bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of thromboxane A2/endoperoxide antagonist SQ29548 on the contractile response to acetylcholine in newborn piglet cerebral arteries.
Authors: Wagerle L C , Busija D W
Published: June 2012

Previous studies have shown that cholinergic stimulation results in a prostanoid-dependent cerebral vasoconstriction in piglets. The present study specifically investigated the contribution of thromboxane A2 (TXA2)/prostaglandin endoperoxide and prostaglandin F2 alpha (PGF2 alpha) to the cerebral vascular response to exogenous acetylcholine (ACh). Effects of TXA2/prostaglandin endoperoxide-receptor antagonist SQ29548 on responsiveness of pial arterioles to ACh (10(-7) and 10(-4) M), PGF2 alpha (10(-7)-10(-5) M), TXA2 mimetic 9,11-methanoepoxy prostaglandin H2 (U46619, 5 and 10 ng/ml), and norepinephrine (10(-6)-10(-4) M) were studied by use of a closed cranial window in 37 anesthetized mechanically ventilated newborn piglets. Pial arteriolar diameter was measured by intravital microscopy. Topical application of exogenous PGF2 alpha and U46619 resulted in dose-dependent cerebral vasoconstriction, and the dose-response curve for each agonist was shifted to the right by the increasing concentrations of SQ29548 (10(-6)-10(-8) M). Topical application of high concentration of ACh (10(-4) M) caused a transient 34 +/- 4% decrease in pial arteriolar diameter from 98 +/- 6 to 65 +/- 5 microns (p less than 0.05). This constriction was attenuated (16 +/- 3%) in the presence of 10(-8) M SQ29548 and abolished with 10(-6) or 10(-4) M SQ29548. SQ29548 (10(-6) M) was without effect on the vasoconstrictor response to exogenous norepinephrine. Low concentration of ACh (10(-7) M) had no consistent effect on pial arterioles in the absence or presence of TXA2/prostaglandin endoperoxide-receptor blockade. The data suggest that vascular prostaglandin/endoperoxide receptors mediate cerebral vasoconstriction upon muscarinic-receptor stimulation.
ATP directly affects junctional conductance between paired ventricular myocytes isolated from guinea pig heart.
Authors: Sugiura H , Toyama J , Tsuboi N , Kamiya K , Kodama I
Published: June 2012

Effects of ATP on junctional conductance (gj) were investigated in paired ventricular myocytes isolated from guinea pig hearts. One cell of the pair was voltage-clamped with a single-patch pipette, and gj was measured after the perforation of the nonjunctional membrane of the partner cell. The current-voltage relation of gj was linear between -30 and +30 mV. The control gj at 5.0 mM ATP in 88 pairs of cells ranged from 100 to 1,055 nS (average, 268 nS). ATP within the range from 0.1 to 5.0 mM increased gj in a dose-dependent manner. The Hill coefficient was 2.6, and the half-maximum effective concentration of ATP was 0.68 mM. Adenylylimidodiphosphate (2 mM) caused a transient increase in gj in the presence of 0.5 mM ATP, but forskolin (30 microM), cyclic AMP (50 microM), catalytic subunit of cyclic AMP-dependent protein kinase (1 microM), and ADP (10 mM) had no significant effect on gj. The temperature coefficient of gj in the presence of 5.0 mM ATP was 1.29. These findings suggest that gj in paired ventricular myocytes is directly regulated by ATP probably through a specific ligand-receptor interaction between ATP and gap junctional channel protein.
Angiotensin II-forming pathways in normal and failing human hearts.
Authors: Urata H , Healy B , Stewart R W , Bumpus F M , Husain A
Published: June 2012

Reduced preload and afterload to the heart are important effects of angiotensin converting enzyme (ACE) inhibitors in the treatment of congestive heart failure. However, since angiotensin II (Ang II) directly increases the strength of myocardial contraction, suppression of Ang II formation by ACE inhibitors could potentially reduce the beneficial effects of Ang II on the failing heart. To study how ACE inhibition suppresses cardiac Ang II formation in man, we characterized ACE-dependent and ACE-independent Ang II-forming pathways in eight normal and 24 failing human hearts obtained at cardiac transplantation. Ang II-forming activity in left ventricular (LV) membrane preparations was assessed by measuring the conversion of [125I]angiotensin I (Ang I) to [125I]Ang II. LV [125I]Ang II-forming activity in normal hearts (35.5 +/- 2.7 fmol/min/mg, n = 8) was not different from that in hearts from patients with ischemic cardiomyopathy (25.5 +/- 2.9 fmol/min/mg, n = 9) and was 48% lower (p less than 0.001) in hearts from patients with idiopathic cardiomyopathy (18.5 +/- 1.9 fmol/min/mg, n = 15).(ABSTRACT TRUNCATED AT 250 WORDS)
Impaired prostaglandin E1/I2 receptor activity of human blood platelets in acute ischemic heart disease.
Authors: Kahn N N , Mueller H S , Sinha A K
Published: June 2012

