bluuebunny/crossref_metadata_2025 huggingface dataset:
Cortical cerebral blood flow cycling: anesthesia and arterial blood pressure
Authors: Jones S. C. , Williams J. L. , Shea M. , Easley K. A. , Wei D.
Published: December 2017

Cycling of various cerebral metabolic substances, arterial vascular diameter, and flow has been noted by many workers at a frequency near 0.1 Hz. Suspicion that this phenomenon is dependent on the type of anesthesia led us to investigate the occurrence of cerebral blood flow (CBF) cycling with different anesthetics. Fifteen Sprague-Dawley rats were anesthetized with either pentobarbital (n = 5, 40–50 mg/kg), alpha-chloralose (n = 5, 60 mg/kg), or halothane (n = 5, 1–0.5%). Body temperature was maintained at 37 degrees C. Femoral arterial and venous catheters were placed, and a tracheotomy was performed, permitting artificial ventilation with 30% O2–70% N2. A closed cranial window was formed over a 3-mm diameter craniotomy. Mean arterial pressure (MABP), arterial partial pressures of CO2 and O2 (PaCO2 and PaO2), and pH were controlled and stabilized at normal values. CBF was determined using laser Doppler flowmetry. To induce cycling, MABP was transiently and repeatedly lowered by exsanguination. Fast Fourier analysis of selected 64-s flow recordings (n = 38) was performed. CBF cycling was observed, independent of the type of anesthesia, in all animals. In 36 epochs, cycling was induced when MABP was reduced to a mean pressure of 65 +/- 1.5 mmHg. The mean frequency and amplitude were 0.094 +/- 0.003 Hz and 6.6 +/- 0.5%, respectively. Cycling occurred without blood withdrawal in two epochs. With the use of the blood-withdrawal epochs (n = 36), all three anesthetics shared a common linear slope between amplitude and blood pressure (P < 0.02) and blood pressure change (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Evidence for CGRP accumulation and activity in experimental neuromas
Authors: Zochodne D. W. , Allison J. A. , Ho W. , Ho L. T. , Hargreaves K. , Sharkey K. A.
Published: December 2017

Calcitonin gene-related peptide (CGRP) is a potent vasodilator and widely distributed neuropeptide that may participate in the injury response of peripheral nerve. We examined evidence for the presence of CGRP immunoreactivity (IR) and its activity in experimental neuromas of Sprague-Dawley rats created by sectioning the midsciatic nerve with resection of 2–3 cm of its distal portion and branches. CGRP activity was evaluated by measuring local blood flow in neuromas using hydrogen polarography and laser-Doppler flowmetry. At all time points studied after nerve section (24 h, 48 h, 7 days, 14 days) there was a rise in local blood flow in the neuroma stumps. At 48 h the hyperemia was maximum but was reversed by topical application of human CGRP(8––37), a specific CGRP-receptor antagonist. CGRP presence was evaluated by immunohistochemistry and radioimmunoassay (RIA). At 24 and 48 h, CGRP IR was intense and distributed in a globular and diffuse pattern apparently not confined to discrete axonlike profiles. At 7 and 14 days, CGRP IR remained prominent and was associated with disorganized axonlike profiles, sometimes directed in a circumferential pattern around the outside of the neuroma. RIA confirmed rises in CGRP content at 24 and 48 h that accompanied the changes in local blood flow and altered distribution of CGRP IR. CGRP accumulates in a time-related fashion within experimental neuromas, where it induces among other possible actions prominent local vasodilatation. CGRP may be important in the regenerative milieu of injured nerves.
Comparison of small artery sensitivity and morphology in pressurized and wire-mounted preparations
Authors: Falloon B. J. , Stephens N. , Tulip J. R. , Heagerty A. M.
Published: December 2017

Two in vitro techniques, the pressurized flow chamber and the wire myograph, commonly employed to study the structure and function of small arteries, were compared. Mesenteric arteries from Wistar-Kyoto (WKY) rats were studied at a transmural pressure (44 +/- 1 mmHg) at which they elicit optimum contraction in each system. Differences in morphological parameters were minor, but there was a marked difference in the vasoconstrictor response of arteries mounted in the wire myograph and pressure system. Endothelium-intact pressurized arteries were significantly more sensitive to norepinephrine and constricted to angiotensin II, whereas wire-mounted vessels did not. These differences in agonist-induced contraction remained after removal of the endothelium. Blockade of amine uptake mechanisms indicated that the difference in norepinephrine sensitivity between the systems resulted from an enhanced influence of neuronal amine uptake in wire-mounted arteries. These data demonstrate that the technique employed has important functional implications for the study of small artery responses in vitro and that the results of investigations into the pathophysiology of small arteries are dependent on the method used and must be interpreted with caution.
Phosphatidylethanolamine and sarcolemmal damage during ischemia or metabolic inhibition of heart myocytes
Authors: Post J. A. , Bijvelt J. J. , Verkleij A. J.
Published: December 2017

