bluuebunny/crossref_metadata_2025 huggingface dataset:
Muscarinic autoreceptors do not modulate kinetics of acetylcholine release in hearts
Authors: Dexter F. , Rudy Y. , Levy M. N.
Published: December 2017

We determined the time course of the cellular mechanism that mediates the attenuation of the chronotropic response in anesthetized dogs to decreases in the time interval (interpulse interval) between pulses of vagal stimuli. We injected propranolol, cut the cervical vagi, and repetitively stimulated the cardiac segment of the right vagus nerve with one brief burst of electrical pulses during each cardiac cycle. We recorded the initial and steady-state changes in cardiac cycle length that were induced by the phasic vagal stimulation. The decrease in the interpulse interval decreased the initial and steady-state responses. The time delay between the release of acetylcholine (ACh) from the vagal nerve endings in the heart and inhibition of the release of additional ACh was less than 4 ms. Published delays between the time of ACh release and the time of the resulting change in membrane potential, in other biological systems, are 30-12,000 ms. We conclude that the time delay was too brief for muscarinic autoreceptors to have mediated the attenuation of ACh release from postganglionic vagal nerve endings in the heart in response to decreases in interpulse interval.
Slowly relaxing caffeine responses in rat ventricle: relationships of ryanodine and caffeine actions
Authors: Hilgemann D. W. , Roos K. P. , Brady A. J.
Published: December 2017

Contractile responses to 20 mM caffeine were compared in arterially perfused rat right ventricle as tension, in intact rat myocytes as shortening, and in Triton X-100-"skinned" rat myocytes as shortening and stiffness. Responses in intact quiescent ventricle and membrane-disrupted myocytes at -log molar Ca concentration (pCa) of 7.0-6.8 were similar; force and stiffness rose quickly on application of caffeine and declined incompletely toward base line over 20 min. Subsequent caffeine responses were blunted. By contrast, in freshly isolated rat myocytes, rapid caffeine exposures induced large phasic contractures, which relaxed for the most part in 2-5 s. These responses were largely suppressed by 0.2 microM ryanodine pretreatment at 35 degrees C but not by high ryanodine concentrations (10 microM). Ryanodine was without effect on slowly relaxing contractile responses in both intact ventricle and Triton X-100-treated myocytes. The results are discussed in relation to the predicted effects of a calcium store leak in a simple model of cardiac excitation-contraction coupling. The results suggest that slowly relaxing caffeine contractures can be caused entirely by direct actions of caffeine on myofilaments.
Persistent right coronary flow reserve at low perfusion pressure
Authors: Murakami H. , Kim S. J. , Downey H. F.
Published: December 2017

To determine whether right coronary (RC) flow reserve persists at perfusion pressures below the apparent autoregulatory range, the RC artery of 18 anesthetized dogs was cannulated and perfused at controlled pressures. RC blood flow (RCBF) fell from 65.3 +/- 6.1 to 33.7 +/- 2.3 ml.min-1.100 g-1 as RC perfusion pressure (RCPP) was reduced from 80 to 40 mmHg. At 40 mmHg, intracoronary adenosine increased RCBF by 97.9 +/- 10.6 ml.min-1.100 g-1 (P less than 0.001). RCBF fell to 9.5 +/- 1.7 ml.min-1.100 g-1 at 20 mmHg, and RCBF did not significantly increase during adenosine, although RC vasodilation was observed in four dogs. Regional right ventricular (RV) blood flows at RCPP of 80 and 40 mmHg were measured by radioactive microsphere technique. Before adenosine infusion, RCBF was distributed uniformly across the RV free wall at normal and low perfusion pressures. During adenosine infusion, blood flow in both regions increased significantly, but the flow reserve was greater in the subendocardial region at both normal and reduced pressures. RV myocardial O2 consumption (MVo2) was decreased significantly at 40 mmHg, however, there was no evidence of ischemia at this pressure, since the RV lactate extraction ratio was normal (n = 8). Thus RV O2 demand fell when RC O2 supply was reduced, although a flow reserve was available. RV MVo2 was restored to normal when right coronary flow reserve was mobilized by adenosine infusion. For RCBF from 65 to 365 ml.min-1.100 g-1, RC venous O2 content rose and RV MVo2 was essentially constant.(ABSTRACT TRUNCATED AT 250 WORDS)
Mechanisms behind increased dermal imbibition pressure in acute burn edema
Authors: Lund T. , Onarheim H. , Wiig H. , Reed R. K.
Published: December 2017