The platelets from 74 patients with acute myocardial infarction or with unstable angina showed decreased prostaglandin E1/I2 receptor activity when compared with that of 56 normal volunteers by using [3H]prostaglandin E1 as a probe. In normals, Scatchard analyses showed the presence of one high-affinity-low-capacity (Kd1 = 9.0 +/- 1.2 nM [mean +/- SD]; n1 = 120 +/- 30 sites/cell) and one low-affinity-high-capacity (Kd2 = 1.1 +/- 0.5 microM; n2 = 1,460 +/- 250 sites/cell) prostaglandin E1/I2 receptor population in platelets. In contrast (p less than 0.01), platelets from patients showed decreased ligand binding (n1 = 40 +/- 20 sites/cell; n2 = 800 +/- 210 sites/cell) with little change in the affinity of the receptors (Kd1 = 7.50 +/- 1.6 nM; Kd2 = 0.68 +/- 0.24 microM). On the other hand, the platelets from the patients with dilated cardiomyopathy (n = 7) who were hospitalized for acute chest pain but had normal coronary arteries did not show any impairment of the receptor activity. The plasma prostacyclin level of the patients with acute ischemic heart disease was similar to that of normal volunteers; this finding indicated that the defective receptor function was not related to the prostaglandin receptors occupancy in vivo. The impaired receptor activity was temporary in nature. The follow-up studies showed that the prostaglandin receptor activity of the patients' platelets improved to "normal" levels within 2-8 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of wall shear rate on thrombogenesis in microvessels of the rat mesentery.
Authors: Sato M , Ohshima N
Published: June 2012

The role of hemodynamics on platelet thrombus formation was studied in venules and arterioles of the rat mesentery. Thrombus formation was induced by the fluorescent dye/light method for examination of the following factors: 1) the effect of wall shear rate on thrombus initiation, 2) the effect of wall shear rate on the growth of thrombi, and 3) the relation between platelet thrombus initiation and intraluminal velocity profile. The range of wall shear rate was up to approximately 1,000 1/sec in venules and from 640 to 2,900 1/sec in arterioles. Platelet thrombus initiation occurred more rapidly at higher wall shear rate in venules and at lower wall shear rate in arterioles. Thrombus initiation time was shortest around a wall shear rate of 900 1/sec in venules and around 700 1/sec in arterioles. Thrombus growth rate in venules was greatest at a wall shear rate of 1,500-2,000 1/sec. Thrombus initiation and its relation to blood flow was also examined in branched and curved microvessels. In these vessels platelet thrombi were also first initiated at the sites of higher wall shear rate in venules and of lower wall shear rate in arterioles.
Collagen and elastin metabolism in hypertensive pulmonary arteries of rats.
Authors: Poiani G J , Tozzi C A , Yohn S E , Pierce R A , Belsky S A , Berg R A , Yu S Y , Deak S B , Riley D J
Published: June 2012

We evaluated the processes controlling the accumulation of collagen and elastin in main pulmonary arteries of rats during an episode of hypoxic pulmonary hypertension. Explant cultures of main pulmonary arteries were incubated with [3H]proline to measure collagen and protein synthesis and percent collagen synthesis. Elastin synthesis was measured by [14C]valine incorporation into insoluble elastin. Relative collagen synthesis increased twofold (from 1.1 +/- 0.2 x 10(3) to 2.0 +/- 1.0 x 10(3) disintegrations per minute [14C]hydroxyproline/vessel/hr/mg protein), relative collagen synthesis doubled (from 2% to 4-5% of total protein synthesis), and elastin synthesis increased ninefold (from 0.4 +/- 0.2 x 10(4) to 3.6 +/- 0.6 x 10(4) dpm [14C]valine/vessel/hr/mg protein) in early hypertension. The level of pro alpha l(I) collagen RNA paralleled the relative collagen synthetic rate during the study period. Within 7 days of recovery from hypoxia, collagen and elastin contents were normal. We conclude that collagen and elastin in main pulmonary arteries are synthesized rapidly during an episode of hypoxic pulmonary hypertension and that collagen and elastin are rapidly removed from the hypertensive vessel during normoxic recovery.
Functional coronary microvascular injury evident as increased permeability due to brief ischemia and reperfusion.
Authors: Dauber I M , VanBenthuysen K M , McMurtry I F , Wheeler G S , Lesnefsky E J , Horwitz L D , Weil J V
Published: June 2012

Although morphological studies suggest that coronary vascular injury is a result of prolonged ischemia and subsequent reperfusion, whether functional coronary microvascular injury develops during brief in vivo ischemia is unclear. In other organs, permeability is a sensitive indicator of functional vascular injury. Therefore, a new double-indicator method of assessing vascular protein permeability, a method that is both sensitive and specific for vascular injury, was used to investigate the effects of ischemia of graded duration followed by reperfusion on coronary microvascular function. To help confirm functional coronary vascular injury, endothelium-dependent vasodilation of isolated coronary vascular rings also was examined. Microvascular permeability was quantitatively assessed as a protein leak index by measuring the rate of extravascular accumulation of radiolabeled protein (indium 113m transferrin) normalized for vascular surface area (technetium 99m erythrocytes). Anesthetized dogs underwent 0 (control), 15, 30, or 60 minutes of left anterior descending coronary artery occlusion followed by 60 minutes of reperfusion. Even 15 minutes of ischemia increased the protein leak index by 50% (3.16 +/- 0.30 ischemic vs. 2.09 +/- 0.11 control). Longer periods of ischemia increased the protein leak index in proportion to the duration of ischemia. The protein leak index increased threefold (6.51 +/- 0.60) after 60 minutes of ischemia. At each duration of ischemia, there was significant regional variation in the protein leak index that correlated with the severity of ischemic blood flow to that region measured with microspheres. Endothelial injury also was evident after 15 and 30 minutes of ischemia as impaired vasodilation of isolated coronary rings in response to the endothelium-dependent vasodilators acetylcholine and the calcium ionophore A23187. Electron microscopy and in vitro direct immunofluorescence revealed evidence of vascular injury after 60 minutes but not after 15 minutes of ischemia. We conclude that even brief ischemia and reperfusion cause functional coronary vascular injury evident as increased microvascular permeability and impaired endothelium-dependent vasodilation and that regional differences in the degree of microvascular injury correlate with differences in the severity of ischemia.
Vasodilatory action of endogenous atrial natriuretic factor in a rat model of chronic heart failure as determined by monoclonal ANF antibody.
Authors: Drexler H , Hirth C , Stasch H P , Lu W , Neuser D , Just H
Published: June 2012