Phosphatidylethanolamine (PE) is a nonbilayer-preferring and fusogenic phospholipid. It is kept in the bilayer configuration by interaction with other phospholipids in biologic membranes. However, reorganization of the membrane phospholipids could lead to expression of the nonbilayer nature of PE and induce bilayer instability. During ischemia a transbilayer reorganization of sarcolemmal PE is observed, and results have been published that suggest a lateral phase separation in the inner sarcolemmal leaflet phospholipids. These reorganizations and the subsequent expression of the nonbilayer behavior of PE are proposed to form the basis for sarcolemma destabilization and destruction. Lowering the PE content of myocytes, especially of the sarcolemma, is then expected to attenuate myocyte damage after simulated ischemia or metabolic inhibition. Culturing neonatal rat heart myocytes in the presence of N,N-dimethylethanolamine resulted in the synthesis of the bilayer-preferring N,N-dimethyl-PE and a lowering of the ratio between nonbilayer- and bilayer-preferring phospholipids from 0.58 to 0.30. This change in phospholipid composition did not impair cell functioning but did result in a strong attenuation of cell damage on ischemia or metabolic inhibition. A good correlation between the nonbilayer-preferring phospholipid content and the degree of cell damage was obtained (r = 0.98). These results provide further evidence that physicochemical properties of the sarcolemmal phospholipids play a crucial role in the sarcolemmal disruption during prolonged ischemia and/or reperfusion.
Systemic and subcutaneous microvascular oxygen tension in conscious Syrian golden hamsters
Authors: Kerger H. , Torres Filho I. P. , Rivas M. , Winslow R. M. , Intaglietta M.
Published: December 2017

Arteriolar and venular oxygen tension distribution was studied in the subcutaneous connective tissue of the chamber window preparation in conscious Syrian golden hamsters as a function of the systemic PO2, PCO2, pH, arterial pressure and hematocrit, microvascular red blood cell (RBC) velocity, vessel diameter, and blood flow in the same microvessels. PO2 was measured with the phosphorescence decay technique using Pd-meso-tetra(4-carboxyphenyl)porphyrin (30 mg/kg body wt iv). Systemic arterial and venous PO2s were 71.6 +/- 13.1 and 28.4 +/- 5.1 mmHg, while oxygen tension was 45.1 +/- 13.3 mmHg in arterioles and 30.1 +/- 10.7 mmHg in venules. The relatively low arteriolar PO2 and the small arteriolar-venular PO2 gradient indicate that some blood oxygen exits directly to the tissue or is shunted before reaching the capillaries. RBC velocity was the strongest correlate of microvascular PO2 (arterial correlation coefficient = 0.503 and venous correlation coefficient = 0.560, P < 0.001). Microvascular PO2 was also correlated with blood flow, vessel diameter, blood pH, and PCO2 but not with systemic PO2. Arterial oxygen tension was only significantly related to PCO2, pH, and hematocrit. These findings suggest that oxygen delivery to the tissue improves with increasing blood flow velocity and that microvascular PO2 is a locally regulated parameter in the absence of major systemic perturbations.
Dichloroacetate stimulates carbohydrate metabolism but does not improve systolic function in ischemic pig heart
Authors: Mazer C. D. , Cason B. A. , Stanley W. C. , Shnier C. B. , Wisneski J. A. , Hickey R. F.
Published: December 2017

Increased carbohydrate utilization may protect the heart during ischemia and reperfusion. Dichloroacetate (DCA) stimulates pyruvate dehydrogenase, which is the rate-limiting step in oxidation of lactate and pyruvate. The purpose of this study was to determine if the myocardial metabolic changes induced by intracoronary DCA during myocardial ischemia were accompanied by improvement in systolic function. A perfusion circuit was created from the carotid to left anterior descending coronary artery (LAD) in 11 anesthetized Yorkshire swine. Data were obtained under strict hemodynamic control at baseline, after 15 min of moderate (30%) LAD flow reduction, and after an additional 15 min of ischemia with either intracoronary DCA (3 mM, n = 6) or saline (n = 5) infusion. DCA decreased lactate release and increased lactate uptake during ischemia as measured by glucose and lactate carbon-labeled tracers. Despite these metabolic changes, no improvement in systolic shortening, microsphere blood flow, or oxygen consumption occurred. Thus, although DCA stimulated carbohydrate metabolism during myocardial ischemia, it did not directly improve systolic function.
Ca(2+)-free, high-Ca2+ coronary perfusion suppresses contractility and excitation-contraction coupling energy
Authors: Araki J. , Takaki M. , Namba T. , Mori M. , Suga H.
Published: December 2017

We studied the mechanoenergetic effects of a short-term Ca(2+)-free, high-Ca2+ Tyrode solution coronary perfusion in eight excised, cross-circulated canine hearts. The perfusion protocol consisted of coronary perfusion with Ca(2+)-free Tyrode solution for 10 min followed by high-Ca2+ (16 mM) Tyrode solution for 5 min. This new protocol successfully induced acute contractile failure in seven hearts, without myocardial ultrastructural changes. We studied the end-systolic pressure-volume relation (slope = Emax, a contractility index) and the relation between oxygen consumption per beat (VO2) and systolic pressure-volume area (PVA) in these failing hearts. These hearts had no increase in end-diastolic pressure at a given volume, a 40% decrease in Emax and a proportional decrease in the PVA-independent VO2 for 1–4 h, but no decrease in the oxygen cost of PVA, defined as the slope of the VO2-PVA relation. The oxygen cost of Emax for Ca2+ handling, defined as the slope of the relation between PVA-independent VO2 and Emax, was unchanged in the failing hearts. We conclude that the present protocol induced left ventricular contractile failure, primarily involving the suppression of Ca2+ handling energy for excitation-contraction coupling.
Training increases collateral-dependent muscle blood flow in aged rats
Authors: Yang H. T. , Ogilvie R. W. , Terjung R. L.
Published: December 2017

