and enhanced platelet adhesion/aggregation at sites of endothelial damage. However, all of these effects were inhibited by local application of 20 micrograms/ml indomethacin (Indo). When 100 micrograms/ml acetylsalicylic acid were used instead of Indo, the acid also blocked the effects of L-NMMA. Superoxide dismutase (SOD; 50 U/ml) blocked the constriction produced by L-NMMA and also blocked the constriction produced by N omega-nitro-L-arginine (NNA). SOD also prevented L-NMMA from blocking dilation by ACh. SOD itself had no effect on diameter or on the response to ACh, norepinephrine, or BaCl2. The effects of L-NMMA and of Indo were also selective. Thus L-NMMA did not inhibit dilation by prostacyclin or bradykinin, and Indo did not inhibit dilation by prostacyclin. Indo did not interfere with the ability of arginase to enhance platelet adhesion/aggregation or with the ability of ACh or L-Arg to inhibit adhesion/aggregation. We conclude that in mouse cerebral microcirculation the ability of L-NMMA and NNA to constrict arterioles, the ability of L-NMMA to inhibit dilation by ACh or L-Arg and the ability of L-NMMA to enhance platelet adhesion/aggregation are all related to interference with phenomena dependent on "classical" endothelium-derived relaxing factor (EDRFACh). However, in this preparation the action of L-NMMA or NNA may not be due to competitive inhibition of the enzyme producing EDRFACh from L-Arg. Rather, L-NMMA and NNA appear to activate cyclooxygenase with resultant production of superoxide, which inactivates EDRFACh.
Epicardial sites for vagal mediation of sinoatrial function
Authors: Mick J. D. , Wurster R. D. , Duff M. , Weber M. , Randall W. C. , Randall D. C.
Published: December 2017

The posterior atrial fat pad (PAFP) has been described as the probable anatomic location of parasympathetic ganglia mediating sinoatrial (SAN) and atrioventricular nodal function in the mammalian heart. This contrasts with recent localizations of such control elements in the pulmonary vein fat pad (PVFP) and in fatty tissues overlying the junction of inferior vena cava-inferior left atrium (IVC-ILA), respectively. Short bursts (5-8 pulses/burst, 3 bursts/train) of electrical current (1-16 Hz, 400 ms, 1-5 mA) applied directly to the ventral right atrial epicardium via a concentric bipolar electrode (separation 0.3-0.6 mm) during the atrial muscle refractory period, activated subepicardial postganglionic pathways from PVFP and entering the SAN; identical stimulation of dorsal right atrial epicardium between PAFP and SAN excited few or no fiber pathways controlling SAN discharge rate or patterns. In a second series of experiments, injection of a neuronal marker (Fast Blue) into and around SAN, with time (5-10 days) allowed for retrograde transport, resulted in staining of many soma in PVFP but none in IVC-ILA or PAFP. These data strongly affirm the primary, and perhaps exclusive, localization of ganglia that mediate parasympathetic regulation of SAN function in PVFP of the dog's heart, with little or no such participation by ganglia within PAFP or IVC-ILA.
Effects of birth-related stimuli on L-arginine-dependent pulmonary vasodilation in ovine fetus
Authors: Cornfield D. N. , Chatfield B. A. , McQueston J. A. , McMurtry I. F. , Abman S. H.
Published: December 2017

To determine the effects of birth-related stimuli on L-arginine-dependent vasodilation or nitric oxide (NO) activity in the perinatal lung, we studied the fetal pulmonary vascular effects of nitro-L-arginine (L-NA), a specific inhibitor of NO formation, during 1) mechanical ventilation without altering fetal blood gas tensions; 2) administration of high oxygen concentrations; and 3) increased flow or shear stress. In the first protocol, 13 late-gestation fetal lambs were ventilated with low fraction of inspired oxygen concentration (FIO2 less than or equal to 0.10) for 60 min after infusion of L-NA or saline into the left pulmonary artery (LPA). In control animals, LPA flow steadily increased during 60 min of ventilation. With L-NA treatment, the rise in flow and decrease in total pulmonary resistance (TPR) were reduced 67% (P less than 0.001 vs. control) and 28% (P less than 0.01 vs. control), respectively. Subsequent ventilation with high FIO2 (1.00) decreased mean pulmonary arterial pressure (PAP) in control but not in L-NA-treated animals. TPR remained fourfold greater in L-NA-treated animals than in control animals (P less than 0.001). In the second protocol, with partial compression of the ductus arteriosus, LPA flow increased 300% and TPR decreased 61% over 30 min. After L-NA treatment the rise in blood flow and decrease in TPR was markedly attenuated (P less than 0.001). We conclude that the perinatal pulmonary vasodilator response to ventilation without changing arterial oxygen tension and ventilation with increased oxygen tension are modulated by NO.(ABSTRACT TRUNCATED AT 250 WORDS)
Role of endothelium-derived relaxing factor in parasympathetic coronary vasodilation
Authors: Broten T. P. , Miyashiro J. K. , Moncada S. , Feigl E. O.
Published: December 2017

