bluuebunny/crossref_metadata_2025 huggingface dataset:
Magnitude of thromboxane receptor antagonism necessary for antithrombotic activity in monkeys
Authors: Schumacher W. A. , Heran C. L. , Goldenberg H. J. , Harris D. N. , Ogletree M. L.
Published: December 2017

SQ 30741 was characterized as a competitive antagonist of thromboxane receptor-mediated platelet activation in vitro that does not inhibit the activity of enzymes involved in prostaglandin, prostacyclin, and thromboxane biosynthesis. The threshold intravenous dose for antithrombotic activity was measured in anesthetized monkeys as the minimum amount of SQ 30741 required to inhibit thrombotic cyclic blood flow reductions in stenotic renal arteries. Platelet responsiveness was measured ex vivo before and during inhibition of thrombosis by the shape-change response to a thromboxane mimetic, U 46619. The threshold antithrombotic SQ 30741 dose (0.32 +/- 0.04 mg/kg; n = 5) was accompanied by an 8.5 +/- 1.1-fold shift to the right of the U 46619 concentration-effect curve, implying antagonism of 87 +/- 3% of platelet thromboxane receptors. The antithrombotic activity of SQ 30741 persisted for 109 +/- 10 min and was not reversed by indomethacin. However, in two out of seven monkeys SQ 30741 (7 mg/kg iv) did not interrupt the cyclical flow reductions. Vehicle treatment did not impede thrombosis and caused a 1.4 +/- 0.3-fold shift of the U 46619 concentration-effect curve (n = 4). In separate monkeys, SQ 30741 (0.33 mg/kg iv) produced identical dose ratios (8.6 +/- 0.7, n = 8) for inhibition of U 46619-induced mesenteric vasoconstriction. Thus the threshold antithrombotic dose of SQ 30741 caused the same magnitude of antagonism of platelet (ex vivo) and vascular (in vivo) thromboxane receptors.
Mechanism for decrease in cardiac output with atrial natriuretic peptide in dogs
Authors: Lee R. W. , Goldman S.
Published: December 2017

To examine the mechanism by which atrial natriuretic peptide (ANP) decreases cardiac output, we studied changes in the heart, peripheral circulation, and blood flow distribution in eight dogs. ANP was given as a bolus (3.0 micrograms/kg) followed by an infusion of 0.3 microgram.kg-1.min-1. ANP did not change heart rate, total peripheral vascular resistance, and the first derivative of left ventricular pressure but decreased mean aortic pressure from 91 +/- 4 to 76 +/- 3 mmHg (P less than 0.001) and cardiac output from 153 +/- 15 to 130 +/- 9 ml.kg-1.min-1 (P less than 0.02). Right atrial pressure and left ventricular end-diastolic pressure also decreased. Mean circulatory filling pressure decreased from 7.1 +/- 0.3 to 6.0 +/- 0.3 mmHg (P less than 0.001), but venous compliance and unstressed vascular volume did not change. Resistance to venous return increased from 0.056 +/- 0.008 to 0.063 +/- 0.010 mmHg.ml-1.kg.min (P less than 0.05). Arterial compliance increased from 0.060 +/- 0.003 to 0.072 +/- 0.004 ml.mmHg-1.kg-1 (P less than 0.02). Total blood volume and central blood volume decreased from 82.2 +/- 3.1 to 76.2 +/- 4.6 and from 19.8 +/- 0.8 to 17.6 +/- 0.6 ml/kg (P less than 0.02), respectively. Blood flow increased to the kidneys. We conclude that ANP decreases cardiac output by decreasing total blood volume. This results in a lower operating pressure and volume in the venous capacitance system with no significant venodilating effects. Cardiac factors and a redistribution of flow to the splanchnic organs are not important mechanisms to explain the decrease in cardiac output with ANP.
Autoradiographic characterization of beta-adrenoceptors in rat heart valve leaflets
Authors: Pinto J. E. , Nazarali A. J. , Torda T. , Saavedra J. M.
Published: December 2017

beta-Adrenoceptors were localized and characterized in valve leaflets of the rat heart. Sixteen micrometer-thick tissue sections containing the mitral and aortic valves were incubated with (-)3-[125I]iodocyanopindolol followed by autoradiography with computerized microdensitometry and comparison with 125I-labeled standards. beta-Adrenoceptors were present in all the valves studied. The selective beta 1-adrenoceptor antagonist CGP 20712 A (100 nM) displaced not more than 20% of the total binding sites, suggesting that most of the beta-adrenoceptors in the valve leaflets are of the beta 2-subtype. Forskolin-binding sites were detected in the mitral valve leaflet by incubation of adjacent tissue sections with [12-3H]forskolin. Our results indicate that catecholamines could regulate the function of the heart valves through stimulation of beta 2-adrenoceptors.
Vasomotor activity of moderately well-developed canine coronary collateral circulation
Authors: Hautamaa P. V. , Dai X. Z. , Homans D. C. , Bache R. J.
Published: December 2017

This study examined the ability of moderately well-developed coronary collateral vasculature to undergo vasoconstriction in response to alpha-adrenergic agonists, vasopressin and angiotensin, and vasodilation in response to nitroglycerin. Studies were performed in 20 dogs 4-16 wk after left anterior descending coronary artery occlusion had been produced by an Ameroid constrictor or hollow intravascular plug. Collateral flow was estimated from retrograde flow from the cannulated left anterior descending artery. Tissue flow was measured with microspheres. Agonists were introduced into the left main coronary artery to reach collaterals arising from the left circumflex and septal arteries. Vasopressin and angiotensin II decreased retrograde flow from 22.7 +/- 5.5 to 15.5 +/- 2.7 and from 19.2 +/- 2.8 to 14.3 +/- 1.9 ml/min, respectively (each P less than 0.05). Both agents also significantly decreased tissue flow to normally perfused and collateral dependent myocardium. Neither the selective alpha 1-adrenergic agonist phenylephrine nor the alpha 2-agonist B-HT 933 decreased retrograde flow. Nitroglycerin increased retrograde flow by 63 +/- 27% (P less than 0.01). Thus, although the moderately well-developed coronary collateral circulation is capable of vasoconstriction in response to vasopressin and angiotensin II, these data fail to support a role for alpha-adrenergic mechanisms in modulating collateral flow.
Arginine vasopressin potentiates natriuretic effect of atrial peptide
Authors: Graczak L. M. , Nicolodi L. K. , Hartupee D. A. , Blaine E. H.
Published: December 2017