Elucidation of the role of (elevated) endogenous atrial natriuretic factor (ANF) in chronic heart failure has been hampered by a lack of specific inhibitors. We used a newly developed monoclonal antibody that has been shown to specifically block both exogenously and endogenously released ANF in vivo. For assessment of the vasodilatory action of ANF in chronic heart failure, either this antibody against ANF or ascites (control serum) was injected in rats with myocardial infarction and failure and in sham animals. Ascites did not alter central hemodynamics in either the sham or infarcted group. Antibody significantly increased right atrial pressure, left ventricular end-diastolic pressure, and systemic vascular resistance (SVR) in the infarction group but did not affect these variables in the sham group. Because renal blood flow, as measured by radioactive microspheres, decreased significantly in all four groups, probably due to nonspecific renal vasoconstrictor effects of the ascites, a separate group of infarcted animals was treated with purified ANF antibody (devoid of nonspecific effects) or mouse IgG as a control injection. In these animals, right atrial pressure increased from 1.1 +/- 0.7 to 2.6 +/- 0.7 mm Hg (p less than 0.001). Although SVR, renal blood flow velocity (measured by Doppler probe), and renal vascular resistance did not change in the infarcted animals after administration of purified ANF antibody, a significant correlation was found between baseline plasma ANF values and the change in SVR exerted by purified ANF antibody (r = 0.758, p less than 0.02, n = 9); that is, SVR increased in rats with high baseline plasma ANF (greater than 350 pg/ml), but decreased in animals with plasma ANF less than 200 pg/ml. These results suggest that moderately elevated endogenous plasma ANF levels in chronic heart failure do affect central hemodynamics, primarily by reducing venous pressure (e.g., by decreasing intravascular volume or by venous dilation). Arterial vasodilation, however, appears to emerge when plasma ANF is greatly increased.
Chronotropic and dromotropic responses to stimulation of intracardiac sympathetic nerves to sinoatrial or atrioventricular nodal region in anesthetized dogs.
Authors: Furukawa Y , Wallick D W , Martin P J , Levy M N
Published: June 2012

We gave atropine intravenously to autonomically decentralized, open-chest, anesthetized dogs and stimulated the discrete intracardiac sympathetic nerve fibers to the sinoatrial (SA) (SAS stimulation) or atrioventricular (AV (AVS stimulation) nodal region. A brief burst of neural stimuli was delivered during each cardiac cycle. SAS stimulation consistently decreased the atrial cycle length but had variable effects on the AV interval. The positive chronotropic response to SAS stimulation increased when the level of stimulation (i.e., stimulus pulse duration, pulse amplitude, and number of pulses per burst) was increased. When the heart rate was held constant by atrial pacing, SAS stimulation did not change the AV interval. AVS stimulation decreased the AV conduction time but did not change the atrial cycle length. The AV conduction response increased when the level of AVS stimulation was increased. A high level of AVS stimulation induced an AV junctional rhythm in seven of eight experiments. When the atrial pacing interval was decreased, the basal AV interval increased, and the decrease in AV interval induced by AVS stimulation was exaggerated. The chronotropic response to SAS stimulation and the dromotropic response to AVS stimulation were abolished by propranolol given systemically and by lidocaine given topically. From these results, we conclude that in anesthetized dogs treated with atropine, activation of the discrete intracardiac sympathetic nerves to the SA and AV nodal regions controls the sinus rate and AV conduction time independently and activation of the discrete sympathetic nerves may shift the dominant pacemaker site to a subsidiary site.
Left ventricular failure induced by long-term hypertension in rats.
Authors: Capasso J M , Palackal T , Olivetti G , Anversa P
Published: June 2012

To determine whether the duration of hypertension is an essential component in the evolution of myocardial dysfunction, renal artery constriction was performed in male Fischer 344 rats at 4 months of age, and in vivo global cardiac performance of sham-operated and experimental animals was evaluated 8 months later. Systemic arterial blood pressure increased to 173 +/- 5 mm Hg 2 weeks after the arteries were clipped and remained elevated for the following 5 months. Blood pressure decreased over the remaining 3 months to a value not significantly different from control rats that were killed, 132 +/- 4 mm Hg. After 8 months of renovascular hypertension, we observed that the elevated level of systolic arterial pressure was accompanied by a distinct absence of left ventricular hypertrophy when measured at the ventricular weight level. Moreover, left ventricular end-diastolic pressure increased in hypertensive animals from 6.0 to 24.0 mm Hg while peak left ventricular pressure was identical to controls. In addition, peak +dP/dt and -dP/dt were depressed in hypertensive animals. Although stroke volume was unaltered, cardiac output in renal artery clipped animals was depressed by 34% while total peripheral resistance was elevated by 50%. Ventricular chamber remodeling in the hearts of hypertensive animals was evidenced as a 19% increase in the transverse and a 16% increase in the longitudinal axes of the left ventricle with a 27% diminution of wall thickness. Myocardial damage, in the form of myocyte loss and replacement fibrosis, increased in the hearts of hypertensive animals resulting in a ninefold augmentation in the volume fraction of collagen within the ventricular wall. These alterations in the architectural properties of chamber geometry coupled with the abnormalities in contractile performance resulted in a severe reduction in ejection fraction from 82% to 47% and a marked elevation in transmural diastolic and systolic stress in hypertensive animals. The gradient in stress across the ventricular wall, from epicardium to endocardium, revealed a direct correlation with the regional distribution of myocardial damage. In conclusion, the loading state of the myocardium, tissue injury, and myocardial fibrosis all appear to be critical determinants in the genesis of left ventricular failure in long-term pressure overload.
Role of the vascular endothelium in regulating the response of small arteries of the dog kidney to transmural pressure elevation and reduced PO2.
Authors: Eskinder H , Harder D R , Lombard J H
Published: June 2012