Vasodilation following the infusion of acetylcholine is due to the release of endothelium-derived relaxing factor (EDRF). However, the role of EDRF in neurogenic coronary vasodilation, when acetylcholine is released outside the vessel at the adventitial-medial junction, has not been established. The action of EDRF in parasympathetic coronary vasodilation was tested in the present study using a specific inhibitor of EDRF synthesis, nitro-L-arginine methyl ester (L-NAME). Experiments were conducted on closed-chest, alpha-chloralose-anesthetized dogs with the heart paced at a constant rate. Phentolamine and propranolol were administered to block alpha- and beta-adrenergic receptors, and ibuprofen was given to inhibit prostaglandin synthesis. Intracoronary infusion of L-NAME decreased the coronary vasodilation in response to intracoronary acetylcholine or vagal stimulation. The coronary response to the endothelium-independent vasodilator nitroglycerin was unaffected by L-NAME. These data demonstrate that L-NAME specifically inhibits coronary vasodilation caused by acetylcholine and vagal stimulation, indicating that parasympathetic coronary vasodilation is dependent on EDRF.
Characterization of Na(+)-H+ exchange in segments of rat mesenteric artery
Authors: Foster C. D. , Hill W. A. , Honeyman T. W. , Scheid C. R.
Published: December 2017

To develop a technique for measuring Na(+)-H+ exchange activity and intracellular pH (pH(i)) “on line” in resistance vessels, we utilized strips of rat mesenteric arteries loaded with the pH-sensitive dye 2',7”-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Strips were held at a fixed length within a 3-ml cuvette, and fluorescence emission was monitored at 530 nm. The spectrofluorimeter was monitored in the ratio mode, and the excitation wavelength was alternated between 440 and 505 nm. Tissues were maintained by perfusing with N-2-hydroxyethylpiperazine-N'-2-ethane-sulfonic acid containing buffers. The introduction of ammonium chloride produced a rapid alkalinization. Washout of ammonium caused rapid acidification. Restoration of pH(i) was Na+ dependent and inhibited by dimethyl amiloride (concentration that produces half-maximal inhibition, K0.5 = 30 microM), features characteristic of Na(+)-H+ exchange. Further studies assessed the transport rate of the exchanger, which averaged 0.19 +/- 0.02 pH U/min (means +/- SE, n = 8). An estimate of the dependence of Na(+)-H+ exchange on external Na+ gave an apparent Michaelis constant for external Na+ of 10 mM and an apparent maximal velocity of 0.1 mM H+/s. Intracellular H+ was found to have a cooperative effect (Hill coefficient = 4) on Na(+)-H+ exchange.
Cyclosporin inhibits mitochondrial calcium efflux in isolated adult rat ventricular cardiomyocytes
Authors: Altschuld R. A. , Hohl C. M. , Castillo L. C. , Garleb A. A. , Starling R. C. , Brierley G. P.
Published: December 2017

Exchangeable intracellular Ca2+ as measured by 45Ca2+ uptake more than doubled when isolated adult rat ventricular cardiomyocytes were incubated 30 min with 8 microM cyclosporin; nevertheless the cells retained a normal rod-shaped morphology. High concentrations of ouabain caused a similar increase in 45Ca2+ uptake, but in this case the Ca2+ overload caused nearly all cells to hypercontract into a round disorganized form. The response to cyclosporin was concentration dependent with an apparent half-maximal effective concentration of 0.5 microM for enhancement of net 45Ca2+ accumulation. Verapamil (1 microM) could not inhibit this cyclosporin effect, but it was abolished by a 5-min preincubation with 12 microM crude ruthenium red. Cyclosporin also decreased the rate of 45Ca2+ efflux from prelabeled myocytes into Ca(2+)-containing and Ca(2+)-free media. These data are consistent with inhibition of mitochondrial 45Ca2+ efflux through the cyclosporin-sensitive mitochondrial inner membrane pore. It would appear that periodic transient increases in mitochondrial inner membrane permeability provide a pathway for mitochondrial Ca2+ extrusion under relatively normal conditions in isolated adult rat heart cells.
Participation of alpha 2-adrenergic receptors in neural vascular tone of canine skeletal muscle
Authors: Kubes P. , Melinyshyn M. , Nesbitt K. , Cain S. M. , Chapler C. K.
Published: December 2017

Studies were carried out in anesthetized, paralyzed, and ventilated dogs to determine whether postsynaptic alpha 2-adrenergic receptors participated in neurally mediated vascular tone in skeletal muscle. Hindlimb skeletal muscle resistance (RL) and blood flow (QL) were determined before, during, and after reversible cold block of the sciatic nerve. This sequence of observations was repeated 30 min after blockade of alpha 1-adrenergic receptors with prazosin. Then the alpha 2-adrenergic receptors were blocked with yohimbine, and the nerve cold block was repeated. When the sciatic nerve was cold blocked before alpha 1-adrenergic blockade, RL decreased approximately 50% and QL increased 75% (P less than 0.05) and then returned to control when the nerve was rewarmed. After alpha 1-block 76% of neural tone remained as assessed by nerve cooling (P less than 0.05). This phenomenon occurred despite effective alpha 1-adrenergic blockade as assessed by the alpha 1-receptor agonist methoxamine. With alpha 1- plus alpha 2-block no change in RL or QL was seen with nerve cold block. The same protocol was repeated in a second series of animals, but mean arterial pressure, which fell after alpha 1-block in the group above, was maintained by dextran infusion at normotensive levels. In these animals, 40% of neural tone remained after alpha 1-block. Both alpha 1- and alpha 2-adrenergic blockers were again needed to abolish the QL and RL response to nerve cold block. In another series of animals, yohimbine was administered before prazosin. In this series, alpha 2-adrenergic blockade greatly reduced neural tone as assessed by nerve cooling.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of general anesthesia on cardiac vagal tone
Authors: Halliwill J. R. , Billman G. E.
Published: December 2017

