bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulmonary vasodilator responses to vagal stimulation and acetylcholine in the cat.
Authors: Nandiwada P A , Hyman A L , Kadowitz P J
Published: June 2012

Responses to vagal stimulation and acetylcholine were investigated in the feline pulmonary vascular bed under conditions of controlled pulmonary blood flow and constant left atrial pressure. Under baseline conditions, electrical stimulation of vagal efferent fibers increases lobar arterial pressure. However, when vasoconstrictor tone was increased, a depressor response was unmasked. The pressor response under baseline conditions and the depressor response under enhanced tone conditions were blocked by phenoxybenzamine and atropine. These data suggest that, in the cat, the vagus is composed of efferent fibers from both the sympathetic and parasympathetic systems. After treatment with 6-hydroxydopamine to destroy the integrity of the sympathetic system, vagal stimulation caused significant frequency-dependent decreases in lobar arterial pressure when lobar vascular tone was increased by infusion of a stable prostaglandin endoperoxide analog or ventilatory hypoxia. Injections of acetylcholine also caused significant dose-related decreases in lobar arterial pressure when lobar vascular resistance was elevated. Depressor responses to vagal stimulation and acetylcholine in 6-hydroxydopamine-treated animals were blocked by atropine and enhanced by physostigmine. Decreases in lobar arterial pressure in response to vagal stimulation in 6-hydroxydopamine-treated animals with enhanced tone were blocked by hexamethonium, whereas responses to injected acetylcholine were not altered by the ganglionic blocking agent. Decreases in lobar arterial pressure in response to vagal stimulation and acetylcholine were similar when the lung was ventilated and when the left lower lobe bronchus was obstructed. In addition, responses to vagal stimulation were similar when systemic arterial pressure was decreased to the level of pressure in the perfused lobar artery. Responses to acetylcholine were not altered after treatment with 5,8,11,14-eicosatetraynoic acid, a lipoxygenase inhibitor. The present data suggest that the feline pulmonary vascular bed is functionally innervated by cholinergic nerves and that vagal stimulation dilates the pulmonary vascular bed by releasing acetylcholine which acts on muscarinic receptors in pulmonary vessels.
Differences in Thallium-201 uptake in reperfused and nonreperfused myocardial infarction.
Authors: Melin J A , Becker L C , Bulkley B H
Published: June 2012

The respective importance of flow and cellular viability in determining initial myocardial thallium uptake was studied in reperfused and nonreperfused experimental myocardial infarction. Open-chest dogs were subjected to permanent coronary artery occlusion of 70-minute (n = 3) or 5-hour duration (n = 5), or to a 3-hour temporary occlusion followed by reflow (n = 14). Thallium uptake 10 minutes after intravenous injection was compared directly with radioactive microspheres in myocardial samples from excised hearts. Triphenyl tetrazolium chloride staining was used to differentiate necrotic and viable samples with confirmation by electron microscopy. In nonreperfused infarcts, thallium uptake occurred despite necrosis, and a close correlation was found between thallium uptake and regional myocardial blood flow. In reperfused infarcts, thallium uptake again occurred, but was reduced relative to flow in necrotic myocardium and, to a lesser extent, in reperfused viable areas. However, because of the high levels of reflow, actual thallium uptake was often more than 50% of normal in reperfused necrotic regions. This study demonstrates that the presence of thallium uptake is an unreliable indicator of myocardial injury and that reperfused necrotic tissue may have remarkably high levels of thallium uptake.
The effect of intracellular oxygen concentration on lactate release, pyridine nucleotide reduction, and respiration rate in the rat cardiac tissue.
Authors: Araki R , Tamura M , Yamazaki I
Published: June 2012

By measuring the absorbance change due to myoglobin oxygenation in hemoglobin-free isolated perfused rat hearts, we analyzed effects of perfusion pressure and heart rate upon the intracellular oxygen concentration. With Langendorff perfusion, the cardiac tissue was kept normoxic (above 50 microM O2) at aortic pressure above 50 cm H2O, but became hypoxic (8 microM O2) at 30 cm H2O. The increase in cardiac work, expressed as the product of peak systolic pressure and heart rate, increased oxygen consumption at aortic pressure of 50-200 cm H2O. The heart was kept normoxic under these conditions. Lactate release, oxygen consumption, and the oxidation-reduction state of pyridine nucleotide were measured as a function of myoglobin oxygenation under various normoxic and anoxic conditions. Pyridine nucleotide fluorescence and lactate release started to increase as the intracellular oxygen concentration decreased to 6 and 10 microM, respectively. Oxygen consumption was kept constant until the oxygen concentration decreased to 10 microM and slowed down below it. A close relationship between oxygen consumption and lactate release was observed. Infusions of epinephrine and norepinephrine under normoxic perfusion conditions increased cardiac work, oxygen consumption, and lactate release. More than 50% of myoglobin was then deoxygenated even under normoxic perfusion conditions. The increase in lactate release was ascribable to the increase in glycolytic flux caused by hypoxia. The change of pyridine nucleotide fluorescence by epinephrine was also explained by hypoxia in cardiac tissue.
Role of intrapulmonary release of eicosanoids and superoxide anion as mediators of pulmonary dysfunction and endothelial injury in sheep with intermittent complement activation.
Authors: Perkowski S Z , Havill A M , Flynn J T , Gee M H
Published: June 2012