We have measured tissue pressures in excised rat skin subjected to in vitro burn injury and investigated the mechanisms behind the increased imbibition (swelling) pressure in burned skin. Skin pieces wrapped in aluminum paper were immersed into boiling hot water for 10, 30, or 60 s. Dermal imbibition pressure was measured with micropipettes and tissue osmometry as interstitial fluid hydrostatic pressure (Pif) and/or interstitial fluid colloid osmotic pressure (COPif). COPif was also measured in interstitial fluid sampled with intradermal wicks. Control values of Pif (micropipettes) and of COPif (wick fluid) averaged -1.5 mmHg and -17.5 mmHg, respectively. An increase in imbibition pressure was seen after thermal injury. After 10 s of heat exposure, the imbibition pressure gain was mainly due to a strongly negative hydrostatic pressure (Pif mean value -33.3 mmHg). Pif became slightly positive and COPif increasingly negative after longer exposure (mean Pif 0.3 and mean COPif -133 mmHg after 60-s exposure). Collagen degradation and water solubility increased with extension of the heat exposure time. Thermal degradation of collagen seems to be the main mechanism responsible for the generation of increased imbibition pressure.
Central autonomic modulation of cardiac baroreflex by corticotropin-releasing factor
Authors: Fisher L. A.
Published: December 2017

The effects of intracerebroventricular administration of corticotropin-releasing factor (CRF) on baroreflex control of heart rate were studied in conscious, unrestrained rats. Stimulus-response curves relating mean arterial pressure (MAP) to pulse interval were constructed for assessment of baroreflex function. CRF, intracerebroventricularly injected, elicited dose-related reductions of resting pulse interval, response range, and reflex gain and elevations of resting arterial pressure and MAP50 (arterial pressure at midrange). Earlier peripheral blockade of cardiac vagal influences with atropine methyl nitrate greatly attenuated the effects of CRF on resting pulse interval, response range, and reflex gain. In contrast, earlier blockade of cardiac sympathetic influences with intravenous propranolol treatment did not alter the ability of CRF to reduce resting pulse interval, response range, and reflex gain. The central nervous system effects of CRF on cardiac baroreflex function were qualitatively similar to the actions of atropine methyl nitrate. It is concluded that CRF alters transmission in central nervous system pathways mediating baroreceptor-induced activation of cardiac vagal motor neurons.
Effects of vagus nerve on heart rate and ventricular contractility in chicken
Authors: Lang S. A. , Levy M. N.
Published: December 2017

We determined the effects of vagus nerve stimulation on cardiac cycle length and on ventricular contraction and relaxation in 18 chickens anesthetized with pentobarbital. Right vagus stimulation at a constant frequency of 35 Hz prolonged cycle length by 190%, whereas left vagus stimulation at the same frequency increased cycle length by 136%. When one burst of stimuli was delivered to the right vagus nerve each cardiac cycle, but the timing of the stimuli was changed within the cardiac cycle, the response of the avian pacemaker cells varied substantially with the timing of the stimuli. Right and left vagus stimulation at a constant frequency of 20 Hz depressed ventricular contraction by 62 +/- 6 and 52 +/- 6%, respectively, and depressed ventricular relaxation by 56 +/- 7 and 53 +/- 7%, respectively. These results indicate that in the chicken the chronotropic effects of right vagus stimulation are greater than those of left vagus stimulation, whereas right and left vagus stimulation are approximately equipotent on ventricular contraction and relaxation.
Acetylcholine increases intracellular sodium activity in sheep cardiac Purkinje fibers
Authors: Iacono G. , Vassalle M.
Published: December 2017