Although it is accepted that general anesthetics alter cardiac vagal tone, the magnitude of this effect was difficult to quantify by noninvasive methods until recently. Twenty-eight mongrel dogs were anesthetized using one of four representative anesthetics: pentobarbital sodium (25 mg/kg iv), morphine (1 mg/kg sc) with alpha-chloralose (50 mg/kg iv), urethan (500 mg/kg iv), thiopental sodium (25 mg/kg iv), and halothane (2% inhalation). Heart period (R-R interval) was recorded, from which the amplitude of the respiratory sinus arrhythmias (RSAs; frequency 0.24-1.04 Hz) was determined by time-series analysis. Morphine with alpha-chloralose-urethan significantly (P less than 0.01) increased RSA (control 8.3 +/- 0.6 ln ms2, anesthesia 9.4 +/- 0.3 ln ms2), whereas thiopental and halothane both significantly (P less than 0.01) decreased RSA (control 8.7 +/- 0.4 ln ms2, thiopental 1.3 +/- 0.4 ln ms2; and control 8.5 +/- 0.6 ln ms2, halothane 3.6 +/- 0.8 ln ms2). Pentobarbital failed to elicit a consistent change in RSA. These data suggest that vagal tone was maintained during morphine with alpha-chloralose-urethan anesthesia but was reduced during thiopental and halothane anesthesia.
Evidence of a K(+)-H(+)-ATPase in vascular smooth muscle cells
Authors: McCabe R. D. , Young D. B.
Published: December 2017

In earlier studies Na(+)-K(+)-adenosinetriphosphatase (ATPase) and Na(+)-K(+)-2Cl- cotransport partially accounted for vascular smooth muscle cell (VSMC) K+ (Rb+) uptake. In other cells Rb+ is taken up by a K(+)-H(+)-ATPase that is sensitive to NC-1300-B, SCH28080, omeprazole, and N-ethylmaleimide (NEM). This study examines the effects of K(+)-H(+)-ATPase inhibitors on VSMC. Rubidium uptake by primary cultures of canine coronary artery (CCA) VSMC or cultured rat aortic (CRA) VSMC line A7r5 was reduced 19-37% by NC-1300-B, SCH28080, or omeprazole. N-ethylmaleimide reduced CCA VSMC K+ content from 1.55 +/- 0.02 to 1.24 +/- 0.06 mu eq/mg protein. The NC-1300-B-sensitive portion of CRA VSMC Rb+ uptake was not blocked by ouabain (0.1 mM) or bumetanide (0.1 mM), but was reduced by alkalinization with 7.5 mM NH4Cl, and increased by acidification with 7.5 mM Na-acetate. Intracellular pH (pHi) of CRA VSMC was reduced 0.14 +/- 0.03 U by NC-1300-B and 0.22 +/- 0.03 U by NEM. pHi of CCA VSMC was reduced 0.20 +/- 0.03 U by omeprazole (1 mM) and 0.20 +/- 0.03 U or 0.20 +/- 0.05 U by amiloride in the absence or presence of omeprazole, respectively. Fluorescence of 2',7'-bis(carboxyethyl)-5-(6')- carboxyethyl)-5-(6')-carboxyfluorescein due to excitation at 500:441 nm in rat aortic strips was reduced by 0.21 +/- 0.02 U by omeprazole and 0.22 +/- 0.03 U by K+ removal and increased by 0.21 +/- 0.06 U by K+ repletion. We conclude that VSMC possess a previously unknown Rb+ uptake mechanism. This newly discovered mechanism helps to maintain K+ gradient and pHi by extruding H+ in exchange for K+, and is presumably a K(+)-H(+)-ATPase similar to those described in other tissues.
Long-term coronary stenosis in rats: cardiac performance, myocardial morphology, and contractile protein enzyme activity
Authors: Anversa P. , Malhotra A. , Zhang X. , Li P. , Scheuer J. , Capasso J. M.
Published: December 2017