In 30 anesthetized sheep, we show that repeated bolus injections of autologous zymosan-activated plasma produce pulmonary hypertension, hypoxemia, intrapulmonary thromboxane release, pulmonary leukostasis, and sustained increases in lung lymph flow and protein clearance. Studies with platelet-rich plasma demonstrated that addition of zymosan-activated plasma does not induce platelet aggregation or thromboxane release. We studied the role of cyclooxygenase products as mediators of these pathophysiological responses by pretreating sheep with either meclofenamate (4 mg/kg) or ibuprofen (12.5 mg/kg). Both drugs inhibited thromboxane release and hypoxemia. Ibuprofen, but not meclofenamate, reproducibly attenuated the hypertensive responses and the increases in lymph flow and protein clearance. Neither drug prevented pulmonary leukostasis. These results demonstrate that cyclooxygenase products mediate the development of complement-induced hypoxemia but are not sole mediators of pulmonary hypertension or increases in vascular permeability. Furthermore, ibuprofen has anti-inflammatory actions, not shared by meclofenamate, which enhance the effectiveness of this drug. Since activated leukocytes release reactive oxygen metabolites, we treated sheep with superoxide dismutase (2800 U/kg per hour) to determine the role of superoxide anions in these responses. This treatment significantly attenuated the increases in lung lymph flow and protein clearance. The results suggest that multiple mediators, which may originate from activated leukocytes sequestered in the pulmonary circulation, contribute to the pathophysiological changes seen with intermittent complement activation. Cyclooxygenase products of arachidonic acid contribute to the hypertension and are solely responsible for the hypoxemia. Reactive oxygen metabolites are important mediators of the complement-induced increases in lung vascular permeability.
Hydrogen peroxide and hydroxyl radical mediation of activated leukocyte depression of cardiac sarcoplasmic reticulum. Participation of the cyclooxygenase pathway.
Authors: Rowe G T , Manson N H , Caplan M , Hess M L
Published: June 2012

Human peripheral blood leukocytes, activated by phorbol myristate acetate, disrupt canine sarcoplasmic reticulum calcium transport, in vitro, by an oxygen-derived free radical mechanism. Activated leukocytes significantly depress Ca++ uptake activity and Ca++ -stimulated, Mg++ -dependent ATPase activity. The depression is completely inhibited by sodium-azide (0.1 mM) or the combination of superoxide dismutase (10 micrograms/ml) and catalase (10 micrograms/ml). Exogenous hydrogen peroxide (0.441-4.41 mM) uncoupled Ca++ uptake activity from ATP hydrolysis, and this effect was inhibited by catalase. Mannitol alone did not inhibit the effects of activated leukocytes, but superoxide plus mannitol (20-100 mM) resulted in normal ATPase activity, while Ca++ uptake remained depressed. In the presence of indomethacin and ibuprofen, activated leukocytes depressed Ca++ uptake and had no effect on ATPase activity. 2-Amino-methyl-4-t-butyl-6-iodophenol (MK-447) further depressed Ca++ uptake and partially inhibited the effect on ATPase activity. Indomethacin plus catalase completely inhibited the effects of activated leukocytes on cardiac sarcoplasmic reticulum. We conclude, first, that activated leukocytes depress canine cardiac sarcoplasmic reticulum Ca++ transport by an oxygen-free radical mechanism with the generation of hydrogen peroxide and hydroxyl radical. In addition to the classical membrane NADPH oxidase system, significant oxygen radical generation can occur through the cyclooxygenase pathway of arachidonic acid metabolism, and seems to be responsible for the generation of the hydroxyl radical.
Relative contribution of vasopressin and angiotensin II to the altered renal microcirculatory dynamics in two-kidney Goldblatt hypertension.
Authors: Ichikawa I , Ferrone R A , Duchin K L , Manning M , Dzau V J , Brenner B M
Published: June 2012

The renal microcirculation was assessed in non-clipped kidneys of 23 Munich-Wistar rats with two-kidney one-clip Goldblatt hypertension. Four weeks after placement of a renal arterial clip, mean systemic arterial pressure averaged 163 +/- 5 mm Hg in hypertensive rats as compared to 108 +/- 2 in sham-operated controls (n = 6 rats). Non-clipped kidneys in hypertensive rats were characterized by higher glomerular capillary hydraulic pressures, single nephron glomerular filtration rate, and afferent arteriolar resistance. The glomerular capillary ultrafiltration coefficient was significantly reduced in hypertensive rats. In 10 of these rats, intravenous infusion of the angiotensin antagonist, saralasin, or the converting enzyme inhibitor, SQ20881, led to significant reductions in systemic arterial pressure and in afferent and efferent arteriolar resistance, on average by 8 +/- 3%, 15 +/- 4%, 28 +/- 5%, respectively. These changes were associated with significant increase in glomerular plasma flow, while ultrafiltration coefficient remained unaffected. In the presence of saralasin or SQ20881, infusion of a specific antagonist of the vascular action of arginine vasopressin led to significant systemic but not renal vasodilation. Thus, whereas systemic arterial pressure fell further, on average by 23 +/- 2%, renal arteriolar resistance remained constant, resulting in marked reduction in glomerular capillary hydraulic pressures (by 18 +/- 2%) and glomerular plasma flow rate (by 28 +/- 10%). Because of these pronounced reductions in glomerular pressures and flows induced by vasopressin antagonist, single nephron glomerular filtration rate fell markedly in hypertensive rats (by 34 +/- 6%) despite normalization of ultrafiltration coefficient. When hypertensive rats (n = 7) were treated with vasopressin antagonist alone, a modest fall in systemic arterial pressure was again observed in the absence of changes in renal arteriolar resistance. Due to this selective extrarenal vasodilatory action of vasopressin antagonist, glomerular capillary hydraulic pressure, plasma flow rate, and single nephron glomerular filtration rate again fell markedly. When these vasopressin antagonist pre-treated hypertensive rats were given saralasin or SQ20881, marked reductions in renal arteriolar resistance were observed in association with a significant increase in glomerular plasma flow rate. These observations made during acute inhibition of angiotensin II and vasopressin indicate that both of these vasopressin hormones may play important roles in maintaining systemic hypertension in hypertensive rat. By virtue of its preferential constrictor effects on extrarenal rather than renal vasculature vasopressin serves to maintain high glomerular pressures and flows in the non-clipped kidney of Goldblatt hypertensive rats.
The effects of adriamycin on normal and ouabain-toxic canine Purkinje and ventricular muscle fibers.
Authors: Binah O , Cohen I S , Rosen M R
Published: June 2012