The potential for physical training to enhance collateral-dependent blood flow (BF) to the hindlimbs of aged male rats (Fischer 344) was evaluated following bilateral femoral artery ligation at 20.5 mo of age. Rats were either limited to cage activity (sedentary, n = 11) or trained by a mild-intensity treadmill program (trained, n = 14), which involved walking twice a day at 15 m/min (15% grade) to fatigue, 5 days/wk for 8–11 wk. Exercise tolerance of the trained rats increased from approximately 5 to approximately 25 min/bout by week 7, whereas exercise tolerance of the sedentary group changed little (to approximately 8 min/bout) during the training period. At approximately 23 mo age, animals were surgically prepared for hindquarter perfusion (aortic pressure = 100 +/- 1.3 mmHg) and force measurement of the left gastrocnemius-plantaris-soleus (GPS) muscle group during isometric contractions at 4, 8, 15, 30, and 45 tetani/min via sciatic nerve stimulation (approximately 6 V, 0.1-ms square waves at 100 Hz for 100 ms). Although initial force development was similar between groups (12.9 N/g), trained rats maintained tension better at 8, 15, 30, and 45 tetani/min (P < 0.01). BF to the entire hindlimb of the trained group, determined with 85Sr 15-microns microspheres, was 43% greater (P < 0.05) than in the sedentary group. Thus collateral-dependent BF was improved by physical training. The greatest increase in BF was to the distal limb muscles (approximately 78%), the tissues most at risk during intermittent claudication.(ABSTRACT TRUNCATED AT 250 WORDS)
Skewness of instantaneous mitral transannular flow-velocity profiles in normal humans
Authors: Kupari M. , Jarvinen V. , Poutanen V. P. , Hekali P.
Published: December 2017

The spatial distribution of instantaneous diastolic flow velocities across the mitral annulus was studied with cardiac gated cine magnetic resonance imaging in 10 healthy persons aged 26–46 yr. Velocity encoding used two interleaved gradient echo pulse sequences with velocity sensitivity in the direction of flow perpendicular to the annular imaging plane. Velocity maps were reconstructed at 30- to 43-ms intervals throughout diastole. Velocity-time curves and mean flow rates were determined in five regions of the mitral annulus using a 0.6-cm2 measurement area. The spatial velocity minimum was consistently in the anterolateral commissural area, whereas the maximum was in the anterior annulus in early diastole shifting posteromedially in late diastole. The mean flow rate (+/- SD) averaged 18.4 +/- 8.1 ml.s-1.cm-2 of annular area centrally, 18.3 +/- 7.2 ml.s-1.cm-2 anteriorly, 16.9 +/- 7.4 ml.s-1.cm-2 posteriorly, 13.0 +/- 7.7 ml.s-1.cm-2 in the anterolateral commissural area, and 23.0 +/- 7.3 ml.s-1.cm-2 in the posteromedial commissural area (P < 0.001). We conclude that mitral transannular flow shows marked spatial inhomogeneity in normal humans. The skewness of flow profiles compromises the use of local velocity measurements as indexes of left ventricular filling.
Reduction of the transient outward potassium current in a canine model of Chagas' disease
Authors: Pacioretty L. M. , Barr S. C. , Han W. P. , Gilmour R. F.
Published: December 2017

The effects of Chagas' disease, an important cause of cardiac arrhythmias and cardiomyopathy, on cellular electrical properties were determined in epicardial tissue from normal dogs and dogs infected with Trypanosoma cruzi for 20–25 days (25 DPI), at the time of maximum parasitemia, and for 125–140 days (140 DPI) after the parasitemia had subsided. At 25 DPI, phase 1 repolarization of the action potential was attenuated and the transient outward current (Ito) was reduced from 10.2 +/- 0.5 to 5.5 +/- 0.6 pA/pF. No differences were apparent between infected and normal cells in the time constants of current decay (25.6 +/- 4.0 and 22.8 +/- 1.3 ms, respectively) or in the steady-state inactivation parameters (V1/2 = -34.1 +/- 3.6 and -34.6 +/- 1.4 mV and k = 6.3 +/- 1.8 and 4.0 +/- 0.3, respectively). The rapid phase of recovery from inactivation was nearly eliminated in infected myocytes, whereas the slower phase was unaffected. Phase 1 repolarization and Ito density at 140 DPI were not significantly different from normal cells. Thus T. cruzi acutely inhibited Ito in epicardial myocytes, an effect that was reversed with abatement of the parasitemia.
Remote effects of pressure changes in arterioles
Authors: Rivers R. J.
Published: December 2017

Blood is distributed to match the demands of the tissue in accordance with the local effectors of pressure, flow, nerves, and metabolites. Influences of these effectors are integrated and communicated to larger vessels to create a coordinated upstream response that allows for the blood required to meet the metabolic demands of the tissue. Each effector's contribution to the communicated response is unknown. In the present study in situ segments of arteriole, within the cheek pouch of the anesthetized hamster, were isolated from the pressure and flow of the surrounding vasculature while maintaining electrotonic continuity. Pressure was transiently increased or decreased (-70 to +120 cmH2O) for 60 s. These pressure changes within the isolated segment caused myogenic responses within the isolated segment as well as changes in diameter at remote arteriolar locations (ranging from -8 to 5 microns) that were outside the isolated segment and insulated from the changes in pressure. The size of the remote response correlated significantly with the change in pressure inside the isolated segment. This demonstrates that the effects of pressure changes in arterioles are communicated to neighboring portions of the vasculature.
Effects of pericardial pressure on systemic and coronary hemodynamics in dogs
Authors: Abel F. L. , Mihailescu L. S. , Lader A. S. , Starr R. G.
Published: December 2017