We investigated potentiation of atrial peptide (AP)-induced natriuresis by vasopressin in anesthetized rats. Increasing doses of vasopressin potentiated AP-induced natriuresis in a dose-dependent manner, e.g., sodium excretion during AP administration (290 ng/min) was 0.66 +/- 0.16, 2.02 +/- 0.68, 5.21 +/- 1.38 and 7.08 +/- 1.96 mu eq/min during infusion of 0.00, 0.78, 1.56, and 3.12 ng.kg-1.min-1 of vasopressin, respectively. Vasopressin alone had no effect on sodium excretion. In a second experiment, vasopressin (1.56 ng.kg-1.min-1) potentiated AP (128 ng/min)-induced natriuresis similar to that seen in the first experiment. In this experiment, glomerular filtration rate (GFR) and mean arterial pressure were monitored. Mean arterial pressure was no different between the groups treated with AP plus vasopressin and AP alone. Glomerular filtration was actually reduced in the group treated with vasopressin plus AP, suggesting that neither changes in GFR nor blood pressure were responsible for potentiation of the natriuresis. A third experiment compared the ability of 1-desamino-8-D-arginine vasopressin (dDAVP), a nonpressor analogue of vasopressin, to vasopressin in enhancing AP (145 ng/min)-induced natriuresis. The nonpressor analogue did not potentiate AP-induced natriuresis, whereas vasopressin had the same effect as in the first two experiments. These are the first studies to report a functional interaction between AP and vasopressin. They show that vasopressin potentiates AP-induced natriuresis without altering mean arterial pressure or GFR.
Impedance of arterial system simulated by viscoelastic t tubes terminated in windkessels
Authors: Liu Z. R. , Shen F. , Yin F. C.
Published: December 2017

An improved asymmetric t-tube model of the arterial system is proposed. The model consists of two viscoelastic tubes of differing lengths, each terminated in a modified windkessel with inductance as well as resistance and compliance. Equations for calculating the input impedance of this model are presented. Using typical data from the literature, the model predicts a more realistic impedance modulus and phase than previous models of the circulation. Parametric analysis shows that when peripheral compliances are altered, sharp peaks in the very low frequency portions of the impedance spectra are produced, whereas alterations of either the characteristic impedances or inductances of the terminations have little effect on input impedance. Alteration of the elasticity or relative lengths of the tubes results in shifts in the positions of the maxima and minima akin to those observed experimentally. Change in the viscosity of the walls or of the blood only affects the fluctuations of the impedance spectra without affecting the positions of the maxima and minima. Thus, with this still simple model, very realistic impedance spectra are obtainable. The model provides more insight than previously proposed models into the individual influence of various parameters of the proximal and peripheral vasculature on central hemodynamics.
Intraocular oxygen tension measured with a fiber-optic sensor in normal and diabetic dogs
Authors: Stefansson E. , Peterson J. I. , Wang Y. H.
Published: December 2017

A new fiber-optic O2 sensor was used to measure the O2 tension in the living dog eye, and the results were compared with simultaneous O2 tension measurements with polarographic electrodes. The fiber-optic sensor and the polarographic electrodes gave similar readings of anterior chamber O2 tension and gave an identical response to elevation of inspired O2 levels. In the preretinal vitreous, the fiber-optic probe measured the O2 tension 26 +/- 5 mmHg (means +/- SD, n = 5), whereas the polarographic electrode showed 23 +/- 7 mmHg (means +/- SD, n = 5) in the contralateral eyes. Breathing 100% O2 raised the preretinal O2 tension similarly with both systems. Preretinal O2 tension was measured with the fiber-optic sensor in seven alloxan diabetic dogs and was 26 +/- 7 mmHg, which is not significantly different from normal dogs. The fiber-optic sensor has some advantages over the polarographic electrodes. The fiber-optic sensor does not consume O2 and is not dependent on the diffusion characteristics of the medium or changes due to stirring or fluid currents.
alpha-Tocopherol attenuates myocardial membrane-related alterations resulting from ischemia and reperfusion
Authors: Massey K. D. , Burton K. P.
Published: December 2017

Myocardial ischemia and reperfusion have been shown to result in damage to the phospholipid components of cardiac myocyte cell membranes as indicated by the tissue accumulation of unesterified fatty acids (UFA). A portion of this damage and subsequent dysfunction may be a consequence of free radical-induced membrane lipid peroxidative events. alpha-Tocopherol, a lipophilic antioxidant, was used in this study as an agent by which the extent of ischemia and reperfusion injury might be decreased. Increasing rat myocardial tissue levels of alpha-tocopherol by 51% was found to attenuate lipid perturbations as determined by the accumulation of tissue UFA in an isolated heart model of global ischemia and reperfusion. Nontreated hearts made ischemic for 25 min with 30 min of reflow had a significantly increased total UFA level of 5,961 +/- 799 nmol/mg protein (P less than 0.05) compared with control perfused hearts containing 3,116 +/- 463 nmol UFA/mg protein and with alpha-tocopherol-treated ischemic and reperfused hearts containing 3,066 +/- 365 nmol UFA/mg protein. Contractile dysfunction, excessive accumulation of tissue calcium, and release of lactate dehydrogenase after ischemia and reperfusion were also reduced, demonstrating protective effects in alpha-tocopherol-treated hearts. Thus alpha-tocopherol proved effective in the attenuation of ischemia and reperfusion damage. These results suggest that reducing lipid alterations may prove beneficial in protecting against membrane damage subsequent to ischemia and reperfusion.
Laser-Doppler assessment of brain microcirculation: effect of local alterations
Authors: Haberl R. L. , Heizer M. L. , Ellis E. F.
Published: December 2017