In the "Na+ lag hypothesis" of cardiac glycoside action, [Ca++]i increases through sodium-calcium exchange following block of the sodium-calcium ATPase. This accumulation of [Ca++]i has been suggested to be responsible for digitalis-induced delayed after depolarizations and arrhythmias. We used standard microelectrode techniques to study the effects of adriamycin, 10-200 microM, on the canine Purkinje fiber transmembrane potential. Adriamycin, 10 and 50 microM, had no effect on the action potential other than inducing a 28% increase in duration at 50 microM (p less than 0.01). Adriamycin, 100 and 200 microM, further prolonged action potential duration and decreased amplitude and Vmax. We then studied the effects of adriamycin, 50 microM (a concentration that purportedly blocks sodium-calcium exchange), on ouabain-induced delayed afterdepolarizations and aftercontractions in Purkinje fiber and ventricular muscle. After initially increasing delayed afterdepolarization amplitude in five of nine Purkinje fibers, adriamycin reversibly reduced their amplitude in all nine, by 78%, at a drive cycle length of 500 msec (P less than 0.01). Adriamycin, 50 microM, had no effect on calcium ion-induced slow response action potentials, suggesting this concentration does not significantly reduce the slow inward current. In ventricular muscle, adriamycin, 50 microM, did not significantly reduce contraction but did depress aftercontractions (P less than 0.025). In sum: in concentrations that have no effect on the AP other than prolonging duration, adriamycin, 50 microM, reversibly depresses ouabain-induced delayed afterdepolarizations and aftercontractions; however, adriamycin, 50 microM, does not depress calcium ion-dependent action potentials. Although the action of adriamycin on delayed afterdepolarizations and aftercontractions is consistent with direct inhibition of the transient inward current and/or an indirect reduction via reduced activity of sodium-calcium exchange, whether either or both of these mechanisms is involved must be defined by further experimentation.
Changes in cardiac transcapillary exchange with metabolic coronary vasodilation in the intact dog.
Authors: Cousineau D , Rose C P , Lamoureux D , Goresky C A
Published: June 2012

The effects of metabolic coronary vasodilation on transcapillary exchange in the heart were examined in anesthetized dogs by use of the multiple indicator dilution technique. Animals were studied under basal conditions and during coronary sinus pacing. To obviate adrenal medullary stimulation, catheters were placed in coronary artery and coronary sinus in a closed chest preparation. Plasma catecholamine concentrations were determined to provide an index of the level of sympathetic tone. Labeled albumin and sucrose were injected into the coronary artery, and outflow dilution curves were secured. Analysis of these, with a model incorporating throughput and returning components, and heterogeneity of capillary transit times, provided parameters reflecting flow, permeability-surface product for sucrose, and capillary heterogeneity. Coronary sinus pacing increased both heart rate and plasma norepinephrine values; in response, myocardial oxygen consumption increased, metabolic vasodilation occurred, and coronary flow increased. The capillary permeability-surface product for sucrose increased with the flow but tended to plateau at higher values, showing a saturation phenomenon. Capillary heterogeneity, present in control animals with low sympathetic tone, was grossly decreased during cardiac metabolic activation. The Crone-Renkin approximation formula for the permeability-surface product yielded values that were too low at low flows and values approaching those from the complete model at high flows. The findings indicate an integrated pattern of circulatory response to cardiac metabolic activation characterized by decreased resistance, increased flow, increased permeability-surface product, and reduced heterogeneity. The last two effects amplify the capacity of increased flow to deliver substrates to heart muscle cells.
Electrical and mechanical restitution of the human heart at different rates of stimulation.
Authors: Franz M R , Schaefer J , Schöttler M , Seed W A , Noble M I
Published: June 2012