The goal of this study was to determine the role of the vascular endothelium in regulating the response of small renal arteries to increased transmural pressure and reduced PO2. Canine small renal arteries (496 +/- 32 microns) were isolated, cannulated with micropipettes, and mounted in an in vitro chamber that allowed transmural pressure, tissue bath PO2, and vessel lumen PO2 to be controlled. In intact arteries, elevation of transmural pressure caused contractile activation and a progressive depolarization (0.17 +/- 0.09 mV/mm Hg pressure increase) of the vascular smooth muscle cells. Endothelial damage by air perfusion caused a 13-14% reduction in resting diameter and an 18 +/- 3 mV depolarization of the vascular smooth muscle, but eliminated the progressive contraction and depolarization that occurred in intact vessels in response to transmural pressure elevation. Reduction of either tissue bath O2 concentration or vessel lumen PO2 significantly enhanced norepinephrine-induced contractions of the arteries. Endothelial damage prevented the enhancement of norepinephrine-induced contractions by reduced PO2 in the vessels. The results of this study suggest that the vascular endothelium regulates both myogenic contraction and the enhancement of norepinephrine-induced contractions by reduced PO2 in small arteries of the dog kidney.
Flow-induced constriction and dilation of cerebral resistance arteries.
Authors: Garcia-Roldan J L , Bevan J A
Published: June 2012

Rabbit pial resistance artery segments were cannulated at both ends so they could be perfused with physiological saline solution and were maintained in a tissue bath of the same solution. Both were kept at 37 degrees C and equilibrated with 95% O2 and 5% CO2. Perfusion pressure and flow were independently controlled by two servo-controlled pumps, and changes in the diameter of the segment were registered by an automated video technique. In the absence of flow, these segments maintained their diameter when intraluminal pressure was changed over the range 30-90 mm Hg. When intraluminal pressure was low (30 mm Hg), flow at 20 microliters/min caused dilation. This is half the rate of flow that causes a maximum flow-induced change under the conditions of these experiments. When pressure was high (90 mm Hg), the same flow rate caused constriction. Both responses usually continued as long as flow was maintained. Thus, flow-induced changes in the diameter of this artery can be initiated and are usually maintained despite the demonstrated capacity of the blood vessel wall to hold its diameter constant when pressure is changed in the absence of flow. The results suggest that these small arteries can independently respond to changes in pressure and flow and that the changes that occur in response to flow are not compensated for by changes in the myogenic response.
Ischemia-induced epicardial vasoconstriction. A potential mechanism for distant myocardial ischemia.
Authors: Chu A , Chambers D E , Lin C C , Kuehl W D , Cobb F R
Published: June 2012

This study evaluated the effects of transient coronary occlusion on the diameter of a nonischemic vessel or a nonischemic coronary segment proximal to the site of occlusion. Awake mongrel dogs chronically instrumented with dimension crystals, Doppler flow probes, and distal pneumatic occluders on the circumflex coronary arteries were subjected to transient 2-minute circumflex occlusions (n = 9) under constant heart rate (120 beats/min). Left ventricular end-diastolic pressure increased by 60% (from 10 +/- 1 to 16 +/- 2 mm Hg), and dP/dt decreased by 8% (from 2,048 +/- 130 to 1,885 +/- 110 mm Hg/sec); systemic hemodynamics were unaltered. Epicardial coronary diameter proximal to the site of occlusion decreased by 4.37% (from 3.62 +/- 0.25 to 3.46 +/- 0.29 mm, p less than 0.05). Constriction began 15-20 seconds after the onset of ischemia and progressed to maximum in 1-2 minutes. Combined alpha- and beta-receptor blockade (n = 8) with phentolamine (2 mg/kg) and propranolol (1 mg/kg) or cyclooxygenase inhibition (n = 5) with indomethacin (7.5 mg/kg) did not attenuate the ischemia-induced vasoconstriction response. Transient 2-minute occlusion of the left anterior descending coronary artery (n = 6) also elicited significant epicardial vasoconstriction in the circumflex coronary artery in the first minute (from 3.88 +/- 0.31 to 3.81 +/- 0.31 mm, p less than 0.05); the constriction was attenuated subsequently by an increase (25.5%) in circumflex flow. When left anterior descending occlusion was repeated (n = 6) with circumflex flow held constant, the ischemia-induced circumflex constriction was augmented; diameter decreased 3.7% (from 3.83 +/- 0.29 to 3.69 +/- 0.29 mm, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Comparison of activation during ventricular fibrillation and following unsuccessful defibrillation shocks in open-chest dogs.
Authors: Chen P S , Wolf P D , Melnick S D , Danieley N D , Smith W M , Ideker R E
Published: June 2012