The effects of pericardial tamponade on coronary capacitance and coronary systemic hemodynamics were calculated in two groups of animals subjected to increases in pericardial pressure (PCP) up to approximately 20 mmHg. In one group (A), flow in the left circumflex artery was measured in the intact animal under conditions of increased PCP. In the second group (B), coronary artery perfusion pressure was maintained constant with a pump while PCP was increased. In group A increased PCP was accompanied by a decrease in arterial pressure. This resulted in a marked decrease in coronary blood flow after vasodilation but without a change in coronary vascular resistance. In group B there was no change in coronary flow or coronary vascular resistance with increased PCP. Microsphere distribution to the left ventricular wall showed less endocardial than epicardial flow but no change in going from low to high PCP. Characteristic impedance was altered in the group B animals after vasodilation at medium and high PCP, indicating a loss of reflection sites and probably increased vessel tethering. The coronary artery in a subgroup of group B animals was also perfused by left ventricular pressure, the time constants for coronary backflow showing an 8–12% decrease in capacitance with low and high PCP; these values represent minimal epicardial capacitances vs. total bed capacitance. A diastolic model for the values for resistance and capacitance in the coronary bed is suggested. As expected, most of the capacitance is in the venous bed and most of the resistance is in the arterial bed.
Activation of thrombin receptor increases intracellular Na+ during myocardial ischemia
Authors: Yan G. X. , Park T. H. , Corr P. B.
Published: December 2017

Recent evidence indicates that factors involved in the activation of the coagulation system eliciting an intracoronary thrombus may contribute importantly to arrhythmogenesis during acute myocardial ischemia. In the present study, the influence of the thrombin receptor activating peptide, SFLLRNPNDKYEPF (SFLL), on intracellular Na+ ([Na+]i) and tissue lysophosphatidylcholine (LPC) content during ischemia was investigated in an isolated, blood-perfused rabbit papillary muscle preparation. During normoxic perfusion, [Na+]i, determined by an intracellular Na(+)-selective electrode, was 11.6 +/- 0.2 mM (n = 14) in the presence of a physiological concentration of LPC (125 microM) bound to albumin (control group). The addition of SFLL (100 microM, n = 12) to the LPC-containing perfusate had no significant additional effects on [Na+]i, twitch tension, action potential duration, or tissue LPC content. During zero flow ischemia, [Na+]i in the control group rose to 15.5 +/- 1.4 mM (P < 0.05) at 6 min, whereas [Na+]i in the group treated with SFLL increased rapidly from the preischemic value of 11.7 +/- 0.3 to 23.5 +/- 1.9 mM (P < 0.01 compared with that in the control group) over the same time period. This rapid rise in [Na+]i was associated with a greater accumulation of tissue LPC, an arrhythmogenic lipid metabolite, and the development of early ventricular arrhythmias. These results indicate that an increase in [Na+]i induced by activation of the thrombin receptor, likely mediated through its effect on the accumulation of LPC within ischemic myocardium, may be responsible for arrhythmogenesis during myocardial ischemia secondary to activation of the coagulation system.
Vascular compliance and mean circulatory filling pressure in trout: effects of ACE inhibition
Authors: Zhang Y. , Jenkinson E. , Olson K. R.
Published: December 2017

Mean circulatory filling pressure (MCFP), whole body vascular compliance (C), and unstressed blood volume (USV) are important indexes of cardiovascular function in mammals, but they have not been measured in fish. In the present experiments, dorsal aortic (PDA) and sinus venosus (PSV) pressures were measured in unanesthetized trout before and during electrical cardiac fibrillation, while blood volume (BV) was manipulated between 50 and 150% of normal. Measurements were repeated after angiotensin-converting enzyme (ACE) inhibition with lisinopril. Cardiac fibrillation (zero-flow condition) rapidly (approximately 5 s) dropped PDA and increased PSV (equals MCFP). MCFP in normovolemic trout (4.8 +/- 0.3 mmHg) varied directly with BV. C determined from in vivo capacitance curves was similar to that obtained gravimetrically, in vitro (3.4 and 3.5 ml.mmHg-1.kg body wt-1, respectively). USV was 13.3 ml/kg body wt (approximately 45% of BV). ACE inhibition reduced PDA in unfibrillated trout at all BV and reduced PDA in fibrillated fish at BV > or = 80%. ACE inhibition did not affect PSV, MCFP, C, or USV. The systemic arteriovenous pressure gradient at zero flow (delta PF0) was greatest at 100% BV (8.2 +/- 0.5 mmHg) and was reduced by ACE inhibition at 80-120% BV. These results show that key indexes of venous function are readily measured in fish and that the trout venous system is not an effector of angiotensin-mediated regulation of arterial blood pressure. Thus angiotensin acts solely on arterial resistance vessels. Furthermore, the drop in delta PF0 during ACE inhibition is due to a decrease in arteriolar resistance.
Altered subcellular Ca2+ regulation in papillary muscles from cardiomyopathic hamster hearts
Authors: Keller E. , Moravec C. S. , Bond M.
Published: December 2017

To investigate whether cardiac dysfunction in prefailure cardiomyopathic (CM) hamster hearts is due to Ca2+ overload or alternatively to decreased availability of Ca2+ in the sarcoplasmic reticulum (SR), the Ca2+ channel agonist, BAY K 8644, was used to compare the effects of increased Ca2+ influx on function and subcellular Ca2+ distribution in papillary muscles from hearts of 110-day-old CM and normal hamsters. A band, mitochondrial, and junctional SR Ca2+ were measured by electron probe microanalysis in CM and normal papillary muscles, which were either untreated or pretreated with BAY K 8644. Muscles were then rapidly frozen during contraction or relaxation. The results showed decreased tension development and decreased inotropic response to BAY K 8644 in CM muscles versus normals. There was no elevation of mitochondrial or A-band Ca2+ in BAY K 8644-treated or untreated CM muscles frozen during contraction or relaxation compared with similarly treated normals. In muscles frozen during relaxation, junctional SR Ca2+ was lower in both untreated and BAY K 8644-treated CM muscles versus comparably treated normals. These results do not support the hypothesis of an increased sensitivity to Ca2+ in hypertrophied, prefailure CM hearts but do indicate that less Ca2+ is available in the SR for activation of contraction.
Effects of nitric oxide synthase inhibitor on hemodynamic change and O2 delivery in septic dogs
Authors: Mitaka C. , Hirata Y. , Ichikawa K. , Uchida T. , Yokoyama K. , Nagura T. , Tsunoda Y. , Amaha K.
Published: December 2017