The objective of this study was to determine whether changes in blood perfusion measured by laser-Doppler (LD) flowmetry correlate with simultaneously measured changes in pial arteriolar diameter after local application of vasoactive agents on the brain surface. A closed cranial window was implanted in anesthetized rabbits. A 0.84-mm-diam LD probe was inserted through one window port and fixed at a distance of 1-2 mm from the cortical surface. The probe detects changes in perfusion within a tissue volume of approximately 1 mm3. The diameter of pial arterioles in the area adjacent to the LD probe was simultaneously measured with a microscope and image-splitting device. Topical application of bradykinin (80 nM to 8 microM), which stimulates the formation of dilator prostaglandins and O2 radicals, induced a dose-dependent arteriolar dilation and increase in LD flow. Topical application of 33 microM 2-chloroadenosine, a stable analogue of adenosine, induced the same degree of pial arteriolar dilation as 8 microM bradykinin but produced a much larger increase in LD flow, probably due to its greater tissue penetration and stability. At 5 min after bradykinin washout the arterioles had nearly returned to their control diameter, whereas LD flow was still increased. Similarly, there was a discrepancy between LD flow and diameter changes after washout of 2-chloroadenosine. We conclude that LD flowmetry is a useful technique for continuous assessment of cortical blood flow in response to topically applied agents.(ABSTRACT TRUNCATED AT 250 WORDS)
Dietary omega 3 fatty acids and endothelium-dependent relaxations in porcine coronary arteries
Authors: Shimokawa H. , Vanhoutte P. M.
Published: December 2017

Dietary supplementation with cod-liver oil significantly augments endothelium-dependent relaxations in porcine coronary arteries. The present study was designed to examine the effect of dietary administration of omega 3 polyunsaturated fatty acids (mainly eicosapentaenoic acid, the major component of fish oil) on endothelium-dependent relaxations in porcine coronary arteries. Male Yorkshire pigs were maintained 4 wk on a regular diet with or without supplementation with purified eicosapentaenoic acid (3.5 g/day) and docosahexaenoic acid (1.5 g/day). Endothelium-dependent relaxations were examined in vitro. In rings from the treated group, endothelium-dependent relaxations were augmented in response to bradykinin, serotonin, and ADP, but not to the calcium ionophore A23187. These augmentations were not altered by indomethacin but were significantly inhibited by methylene blue, an inhibitor of guanylate cyclase. In the treated group, endothelium-dependent relaxations to aggregating platelets also were significantly augmented; platelet-induced contractions of quiescent rings were inhibited more by the presence of the endothelium than in arteries from the control group. Bioassay experiments demonstrated that the release of endothelium-derived relaxing factor(s) by bradykinin and relaxations of the vascular smooth muscle to the factor(s) were greater in arteries from the treated group. These observations indicate that dietary omega 3 polyunsaturated fatty acids augment receptor-operated endothelium-dependent relaxations, partly due to the augmented release of endothelium-derived relaxing factor(s) and partly due to the augmented relaxation of the vascular smooth muscle to the factor(s).
Alveolar hypoxia is a powerful stimulus for ANF release in conscious lambs
Authors: Baertschi A. J. , Teague W. G.
Published: December 2017

The effect of acute alveolar hypoxia [fractional concentration of O2 in inspired gas (FIo2) = 0.1] for 10 min [arterial PO2 = 37 +/- 4 (SE) mmHg] and of blood volume expansion (7 and 15% of calculated blood volume) on atrial natriuretic factor (ANF) release was examined in groups of awake, instrumented young lambs. Systemic venous plasma ANF concentrations increased 1.6-fold (P less than 0.01) during blood volume expansion of 7%, 1.9-fold (P less than 0.01) during acute hypoxia, and 2.2-fold (P less than 0.005) during blood volume expansion of 15%. In lambs with prior 15% blood volume expansion, alveolar hypoxia further increased ANF concentrations 3.1-fold (P less than 0.01), suggesting synergism between volume and hypoxia stimuli. Hypoxia-induced ANF release correlated best with increased pulmonary arterial pressure, a potential mediator of the ANF response (r = 0.67; P less than 0.016). Increased differences between pulmonary arterial and systemic venous plasma ANF concentrations (from 11 to 134 pg/ml) indicate that hypoxia causes increased release of ANF from the heart rather than decreased metabolism of circulating ANF. Pulmonary arterial plasma ANF during hypervolemic hypoxia had immunological and chromatographic (high-performance liquid chromatography) properties of Pro-ANF-(99-126) [alpha-ANF-(1-28)]. Thus alveolar hypoxia (FIo2 = 0.1) is as potent as 15% blood volume expansion in increasing the concentration of circulating ANF. This newly described endocrine response could be important during alveolar hypoxia to decrease pulmonary vasoconstriction and fluid accumulation in the lung.
Vascular responsiveness in adrenalectomized rats with corticosterone replacement
Authors: Darlington D. N. , Kaship K. , Keil L. C. , Dallman M. F.
Published: December 2017