The purpose of this study was to map in detail the spread of activation away from sites of early postshock excitation following unsuccessful defibrillation to determine whether these activation fronts are the unaltered continuation of activation fronts present just before the shock. We recorded simultaneously from 120 bipolar electrodes on 40 plunge needles in a 20 x 35 x 5-mm volume of tissue of the right ventricular outflow tract immediately before and after shocks of 190-350 V were given via electrodes on the right atrium and left ventricular apex to six open-chest dogs with electrically induced ventricular fibrillation. For 20 shocks approximately 100 V below the defibrillation threshold, the site of earliest recorded activation following the shock was near the center of the mapped region. At the earliest recorded activation sites, there was an isoelectric window in the immediate postshock period lasting 42 +/- 15 msec after which activation fronts either spread away from a site in all directions in a focal pattern (12 episodes) or else spread away in only one direction (eight episodes). Comparison of activation patterns immediately before and after the shock revealed that in 18 of the 20 episodes, the location and pathway of activation fronts after the shock were markedly different from those before the shock. The preshock intervals at the sites of earliest activation following the shock, that is, the interval between the last activation at the site and the time of the shock, were not randomly distributed but were similar, averaging 64 +/- 11 msec, and were negatively correlated with the isoelectric postshock window (r = -0.70, p = 0.0001). These findings indicate that the presence and the site of origin of activation fronts after the shock are influenced by at least two factors: the shock itself and the electrophysiological state of the myocardium at the time of the shock. Thus, epicardial shocks approximately 100 V below the defibrillation threshold markedly alter the activation sequences of fibrillation but are unsuccessful because the activation fronts following the shock reinitiate fibrillation.
Direct neurohumoral evidence for isolated sympathetic nervous system activation to skeletal muscle in response to cardiopulmonary baroreceptor unloading.
Authors: Baily R G , Prophet S A , Shenberger J S , Zelis R , Sinoway L I
Published: June 2012

It has been postulated that cardiopulmonary baroreceptor unloading in humans results in nonuniform activation of the sympathetic nervous system. We reasoned that simultaneous measurements of arterial and venous norepinephrine (NE) spillover and clearance (using NE kinetics), muscle sympathetic neural activity (using microneurography), forearm blood flow (using plethysmography), and skin blood flow (using laser Doppler velocimetry) during lower body negative pressure at -15 mm Hg would isolate the location and extent of cardiopulmonary baroreceptor-mediated sympathetic nervous system activation. We exposed normal subjects (n = 8) to lower body negative pressure for 30 minutes, with measurements obtained at baseline, 5-10 minutes (EARLY), and 25-30 minutes (LATE). We found that arterial NE spillover, reflecting systemic sympathetic nervous system activation, did not increase significantly, whereas arterial NE clearance decreased significantly. In contrast, forearm venous NE spillover, reflecting skin and muscle sympathetic nervous system activation, increased by 17% and muscle sympathetic neural activity by 35% EARLY, whereas venous clearance did not change significantly. Although laser Doppler skin blood flow did not change, plethysmographic forearm blood flow (combined muscle and skin blood flow) decreased by 28%. All changes were sustained throughout 30 minutes of lower body negative pressure. Our data suggest that sympathetic vasoconstriction to muscle is greater than it is to skin in response to cardiopulmonary baroreceptor unloading. Moreover, our data suggest that reduced NE clearance in the arterial circulation is the primary mechanism by which arterial NE concentrations rise. Conversely, NE spillover appears to be the primary mechanism responsible for increasing venous NE concentrations measured from the forearm during cardiopulmonary baroreceptor unloading.
Fluoromisonidazole. A metabolic marker of myocyte hypoxia.
Authors: Martin G V , Cerqueira M D , Caldwell J H , Rasey J S , Embree L , Krohn K A
Published: June 2012

Fluoromisonidazole is metabolically trapped in viable hypoxic cells in vitro. This property is the basis for the hypothesis that [18F]fluoromisonidazole can be used to detect hypoxic tissues noninvasively using positron emission tomography. To assess the potential usefulness of this compound as a marker for hypoxic myocardium, we measured the accumulation of [3H]fluoromisonidazole in isolated adult rat myocytes under normoxic, hypoxic (5,000 ppm O2), and anoxic conditions. Both anoxia and hypoxia caused a marked increase in [3H]fluoromisonidazole accumulation. Relative to uptake during normoxia, uptake during anoxia was increased by 8.4-fold at 60 minutes and 26.5-fold at 180 minutes (p less than 0.001). During hypoxia, uptake was increased by 4.4-fold at 60 minutes and by 15.3-fold at 180 minutes (p less than 0.0001) and occurred in the absence of significant cell injury as measured by release of creatine kinase and changes in cell morphology. Additional studies demonstrated a slow oxygen-insensitive efflux of fluoromisonidazole or labeled metabolite(s) from myocytes reincubated in drug-free medium. We conclude that fluoromisonidazole is avidly retained in hypoxic myocytes and thus may be suitable for noninvasive detection of hypoxic myocardium using positron emission tomography.
Patterns of interaction between anthraquinone drugs and the calcium-release channel from cardiac sarcoplasmic reticulum.
Authors: Holmberg S R , Williams A J
Published: June 2012