To determine the effects of chronic nonocclusive coronary constriction on cardiac hemodynamics, myocardial structure, and contractile protein enzyme activity, the left coronary artery was narrowed in rats, and measurements of ventricular pump function, extent and localization of tissue damage, and myofibrillar Mg2+ and Ca2+ myosin adenosinetriphosphatase (ATPase) activities were measured 3 mo later. In the presence of coronary artery stenosis averaging 56%, two different degrees of depression in global cardiac performance were identified, and the animals were divided in two groups. In the first group, left ventricular end-diastolic pressure (LVEDP) was increased and LV+ and/or--the first derivative of LV pressure (dP/dt) were decreased, whereas in the second group end-diastolic and peak systolic LV pressures, LV+ and -dP/dt and right ventricular dynamics were all impaired. Thus left ventricular dysfunction and failure occurred with coronary narrowing. Structurally, multiple foci of replacement fibrosis were found across the left ventricular wall, but the number of these lesion profiles was 2.6-fold larger in failing animals than in rats with cardiac dysfunction. Biochemically, Mg(2+)-ATPase activity in myofibrils and Ca2+ myosin ATPase were not altered biventricularly. On the other hand, a shift from V1 to V3 myosin isoenzymic content occurred in the failing left ventricle. In conclusion, the late impairment in ventricular pump function associated with prolonged coronary artery stenosis appears to be sustained more by the magnitude of myocardial damage than by defects in contractile protein enzyme activity.
Sodium and left ventricular mass in untreated hypertensive and normotensive subjects
Authors: Du Cailar G. , Ribstein J. , Daures J. P. , Mimran A.
Published: December 2017

To determine whether urinary sodium excretion (a rather rough estimate of sodium intake) can influence left ventricular mass independently of arterial pressure, 91 untreated subjects with essential hypertension and 50 normotensive subjects of similar age were studied. Left ventricular mass index (M-mode echocardiography) was positively correlated with urinary sodium excretion in hypertensive (r = 0.22, P less than 0.01) as well as normotensive subjects (r = 0.22, P less than 0.05), and systolic arterial pressure was correlated only in hypertensive subjects (r = 0.23, P less than 0.01). When hypertensive subjects were divided into groups with appropriate or inappropriate left ventricular mass by reference to a theoretical optimal left ventricular mass for each subject's level of systolic arterial pressure, left ventricular mass was appropriate in 68% and inappropriate in 32% of subjects. Urinary sodium excretion was higher in subjects with inappropriate left ventricular mass compared with those with appropriate left ventricular mass. In conclusion, sodium excretion may be an important modulator of the influence of arterial pressure on the left ventricle in normotensive subjects and subjects with essential hypertension.
Acute effect of 17 beta-estradiol on rabbit coronary artery contractile responses to endothelin-1
Authors: Jiang C. , Sarrel P. M. , Poole-Wilson P. A. , Collins P.
Published: December 2017

We assessed the acute effect of 17 beta-estradiol on coronary artery constrictor responses to endothelin-1. 17 beta-Estradiol significantly shifted endothelin-1, calcium, or BAY K 8644 concentration-dependent contraction curves to the right in endothelium-denuded coronary arteries isolated from nonpregnant female rabbits. The -log 50% effective dose (ED50) of calcium in high KCl medium (100 mM) was 3.8 +/- 0.11 in control and 3.2 +/- 0.1 and 2.8 +/- 0.12 after incubation with 17 beta-estradiol (1 and 10 microM, respectively). The -log ED50 of BAY K 8644 (KCl 15 mM) was 7.8 +/- 0.1 in control and 7.4 +/- 0.08 and 7.2 +/- 0.05 in the presence of 17 beta-estradiol (1 and 10 microM, respectively). The -log ED50 of endothelin-1 was 9.2 +/- 0.08 in control and 8.8 +/- 0.1, 8.4 +/- 0.07, and 8.1 +/- 0.12 after incubation with 17 beta-estradiol (3, 10, and 30 microM, respectively). Similar results were obtained from coronary arteries of male rabbits. These increases of -log ED50 values were significant (P less than 0.05 or 0.01). 17 beta-Estradiol and verapamil induced dose-dependent relaxation in both endothelium-intact or -denuded coronary arteries submaximally precontracted by endothelin-1. NG-monomethyl-L-arginine had no effect on relaxation induced by 17 beta-estradiol, whereas it eliminated relaxation induced by acetylcholine in rings with an intact endothelium. These data suggest that 17 beta-estradiol attenuates the rabbit coronary artery contraction induced by endothelin-1 via an endothelium-independent mechanism, possibly by affecting calcium influx.
How to encode arterial pressure into carotid sinus nerve to invoke natural baroreflex
Authors: Kubota T. , Chishaki H. , Yoshida T. , Sunagawa K. , Takeshita A. , Nose Y.
Published: December 2017

The purpose of this study was to develop an artificial baroreceptor that was capable of invoking the "natural" baroreflex by electrically stimulating the afferent nerve. In six anesthetized, vagotomized dogs, we first identified, using the white-noise method, the transfer function from carotid sinus pressure to aortic pressure (HCSP.AoP) and that from the electrical carotid sinus nerve stimulation to aortic pressure (HCSN.AoP). We then backcalculated the transfer function required for the artificial baroreceptor (HCSP.CSN) as the ratio of HCSP.AoP to HCSN.AoP. To activate the artificial baroreceptor, we electrically stimulated the carotid sinus nerve with the frequency-modulated pulse train obtained in real time by convolving the impulse response of HCSP.CSN with instantaneous aortic pressure. We tested performance of the artificial baroreceptor by imposing random changes in blood volume. The pressure-stabilizing effects of the artificial baroreceptor were indistinguishable from those of the native one. We conclude that the artificial baroreceptor can invoke the natural baroreflex. The proposed framework generally would be applicable to interface artificial devices with the central nervous system.
Glibenclamide decreases basal coronary blood flow in anesthetized dogs
Authors: Imamura Y. , Tomoike H. , Narishige T. , Takahashi T. , Kasuya H. , Takeshita A.
Published: December 2017