The action of acetylcholine (ACh) on intracellular sodium activity (alpha iNa) was studied in sheep Purkinje fibers by means of a Na+-selective microelectrode technique while transmembrane potentials and contractile force were simultaneously recorded. In quiescent fibers, 10(-4) to 10(-5) M ACh shifted the resting potential to less negative values and increased alpha iNa from 5.57 +/- 0.21 to 6.45 +/- 0.35 mM (+15.8%, P less than 0.005). In other experiments, ACh induced a depolarization that initiated spontaneous activity. In fibers driven at 60 beats/min, ACh prolonged the action potential, increased alpha iNa from 7.98 +/- 0.15 to 9.36 +/- 0.3 mM (+17.29%, P less than 0.005), and increased contractile force. Norepinephrine (10(-5) to 10(-6) M) increased contractile force and decreased alpha iNa, but in its presence ACh still increased force and alpha iNa and vice versa. Strophanthidin (10(-4) M) increased alpha iNa, and 3 x 10(-6) M propranolol and 10(-6) M atropine decreased alpha iNa. Both strophanthidin and atropine (but not propranolol) prevented the increase in alpha iNa by ACh. It is concluded that the ACh increases alpha iNa and contractile force through the inhibition of the sodium pump and that these actions are due to the activation of the muscarinic receptor and not to endogenously released norepinephrine.
Effects of hydrodynamic forces on coronary production of prostacyclin and purines
Authors: Karwatowska-Prokopczuk E. , Ciabattoni G. , Wennmalm A.
Published: December 2017

Prostacyclin and purine efflux rates from the isolated rabbit heart in response to variations of flow rate or perfusion pressure were investigated. Increases in coronary flow by 25, 50, and 100% augmented the effluxes of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and purines equally, by up to four times. Increases in coronary pressure by 25, 50, and 100% augmented the outflow of 6-keto-PGF1 alpha by up to 20 times, whereas the outflow of purines increased no more than 6.5 times. Neither reduction of perfusate Ca2+ by 50% nor administration of quinacrine (1 microM) affected the basal efflux of 6-keto-PGF1 alpha or its response to an increase in coronary pressure. Both interventions did, however, reduce the pressure-induced purine efflux by approximately 50%. Pulsatile flow did not affect either the outflow of 6-keto-PGF1 alpha or that of purines, in comparison to steady flow at the same rate. The data demonstrate that an increase in coronary pressure activates a specific mechanism for prostacyclin production that appears independent of extracellular Ca2+ and of phospholipase activity.
Increased transvascular protein transport in lungs induced by nonthrombogenic gamma-thrombin
Authors: Garcia-Szabo R. R. , Fenton J. W. , Lo S. K. , Hussain M. , Malik A. B.
Published: December 2017

Infusion of 1.2 nmol/kg body wt of alpha-thrombin (2.6 clotting U/micrograms) or 12 nmol/kg of gamma-thrombin (less than 0.005 U/microgram) into the pulmonary artery of halothane-anesthetized sheep produced two-to threefold increases in mean pulmonary arterial pressure (Ppa), mean pulmonary arterial wedge pressure (Ppw), and pulmonary vascular resistance (PVR). Pulmonary lymph flow (Qlym) also increased two- to threefold without significant changes in the lymph-to-plasma protein concentration ratio (L/P). Leukocyte counts decreased 75% in both groups and rebounded in the gamma-thrombin group but remained depressed in the alpha-thrombin group. Platelet counts decreased 30 and 85% in alpha- and gamma-thrombin groups, respectively, and remained low at 4 h postinfusion in both groups. Plasma fibrinogen concentrations decreased similarly within 15 min after thrombin infusion in both groups, and concentrations of fibrin(ogen) degradation products (FDP) increased similarly. Fibrin was present in pulmonary vessels after alpha-thrombin challenge but not after gamma-thrombin challenge. In contrast, infusion of 1.2 nmol/kg of gamma-thrombin (matching the alpha-thrombin dosage) produced no significant increases in Ppa, Ppw, PVR, Qlym or in the leukocyte and platelet counts. These data demonstrate that high concentrations of the nonthrombogenic gamma-thrombin increase lung transvascular protein transport independent of intravascular clotting in the lung.
Electrophysiological effect of volume load in isolated canine hearts
Authors: Calkins H. , Maughan W. L. , Kass D. A. , Sagawa K. , Levine J. H.
Published: December 2017