To determine under resting, unstressed conditions the circulating glucocorticoid concentrations that best maintain sensitivity of the vascular smooth muscle and baroreceptor responses to vasoactive agents, rats with vascular cannulas were sham-adrenalectomized (sham) or adrenalectomized (ADRX) and provided with four levels of corticosterone replacement (approximately 100 mg fused pellets of corticosterone: cholesterol 0, 20, 40, and 80% implanted subcutaneously at the time of adrenal surgery). Changes in vascular and baroreflex responses were determined after intravenous injection of varying doses of phenylephrine and nitroglycerin with measurement of arterial blood pressure and heart rate in the conscious, chronically cannulated rats. Vascular sensitivity was decreased, and resting arterial blood pressure tended to be decreased in the adrenalectomized rats; both were restored to normal with levels of corticosterone (40%), which also maintained body weight gain, thymus weight, and plasma corticosteroid binding globulin concentrations at normal values. The baroreflex curve generated from the sham group was different from the curves generated from the ADRX+0, 20, and 40% groups, but not different from that of the ADRX+80% group, suggesting that the baroreflex is maintained by higher levels of corticosterone than are necessary for the maintenance of the other variables. These data demonstrate that physiological levels of corticosterone (40% pellet) restore vascular responsiveness, body weight, thymus weight, and transcortin levels to normal in ADRX rats, whereas higher levels (80% pellet) are necessary for restoration of the baroreflex.
Two types of calcium channels in isolated smooth muscle cells from rat tail artery
Authors: Wang R. , Karpinski E. , Pang P. K.
Published: December 2017

Whole cell patch-clamp recordings were carried out on smooth muscle cells from rat tail artery in short-term culture to verify the existence of and to characterize the calcium channels that are present. Two types of voltage-dependent calcium channels were identified in 55 of 63 cells studied. The T-type calcium channel was activated at -50 mV, and the peak inward current occurred at -10 mV, whereas the L-type channel was activated at -20 mV, and the peak inward current occurred at +10 or +20 mV. The T-type channel current inactivated quickly in contrast to the much slower inactivation of the L-channel current. The voltage dependence of steady-state inactivation of the two channels was similar to that reported for other vascular smooth muscle preparations. An internal solution containing Cs2-aspartate maintained the calcium-channel currents for at least 20 min with only a 5-10% decline. BAY K 8644 had no effect on T-channel currents, but the L-channel current was increased by at least a factor of two. In addition, BAY K 8644 shifted the activation threshold, the peak inward current, and the steady-state inactivation-activation curves of L-type channel currents in the direction of hyperpolarization.
Age-related central and baroreceptor impairment in female Sprague-Dawley rats
Authors: Tanabe S. , Bunag R. D.
Published: December 2017

To determine whether baroreflex sensitivity changes with age, we compared drug-induced reflex responses in 2- and 9-mo-old female Sprague-Dawley rats anesthetized with urethan-chloralose. Baroreflexes were stimulated by elevating or lowering blood pressure with intravenous infusions of phenylephrine or sodium nitroprusside. Reflex responses in heart rate and sympathetic nerve activity during phenylephrine infusions were weaker in 9- than in 2-mo-old rats, as were reflex tachycardia during sodium nitroprusside infusion and decreases in heart rate and sympathetic nerve activity elicited by electrical stimulation of the left aortic depressor nerve. Afferent aortic nerve activity was also appreciably lower in 9-mo-old rats at pressures greater than 130 mmHg but did not differ between rat groups at normotensive pressures. These results suggest that baroreflex sensitivity in 9-mo-old rats can be characterized as follows: 1) impaired at pressures greater than 130 mmHg but still adequate at normotensive pressures, and 2) all reflex arc components may be impaired.
Influence of site of regional ischemia on nonischemic thickening in anesthetized dogs
Authors: Marino P. N. , Kass D. A. , Becker L. C. , Lima J. A. , Weiss J. L.
Published: December 2017

The effect of varying the site of acute regional ischemia on nonischemic myocardial function was examined by comparing regional thickening during 2-3 min circumflex (Circ) vs. left anterior descending (LAD) coronary artery occlusions in eight open-chest dogs. Cross-sectional midwall two-dimensional echocardiograms were obtained, and systolic thickening was measured at 16 equal-spaced points around the circumference. The distribution and extent of hypoperfusion was assessed by radiolabeled microspheres. The echo slice was subdivided into a hypoperfused region (Hypo), four adjacent nonischemic regions (ADJ1-4), and the remaining remote segments (Remote). The extent of hypoperfusion (%LV mass) was similar with both sets of occlusions (LAD, 29.4 +/- 2.8%; Circ, 26.0 +/- 4.4%; P = NS), as was endo- and epicardial flow in the nonischemic regions. Yet, even with like-sized Hypo regions, thickening of nonischemic myocardium was significantly greater during Circ than during LAD occlusions (P less than 0.001). These results are consistent with recently reported disparities of global functional impairment during LAD vs. Circ ischemia. The responses likely reflect differences in regional wall geometry, loading, and the three-dimensional distribution of coronary hypoperfusion between the two vascular territories.
Effect of salt deprivation on blood pressure in rats
Authors: Ott C. E. , Welch W. J. , Lorenz J. N. , Whitescarver S. A. , Kotchen T. A.
Published: December 2017