To elucidate the role of nitric oxide (NO) in septic shock, we measured hemodynamic and pulmonary gas changes in anesthetized dogs after intravenous administration of bacterial lipopolysaccharide (LPS) with or without NO synthase inhibitor, NG-nitro-L-arginine (L-NNA). Infusion of LPS (250 ng.kg-1.min-1) for 2 h decreased mean arterial pressure over 1-4 h. Although L-NNA (10 mg/kg) blocked LPS-induced hypotension, it decreased cardiac index, oxygen delivery index, arterial pH, and arterial PO2 and increased systemic vascular resistance index in the presence or absence of LPS. Administration of NG-nitro-D-arginine (D-NNA, 10 mg/kg) alone caused fewer hemodynamic effects (increased systemic vascular resistance index and decreased cardiac index) than L-NNA alone. Our study provides evidence that L-NNA prevents endotoxin-induced hypotension but decreases cardiac output and oxygen delivery, effects that may, in part, be due to a nonspecific NO synthase-independent event. Thus clinical use of NO synthase inhibitors for the treatment of septic shock should be cautiously considered.
Electrophysiological effects of alpha 2-adrenergic stimulation in canine cardiac Purkinje fibers
Authors: Samson R. A. , Cai J. J. , Shibata E. F. , Martins J. B. , Lee H. C.
Published: December 2017

The effects of alpha 2-adrenergic stimulation on action potentials were measured in isolated canine Purkinje fibers. Action potential durations at 50 and 90% of repolarization (APD50 and APD90) were significantly prolonged by 0.25 microM l-norepinephrine + 0.5 microM dl-propranolol (NE+P) from baseline values of 166 +/- 7 and 249 +/- 9 (SE) ms (n = 7) to 174 +/- 7 and 265 +/- 9 ms, respectively (P < 0.05 for both). Selective alpha 2-blockade with 0.01 microM yohimbine (YO) reduced this prolongation by NE+P in APD50 and APD90 to 169 +/- 7 and 256 +/- 8 ms, respectively (P < 0.05 compared with NE+P). Additional selective alpha 1-blockade with 0.01 microM prazosin (PZ) completely blocked the effects of NE+P, returning APD50 and APD90 to 163 +/- 7 and 250 +/- 9 ms (not different from baseline). After incubation of isolated Purkinje fibers with pertussis toxin (1 microgram/ml), which reduced the availability of a 41-kDa membrane protein for ADP ribosylation by 70 +/- 7% (n = 4, P < 0.05), YO failed to reverse the prolongation in action potential durations brought on by NE+P, but the effects of PZ were intact. The effects of alpha 2-stimulation on beta-adrenergic-induced delayed afterdepolarizations (DADs) were studied by burst pacing of Purkinje fibers in Tyrode solution containing 7.5 mM Ca2+. The DADs induced in the presence of NE+PZ (beta- + alpha 2-stimulation) were significantly smaller in amplitude and required a shorter pacing cycle length to reach threshold than those induced in the presence of NE+PZ+YO (unopposed beta-adrenergic stimulation). Furthermore sustained triggered activity, seen in five of eight preparations under beta-stimulation, could no longer be elicited in the presence of beta- + alpha 2-stimulation. These results suggest that the postjunctional alpha 2-adrenergic receptors in canine Purkinje fibers are coupled to a pertussis toxin-sensitive G protein and that stimulation of these receptors leads to action potential prolongation and suppression of DADs induced by beta-adrenergic stimulation.
Modeling pressure-area relations of coronary blood vessels embedded in cardiac muscle in diastole and systole
Authors: Vis M. A. , Sipkema P. , Westerhof N.
Published: December 2017

Pressure-cross-sectional area (P-A) relations of a (thick-walled) arteriole and (thin-walled) small vein (both maximally dilated), embedded in cardiac muscle in both static systole and diastole at slack length and at 90% of maximal length (Lmax), were calculated. The elastic properties of cardiac muscle and vessel wall per se were taken into account. Muscle fibers and vessels were assumed to run in parallel. The muscle tissue (fibers + collagen) was assumed to be incompressible, homogeneous, nonlinearly elastic, and transversely isotropic. Cross-fiber stress-strain relations were assumed to be proportional to those in fiber direction. It is predicted that cardiac muscle in diastole has little effect on the P-A relation of the arteriole but strongly affects that of the small vein. In systole, the myocardium strongly affects the P-A relations of both vessels. Isometric transition from static diastole to static systole (isometric "contraction") was found to reduce arteriolar and venous area (at constant pressures of 35 and 7 mmHg, respectively) by approximately 50 and 40, respectively. Contraction with a 14% shortening was found to reduce these areas by 48 and 32%, respectively. The differences in the results for the two vessels were found to be determined mainly by their difference in the ratio of outer to inner radius. Furthermore, it was found that the area reductions are much larger for contractions (with or without shortening) than for muscle stretch per se. It is concluded that the change in elastic properties and, more specifically, development of stress in cross-fiber direction of the cardiac muscle during contraction causes the area reductions of coronary vessels.
Hemodynamic basis of oscillations in systemic arterial pressure in conscious rats
Authors: Janssen B. J. , Oosting J. , Slaaf D. W. , Persson P. B. , Struijker-Boudier H. A.
Published: December 2017