The effects of ATP-sensitive K+ channel blockade on coronary blood flow were studied in 13 anesthetized open-chest dogs. A specific ATP-sensitive K+ channel blocker, glibenclamide, was infused into the left circumflex coronary artery (LCx). Coronary blood flow of LCx and systolic segment shortening at the LCx area were measured. Intracoronary infusion of glibenclamide (0.5, 5, and 50 micrograms.kg-1.min-1) decreased coronary blood flow dose dependently. Glibenclamide at the dose of 50 micrograms.kg-1.min-1 decreased LCx coronary blood flow by 55 +/- 4% (P less than 0.01), which was accompanied by a decrease in percentage segment shortening at the LCx area (P less than 0.01) and ST elevation. When coronary blood flow was maintained at the baseline level by simultaneous infusion of sodium nitroprusside (1-3 micrograms/min ic) or pinacidil (0.3-0.6 mg/min ic), glibenclamide did not alter percentage segment shortening or produced ST elevation. The latter results suggest that glibenclamide decreased coronary blood flow, which secondarily induced myocardial ischemia and dysfunction. Our results suggest that ATP-sensitive K+ channels of coronary arteries are involved in maintaining the level of resting coronary blood flow under physiological conditions in anesthetized dogs.
Pial vessel caliber and cerebral blood flow become dissociated during ischemia-reperfusion in cats
Authors: Tasdemiroglu E. , Macfarlane R. , Wei E. P. , Kontos H. A. , Moskowitz M. A.
Published: December 2017

The relationship between pial arteriolar caliber and cerebral blood flow (CBF) was examined in 11 cats subjected to reperfusion for up to 120 min after 10 min of global cerebral ischemia induced by four-vessel occlusion and systemic hypotension. Thirty minutes after reperfusion CBF, as assessed by radiolabeled microsphere injection, had increased to 588% of control in middle cerebral artery (MSEC) cortical gray matter territory. The caliber of MSEC pial arterioles measured using the closed cranial window technique (greater than 33 to less than 213 microns) increased to 172% of baseline. By 60 min of reperfusion, CBF was 76% of basal levels, but pial arterioles remained 133% of baseline. After 120 min, CBF approximated baseline values, but pial dilatation persisted (115% of control). Intracranial pressure measurements did not differ significantly from resting values. At 45 min and beyond, total cerebrovascular resistance did not differ from resting values. The coexistence of vasodilatation within pial arterioles and normal blood flow in cortical gray matter indicates that pial vessels (greater than 33 microns) cannot be responsible for normal blood flow restoration following postocclusive hyperemia. Resistance during the posthyperemic phase must be increased selectively within parenchymal vessels to account for normal total cerebrovascular resistance, pial vessel dilatation, and normal-low parenchymal blood flow. Whether obstruction rather than vasoconstriction explains the resistance changes within intraparenchymal vessels remains for further study.
Stretch-induced depolarizations as a trigger of arrhythmias in isolated canine left ventricles
Authors: Stacy G. P. , Jobe R. L. , Taylor L. K. , Hansen D. E.
Published: December 2017

Transient diastolic stretch of the left ventricle predictably elicits arrhythmias. To investigate the mechanism of such stretch-induced arrhythmias, monophasic action potentials were recorded from six blood-perfused isolated canine left ventricles with an epicardial contact electrode. Stretch-induced arrhythmias were elicited using a computerized servo-pump system that increased left ventricular volume for 250 ms during early diastole. Depolarizations that coincided with the onset of stretch were observed that always preceded the stretch-induced arrhythmia. As stretch volume (delta V) increased from 10 to 30 ml, the amplitude of the stretch-induced depolarization increased progressively and the probability of eliciting an arrhythmia rose from 30 to 94%. To exclude motion artifact, additional recordings were made after the heart was depolarized by increasing the perfusate K+ concentration to 154 mM (K arrest). After K arrest, the stretch-induced depolarizations were reduced by 95% or more (P less than 0.05) at all stretch volumes. Thus the change in monophasic action potential signal during transient diastolic stretch reflects actual depolarization of the myocardium with negligible motion artifact. When the stretch-activated channel blocker, Gd3+ (10 microM), was administered, which produces potent inhibition of stretch-induced arrhythmias in our model, the stretch-induced depolarizations were substantially reduced in magnitude. Our results show that as diastolic stretch increases, stretch-induced depolarizations become larger and reach threshold potential more often; consequently, the probability of eliciting a stretch-induced arrhythmia increases. This mechanism of arrhythmogenesis may be particularly important in patients with regionally or globally dilated left ventricles.
CGRP and somatostatin modulate chronic hypoxic pulmonary hypertension
Authors: Tjen-A-Looi S. , Ekman R. , Lippton H. , Cary J. , Keith I.
Published: December 2017