In most cases blood pressure (BP) is directly related to NaCl intake. In some studies, BP is increased by low salt intake. The effect of Na and Cl deprivation or selective Na deprivation on BP in the normotensive Sprague-Dawley rat was investigated. In study 1, rats were uninephrectomized and fed low NaCl, normal NaCl, or low Na-normal Cl for 3 wk. BP was higher (P less than 0.05) in rats fed low NaCl and low Na-normal Cl than normal NaCl. Plasma renin activity was stimulated by low NaCl intake but was not different between the other two groups. After captopril treatment, BP was lower in the low NaCl group (73.1 +/- 3.6 mmHg) than in the normal-NaCl (99.2 +/- 6.7 mmHg) or low Na-normal Cl (92.0 +/- 6.7 mmHg) groups. In study 2, intact rats (n = 8 per group) were fed low (less than 0.01%), normal (1%), or high NaCl (4%) for 1 wk. BP and heart rate were higher in the low-NaCl group (P less than 0.05) than in the other two groups. Plasma volumes were not different among the groups. In study 3, two groups of eight rats were given either low NaCl or 2% NaCl for 2 wk. BP (131.4 +/- 3.6 mmHg) and heart rate (402 +/- 11 beats/min) were higher in the low-NaCl group than in the 2% NaCl group (121.1 +/- 3.2 mmHg and 369 +/- 9 beats/min, respectively). In the normotensive Sprague-Dawley rat, low NaCl intake elevated BP when compared with normal or high NaCl intake. Part of the increase in the uninephrectomized, Cl-supplemented group is not dependent on the renin-angiotensin system.
Frog ventricle: participation of SR in excitation-contraction coupling
Authors: Anderson M. E. , Fox I. J. , Swayze C. R. , Donaldson S. K.
Published: December 2017

Activation of the first beat (B1) following a 60-s pause is diminished in isometrically contracting frog ventricular strips, in contrast to the augmentation documented for sarcoplasmic reticulum (SR)-dependent mammalian myocardium. However, treatment of frog ventricular strips with ouabain, an indirect inhibitor of the sarcolemmal Na+-Ca2+ exchanger, selectively enhanced postpause beats suggesting that in the absence of ouabain significant extrusion of cellular Ca2+ occurred during the pause. Because resting tension did not increase during the pause in ouabain-treated strips, the nonextruded Ca2+ must have been sequestered into a compartment such as SR. Steady-state beats were not affected by ouabain; its actions appeared to be separate from its known positive inotropism. Caffeine, a direct SR stimulus, initially enhanced B1 and subsequently decreased activation of all beats, which was consistent with initial augmentation of SR Ca2+ release and subsequent depletion of SR Ca2+ stores. Ouabain both potentiated the stimulatory effects and blocked the inhibitory effects of caffeine, suggesting that ouabain increased Ca2+ stores in the same intracellular Ca2+ pool as that acted on by caffeine, the SR. Ryanodine, an inhibitor of SR in mammalian myocardium, did not affect activation of frog myocardium. SR may be an important site for activator Ca2+ cycling in frog myocardium under control conditions as well as after long diastolic intervals in the presence of ouabain.
Cumulative deterioration of myocardial function after repeated episodes of exercise-induced ischemia
Authors: Homans D. C. , Laxson D. D. , Sublett E. , Lindstrom P. , Bache R. J.
Published: December 2017

To determine whether progressive regional myocardial dysfunction occurs after repetitive episodes of exercise-induced ischemia, 10 dogs were instrumented with ultrasonic microcrystals for determination of regional myocardial wall thickening, circumflex artery electromagnetic flow probes, and hydraulic coronary artery occluders. Dogs performed treadmill exercise in the presence of a coronary artery stenosis, which limited coronary blood flow to control levels. Dogs performed a single 10-min exercise period one day and three identical runs separated by 1-h rest periods on the alternate day. At rest before the first exercise period, circumflex wall thickening was 18.8 +/- 6.7% and increased to 25.5 +/- 10.6% during exercise before the application of coronary stenosis. On the day that three exercise trials were performed, circumflex systolic wall thickening at rest before the third exercise period (9.7 +/- 4.0%) and during exercise without coronary stenosis (17.3 +/- 7.3%) were both significantly lower than during the first exercise period (P less than 0.0125). During exercise with stenosis, circumflex systolic wall thickening fell to 4.6 +/- 4.7% during a single run, and 5.0 +/- 2.0% during the third of three consecutive runs. Wall thickening was significantly lower 2 h after the third consecutive run (9.1 +/- 2.4%) than 2 h after a single period of exercise-induced ischemia (14.8 +/- 7.6%; P 0.0125). Transmural myocardial blood flow to circumflex myocardium during the third period of exercise-induced ischemia (0.93 +/- 0.47 ml.min-1.g-1) was not different than during the single period of exercise (0.84 +/- 0.47 ml.min-1.g-1). It is concluded that repetitive episodes of exercise-induced ischemia result in cumulative postexercise regional myocardial dysfunction.
Noninvasive determination of hemoglobin saturation in dogs by derivative near-infrared spectroscopy
Authors: Ferrari M. , Wilson D. A. , Hanley D. F. , Hartmann J. F. , Rogers M. C. , Traystman R. J.
Published: December 2017

An in vivo method utilizing derivative near-infrared spectroscopy was developed to noninvasively determine cerebral venous hemoglobin O2 saturation (SVO2). The method was tested on eight pentobarbital-anesthetized dogs ventilated with differing inspired O2 mixtures to force changes in SVO2 over a wide range. Spectral data obtained by transilluminating the tissues surrounding the superior sagittal sinus (SS) were transformed into first derivative units for correlation with SVO2 data measured from the SS. Linear regression analysis was applied to data obtained from five dogs and used to build a three-wavelength algorithm for predicting brain SVO2. In three dogs, SVO2 was varied to test this equation ability to predict SVO2. The standard deviation of differences between measured SVO2 and SVO2 predicted from 31 separate spectra was 3.2%. These predicted values, when regressed against the sampled SVO2, yielded an r value of 0.97. The results demonstrate that during hypoxic hypoxia (HH) it is possible to noninvasively quantify SVO2 with the use of infrared spectroscopy.
A novel effect of norepinephrine on cardiac cells is mediated by alpha 1-adrenoceptors
Authors: Fedida D. , Shimoni Y. , Giles W. R.
Published: December 2017