In conscious resting rats, beat-to-beat fluctuations in systemic mean arterial pressure (MAP) were compared with those in cardiac output and those in blood flow in the renal, mesenteric, and hindquarter vascular beds. Spontaneous oscillations (lability) in MAP were observed in frequency bands centered about 1.6 Hz (high: HF), 0.4 Hz (mid: MF), and 0.13 Hz (low: LF). Lability of MAP was confined within the LF (approximately 8 s) band. Lability of cardiac output, on the other hand, showed primary HF oscillations. LF oscillations in regional blood flow were most prominent in the mesenteric and renal vascular beds. In these beds, LF oscillations in blood flow showed negative phase angles with MAP, whereas those between MAP and hindquarter blood flow were positive. Cross correlation analysis indicated that approximately 2 s following a LF change in MAP, LF changes in mesenteric and renal blood flow occurred opposite to those of MAP. Changes in hindquarter flow were negatively correlated with those in MAP about zero time delay. Admittance gains were > or = 1 across all frequencies for all vascular beds, indicating the absence of autoregulation. This hemodynamic pattern suggests that myogenic mechanisms predominantly control mesenteric and renal blood flow in a nonautoregulatory but rather superregulatory manner, while autonomic mechanisms regulate hindquarter blood flow. Thus, in conscious resting rats, spontaneous fluctuations in systemic arterial pressure predominantly exhibit slow (approximately 8 s) oscillations, which do not arise from fluctuations in cardiac output, but originate from regionally specific myogenic oscillatory mechanisms contributing to resistance to flow.
Biaxial mechanics of excised canine pulmonary arteries
Authors: Debes J. C. , Fung Y. C.
Published: December 2017

A new method has been developed for measuring the stress-strain relationship in excised canine pulmonary arteries. Segments of dog main right pulmonary arteries were isolated by making two transverse cuts at each end of a segment near the bifurcations, yielding short cylinders, which were then cut radially, relieving the residual stress, causing the cylindrical shells to spring open to approximately flat rectangular slabs with dimensions approximately 1.0 x 3.0 x 0.1 cm. The specimens were then tested using a biaxial tensile testing machine. The resulting data show an approximately linear relationship between Kirchhoff stress and Lagrangian strain with very little hysteresis. The following pseudostrain energy function serves as a practical approximation for pulmonary arteries subjected to physiological levels of stress and strain: rho 0W(2) = 1/2(a1E2xx + a2E2yy + 2 a4ExxEyy), where rho 0 is the density of the wall (mass per unit volume), W is the energy per unit mass [superscript "(2)" indicates this is a 2-dimensional strain energy function], E is strain, a1, a2, and a4 are material constants with units of stress, and the subscripts x and y refer to the circumferential and axial axes, respectively, of the artery. To assess the physiological level of strain in the main right pulmonary artery, vessels were perfused in situ at physiological pressure (26 cmH2O) with silicone elastomer. The arteries were then excised and marked with small ink spots. Photographs of the spots on four tangent planes of the excised artery indicate a maximum circumferential strain of 21.5% and a maximum axial strain of 36.5% relative to the zero-stress state. These values are within the range of strain used in the biaxial tests. The relationship between Kirchhoff stress and Green's strain is approximately linear within the physiological range. The stress levels required to cause tissue failure are at least 10 times greater than the estimated normal physiological level.
A rapidly activating delayed rectifier K+ channel in rabbit sinoatrial node cells
Authors: Ito H. , Ono K.
Published: December 2017

The single-channel current of the delayed rectifier K+ current (IK) was recorded in rabbit sinoatrial node cells. In the cell-attached patch, depolarization from -70 mV to potentials more positive than -50 mV activated the IK channel while repolarization deactivated it. The single-channel conductance was 7.8 pS for the outward current and 10.8 pS for the inward current (n = 6). The steady-state open probability (NPo) was maximum at around -30 mV and markedly decreased at more positive potentials. On repolarization from positive potentials, the channel was initially closed and then rapidly opened. The ensemble average showed an initial rise to a peak followed by the deactivation time course. Because the channel events were completely blocked by E-4031, the drug-sensitive component was examined in the whole cell current. The steady-state current-voltage relation of the drug-sensitive current showed a marked negative slope at potentials more positive than -10 mV. Upon repolarization, the drug-sensitive current initially increased (removal of inactivation) to the peak of the outward tail current, which was in agreement with the ensemble average of the single-channel current. We conclude that IK in the sinoatrial node cells is largely composed of the rapidly activating IK (IK,r) channels and that the inward rectification of IK,r, which is more marked than had been assumed in previous studies, is due to the decrease in NPo.
Alleviation of contractile dysfunction in ischemic hearts by slowly inactivating Na+ current blockers
Authors: Le Grand B. , Vie B. , Talmant J. M. , Coraboeuf E. , John G. W.
Published: December 2017

We hypothesized that the slowly inactivating component of Na+ current, which is an integral part of the Na+ window current, is a major pathway for Na+ loading during myocardial ischemia. The putative protective effects of tetrodotoxin (TTX) and R-56865, at concentrations that selectively blocked the Na+ window current, as assessed by action potential plateau shortening without affecting maximum upstroke velocity (Vmax), were examined in isolated Langendorff-perfused guinea pig hearts subjected to 50 min of normothermic global ischemia and 60 min of reperfusion. In papillary muscles, TTX reduced action potential duration at > or = 10 nM but reduced Vmax only at > or = 1 microM. R-56865 (10 nM-10 microM) failed to affect Vmax but concentration dependently reduced action potential duration. Ischemia-induced cardiac dysfunction, including increases in left ventricular end-diastolic pressure and lactate dehydrogenase and creatine phosphokinase release at reperfusion, was attenuated by TTX and R-56865 (0.1-320 nM). Ischemic contracture (increase in left ventricular end-diastolic pressure) was abolished by drug concentrations as low as 1 nM, whereas higher concentrations (> 10 nM) of TTX and R-56865 were required to restore systolic function at reperfusion. TTX and R-56865 had little or no effect on hemodynamic variables. Evidence is provided of pronounced and direct cardioprotective effects of low concentrations of R-56865 and TTX in cardiac muscle during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Laminar structure of the heart: ventricular myocyte arrangement and connective tissue architecture in the dog
Authors: LeGrice I. J. , Smaill B. H. , Chai L. Z. , Edgar S. G. , Gavin J. B. , Hunter P. J.
Published: December 2017