In isolated isovolumic ventricles and in in situ ventricles under nonsteady-state conditions, alterations in load have been shown to affect electrophysiological properties via contraction-excitation feedback. However, the effect of alterations in loading conditions on electrophysiological properties in normal ventricles under physiological loading conditions remains unknown. Furthermore, the arrhythmogenic significance of these load-induced electrophysiological changes is uncertain. We increased end-diastolic volume (27 +/- 4 ml vs. 51 +/- 6 ml) and assessed conduction, refractoriness, ventricular fibrillation thresholds (VFTs), and inducibility of ventricular arrhythmias in 14 isolated blood-perfused ejecting canine ventricles under steady-state conditions. We also examined the effect of increased end-diastolic volume on refractoriness and monophasic action potential (MAP) duration and contour under isovolumic versus ejecting conditions. Under ejecting conditions, increased end-diastolic volume resulted in very small (less than 1.5%) changes in the absolute refractory period (10 mA) and in local activation time but no change in local electrogram duration, overall dispersion of refractoriness, MAP duration or contour, VFT, or inducibility of ventricular arrhythmias. Increased volume loading under isovolumic conditions resulted in a very slight (less than 1%) shortening of MAP duration and refractoriness but had no effect on the MAP contour. These findings provide strong evidence that alterations in volume load are of little electrophysiological or arrhythmogenic importance in normal canine ventricles under physiologically loaded conditions (contraction-excitation feedback, load and arrhythmias, volume load).
Hemodynamic effects of endothelin in conscious rats
Authors: Hinojosa-Laborde C. , Osborn J. W. , Cowley A. W.
Published: December 2017

The hemodynamic responses to endothelin, a recently isolated vasoconstrictor peptide, were determined in conscious rats with and without the three major known neurohumoral control systems. Rats (n = 6) were instrumented with arterial and venous catheters and an electromagnetic flow probe around the ascending aorta. Neurohumoral blockade was achieved with 10 mg/kg chlorisondamine, 0.5 mg/kg methscopolamine, 1 mg/kg captopril, and 10 micrograms/kg d(CH2)Tyr5(Me)AVP. Resting mean arterial pressure (MAP), cardiac output (CO), and total peripheral resistance (TPR) in areflexic rats were restored to normal levels with a constant norepinephrine infusion. Endothelin was infused intravenously for 25 min in doses ranging from 0.01 to 1,000 ng.kg-1.min-1. Rats with intact reflexes did not respond significantly until a dose of 100 ng.kg-1.min-1 that increased MAP 20%, decreased CO 22% and increased TPR 58%. At a dose of 1,000 ng.kg-1.min-1 of endothelin (infused for 10 min), MAP increased 35%, CO decreased 66%, and TPR increased 303%. In areflexic rats, 1 ng.kg-1.min-1 of endothelin caused significant increases in MAP (14%), small decreases in CO (-5%), and a 20% increase in TPR. At a dose of 10 ng.kg-1.min-1, MAP increased 17%, CO decreased 3%, and TPR increased 21%; at 100 ng.kg-1.min-1, MAP increased 40%, CO decreased 13%, and TPR increased 67%; at 1,000 ng.kg-1.min-1, MAP increased 48%, CO decreased 61%, and TPR increased 319%. The pressor effects of endothelin were therefore significantly buffered by neurohumoral systems; however, the decreases in CO caused by high doses of endothelin were independent of neurohumoral control.
Mechanisms underlying response to hypercapnia and bicarbonate of isolated dog cerebral arteries
Authors: Toda N. , Hatano Y. , Mori K.
Published: December 2017