Chronic hypoxic pulmonary hypertension (PH), associated with increased pulmonary arterial pressure (PPA) and right ventricular hypertrophy (RVH), correlates significantly with calcitonin gene-related peptide (CGRP) and somatostatin (SOM) levels in lung and blood. CGRP's role in regulation of PPA in chronic hypoxia and its potential interactions with SOM were investigated. CGRP, its antibody (ab) and blocker, CGRP-(8–37), SOM-14, SOM-28, and SOM-ab, respectively, were infused into the pulmonary circulation of hypobaric hypoxia rats for 4, 8, and 16 days. Thereafter, under pentobarbital sodium anesthesia, PPA was measured in the right ventricle and main pulmonary artery. Chronic CGRP infusion prevented PH at all times, whereas immunoneutralization and receptor blocking exacerbated PH. SOM-28 also exacerbated while SOM-14 and SOM-ab decreased PH. RVH generally reflected the PPA. Radioimmunoassay confirmed successful infusion of the peptides with negligible peptide degradation in the pumps throughout 16 days and showed complete immunoneutralization of CGRP with its ab. Peptide levels in lung tissue suggest inhibition of CGRP release by SOM-28 and increased plasma SOM with CGRP infusion. In vitro pharmacological studies suggest that CGRP exerts a receptor-mediated nonadrenergic, nonmuscarinic vasodilatory effect in the lung which is independent of endothelium-derived relaxing factor and does not involve ATP-dependent potassium channels. We conclude that endogenous CGRP plays an important role in pulmonary pressure homeostasis during hypoxia, by directly dilating pulmonary vasculature, thus ameliorating the development of chronic hypoxic pulmonary hypertension in rats.
Concurrent increases in regional hematocrit and blood flow in diabetic rats: prevention by sorbinil
Authors: Sutera S. P. , Chang K. , Marvel J. , Williamson J. R.
Published: December 2017

These studies were undertaken to investigate the relationship between regional hemodynamic and hemorheological changes in the microvasculature of diabetic rats. Diabetes was induced in male Sprague-Dawley rats by injection of streptozotocin (55 mg/kg body wt). Control rats were injected with vehicle (sodium citrate buffer). A subgroup of diabetic rats was treated with an aldose reductase inhibitor (sorbinil) added to the diet in an amount to provide a daily dose of approximately 0.2 mmol.kg-1.day-1. Three weeks later all animals were anesthetized with thiobutabarbital sodium (Inactin, 100 mg/kg injected intraperitoneally) for assessment of blood flow (by injection of 15 microns microspheres) and regional hematocrit (determined by isotope-dilution techniques using 51Cr-labeled red blood cells and 125I-labeled bovine serum albumin) in selected tissues. The hematocrit in arterial blood samples was identical (approximately 46%) in controls and in diabetics. Regional hematocrits were much lower than arterial hematocrits in control rats and ranged from approximately 20% in ocular tissues, sciatic nerve, diaphragm, and skin to approximately 30% in brain, skeletal muscle, heart, and fat. Hematocrits of diabetic rats were markedly increased in ocular tissues, sciatic nerve, and skin but not in brain, heart, or skeletal muscle. These increases in regional hematocrit were associated with increases in blood flow and were largely prevented by sorbinil. Diabetes induced significant decreases in the mean transit times for whole blood and erythrocytes in all tissues examined except brain, retina, and skin.(ABSTRACT TRUNCATED AT 250 WORDS)
Local temperature modulates alpha 1- and alpha 2-adrenergic vasoconstriction in men
Authors: Freedman R. R. , Sabharwal S. C. , Moten M. , Migaly P.
Published: December 2017

Previous work in the canine saphenous vein has shown that cooling augments alpha 2- but not alpha 1-mediated contractile responses and that warming produces the opposite effects. Here we sought to determine whether these results occur in the human finger, a cutaneous vascular bed. Healthy men received brachial artery infusions of phenylephrine and clonidine with and without yohimbine while sympathetic tone was reduced by hearing the legs. Finger blood flow was recorded by venous occlusion plethysmography from two fingers, one cooled and one uncooled, on each hand. Cooling augmented alpha 2-adrenergic vasoconstriction produced by clonidine; this effect was reduced by yohimbine, an alpha 2-adrenergic antagonist. In contrast, cooling abolished alpha 1-adrenergic vasoconstriction produced by phenylephrine, which was not affected by yohimbine. Further studies were conducted in which fingers were warmed rather than cooled. Warming augmented alpha 1- but reduced alpha 2-adrenergic vasoconstriction. Thus, in human fingers, cooling augments alpha 2- and suppresses alpha 1-adrenergic vasoconstriction, whereas warming produces the opposite effects.
PEG-SOD improves postischemic functional recovery and antioxidant status in blood-perfused rabbit hearts
Authors: Qiu Y. , Galinanes M. , Ferrari R. , Cargnoni A. , Ezrin A. , Hearse D. J.
Published: December 2017