Action potential duration and contractility are reduced following premature excitations, and gradually increase as the stimulus interval is lengthened. To examine these phenomena of electrical and mechanical restitution in the human heart, we simultaneously measured action potential duration and the maximum rate of left ventricular pressure in five patients undergoing electrophysiological study. Test beats were introduced at varying intervals after the last of a series of steady state intervals. By plotting action potential duration and maximum rate of left ventricular pressure as a function of the test interval, we formed electrical and mechanical restitution curves. When the rate of steady state pacing was increased, there was a decrease in action potential duration and an increase in the maximum rate of left ventricular pressure for all test intervals; i.e., a change in pacing rate affected action potential duration and maximum rate of left ventricular pressure of test responses in a reciprocal fashion. In addition, a higher steady state pacing rate allowed action potentials and contractile responses to be elicited at shorter test intervals, thereby displacing the electrical and mechanical restitution curves to the left. The magnitude of the leftward shift of both curves corresponded closely to the shortening of the steady state action potential duration induced by the increase in pacing rate. These findings confirm for the human heart that both electrical and mechanical restitution occur after membrane repolarization, i.e., as a function of the electrical diastolic interval preceding a beat, and not the stimulus interval.
Left ventricular adaptation to sustained pressure overload in the conscious dog.
Authors: Crozatier B , Caillet D , Bical O
Published: June 2012

The early adaptation to aortic stenosis was studied in eight conscious dogs previously instrumented with a left ventricular micromanometer and ultrasonic crystals measuring left ventricular minor equator, left ventricular major axis, and ventricular wall thickness. Data were compared during control, acute inflation of a supravalvular aortic cuff occluder and 24 hours after aortic stenosis with and without beta-blockade. Acute aortic stenosis increased peak systolic pressure and end-systolic pressure with a decrease of percent systolic shortening of minor diameter (% delta L). Twenty-four hours after aortic constriction for heart rates, end-diastolic dimensions, and systolic pressures similar to those measured during acute aortic stenosis, % delta L was significantly increased, compared with acute aortic constriction, and was close to control values. End-systolic diameter was not significantly different from control during sustained pressure overload, although end-systolic stress was increased by 26.7 +/- 6.1% (P less than 0.01 with control), representing a leftward shift of the end-systolic stress-diameter relation. Similar results were obtained under beta-blockade. We conclude that there is, in this model of moderate pressure overload, a nonsympathetic increased inotropic state very early after aortic constriction.
Intra- and extracellular potassium activities, acetylcholine and resting potential in guinea pig atria.
Authors: Baumgarten C M , Singer D H , Fozzard H A
Published: June 2012

Intracellular potassium activity in guinea pig left atria was measured using potassium ion-selective microelectrodes and conventional microelectrodes. The effects of extracellular potassium concentration and acetylcholine on both intracellular potassium activity and the relationship between the resting membrane potential and the potassium equilibrium potential were investigated. Intracellular potassium activity was 102.1 mM in bathing media with a potassium concentration of 5 mM. Neither increasing extracellular potassium concentration to 10 mM nor exposure to acetylcholine (2 x 10(-6) to 10(-3) M) significantly altered intracellular potassium activity. In contrast, intracellular potassium activity decreased to 92.9 mM in 2.5 mM potassium concentration solutions. Resting membrane potential was 18.6, 9.6, and 7.3 mV positive to the potassium equilibrium potential in 2.5, 5, and 10 mM potassium, respectively. Acetylcholine caused a significant hyperpolarization at each extracellular potassium activity, confirming that resting membrane potential was positive to the potassium equilibrium potential. Even after exposure to 10(-3) M acetylcholine, the resting membrane potential apparently remained positive to the potassium equilibrium potential. If potassium accumulates in extracellular clefts during acetylcholine exposure, the calculated potassium equilibrium potentials are too negative, and the resting membrane potential might closely approximate the potassium equilibrium potential under these conditions. Fading of the acetylcholine-induced hyperpolarization and overshoot of the resting membrane potential on washout of acetylcholine were observed and are consistent with an accumulation of potassium during exposure to acetylcholine. In 5.0 mM potassium bathing solution, preparation-to-preparation variability of resting membrane potential can largely be explained by variability of intracellular potassium activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Myocardial micronecrosis produced by microsphere embolization. Role of an alpha-adrenergic tonic influence on the coronary microcirculation.
Authors: Eng C , Cho S , Factor S M , Sonnenblick E H , Kirk E S
Published: June 2012

Microspheres approximately 25 or 50 micrometers in diameter were systemically embolized from the left ventricular cavity. The number of microspheres given was empirically chosen to minimize the possibility of more than one microsphere lodging in an arteriole (3 mg/kg), yet was sufficient to allow for adequate histological assessment. The dogs were sacrificed after 24 hours, and focal areas of myocytolytic necrosis were noted in the myocardium. Groups of dogs were given pretreatment with drugs 10 minutes before embolization. Dogs pretreated with phentolamine (n = 8) and prazosin (n = 2) did not reveal any areas of myocardial necrosis after embolization with 25-micrometers microspheres. Cardiac lesions were also prevented in four of five dogs pretreated with verapamil. In contrast, cardiac lesions were not prevented by pretreatment with yohimbine (n = 2), dipyridamole (n = 3), propranolol (n = 2), or atropine (n = 2). Drug pretreatment with phentolamine or verapamil was not able to prevent cardiac lesions after embolization with 50-micrometers microspheres. Furthermore, despite a greater number of microspheres physically present in the subendocardial layer, the necrotic lesions were more frequent in the mid-wall and epicardial layers. Lesions produced by 25- or 50-micrometers emboli were also significantly smaller in the endocardium. Systemic embolization with microspheres excluding the coronary circulation did not produce cardiac lesions. We conclude that mechanical interruption of the coronary circulation with a 25-micrometers microsphere may be a necessary but not sufficient condition to produce cardiac necrosis. An alpha 1-adrenergic mechanism is also involved in the production of these lesions.(ABSTRACT TRUNCATED AT 250 WORDS)
Micropuncture measurement of lung microvascular pressure profile during hypoxia in cats.
Authors: Nagasaka Y , Bhattacharya J , Nanjo S , Gropper M A , Staub N C
Published: June 2012