In helical strips of dog cerebral arteries contracted with K+ or prostaglandin F2 alpha, the increase in CO2 from 5 to 15% in the gas aerating the bathing media produced a persistent relaxation in association with a rise of PCO2 and a fall of pH and PO2. Elevation of the NaHCO3 concentration from 25 to 75 mM in the bathing media under hypercapnia almost reversed the arterial tone when the osmolarity was balanced; the pH was completely reversed, whereas PCO2 was maintained at the high level. When 50 mM NaHCO3 were applied to the hypercapnic media without having the osmolarity balanced, the arteries relaxed further. Infusions of the HCl solution lowered the pH and relaxed the arterial strips; however, such a relaxation was significantly less than that caused by hypercapnia-induced acidosis. Relaxant responses to hypercapnia were attenuated by treatment with ouabain but were not influenced by amiloride and superoxide dismutase or by removal of endothelium. Relaxations due to hypertonic NaHCO3 were abolished or reversed to contractions by ouabain and were reduced by treatment with amiloride. It may be concluded that the hypercapnia-induced cerebroarterial relaxation is associated mainly with a fall of extracellular pH and is mediated partly by an activation of the electrogenic Na+ pump. Cerebral vasodilatation by increased osmolarity with NaHCO3 appears to result from stimulated Na+-H+ exchange and activated Na+ pump.
Cholesterol-induced changes in rabbit arterial smooth muscle sensitivity to adrenergic stimulation
Authors: Broderick R. , Bialecki R. , Tulenko T. N.
Published: December 2017

We evaluated the effects of exposure to high cholesterol levels for 3 h on arterial smooth muscle responses to adrenergic stimulation. Femoral arteries from Dutch belted rabbits were perfused in vitro with a constant-flow variable-pressure perfusion apparentus. After equilibration the vessels were perfused for 180 min more with media supplemented with cholesterol-phospholipid (C/PL) liposomes of molar ratios of 2:1 or 0.5:1. Although resting vascular resistance was unchanged, norepinephrine (NE) concentration-response analyses revealed a fivefold increase in NE sensitivity (P less than 0.001) in the arteries perfused with the cholesterol-enriched liposomes (2:1) compared with control arteries perfused with the 0.5:1 liposome medium. The arteries perfused with the cholesterol-enriched liposomes demonstrated a 60% increase in cholesterol content and a marked (90%) reduction in Na+-K+-ATPase activity. The increased sensitivity of the cholesterol-enriched arteries was not mediated by acute reductions in Na-pump activity, altered endothelial function, adrenergic nerve function, or prostaglandin production. Cholesterol-induced sensitization to NE did demonstrate an absolute dependence on extra-cellular calcium. These findings suggest that an increase in the free cholesterol content of the arterial smooth muscle cell plasma membrane alters membrane permeability to extracellular calcium during adrenergic stimulation.
Regional vascular responses to prolonged lower body negative pressure in normal subjects
Authors: Hirsch A. T. , Levenson D. J. , Cutler S. S. , Dzau V. J. , Creager M. A.
Published: December 2017