In the heart, alpha-adrenergic agonists have long been known to produce a positive inotropic effect that is rate dependent and associated with action potential prolongation but is not accompanied by adenosine 3',5'-cyclic monophosphate (cAMP) elevation. The ionic mechanism of these effects is unknown. We report that a transient outward K+ current, a major determinant of plateau duration in rabbit and human atria, is strongly inhibited by norepinephrine and the alpha-adrenoceptor agonists methoxamine and phenylephrine. These effects of alpha-stimulation can be blocked by prazosin. The reduction in the transient outward current substantially slows action potential repolarization. These results can explain the regional and species-dependent positive inotropic effects of alpha-adrenergic stimulation in the heart and give important new insight into the autonomic regulation of cardiac function. In addition, reduction in this repolarizing current during the enhanced alpha-adrenergic responsiveness of myocardial ischemia may be a factor in the genesis of arrhythmias produced by catecholamines.
Responses of thoracolumbar spinal neurons to renal artery occlusion
Authors: Ammons W. S. , Sinha R.
Published: December 2017

Experiments were performed to examine responses of spinal neurons to activation of renal chemoreceptors during renal artery occlusion (RAO). One hundred twenty-two spinal neurons were studied in 33 cats that were anesthetized with alpha-chloralose. Cells studied in the L2-T11 segments were excited by electrical stimulation of the renal nerves and responded to stimulation of somatic structures. RAO (90 s) excited 67 cells (55%). Twenty-eight cells were excited at the onset of occlusion (from 5 +/- 1 to 27 +/- 5 spikes/s) and then either completely or partially adapted (ON responses). Another 39 cells were excited at the onset of occlusion, adapted to varying degrees, and then exhibited a second increase in activity beginning 41 +/- 7 s into the occlusion period [onset-ischemic (ON/IS) responses]. The secondary increase reached a peak of 15 +/- 2 spikes/s 65 s after occlusion. Among the responding cells, ON responses were associated with cells receiving A delta only or with cells with A delta- and C-fiber renal inputs. In contrast, 100% of cells with ON/IS response received both A delta- and C-fiber inputs. Probability of finding responding cells was greatest in the most rostral segments. We conclude that ON responses to RAO are due to activation of mechanoreceptors in the renal artery. ON/IS responses must have resulted from activation of mechanoreceptors followed by activation of renal chemoreceptors in association with development of renal ischemia. These data provide evidence for activation of spinal neurons by RAO. These neurons may be important for renal reflexes of chemoreceptor origin.
Vasopressin potentiates ventricular and arterial reflexes in the conscious nonhuman primate
Authors: Barazanji M. W. , Cornish K. G.
Published: December 2017

The effect of arginine vasopressin (AVP) on the arterial baroreflex control of heart rate (HR) was studied in intact and sinoaortic-denervated (SAD) conscious, unrestrained monkeys. A baroreflex curve for mean arterial blood pressure (MABP) and HR was determined before and during intravenous infusion of AVP (2-4 mU.kg-1.min-1) and after the AVP vascular antagonist "Manning compound" [( d(CH2)5Tyr(Me)]AVP, 40 micrograms/kg), while AVP infusion was kept running. The sensitivity (slope) of the arterial baroreflex, as well as the reflex bradycardia induced by high blood pressure, increased significantly during AVP and returned to the control level after Manning compound. The effect of AVP on the Bezold-Jarisch reflex (induced by stimulating left ventricular receptors with 4 micrograms/kg veratridine injected in the left atrium) was also studied. The cardiovascular responses to veratridine were examined before and during AVP and after administration of Manning compound together with AVP infusion. AVP significantly potentiated the hypotension and the bradycardia produced by veratridine, whereas Manning compound blunted this potentiation. The ventricular reflex in SAD monkeys was significantly greater than in intact monkeys. We conclude that, in the conscious nonhuman primate, AVP potentiates the sensitivity of the baroreflex control of HR as well as the Bezold-Jarisch reflex. The potentiation of the Bezold-Jarisch reflex by AVP in the SAD animals is consistent with a central action, since the baroreceptors and ventricular receptors both have connections in the nucleus tractus solitarius. However, it does not rule out the possibility of peripheral actions on receptors or end organs.
An automatic syringe for coronary occlusion in long-term collateralization studies
Authors: Caldwell W. M. , McKown D. P. , Bleck J. A. , Hartley J. W. , Erdal T. , Barrett E. E. , Franklin D.
Published: December 2017

A portable apparatus for performing repeated, brief coronary artery occlusions automatically in long-term chronic studies involving dogs and larger animals is described. The battery-operated, back-pack-carried device uses a motorized syringe driven by a digital-programmable timing circuit to inflate a coronary artery occluder for durations of 10 s to 3 min at intervals from 14 s to 16 h. A single battery charge produces 450 occlusions. The generated pressure is adjustable to 1,000 mmHg maximum. A separate fail-safe circuit monitors system operation to open a pressure-relief valve if occlusions exceed a preset duration.
Mechanism of membrane phospholipid degradation in ischemic-reperfused rat hearts
Authors: Otani H. , Prasad M. R. , Jones R. M. , Das D. K.
Published: December 2017