To determine the lung microvascular pressure profile during hypoxia, we micropunctured the subpleural microcirculation of isolated perfused cat lungs. Our procedures involved exsanguinating a cat, then cannulating its pulmonary artery, left atrium, and trachea. Using the cat's own blood, we perfused the lungs at pulmonary artery and left atrial pressures of 18 and 9 cm water, respectively, to obtain lung blood flow of 81 +/- 29 ml/(kg body weight x min), which we held constant throughout the experiment. We stabilized the lung surface with a vacuum ring and micropunctured 30- to 50-micrometers arterioles and venules to measure microvascular pressure by the servo-null method. During micropuncture, we held the lungs at constant inflation using airway pressure of 8 cm water. We varied the oxygen concentration of the inflation gas from 30% during baseline to 2% during hypoxia. We studied groups with high (more than 7.5) or normal pH. During normoxia, 27, 44, and 29% of the pressure drop occurred in the arterial, capillary and venous segments, respectively. During hypoxia, the increase in pulmonary vascular resistance, which was marked in both groups, was significantly greater in the normal pH group. All segmental pressure drops increased significantly during hypoxia. However, the predominant increase occurred in the arteries where segmental pressure drop increased by 148% and 210%, respectively, in the high and normal pH groups. We conclude that the major site of hypoxic vasoconstriction is in the pulmonary arteries.
The angiotensin II pressor system of the rat forebrain.
Authors: Hartle D K , Brody M J
Published: June 2012

An anterior hypothalamic knife cut that leaves intact two central sites of action of angiotension II produces the same deficits in the pressor responses to angiotensin II that have been attributed to destruction of two circumventricular organs (the subfornical organ and the organum vasculosum of the lamina terminalis). The central pressor actions of angiotensin II are necessary for the full expression of renin-dependent renal hypertension. The anterior hypothalamic knife cut attenuates renin-dependent aortic ligation hypertension. It has been shown that electrolytic destruction more anterior to this knife cut, in the anteroventral 3rd ventricle region, also attenuates two forms of renin-dependent hypertension, aortic ligation hypertension and two-kidney Goldblatt hypertension in the rat. Electrolytic lesions in the subfornical organ also reduce renin-dependent, two-kidney Goldblatt hypertension. These data are consistent with the hypothesis that a common efferent system from the organum vasculosum of the lamina terminalis and subfornical organ mediates the central pressor response to angiotensin II and is involved in the development of renin-dependent hypertension. A model is proposed for the circuitry in the rat forebrain that is involved in the pressor response to angiotensin II.
Mechanism of impaired baroreflex control in prehypertensive Dahl salt-sensitive rats.
Authors: Gordon F J , Mark A L
Published: June 2012

Dahl salt-sensitive rats fed a low salt diet demonstrate functional impairment in baroreflex control of cardiovascular function prior to the development of hypertension. The purpose of this study was to identify the mechanism(s) responsible for impaired baroreflex control in prehypertensive Dahl salt-sensitive rats. To examine the central and efferent portions of the baroreflex arc, we electrically stimulated the aortic depressor nerve of urethane anesthetized Dahl salt-sensitive and Dahl salt-resistant rats while recording arterial pressure, heart rate, and sympathetic nerve activity. Aortic nerve stimulation produced equivalent responses in both groups, indicating that central and efferent mechanisms could not account for functional baroreflex impairment. In separate groups of Dahl rats, multifiber afferent aortic baroreceptor discharge was recorded while arterial pressure was increased with phenylephrine. Prehypertensive Dahl salt-sensitive rats demonstrated significantly less baroreceptor activation than Dahl salt-resistant rats, indicating that impaired baroreceptor discharge is the mechanism responsible for baroreflex abnormalities. Aortic arch distensibility was not different between Dahl strains, suggesting that impaired baroreceptor discharge in Dahl salt-sensitive rats is probably not due to abnormalities in vessel wall distensibility. Since arterial pressure of both Dahl strains was in the normotensive range and did not differ significantly between Dahl salt-sensitive and salt-resistant rats, baroreceptor impairment appears to be a primary defect in Dahl salt-sensitive rats, rather than being secondary to hypertension. We speculate that this impairment in baroreceptor function in Dahl salt-sensitive rats prior to any elevation in arterial pressure may contribute to the Dahl salt-sensitive rat's genetic propensity to develop hypertension.
The role of cardiac receptor and arterial baroreceptor reflexes in control of the circulation during acute change of blood volume in the conscious rabbit.
Authors: Ludbrook J , Graham W F
Published: June 2012