The purpose of this study was to determine the effects of sustained unloading of baroreceptors in humans. The regional hemodynamic responses to lower body negative pressure (LBNP) were determined in 20 normal subjects. LBNP at -10 mmHg for 1 h decreased central venous pressure (CVP) without affecting blood pressure or heart rate, suggesting that only cardiopulmonary baroreceptors were unloaded. Forearm blood flow (FBF) and splanchnic blood flow (SBF) both decreased. Renal blood flow (RBF) did not change, but glomerular filtration rate (GFR) increased. Plasma renin activity rose slightly, whereas plasma norepinephrine levels did not change. Peak LBNP (either -20 or -40 mmHg for 1 h) caused a further decline in CVP and narrowed pulse pressure, thus unloading both arterial and cardiopulmonary baroreceptors. FBF returned to base-line values and SBF decreased further. RBF fell and the GFR remained increased. Plasma renin activity increased further, and plasma norepinephrine level rose. Thus the forearm and splanchnic circulations are sensitive to sustained unloading of cardiopulmonary baroreceptors; renal vasoconstriction occurs with additional unloading of arterial baroreceptors. Renin-angiotensin system activation during LBNP may be pertinent to the preservation of glomerular filtration.
O2 uptake in bled dogs after resuscitation with hypertonic saline or hydroxyethylstarch
Authors: Reinhart K. , Rudolph T. , Bredle D. L. , Cain S. M.
Published: December 2017

Hemodynamic and metabolic variables were measured for the whole body and isolated hindlimb of anesthetized dogs during resuscitation from hemorrhagic shock, using a small volume of hypertonic saline or a larger volume of hydroxyethylstarch. Twelve dogs were bled and maintained at a mean arterial pressure (MAP) of 40 mmHg for 30 min. Six dogs were then infused with 7.5% NaCl in 5 ml/kg hydroxyethylstarch (HTS group), and six received 6% hydroxyethylstarch alone (HES group) in an amount to approximate the maximum MAP achieved with hypertonic saline. Hypertonic saline replacement was approximately 16% of shed blood volume compared with 66% for hydroxyethylstarch. With hypertonic saline, cardiac output returned to base line, but O2 delivery did not. Hydroxyethylstarch increased cardiac output above base line, and O2 delivery was near base line. O2 uptake with hydroxyethylstarch peaked at 40% above control at 10 min of resuscitation. Excess O2 uptake in recovery was higher than O2 deficit in hemorrhage with the HES group but not with the HTS group. In the isolated hindlimb, vascular resistance decreased rapidly on hypertonic saline infusion but reached similar levels at 10 min of resuscitation with both fluids. With progressive lowering of blood flow to the pump-perfused hindlimb, ability of limb muscle to extract O2 was the same for the HTS and HES groups. With hemodilution by volume replacement with acellular fluid after hemorrhage, a seemingly adequate cardiac output and arterial pressure may be underresuscitation if O2 delivery does not meet the increased O2 demand.
Lethal ischemia due to intracoronary endothelin in pigs
Authors: Ezra D. , Goldstein R. E. , Czaja J. F. , Feuerstein G. Z.
Published: December 2017

Endothelin is a recently discovered endothelium-derived peptide with potent coronary constrictor properties in vitro. To evaluate endothelin's cardiac actions in vivo, we measured coronary flow and regional myocardial shortening when intracoronary porcine endothelin was given to anesthetized open-chested pigs. Bolus adminstration into the left anterior descending (LAD) coronary artery of six pigs caused dose-related rapidly reversing depression of LAD flow and local shortening. Marked reductions in flow [-71 +/- 8 (SE) %] and shortening (-83 +/- 2%) after 30 pmol/kg demonstrated endothelin's potency in cardiac tissues. Systemic hemodynamic values were unaltered except for transient rises in left ventricular end-diastolic pressure. Endothelin-induced decrement in LAD flow was accompanied by electrocardiographic signs of myocardial ischemia and net release of local myocardial lactate. Intracoronary infusion of endothelin, 15 pmol.kg-1.min-1, caused progressive decline in LAD flow and local shortening followed by severe persistent hypotension and terminal ventricular fibrillation in four of five pigs. Unlike intracoronary delivery of other potent coronary constrictors, intracoronary administration of endothelin did not lead to rapid escape from the peptide's deleterious influence. Coronary exposure to endothelin under pathophysiological circumstances could result in uniquely persistent decrements in myocardial perfusion and contractile function.
Cardiovascular effects produced by L-glutamate stimulation of the lateral hypothalamic area
Authors: Spencer S. E. , Sawyer W. B. , Loewy A. D.
Published: December 2017