We investigated the mechanism of membrane phospholipid degradation during reperfusion of ischemic myocardium using isolated and perfused rat hearts. Thirty min of myocardial reperfusion after 30 min of normothermic global ischemia resulted in a significant decrease of phosphatidylcholine (PC) content associated with a small but significant increase in lysophosphatidylcholine (LPC) content. Myocardial ischemia for up to 60 min caused no significant loss of any of the major phospholipids. Isotopic incorporation of [14C]arachidonic acid (AA) as well as [3H]-glycerol into PC was significantly attenuated in the ischemic-reperfused heart compared with the normally perfused heart, suggesting that both reacylation and de novo pathways for PC synthesis were inactivated during reperfusion. In the heart prelabeled with [14C]AA, the radiolabeled PC was decreased significantly during reperfusion, associated with a small but significant increase in [14C]AA accumulation. The decreases of PC content and incorporation of [14C]AA into PC, as well as the increases of LPC content and the [14C]AA during reperfusion, were prevented by reperfusion with low Ca2+ (50 microM) buffer or by pretreatment with trifluoperazine (10 microM) or mepacrine (50 microM), but not with verapamil (1 microM). The inhibition of loss of PC was associated with significant diminution of creatine kinase release from the reperfused hearts. The present study indicates that the net loss of membrane phospholipids, especially with respect to PC during reperfusion, may result from 1) inhibition of reacylation of AA, 2) inhibition of de novo synthesis, and 3) stimulation of phospholipase activity. These results are consistent with an influx of Ca2+, although other interpretations are also possible.
Pressure response to quick volume changes in tetanized isolated ferret hearts
Authors: Campbell K. B. , Rahimi A. R. , Bell D. L. , Kirkpatrick R. D. , Ringo J. A.
Published: December 2017

Observed pressure responses to quick volume changes in the isolated tetanized heart of ferrets were compared with previously reported tension responses to quick length changes in isolated cardiac muscle. Hearts were isolated from ferrets, perfused with ryanodine solution, and stimulated rapidly (50 ms between stimulations) to produce repeated 4-s intervals of tetanus. During each tetanus interval, volume increments of different amplitudes were rapidly removed and then reinfused into the left ventricular chamber. The pressure responses to these volume changes were evaluated for differences between withdrawals and infusions and for dependence on the amplitude of the volume change. It was found for both withdrawal and infusion that the response could be divided into three phases: 1) an immediate phase coincident with volume change, 2) a fast-recovery phase, and 3) a slow-recovery phase. The amplitude of the immediate phase was linearly dependent on the volume change so that a single regression line fit all the data (withdrawal and infusion). The fast recovery phase was 2.5 times faster for infusion than for withdrawal and generated a rebound effect with the pressure going below the initial pressure in the response to infusion. The pressure never went above the initial pressure in the response to withdrawal. The slow-recovery phases in infusion and withdrawal did not differ. These responses in the isolated heart bear striking similarities to tension responses to quick length changes in isolated constantly activated cardiac muscle. We concluded that muscle fiber dynamics were being faithfully transformed to left ventricular (LV) chamber dynamics without appreciable distortion because of the many intervening factors between the wall muscle fiber and the LV chamber.(ABSTRACT TRUNCATED AT 250 WORDS)
Degradation of adenine nucleotides in ischemic and reperfused rat heart
Authors: Van Bilsen M. , van der Vusse G. J. , Coumans W. A. , de Groot M. J. , Willemsen P. H. , Reneman R. S.
Published: December 2017

Complete cessation of flow in isolated rat hearts for 90 min resulted in a gradual breakdown of ATP and concomitant accumulation of degradation products, such as adenosine, inosine (major break-down product), hypoxanthine, and, to a lesser extent, xanthine. After 45 min of ischemia, the content and relative composition of purines hardly changed, whereas the AMP content continued to rise. This finding points to constraints on AMP degradation and flux through the degradation pathway from adenosine to uric acid in the ischemic heart. In myocardial preparations, the cells of which were deliberately disrupted by freezing and thawing before anoxic incubation, AMP did not accumulate and was finally converted to hypoxanthine. These results indicate that compartmentalization of substrates and enzymes is responsible for the observed preferential accumulation of AMP and inosine in the ischemic heart. Inhibition of hypoxanthine degradation is explained by the absence of oxygen. Restoration of flow and oxygen supply abolished the inhibition of metabolic flux. Accumulated purines were released into the coronary effluent and, concomitantly, further metabolized. Comparison of tissue levels of hypoxanthine, xanthine, and uric acid before reperfusion and the amounts released during reperfusion indicates that in rat myocardium substantial amounts of potentially hazardous xanthine oxidase-derived reactive oxygen species are likely to be formed during the early reperfusion phase.
Effect of coronary occlusion and reperfusion on myocardial blood flow during infarct healing
Authors: Connelly C. M. , Leppo J. A. , Weitzman P. W. , Vogel W. M. , Apstein C. S.
Published: December 2017

Coronary occlusion (CO) of 1 h or longer causes transmural myocardial infarction (MI) in the rabbit. We studied how reperfusion of an infarct affected myocardial blood flow (MBF) acutely and after 3 wk of healing. CO was performed in rabbits for 60 or 180 min (n = 22) followed by reperfusion, and MBF to normal and infarcted zones was determined by radioactive microspheres. In a separate series (n = 23), MBF was measured at 21-25 days post-CO in three groups that had either permanent CO or reperfusion after 60 or 180 min of CO. MBF to the infarct was approximately 8 +/- 3% (+/-SE) of normal MBF (3.8 +/- 0.5 ml.min-1.g-1) during 60-180 min of CO but 3 wk later had increased to 33 +/- 6% of normal MBF (P less than 0.005). Reperfusion after 60 or 180 min of CO resulted in 74 +/- 6% and 41 +/- 5% return of normal MBF, respectively, but 3 wk later, MBF had decreased to 25 +/- 5% (P less than 0.001) and 24 +/- 4% (P less than 0.025) of normal MBF, respectively. Thus after 3 wk of postinfarction healing, MBF to the permanently occluded infarcts increased fourfold, whereas MBF decreased by 50% in the reperfused infarcts so that MBF to the scar tissue was comparable among the three groups and was not influenced by acute post-MI reperfusion.
Possible inhibition of canine ventricular sarcoplasmic reticulum by BAY K 8644
Authors: Hryshko L. V. , Kobayashi T. , Bose D.
Published: December 2017