We have studied overall reflex control of the circulation by the arterial baroreceptors and cardiac receptors during acute change of blood volume in seven conscious rabbits. A factorial experimental design allowed analysis of the direction, magnitude, and significance of the reflex effects of independent input from each set of receptors, and the reflex interactions when the inputs were combined. Right atrial pressure, arterial pressure, systemic vascular resistance, cardiac output, and heart rate were measured during acute, graded, isohemic change of blood volume over the range +/- 27%. This was done with both reflexes present, only the arterial baroreceptor reflex present (intrapericardial 2% procaine), only the cardiac receptor reflex present (surgical baroreceptor denervation), and with both reflexes absent. As blood volume was depleted, the arterial baroreceptor reflex independently increased systemic vascular resistance and sustained arterial pressure, but the cardiac receptor reflex had no significant independent or interactive effects. As blood volume was expanded, each reflex had an independent effect in decreasing systemic vascular resistance and preventing arterial pressure from rising, the cardiac receptor reflex being the more powerful. Their effect in combination on systemic vascular resistance and arterial pressure was only two-fifths of the sum of their independent effects, so that they interacted negatively. In combination, the reflexes supported right atrial pressure during blood loss, despite their negative interaction, but did not significantly affect the relation of cardiac output to blood volume change in either direction. Thus both reflexes have important actions in moderating the overall effects of acute blood volume changes in conscious rabbits, but these are markedly diminished by their interactions.
Identification of vascular postsynaptic alpha 1- and alpha 2-adrenoceptors in man.
Authors: Jie K , van Brummelen P , Vermey P , Timmermans P B , van Zwieten P A
Published: June 2012

We studied postsynaptic alpha-adrenoceptors in human blood vessels by measuring the influence on forearm blood flow induced by intra-arterial infusions of selective alpha 1- and alpha 2-adrenoceptor agonists (methoxamine, B-HT 933, clonidine and guanfacine) and antagonists (doxazosin and yohimbine). The studies were done in healthy volunteers, and forearm blood flow was measured by plethysmography. All agonists produced a significant and dose-dependent vasoconstriction. The effect of B-HT 933 was completely abolished by the concomitant infusion of yohimbine, whereas it was hardly influenced by doxazosin. The effect of methoxamine was prevented by doxazosin and little influenced by yohimbine. The vasoconstriction by clonidine and guanfacine was partially prevented by both doxazosin and yohimbine. The single intra-arterial infusion of yohimbine, as well as doxazosin, resulted in vasodilation. These findings provide strong evidence for the existence of postsynaptic alpha 1- as well as alpha 2-adrenoceptors, both mediating vasoconstriction and contributing to basal vascular tone. The (patho-)physiological significance of this subdivision of alpha-adrenoceptors remains to be elucidated.
Myocardial monovalent cation transport during the quinidine-digoxin interaction in dogs.
Authors: Warner N J , Barnard J T , Leahey E B , Hougen T J , Bigger J T , Smith T W
Published: June 2012

To study the relationship of the serum digoxin concentration to the digoxin effect on monovalent cation transport during the quinidine-digoxin interaction, we used radiolabeled rubidium to measure monovalent cation active transport in myocardial biopsy samples from dogs. In a preliminary study, we showed that quinidine did not affect rubidium uptake by myocardial samples from intact dogs. Then, we studied four groups, each consisting of 13 dogs, which received either saline, low dose digoxin, high dose digoxin, or low dose digoxin plus quinidine treatment. In these groups of dogs, the following steady state serum digoxin concentrations were achieved: saline-treated, 0 ng/ml; low dose digoxin, 1.2 +/- 0.2 ng/ml (mean +/- SD); high dose digoxin, 2.4 +/- 0.4 ng/ml; and low-dose digoxin plus quinidine treated, 2.3 +/- 1.1 ng/ml. Compared to control values, rubidium uptake was decreased by 17% in dogs treated with low dose digoxin (P less than 0.05) and by 38% in dogs treated with high dose digoxin (P less than 0.01 vs. saline-treated, P less than 0.01 vs. low dose digoxin). Although low dose digoxin plus quinidine-treated dogs had the same mean serum digoxin concentration as the high dose digoxin-treated dogs, rubidium uptake in low dose digoxin plus quinidine-treated dogs was decreased by only 17% compared to control (P less than 0.05 vs. saline-treated, (P less than 0.01 vs. high dose digoxin). During the quinidine-digoxin interaction in the intact dog, the reduction in myocardial rubidium uptake is less than expected from the increase in serum digoxin concentration.
Quantitative comparison of the force-interval relationships of the canine right and left ventricles.
Authors: Burkhoff D , Yue D T , Franz M R , Hunter W C , Sunagawa K , Maughan W L , Sagawa K
Published: June 2012

We quantitatively compared the extrasystolic and postextrasystolic responses of the right ventricle and left ventricle of the same heart, which have vastly different geometries, architectures, and muscle masses. We studied nine isolated, supported canine hearts whose right and left ventricles were made to contract isovolumically with balloons placed in both chambers. The ventricles were paced with the following pattern: 20 regularly timed priming stimulations, followed by a test stimulation at a variable test pulse interval, and, finally, by a second test stimulation which was always delivered 1200 msec after the first test pulse. In each heart, approximately 15 different test pulse intervals between 300 and 1200 msec were investigated. Both the maximum developed pressure and maximum rate of pressure development, expressed as a percentage of their steady state values during the priming period were used to quantify the extra- and postextrasystolic responses. For each extrasystolic and postextrasystolic test beat, the normalized response of the right ventricle was plotted vs. that of the left ventricle. The regression line and correlation coefficient between the two were determined. The average result from nine hearts gave a slope of 0.96 +/- 0.05, an intercept of 4.52 +/- 4.05% and a correlation coefficient of 0.995 +/- 0.004. This analysis indicated that, despite the differences in right and left ventricular geometry, architecture, and mass, their force-interval behaviors were nearly identical.
Adenine nucleotide metabolism and compartmentalization in isolated adult rat heart cells.
Authors: Geisbuhler T , Altschuld R A , Trewyn R W , Ansel A Z , Lamka K , Brierley G P
Published: June 2012