We have studied the effects of clinically useful anthraquinones on the cardiac sarcoplasmic reticulum calcium-release channel. Micromolar concentrations of doxorubicin and other anthracyclines at the cytosolic face of the channel significantly and reversibly increase the open probability of single channels in artificial phospholipid bilayers. Lifetime analysis shows that anthracyclines and calcium are synergistic activators of the calcium-release channel. Radiolabeled ryanodine binding suggests that all the anthracyclines studied are equally potent as channel activators in vitro. Mitoxantrone, an anthracenedione derivative, variably increases channel open probability at low (1-10 microM) concentrations. Higher concentrations are associated with the appearance of channel currents with lower amplitudes than the fully open state, and normal openings are reduced in frequency. At these concentrations, the interaction of mitoxantrone with the channel reduces the level of ryanodine binding. Abnormal function of the cardiac calcium-release channel will alter calcium handling within the myocyte and may be the basis for anthraquinone-related cardiotoxicity.
Profound spatial heterogeneity of coronary reserve. Discordance between patterns of resting and maximal myocardial blood flow.
Authors: Austin R E , Aldea G S , Coggins D L , Flynn A E , Hoffman J I
Published: June 2012

We examined the ability of individual regions of the canine left ventricle to increase blood flow relative to baseline rates of perfusion. Regional coronary flow was measured by injecting radioactive microspheres over 90 seconds in seven anesthetized mongrel dogs. Preliminary experiments demonstrated a correlation between the regional distributions of blood flow during asphyxia and pharmacological vasodilatation with adenosine (mean r = 0.75; 192 regions in each of two dogs), both of which resulted in increased coronary flow. Subsequent experiments, during which coronary perfusion pressure was held constant at 80 mm Hg, examined the pattern of blood flow in 384 regions (mean weight, 106 mg) of the left ventricular free wall during resting flow and during maximal coronary flow effected by intracoronary adenosine infusion. We found that resting and maximal flow patterns were completely uncorrelated to each other in a given dog (mean r = 0.06, p = NS; n = 3 dogs). Furthermore, regional coronary reserve, defined as the ratio of maximal to resting flow, ranged from 1.75 (i.e., resting flow was 57% of maximum) to 21.9 (resting flow was 4.5% of maximum). Thus, coronary reserve is spatially heterogeneous and determined by two distinct perfusion patterns: the resting (control) pattern and the maximal perfusion pattern. Normal hearts, therefore, contain small regions that may be relatively more vulnerable to ischemia. This may explain the patchy nature of infarction with hypoxia and at reduced perfusion pressures as well as the difficulty of using global parameters to predict regional ischemia. Despite the wide dispersion of coronary reserve, we found, by autocorrelation analysis, that reserve in neighboring regions (even when separated by a distance of several tissue samples) was significantly correlated. This also applied to patterns of resting myocardial flow. Thus, both resting coronary blood flow and reserve appear to be locally continuous and may define functional zones of vascular control and vulnerability, respectively.
Prolonged impairment of coronary vasodilation after reversible ischemia. Evidence for microvascular "stunning".
Authors: Bolli R , Triana J F , Jeroudi M O
Published: June 2012

Reperfusion after brief, reversible myocardial ischemia is associated with prolonged depression of contractile function (myocardial "stunning"); however, the effect on coronary vascular function has not been defined. Thus, open-chest dogs (n = 14) underwent a 15-minute left anterior descending coronary artery (LAD) occlusion followed by reflow. Four hours after reperfusion, regional myocardial blood flow (microspheres) was significantly (p less than 0.01) lower and coronary vascular resistance significantly (p less than 0.01) higher in the postischemic as compared with the nonischemic endocardium. Furthermore, during maximal vasodilation elicited by intravenous adenosine (n = 6), myocardial blood flow was lower (p less than 0.05) and coronary vascular resistance higher (p less than 0.05) in the postischemic as compared with the nonischemic myocardium, both in the endocardial and in the epicardial layers. Similarly, during maximal dilation elicited by intravenous papaverine (n = 8), myocardial blood flow was lower (p less than 0.05) and vascular resistance higher (p less than 0.05) in the postischemic as compared with the nonischemic endocardium; a directionally similar trend was observed in the epicardium. Four hours after reperfusion, all indexes of reactive hyperemia after a 40-second coronary occlusion were significantly lower in the LAD than in the control circumflex coronary artery (n = 8). There was no appreciable correlation between systolic wall thickening in the stunned myocardium and 1) the resting myocardial perfusion, 2) the hyperemia attained during adenosine or papaverine, and 3) the hyperemic response to a 40-second coronary occlusion. In control dogs that did not undergo a 15-minute LAD occlusion (n = 15), there were no differences in myocardial blood flow or vascular resistance between the LAD-dependent and the circumflex-dependent bed, either before or during adenosine (n = 7) or papaverine (n = 8). Furthermore, reactive hyperemia after a 40-second occlusion did not differ between the LAD and the circumflex artery (n = 8). In conclusion, a brief (15 minute), reversible ischemic insult causes a prolonged increase in resting vascular resistance and a prolonged impairment in vasodilator responsiveness, both of which persist for at least 4 hours. The severity of these vascular derangements is not related to the severity of contractile depression, suggesting that they may represent a relatively independent phenomenon. It is proposed that, in addition to myocardial "stunning," reversible ischemia also causes a microvascular "stunning."
Phospholamban and troponin I are substrates for protein kinase C in vitro but not in intact beating guinea pig hearts.
Authors: Edes I , Kranias E G
Published: June 2012