The isolated blood-perfused rabbit heart, subjected to 60 min of cardioplegic arrest and 60 min of reperfusion, was used to assess the effects of polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) on postischemic recovery of left ventricular developed pressure (LVDP), the tissue activity of SOD, and tissue redox state. The five groups studied were the following: PEG-SOD-free control (group A), PEG-SOD as a pretreatment and as an additive during cardioplegia and reperfusion (group B), PEG-SOD as a pretreatment and a cardioplegic additive (group C), PEG-SOD in cardioplegia alone (group D), and PEG-SOD in reperfusion alone (group E). The results show that pretreatment with PEG-SOD improves postischemic recovery of LVDP (72 +/- 2% and 66 +/- 7 vs. 47 +/- 4% in groups B, C, and A, respectively). This protection was associated with an improved tissue redox state. Thus the ischemia-induced rise in oxidized glutathione was reduced from 313 +/- 26% (group A) to 162 +/- 15 and 138 +/- 14% (groups B and C, respectively), and the fall in reduced glutathione was attenuated from 51 +/- 5% to 35 +/- 6 and 13 +/- 5%, respectively. Tissue Mn-SOD activity was also conserved from 36 +/- 4% (group A) to 71 +/- 6 and 94 +/- 4% (groups B and C, respectively). No significant effect was seen when PEG-SOD was applied in cardioplegia or during reperfusion alone.
Tonic sympathetic excitation and vasomotor control from pontine reticular neurons
Authors: Hayes K. , Weaver L. C.
Published: December 2017

The pontine reticular formation (PRF) was explored for regions providing tonic control of arterial pressure, heart rate, and activity of sympathetic nerves. In Saffan (alfaxalone-alfadolone)-anesthetized rats, discharge of neurons in the PRF or rostral ventrolateral medulla (RVLM) was inhibited by microinjections of glycine (1 M; 65 +/- 2 nl). PRF blockade caused large, short-lasting (116 +/- 17 s) decreases in arterial pressure and equal decreases in renal (-47 +/- 4%) and splenic (-45 +/- 4%) nerve activity, indicating that PRF neurons contribute to resting control of vasomotor discharge. In contrast, RVLM blockade caused long-lasting (41 +/- 3 min) decreases in arterial pressure and unequal decreases in activity of renal (-50 +/- 4%) and splenic (-31 +/- 6%) nerves. The short duration of the responses to PRF blockade could not be attributed to compensation by baroreceptors or by actions specific to glycine. Excitation of PRF neurons with amino acids caused increases as well as decreases in arterial pressure and sympathetic activity, and therefore activated neurons distinct from those that are tonically active. These results identify a source of cardiovascular control in the reticular formation of the pons that provides tonic excitatory drive to sympathetic nerves and that differs from the well-known source in the RVLM.
Chronic administration of cardiovascular drugs: altered energetics and transmembrane signaling
Authors: Chapados R. A. , Gruver E. J. , Ingwall J. S. , Marsh J. D. , Gwathmey J. K.
Published: December 2017

The effects of clinically used cardioactive agents in furazolidone-induced cardiomyopathy in the turkey poult have been recently reported, and note-worthy differences in cardioprotective efficacy of adrenergic effectors, calcium channel blockers, and cardiac glycosides have been noted in animal and human studies of heart failure. We therefore investigated the effects of chronic oral administration of cardioactive agents on ventricular tissue from normal turkey poults, and we determined whether these agents altered cardiac function, energetics, or transmembrane signaling pathways in a manner that might contribute to the varying degrees of cardioprotection and therapeutic efficacy reported previously. Creatine content was significantly higher in propranolol- and atenolol-treated animals. There was also higher lactate dehydrogenase and creatine kinase activities, reflecting an overall increase in energy reserve. Treatment with the calcium channel antagonists verapamil and nifedipine produced a significant increase in adenylyl cyclase activity and beta-adrenergic receptor density. Nifedipine treatment resulted in upregulation of both beta-adrenergic receptors and dihydropyridine receptors. This finding was associated with enhanced peak twitch force at all extracellular Ca2+ concentrations. We demonstrate for the first time that clinically used pharmacological agents (nifedipine and propranolol) result in alteration in two transmembrane signaling pathways, with associated alterations in physiological performance. Moreover, agents without cardioprotective effect in furazolidone-induced cardiomyopathy did not induce alterations in transmembrane signaling or energetics in normal hearts.
Absence of right ventricular isovolumic relaxation in open-chest anesthetized dogs
Authors: Myhre E. S. , Slinker B. K. , LeWinter M. M.
Published: December 2017