We have studied the three-dimensional arrangement of ventricular muscle cells and the associated extracellular connective tissue matrix in dog hearts. Four hearts were potassium-arrested, excised, and perfusion-fixed at zero transmural pressure. Full-thickness segments were cut from the right and left ventricular walls at a series of precisely located sites. Morphology was visualized macroscopically and with scanning electron microscopy in 1) transmural planes of section and 2) planes tangential to the epicardial surface. The appearance of all specimens was consistent with an ordered laminar arrangement of myocytes with extensive cleavage planes between muscle layers. These planes ran radially from endocardium toward epicardium in transmural section and coincided with the local muscle fiber orientation in tangential section. Stereological techniques were used to quantify aspects of this organization. There was no consistent variation in the cellular organization of muscle layers (48.4 +/- 20.4 microns thick and 4 +/- 2 myocytes across) transmurally or in different ventricular regions (23 sites in 6 segments), but there was significant transmural variation in the coupling between adjacent layers. The number of branches between layers decreased twofold from subepicardium to midwall, whereas the length distribution of perimysial collagen fibers connecting muscle layers was greatest in the midwall. We conclude that ventricular myocardium is not a uniformly branching continuum but a laminar hierarchy in which it is possible to identify three axes of material symmetry at any point.
Effects of PKC downregulation on norepinephrine- and prostaglandin F2 alpha-induced contraction in rat aorta
Authors: Rapoport R. M. , Campbell A. K. , Bazan E.
Published: December 2017

The purpose of this study was to investigate, through phorbol ester-induced protein kinase C (PKC) downregulation, the role of PKC in the regulation of alpha-adrenergic agonist- and prostaglandin (PG) F2 alpha-induced contraction in vascular smooth muscle. In rat aorta, long-term phorbol ester exposure (10 microM phorbol dibutyrate for 17 h), a procedure that decreased PKC activity by > 95%, and maximal phorbol myristate acetate (PMA)-induced contraction by approximately 75%, decreased tissue sensitivity to norepinephrine (NE) and PGF2 alpha 2.8- and 4.6-fold, respectively, while maximal contraction was not significantly decreased. In contrast, long-term phorbol ester exposure did not alter tissue sensitivity to KCl, while maximal KCl contraction was decreased by 40%. Long-term phorbol ester exposure, as well as short-term phorbol ester exposure (1 microM PMA for 1 h), abolished the initial transient NE contraction elicited in Ca(2+)-free solution. In contrast, long-term phorbol ester exposure did not alter the plateau NE or PGF 2 alpha contraction elicited in Ca(2+)-free solution. Short-term phorbol ester exposure of PKC-downregulated tissues potentiated the plateau PGF2 alpha contraction elicited in Ca(2+)-free solution, although the magnitude of potentiation was less than that observed in non-PKC downregulated tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
Mechanical determinants of myocardial oxygen consumption in conscious dogs
Authors: Elbeery J. R. , Lucke J. C. , Feneley M. P. , Maier G. W. , Owen C. H. , Lilly R. E. , Savitt M. A. , Hickey M. S. , Gall S. A. , Davis J. W.
Published: December 2017

A new practical descriptor of metabolic to mechanical myocardial energy transfer (MET), termed the virtual work model, was evaluated in 32 conscious dogs and in 8 isolated canine hearts. An index of total mechanical energy expenditure (TME) was calculated as the sum of external energy (stroke work) and an internal energy index of heat (left ventricular end-diastolic volume times left ventricular mean ejection pressure). Physiological comparison of TME (x-axis) and myocardial oxygen consumption (MVO2; y-axis) yielded highly linear MET relationships (mean r = 0.93 +/- 0.07), with an average slope of 0.86 +/- 0.39 (SD) and a y-intercept of 9.1 +/- 6.4 mW/ml myocardium. The linear MVO2-TME relationship did not vary under steady-state vs. dynamic vena caval occlusion, increased heart rate, increased afterload, or increased inotropic state with calcium infusion. Compared with five other indexes of myocardial energetics, the virtual work model of MET was the most linear, the most practical in not requiring determination of the end-systolic pressure-volume relationship, and the most accurate predictor of MVO2 under normal and altered hemodynamic conditions.
Reduced parasympathetic control of heart rate in obese dogs
Authors: Van Vliet B. N. , Hall J. E. , Mizelle H. L. , Montani J. P. , Smith M. J.
Published: December 2017