The incorporation of [32P]inorganic phosphate into membranous, myofibrillar, and cytosolic proteins was studied in Langendorff-perfused guinea pig hearts treated with phorbol 12-myristate 13-acetate (PMA) or 1,2-dioctanoylglycerol (D8G), which are potent activators of protein kinase C. Control hearts were perfused with an inactive phorbol ester (4 alpha-phorbol 12,13-didecanoate), which does not cause activation of protein kinase C. To ensure the blockade of different receptor systems, the perfusions were carried out in the presence of prazosin, propranolol, and atropine. Perfusion of hearts with either PMA (4 microM) or D8G (200 microM) was associated with a negative effect on left ventricular inotropy and relaxation. Examination of the 32P incorporation into various fractions revealed that there were no increases in the degree of phosphorylation of phospholamban in sarcoplasmic reticulum, and troponin I and C protein in the myofibrils, although these proteins were found to be substrates for protein kinase C in vitro. However, in the same hearts, there were significant changes in the 32P incorporation into a 28-kDa cytosolic-protein. Examination of the activity levels of protein kinase C in hearts perfused with PMA indicated a redistribution of this activity from the cytosolic to the membrane fraction, suggesting the activation of the enzyme in vivo. These findings indicate that cardiac regulatory phosphoproteins, which may be phosphorylated by protein kinase C in vitro, are not substrates for protein kinase C in beating hearts perfused with phorbol esters or diacylglycerol analogues.
Differential alteration of vascular reactivity in rabbit aorta with modest elevation of serum cholesterol.
Authors: Merkel L A , Rivera L M , Bilder G E , Perrone M H
Published: June 2012

The effect of diet-induced, moderate elevation of serum cholesterol on vascular reactivity in isolated rabbit abdominal aortic rings was examined by using a series of vasoconstrictor and vasodilator agonists. Serum cholesterol of rabbits that were fed a cholesterol-free, casein-rich diet for 10 weeks was elevated approximately 4.5-fold compared with values found in control rabbits that were fed standard lab chow (223 +/- 41 versus 51 +/- 5 mg/dl, respectively). Relaxation responses to carbamylcholine chloride and (+/-)-isoproterenol hydrochloride in vessels from hypercholesterolemic rabbits were markedly inhibited in the presence of norepinephrine, prostaglandin F2 alpha, 5-hydroxytryptamine, and angiotensin II but not in the presence of phorbol 12,13-dibutyrate. The depressed vasodilation in hypercholesterolemic vessels appeared to depend on the agonist initiating the contraction. Sodium nitroprusside-induced relaxations were unchanged in rings from hypercholesterolemic rabbits compared with rings from control rabbits for all contractile agonists except KCl. Isolated aortic rings from hypercholesterolemic rabbits exhibited a slight but significantly increased vasoconstrictor sensitivity to 5-hydroxytryptamine and KCl but not to norepinephrine, prostaglandin F2 alpha, angiotensin II, or phorbol 12,13-dibutyrate compared with aortic rings from control rabbits. These results demonstrate that modest elevation of serum cholesterol is sufficient to depress vasodilator and enhance vasoconstrictor responses to certain agonists. Vasodilator effects are impaired to a greater extent by a small increase in serum cholesterol than are responses to vasoconstrictor agonists. It is postulated that the induction of differential alterations in vascular reactivity with moderate increase in serum cholesterol may represent important early events predisposing arteries to vasospasm.
Insignificant bilateral convergence of preganglionic vagal fibers on postganglionic neurons to the canine heart.
Authors: Lang S A , Zieske H , Levy M N
Published: June 2012

We determined the extent of convergence of preganglionic fibers from the right and left vagus nerves on postganglionic neurons that supply the sinoatrial node in chloralose-anesthetized dogs. We administered hemicholinium-3 and stimulated the right vagus nerve at a high frequency to deplete acetylcholine from the postganglionic parasympathetic neurons supplied by that nerve. We compared the effects of this "depletion regimen" with the responses in two control groups: a stimulation control group, which was subjected to high-frequency right vagus stimulation only, and a drug control group, which received a hemicholinium-3 infusion only. The effects of right vagus stimulation did not differ from those of left vagus stimulation in either of the control groups. In the animals subjected to the depletion regimen, the responses to right vagus stimulation were almost abolished. However, the left vagus nerve retained its ability to prolong cardiac cycle length in these animals. Thus, our experiments indicate that left vagus preganglionic fibers do not converge with right vagus preganglionic fibers on a substantial pool of postganglionic neurons that innervate the canine sinoatrial node.
In vivo significance of T cells in the development of Coxsackievirus B3 myocarditis in mice. Immature but antigen-specific T cells aggravate cardiac injury.
Authors: Kishimoto C , Abelmann W H
Published: June 2012

Acute myocardial damage similar to that seen in human myocarditis occurs in BALB/c mice after infection with coxsackievirus B3 (CB3) or encephalomyocarditis virus (EMC). To investigate the role of antigen-specific T cells in the pathogenesis of this disorder, we compared CB3 disease expression in T cell-deficient, athymic nude (nu/nu) mice, in heterozygote (nu/+) mice with normal T cell function, and in nu/nu mice reconstituted with spleen cells from CB3- or EMC-infected nu/+ mice. Acute myocarditis occurred in both nu/nu and nu/+ mice. Severe myocarditis, however, developed only in nu/+ and nu/nu mice reconstituted with CB3-sensitized T cells, but not in those reconstituted with EMC-sensitized T cells. Myocardial virus titer and serum anti-CB3 antibody production were similar in nu/+ and nu/nu groups. Additionally, the presence of Thy 1.2 (pan T), Ly 1 (precursor of other T cell subsets), and Ly 2 (suppressor/cytotoxic T) positive cells was demonstrated in the myocardium in nu/+ and nu/nu mice reconstituted with CB3-sensitized T cells, but not with T cells sensitized by another virus, EMC. These results indicate that immature but antigen-specific T cells play a role in the pathogenesis of ongoing myocarditis.
Changes in cerebrovascular prostaglandins and thromboxane as a function of systemic blood pressure. Cerebral blood flow autoregulation of the newborn.
Authors: Chemtob S , Beharry K , Rex J , Varma D R , Aranda J V
Published: June 2012