The calcium-channel agonist-antagonist racemic mixture of BAY K 8644 as well as the pure calcium-channel agonist enantiomer, converted rest potentiation in canine ventricular muscle to rest depression. The depressed postrest beats had increased action potential plateau heights and durations, suggesting that extracellular calcium entry was enhanced. BAY K 8644 did not alter the time to peak tension of either steady-state or postrest beats. Although BAY K 8644 slightly increased the amplitude of rapid-cooling contractures (RCC) immediately after an electrically evoked steady-state contraction (RCCss), the RCC amplitude rapidly decreased with increasing durations of rest. These results suggest that increased calcium influx because of BAY K 8644 increases the pool of releasable calcium during steady-state stimulation. However, they also indicate that BAY K 8644 causes acceleration of diastolic loss of calcium from the sarcoplasmic reticulum (SR). Scattered light intensity fluctuation measurements showed that the negative inotropic effect of BAY K 8644 on postrest contraction was not caused by calcium overloading of the SR, since BAY K 8644 reduced asynchronous myofilament motion. A negative relationship found between extracellular calcium and BAY K 8644-induced postrest depression also rules out the possibility that the latter effect is caused by intracellular calcium overload. BAY K 8644 seems to accelerate the loss of calcium from the SR during diastole by a pathway that does not appear to pass through the myofilaments.
Effect of oxygen deprivation on metabolism of arachidonic acid by cultures of rat heart cells
Authors: Freyss-Beguin M. , Millanvoye-van Brussel E. , Duval D.
Published: December 2017

To investigate the mechanisms responsible for the impairment of phospholipid metabolism observed in ischemic cells, we have studied the effect of conditions simulating ischemia on the metabolism of arachidonic acid (AA) by muscle (M-) and nonmuscle (F-) cells isolated from newborn rat hearts and cultured separately. In muscle cells, oxygen deprivation induces a significant stimulation of the release of [14C]AA from prelabeled cells associated with a preferential redistribution of [14C]AA into cell triglycerides but not formation of radioactive prostaglandins. Moreover, the fatty acid content of phospholipids, as measured by capillary gas chromatography, appears markedly reduced in ischemic myocardial cells. This fact may be related to phospholipase stimulation during ischemia as suggested by the antagonistic effect of mepacrine or p-bromophenacyl bromide. In contrast, oxygen deprivation failed to induce any significant alteration of AA metabolism in fibroblast-like heart cells. Our results indicate that these cultures of newborn rat heart cells, which exhibit many of the features observed in intact organ during ischemia, may represent a useful experimental model to investigate the pharmacological control of the membrane phospholipid turnover.
Somatostatin stimulates acetylcholine release in the canine heart
Authors: Wiley J. W. , Uccioli L. , Owyang C. , Yamada T.
Published: December 2017

Previous reports of somatostatin's atropine-sensitive negative inotropic effect on cardiac function prompted the present studies to characterize the molecular forms and actions of somatostatin in the canine heart. Radioimmunoassay of cardiac extracts revealed concentrations of somatostatin-like immunoreactivity ranging from 0.50 +/- 0.13 pmol/g tissue (means +/- SE, n = 6) in the pulmonary artery to 0.78 +/- 0.23 pmol/g tissue in the right ventricle. On gel filtration of the extracts, two major molecular forms of somatostatin-like immunoreactivity were elicited, the predominant one coeluting with somatostatin-14 and a minor peak corresponding to somatostatin-28. Experiments performed with slices of atrial septum indicated that somatostatin-14 (10(-10) to 10(-7) M) stimulated the release of acetylcholine in a dose-dependent manner. This action of somatostatin-14 was additive with K+-evoked acetylcholine release, unaffected by hexamethonium, and blocked by tetrodotoxin, suggesting mediation via a nonnicotinic postganglionic neural pathway. Our studies lead us to conclude that somatostatin may function as a neurotransmitter in the heart, which exerts its negative inotropic action by promoting the release of acetylcholine.
Mechanism mediating hypotensive effect of ANF in sodium-depleted dogs
Authors: Granger J. P. , Meadows E. , Sooudi S. , Stacy D. L.
Published: December 2017

Previous studies have indicated that suppression of renin release and antagonism of the vasoconstrictor actions of angiotensin II (ANG II) may be important mechanisms whereby atrial natriuretic factor (ANF) decreases arterial pressure (AP). The objective of this study was to determine the importance of renin suppression and ANG II antagonism in mediating the hypotensive effects of ANF in Na-depleted, high-renin dogs. Infusion of ANF (300 ng.kg-1.min-1) for 45 min in Na-depleted dogs decreased plasma renin activity (PRA) from 7.5 +/- 2.3 to 3.1 +/- 1.1 ng ANG I.ml-1.h-1. Associated with this fall in PRA was a significant reduction in AP and total peripheral resistance (TPR). Although cardiac output (CO) tended to fall, statistically significant reductions in CO (2.11 +/- 0.19 vs. 1.99 +/- 0.10 l/min) did not occur. In contrast to these findings, infusion of ANF (300 ng.kg-1.min-1) in Na-depleted dogs with fixed circulating levels of ANG II had no significant effect on AP or TPR. Results from this study suggest that renin suppression may be an important mechanism whereby ANF reduces AP in Na-depleted dogs. The results also suggest that antagonism of the vasoconstrictor actions of ANG II is not a potent mechanism whereby ANF decreases AP.