We investigated why resting heart rate is elevated in dogs fed a high saturated fat diet for 12.7 +/- 1.8 wk. Obese dogs exhibited elevated body weight (59%), blood pressure (14%), and heart rate (25%). Differences in resting heart rate (control, 58 +/- 5 beats/min; obese, 83 +/- 7 beats/min) were abolished after hexamethonium, indicating an autonomic mechanism. Hexamethonium also reduced blood pressure in obese (20 +/- 4 mmHg) but not control (9 +/- 6 mmHg) animals. Propranolol did not affect heart rate in either group, excluding a beta-adrenergic mechanism. Subsequent administration of atropine increased heart rate more in control than in obese dogs (110 +/- 9 vs. 57 +/- 11 beats/min). The sensitivity of the cardiac limb of the baroreflex (Oxford method) was reduced by 46% in the obese group, confirming impairment of the parasympathetic control of heart rate. The standard deviation of blood pressure measurements was normal when expressed as a percentage of the mean arterial blood pressure (control, 11.2 +/- 0.4%; obese, 11.2 +/- 0.5%). Our results indicate that the development of obesity in dogs fed a high saturated fat diet is accompanied by an attenuated resting and reflex parasympathetic control of heart rate.
PAF induces relaxation of pulmonary arteries but contraction of pulmonary veins in the ferret
Authors: Gao Y. , Zhou H. , Raj J. U.
Published: December 2017

The present study was designed to determine whether platelet-activating factor (PAF) has different effects on pulmonary arteries and veins. Third-order pulmonary arterial and venous rings of the ferret were suspended in organ chambers filled with modified Krebs-Ringer bicarbonate solution (95% O2-5% CO2, 37 degrees C) and their isometric tension was recorded. Under basal conditions, PAF had no effect on the resting tension of arteries but induced an endothelium-dependent contraction of veins. The contraction was not affected by BW-755C (an inhibitor of cyclooxygenase and lipoxygenase), BQ-123 [an antagonist of endothelin (ET) A (ETA) receptors)], or IRL-1038 (an antagonist of ETB receptors). PAF had no effect on veins during contraction to prostaglandin F2 alpha (PGF 2 alpha) but induced an endothelium-dependent relaxation of arteries. The relaxation was abolished by N omega-nitro-L-arginine. Incubation with PAF for 30 min augmented contractions of veins with endothelium to PGF 2 alpha. The augmentation was not affected by BW-755C, BQ-123, or IRL-1038. Pretreatment with PAF had no effect on the response of veins to phenylephrine or on the response of arteries to either PGF 2 alpha or phenylephrine. These observations demonstrated that, in the ferret, PAF affected differently the response of pulmonary arteries and veins and that the endothelium plays a critical role in the PAF-induced effects. Furthermore, the PAF-induced effects appear not to be mediated by metabolites of arachidonic acid and ET.
Expression of protein kinase C isoforms during cardiac ventricular development
Authors: Clerk A. , Bogoyevitch M. A. , Fuller S. J. , Lazou A. , Parker P. J. , Sugden P. H.
Published: December 2017

The expression of protein kinase C (PKC) isoforms (PKC-alpha, PKC-beta 1, PKC-delta, PKC-epsilon, and PKC-zeta) was studied by immunoblotting in whole ventricles of rat hearts during postnatal development (1-26 days) and in the adult. PKC-alpha, PKC-beta 1, PKC-delta, PKC-epsilon, and PKC-zeta were detected in ventricles of 1-day-old rats, although PKC-alpha and PKC-beta 1 were only barely detectable. All isoforms were rapidly downregulated during development, with abundances relative to total protein declining in the adult to < 25% of 1-day-old values. PKC-beta 1 was not detectable in adult ventricles. The specific activity of PKC was also downregulated. The rat ventricular myocyte becomes amitotic soon after birth but continues to grow, increasing its protein content 40- to 50-fold between the neonate and the 300-g adult. An important question is thus whether the amount of PKC per myocyte is downregulated. With the use of isolated cells, immunoblotting showed that the contents per myocyte of PKC-alpha and PKC-epsilon increased approximately 10-fold between the neonatal and adult stages. In rat ventricles, the rank of association with the particulate fraction was PKC-delta > PKC-epsilon > PKC-zeta. Association of these isoforms with the particulate fraction was less in the adult than in the neonate. In primary cultures of ventricular myocytes prepared from neonatal rat hearts, 1 microM 12-O-tetradecanoylphorbol-13-acetate (TPA) elicited translocation of PKC-alpha, PKC-delta, and PKC-epsilon from the soluble to the particulate fraction in < 1 min, after which time no further translocation was observed. Prolonged exposure (16 h) of myocytes to 1 microM TPA caused essentially complete downregulation of these isoforms, although downregulation of PKC-epsilon was slower than for PKC-delta. In contrast, PKC-zeta was neither translocated nor downregulated by 1 microM TPA. Immunoblotting of human ventricular samples also revealed downregulation of PKC relative to total protein during fetal/postnatal development.
Nifedipine inhibits movement of cardiac calcium channels through late, but not early, gating transitions
Authors: Hadley R. W. , Lederer W. J.
Published: December 2017

L-type Ca2+ channels were studied in guinea pig ventricular myocytes by examining how photoinactivation of nifedipine affected the Ca2+ current (ICa) and the Ca2+ channel gating current (Ig). ICa, blocked by nifedipine, reappeared in qualitatively different phases (immediate and delayed) following photoinactivation of nifedipine. Immediate recovery was attributed to unblock of closed Ca2+ channels, while delayed recovery was attributed to unblock of inactivated channels. In contrast to the ICa results, photoinactivation of nifedipine produced only delayed recovery of Ig. Analysis of these results suggests the following conclusions. First, the actions of inhibitory dihydropyridines can be attributed to binding to either the inactivated or the closed conformation, but only binding to the inactivated state is associated with reduction of Ig. Second, the action of inhibitory dihydropyridines on closed channels is to retard their movement through a final, voltage-independent transition to the open state. This effect seems to be the converse of a major action of stimulatory dihydropyridines and thus is the principal mechanistic difference between stimulatory and inhibitory dihydropyridines.