Cerebrovascular concentrations of prostaglandin E (PGE), prostaglandin F2 alpha (PGF2 alpha), 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TXB2) were determined over a blood pressure range of 17-117 mm Hg (induced by inflation of balloon-tipped catheters placed in the thoracic descending aorta and at the aortic root) in eight newborn piglets to access the role of prostanoids in cerebral blood flow (CBF; measured using radioactive microspheres) autoregulation. Basal systemic blood pressure, heart rate, blood gases, total CBF, and prostanoid concentrations were stable. CBF was constant between 50 and 90 mm Hg, but beyond this range CBF varied directly with blood pressure (tau = 0.48; p less than 0.05). Sagittal sinus concentrations of PGE, PGF2 alpha, and 6-keto-PGF1 alpha varied with blood pressure according to a quadratic function (R2 = 0.92 to 0.96; p less than 0.0001), exhibiting lowest values between mean blood pressures of 60 and 90 mm Hg. During hypotension (17-49 mm Hg), there was a greater relative increase in sagittal sinus concentrations of TXB2 than of PGE, PGF2 alpha, and 6-keto-PGF1 alpha; at the lowest blood pressures, TXB2 increased by 658 +/- 44%, and prostaglandins increased on the average by 331 +/- 49% (p less than 0.01) from their values during normotension (50-90 mm Hg). During hypertension (91-117 mm Hg), cerebrovascular production and concentrations of prostaglandins increased by 142 +/- 31% and 45 +/- 10%, respectively, but did not change for TXB2.(ABSTRACT TRUNCATED AT 250 WORDS)
Disruption of microtubules as an early sign of irreversible ischemic injury. Immunohistochemical study of in situ canine hearts.
Authors: Iwai K , Hori M , Kitabatake A , Kurihara H , Uchida K , Inoue M , Kamada T
Published: June 2012

Structural disruption of the cytoskeleton may be involved in irreversible ischemic injury. In the present study, ischemic changes in microtubules during various periods of myocardial ischemia were studied with an immunohistochemical technique in open-chest dogs. In intact myocardium, microtubules were stained as a filamentous network throughout cytoplasm and a circular network around the nucleus, which disappeared with colchicine treatment. In brief ischemia of less than 15 minutes, microtubule patterns were unaltered. After 20 minutes, however, characteristic microtubule stains were partly lost in patchy lesions. As an increase in ischemic period, lesions of loss of microtubule stains were increased in number and size. After 120 minutes of reperfusion following 60 minutes of ischemia, the lesions with intact actin filaments but with disrupted microtubules were replaced by the severely injured cells in which the regular myofibrillar registrations were distinctly disrupted. After 24 hours of reperfusion following 40 minutes of occlusion of the left circumflex artery, the percent area of disrupted microtubules at 40 minutes of ischemia was replaced by that of irreversibly injured lesions in the posterior papillary muscle. These results indicate that disruption of microtubules during ischemia heralds irreversible ischemic injury. However, in in vitro study, the myocardium incubated in hypoxic solution for 60-120 minutes demonstrated earlier disruption of the microtubules than the vinculin. Electron microscopic study also showed minimal irreversible changes in the lesions with disrupted microtubules. Thus, taken together, we conclude that microtubules that support the structural integration of myofibrils and other organelles are disrupted in severe myocardial ischemia before the irreversible injury, promoting the irreversible change after reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Experimental sympathetic activation causes endothelial injury in the rabbit thoracic aorta via beta 1-adrenoceptor activation.
Authors: Pettersson K , Bejne B , Björk H , Strawn W B , Bondjers G
Published: June 2012

Sympathetic activation appears to accelerate the development of atherosclerosis, an effect that may be inhibited by beta-receptor blockade. It is unclear, however, which mechanisms mediate this effect. In view of the significance attached to endothelial injury in the initial phases of atherogenesis, we decided to test whether sympathetic activation might lead to an increase in endothelial injury. Chloralose anesthesia was used to induce sympathetic activation and the presence of intracellular IgG as a criterion of endothelial cell injury. The beta 1-selective beta-blocker metoprolol was used to evaluate if the effect(s) of sympathetic activation might be mediated by beta 1-adrenoceptors. In normal rabbits, the frequency of injured endothelial cells in unbranched areas of the thoracic aorta was 0.23%, compared with 1.93% in circumostial areas. Chloralose anesthesia caused significant increases in blood pressure, heart rate, and plasma norepinephrine, that is, caused sympathetic activation, and led to an approximately fivefold increase in the number of injured cells both in unbranched and in circumostial areas. This increase was totally inhibited by metoprolol pretreatment, indicating that it was mediated by beta 1-receptors. These observations suggest one possible mechanism that may connect sympathetic activation with atherogenesis and explain why beta-blockade protects against atherosclerosis.