During the left ventricular (LV) pump cycle, peak negative first derivative of pressure vs. time (dP/dt) occurs very close to the end of LV ejection, and there is a well-defined isovolumic relaxation period. Despite similarities between the right ventricular (RV) and LV pump cycles, recent studies indicate uncertainty as to whether peak negative RV dP/dt occurs simultaneously with RV end ejection and whether there is an isovolumic relaxation period during the RV pump cycle. To study these questions, we recorded relative timing of peak negative RV dP/dt, RV end ejection, and right atrial-RV pressure crossover in the open-chest anesthetized dog. The data demonstrate that peak negative RV dP/dt occurs an average of 60 ms before end ejection and that there is no RV isovolumic relaxation period. These findings have implications for the possible use of peak negative RV dP/dt as a marker of RV end ejection and for how time constants of pressure decay obtained during RV relaxation can be interpreted.
L-arginine decreases infarct size caused by middle cerebral arterial occlusion in SHR
Authors: Morikawa E. , Huang Z. , Moskowitz M. A.
Published: December 2017

L-Arginine, but not D-arginine, serves as a precursor for the synthesis of nitric oxide (NO), a potent dilator of cerebral blood vessels. We examined the effects of administering L-arginine (300 mg/kg ip) on the volume of infarction in two models of focal cerebral ischemia in spontaneously hypertensive rats (SHR). L-Arginine was administered before (16 and 3 h) and after (5 min and 2 h) vessel occlusion, and animals were killed 24 h later. L-Arginine treatment decreased infarct size in rats subjected to distal middle cerebral arterial (MCA) plus ipsilateral common carotid arterial (CCA) occlusion by 31% [147 +/- 12 (saline) vs. 101 +/- 9 mm3 (L-arginine), P < 0.05]. D-Arginine, administered according to the same dosage and protocol, was without effect. In the group subjected to proximal MCA occlusion, L-arginine decreased infarction size in the striatum by 28% [47 +/- 5 (saline) vs. 34 +/- 3 mm3 (L-arginine), P < 0.05] and neocortex by 11% [193 +/- 7 (saline) vs. 171 +/- 8 mm3 (L-arginine), P < 0.05]. Changes in blood pressure or other measured physiological parameters did not account for the observed differences. The possible use of L-arginine for the treatment of focal cerebral ischemia merits further investigation.
Phalloidin prevents leukocyte emigration induced by proinflammatory stimuli in rat mesentery
Authors: Asako H. , Wolf R. E. , Granger D. N. , Korthuis R. J.
Published: December 2017

The objective of this study was to determine whether phalloidin, a potent microfilament stabilizer, can modify inflammatory mediator-induced leukocyte adhesion and extravasation in postcapillary venules of the rat mesentery. To address this issue, the rat mesentery was prepared for in vivo microscopic observation. Venules with initial diameters ranging between 25 and 35 microns were selected for study. Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and the number of adherent (stationary for 30 s) and emigrated leukocytes were initially determined during superfusion of the mesentery with phosphate-buffered saline. After these variables were recorded during the control period, either 100 nM platelet-activating factor (PAF), 20 nM leukotriene B4 (LTB4), or 1 microM N-formyl-methionyl-leucyl-phenylalanine (FMLP) was added to the superfusate. Repeat measurements were obtained between 50 and 60 min after initial exposure to the inflammatory mediator. In some experiments, rats were given phalloidin (25 or 500 micrograms/kg iv) 30 min before superfusion with the inflammatory mediators. Superfusion of the mesentery with either PAF, LTB4, or FMLP enhanced leukocyte adherence and emigration and reduced leukocyte rolling velocity. Pretreatment with the low dose of phalloidin effectively prevented leukocyte emigration but had no effect on the increased leukocyte adherence elicited by the three inflammatory mediators. However, when administered at the higher dose, phalloidin prevented both leukocyte adherence and emigration. Neither dose of phalloidin altered the upregulation of neutrophil membrane CD11/CD18 glycoprotein adherence complex induced by PAF or LTB4. These results are consistent with the concept that PAF, LTB4, and FMLP increase leukocyte extravasation by a process that may involve alterations in the endothelial cell cytoskeleton.
Heart size and maximal cardiac output are limited by the pericardium
Authors: Hammond H. K. , White F. C. , Bhargava V. , Shabetai R.
Published: December 2017

We tested the hypothesis that the pericardium, by restricting heart size, limits maximal cardiac output and oxygen consumption. We studied 15 pigs. Five underwent maximal treadmill running before and 14–21 days after thoracotomy and pericardiectomy; these pigs also received sequential volume infusions to determine end-diastolic pressure-dimension relationships. Five underwent maximal treadmill running before and 14–21 days after thoracotomy (pericardium undisturbed) to determine the effect of thoracotomy on exercise performance. Finally, five underwent thoracotomy, instrumentation, loose closure of the pericardium, and sequential volume infusions to determine the effect of thoracotomy without pericardiectomy on end-diastolic pressure-dimension relationships. Pericardiectomy caused similar increases in maximal cardiac output (29% increase; P = 0.007) and maximal oxygen consumption (31% increase; P = 0.02). These results were associated with increased left ventricular end-diastolic dimension (10% increase; P = 0.01) and an estimated 33% increase in end-diastolic volume. In addition, left ventricular mass was increased by pericardiectomy (18% increase; P < 0.04). Thus the pericardium, by limiting utilization of the Starling mechanism, limits maximal cardiac output, and the limit to cardiorespiratory performance lies not in oxygen utilization, but in oxygen delivery. Furthermore, removal of pericardium is associated with myocardial hypertrophy.