The metabolism and intracellular compartmentalization of adenine nucleotides in a preparation of adult rat heart myocytes showing good morphology, viability, and tolerance to calcium ion has been examined by high performance liquid chromatography. These myocytes contain an average of 23 nmol adenine nucleotide per milligram protein which is about 60% of the adenine nucleotide content of intact rat heart tissue. The loss of adenine nucleotide occurs during the incubation and washing steps that increase the yield of viable cells, rather than during the collagenase perfusion. An analysis of cellular compartments shows that the adenine nucleotide of the cell consists of 17 nmol adenine nucleotide in the cytosol, 5 nmol in the mitochondria, and 1.3 nmol adenosine diphosphate bound to myofibrils per milligram cell protein. Myocytes lose both adenosine triphosphate and adenine nucleotide when incubated anaerobically in the absence of glucose, and the lost adenine nucleotide can be accounted for as increased inosine, adenosine, and inosine monophosphate. Myocytes that contain less than 0.1 nmol of cytosol adenosine triphosphate per milligram cell protein maintain an intact sarcolemma, but are unable to carry out anaerobic glycolysis. Reoxygenation of anaerobic cells results in restoration of energy charge and a net resynthesis of about 2 nmol adenine nucleotide per milligram protein. Adenosine and inosine monophosphate decrease on reaeration of anaerobic cells, whereas inosine levels increase. When iodoacetate is added to block glycolysis, the decline in adenine nucleotide and production of inosine monophosphate are accelerated and there is no resynthesis of adenine nucleotide when anaerobic cells are reoxygenated . Large accumulations of inosine monophosphate are also seen in myocytes treated with an uncoupler of oxidative phosphorylation.
Chronic cerebroventricular infusion of hypertonic sodium chloride in rats reduces hypothalamic sympatho-inhibition and elevates blood pressure.
Authors: Miyajima E , Buñag R D
Published: June 2012

To determine whether or not salt loading restricted to the brain would elevate blood pressure, chronically implanted osmotic minipumps were used to infuse hypertonic sodium chloride solutions made in artificial cerebrospinal fluid into a jugular vein intravenously or the third cerebral ventricle, intracerebroventricularly, for 11 days in awake rats. During intracerebroventricular infusion of hypertonic sodium chloride, tail-cuff systolic pressures began to rise on day 4 and were significantly elevated by day 9. In contrast, infusions of either artificial cerebrospinal fluid alone, intracerebroventricularly, or hypertonic sodium chloride, intravenously, were ineffective. Confirming the blood pressure elevation thereby detected, systolic and mean pressures recorded directly from indwelling aortic catheters after the same rats had been anesthetized with urethane on day 11, were also significantly higher following intracerebroventricular infusion of hypertonic sodium chloride than after infusion of artificial cerebrospinal fluid alone. Magnitude of depressor and sympatho-inhibitory responses elicited by graded electrical stimulation of the anterior hypothalamus invariably increased with the current strength used for stimulation. At all current strengths used for hypothalamic stimulation, depressor responses as well as attendant decreases in sympathetic neural firing, were smaller in rats that had been infused intracerebroventricularly with hypertonic sodium chloride than in any of the controls. Inhibition seemed specific for the anterior hypothalamus because pressor responses to stimulation of the ventromedial hypothalamus were the same whether or not the intracerebroventricular infusion contained hypertonic sodium chloride. An explanation based on diminished cardiovascular sensitivity also appeared unlikely, since depressor responses to intravenously injected histamine were almost equal in both groups. Our results are compatible with the interpretation that hypertonic sodium chloride infused chronically into the 3rd ventricle acts by reducing anterior hypothalamic inhibition of sympathetic vasomotor tone, and that this, in turn, then elevates blood pressure.
Interactions of granulocytes with the lungs.
Authors: Brigham K L , Meyrick B
Published: June 2012

Under normal conditions, there is a sizeable pool of marginated granulocytes in the lung circulation which is in dynamic equilibrium with the circulating granulocyte pool. The number of granulocytes in the lungs' microcirculation may depend on pulmonary blood flow or biochemical interactions between granulocytes and pulmonary vascular endothelium, or both. There is some evidence that normal lung function may be affected by granulocytes. Several acute and chronic diseases may result, at least in part, from interactions of granulocytes with the lungs. Acute diffuse lung injury (adult respiratory distress syndrome) is characterized by diffuse pulmonary inflammation, and, in animal models, some of the lung dysfunction depends on the presence of granulocytes. Bronchoconstriction and airway hyperreactivity, characteristic of asthma, may be influenced by granulocyte-generated products of arachidonic acid. Granulocyte-derived proteases and oxidants may contribute to the pathogenesis of pulmonary emphysema and may affect connective tissue synthesis in interstitial pulmonary fibrosis. There is some evidence suggesting a connection between granulocytes and chronic pulmonary hypertension. The fact that some interventions which cause pulmonary leukostasis do not cause severe, persistent lung injury indicates that as yet unknown factors may determine whether interactions of granulocytes with the lungs are benign or pathological. Such factors could include the generation of humoral substances, and metabolites of arachidonic acid are particularly interesting in this regard. Research related to interactions of granulocytes with the lungs suggests strongly that such interactions are integral to the pathogenesis of several lung diseases. Understanding those diseases will require further basic studies of granulocyte behavior and the modes of communication between cells intrinsic to the lung and granulocytes.
The phase-dependency of the cardiac chronotropic responses to vagal stimulation as a factor in sympathetic-vagal interactions.
Authors: Yang T , Levy M N
Published: June 2012

We determined the effects of the timing of repetitive bursts of vagal stimulation on the positive chronotropic responses of the heart to trains of cardiac sympathetic nerve stimulation in open-chest anesthetized dogs. Trains of sympathetic stimulation alone, at frequencies of 2 and 4 Hz, decreased the cardiac cycle length by 176 +/- 19 msec (mean +/- SE) and 190 +/- 22 msec, respectively. When bursts of vagal stimuli were given once each cardiac cycle and they were placed at their least effective time in the cycle, sympathetic stimulation at frequencies of 2 and 4 Hz decreased cardiac cycle length by only 107 +/- 8 and 120 +/- 8 msec, respectively. However, when the bursts of vagal stimuli were delivered at their most effective time in each cycle, the same levels of sympathetic stimulation elicited much larger reductions in cardiac cycle length (285 +/- 32 and 330 +/- 32 msec, respectively). Therefore, the effects of sympathetic stimulation were significantly attenuated by the vagal stimuli when the vagal bursts were relatively ineffective. Conversely, the chronotropic effects of the sympathetic stimulation were exaggerated substantially when the vagal stimulus bursts were initially positioned at their most effective time in the cardiac cycle. This latter response is contrary to the characteristic "accentuated antagonism," wherein the effect of any given level of sympathetic stimulation is diminished as the level of vagal activity is increased. This vagally mediated enhancement of the positive chronotropic response to sympathetic stimulation occurs because the phase dependency of the response of the automatic cells to the bursts of vagal stimulation is altered by the increased sympathetic activity.
Flow into ischemic myocardium and across coronary collateral vessels is modulated by a waterfall mechanism.
Authors: Eng C , Kirk E S
Published: June 2012

If a coronary artery is ligated and the distal end cannulated, blood flows retrograde from the cannula when vented to the atmosphere. By varying the height of the outflow tubing, and thereby changing the outflow pressure, pressure-flow relationships can be constructed. We used this technique in eight dogs to assess the characteristics of blood flow into ischemic myocardium. Above a back pressure of 10 mm Hg, increasing back pressure resulted in a decrease of retrograde blood flow. However, below a back pressure of about 10 mm Hg (10.7 +/- 2.7 mm Hg), alterations in back pressure did not result in changes in retrograde blood flow (back pressure-independent region). The transition at 10 mm Hg is interpreted as the critical waterfall pressure in ischemic myocardium. In another group of eight dogs, the ischemic bed was completely embolized with 25-micron sized microspheres to prevent RBF from entering the tissue as back pressure was raised. Pressure-flow relationships performed in this group revealed a back pressure-independent region that extended to approximately 20 mm Hg (23.0 +/- 2.5 mm Hg). This behavior of the pressure-flow relationship is consistent with a waterfall phenomenon on the collateral vessels. To the extent that collateral vessels in the dog are mainly epicardial in location, the findings suggest that extravascular pressures of 20 mm Hg can occur in the more superficial layers of the heart. In addition, the waterfall on the collaterals indicates that this mechanism can operate on nonvenous vessels. Our results suggest separate waterfall phenomena operating on the collateral vessels (20 mm Hg) and on the vessels in the ischemic myocardium (10 mm Hg).
Differential sensitivity of canine cardiac sarcolemmal and microsomal enzymes to inhibition by free radical-induced lipid peroxidation.
Authors: Kramer J H , Mak I T , Weglicki W B
Published: June 2012

Sarcolemmal and microsomal membranes prepared from adult canine cardiac myocytes (sarcolemmal Na+, K+-ATPase = 71.8 mumol/mg per hr and microsomal rotenone-insensitive NADH cytochrome c reductase = 114 mumol/mg per hr) were each preincubated at 37 degrees C in the presence of a free radical generating system consisting of dihydroxyfumarate and Fe -ADP; loss of the Na+, K+-ATPase and reductase activities, as well as the associated increases in lipid peroxidation, measured by malondialdehyde formation, were temporally correlated in both systems. The ATPase was inhibited 70% when the malondialdehyde was 71 nmol/mg protein at 20 minutes and 90% when malondialdehyde was 138 nmol/mg protein at 90 minutes. Inhibition of reductase activity occurred more gradually, displaying a 27% loss of activity when malondialdehyde reached 34 nmol/mg protein at 20 minutes and 60% with a malondialdehyde value of 67 nmol/mg protein at 90 minutes. The greater susceptibility of the sarcolemma to free radical-induced membrane damage may be due to the higher content of unsaturated fatty acids in this membrane, compared to microsomes.