L-Glutamate microinjections into the tuberal region of the lateral hypothalamic area (LHAt) caused a fall in blood pressure and heart rate in pentobarbital-anesthetized rats. The bradycardia was mediated by both beta-adrenergic and muscarinic mechanisms as demonstrated with pharmacological blockade. The hypotension was due to a decrease in cardiac output, not a decrease in total peripheral resistance. In addition, there was a reduction in coronary blood flow. If heart rate was held constant by pharmacological blockade or by electrical cardiac pacing, L-glutamate stimulation of the LHAt still caused a fall in blood pressure. When the electrically paced model was used, this hypotension was due to a fall in cardiac output. In contrast, with the pharmacological blockade of the heart, the hypotension was due to a decrease in the total peripheral resistance. The cardiac output reduction in the paced condition was not mediated solely by either beta-sympathetic or parasympathetic mechanisms as determined by pharmacological blockade. With heart rate held constant by either drugs or pacing, LHAt stimulation did not alter regional blood flow or resistance in any vascular bed, including the coronary circulation. We conclude that L-glutamate stimulation of the LHAt lowers the cardiac output and heart rate by both parasympathetic and beta-adrenergic mechanisms and elicits hypotension by lowering cardiac output in the naive and electrically paced model.
Histamine-induced calcium transients in vascular smooth muscle cells: effects of verapamil and diltiazem
Authors: Matsumoto T. , Kanaide H. , Nishimura J. , Kuga T. , Kobayashi S. , Nakamura M.
Published: December 2017

We investigated the effects of verapamil and diltiazem on histamine-induced Ca2+ transients in vascular smooth muscle. 1) With the use of quin2 microfluorometry, cytosolic Ca2+ concentrations were directly measured in cultured vascular smooth muscle cells of the rat aorta. In the presence of extracellular Ca2+, histamine induced an elevation of cytosolic Ca2+ concentrations of a peak and plateau type. The peak component is due to a release of Ca2+ from cellular store sites, and the plateau component depends on extracellular Ca2+. Verapamil and diltiazem inhibited the plateau component, and the 50% inhibitive concentration (IC50) of verapamil and diltiazem for 10 microM histamine was 0.09 and 0.18 microM, respectively. Only at high concentrations did verapamil (IC50 = 8.7 microM) and diltiazem (IC50 = 95.7 microM) inhibit the Ca2+ release from the cellular store sites, as induced by 10 microM histamine. 2) Histamine, verapamil, and diltiazem competed with [3H]mepyramine for binding to the porcine aortic membranes, the order of potency being verapamil (Ki = 7.1 microM) greater than histamine (Ki = 18 microM) greater than diltiazem (Ki = 114 microM). From these results, we conclude that verapamil and diltiazem strongly inhibit the histamine-mediated, extracellular Ca2+-dependent intracellular [Ca2+] increase. In addition, verapamil and diltiazem seem to inhibit the release of Ca2+ from intracellular store sites, only at high concentrations, and probably by competing with histamine for binding to the H1-receptor. The inhibitory effects of Ca2+ antagonists on the histamine-induced contraction or spasm of vascular smooth muscle may well relate to these mechanisms.
Effects of intravenous AVP on cardiac output, mesenteric hemodynamics, and splanchnic nerve activity
Authors: Veelken R. , Danckwart L. , Rohmeiss P. , Unger T.
Published: December 2017

To elucidate the effects of intravenous arginine vasopressin (AVP) on the neural control of the circulation, we investigated the action of AVP on neural circulatory control with respect to its influence on cardiac output (CO), mesenteric blood flow (MBF), and splanchnic nerve activity (SpNA) in conscious rats. We implanted Doppler flow probes and bipolar electrodes into seven Wistar rats for continuous monitoring of CO, MBF, and SpNa. After the infusion of four different equipressor doses of AVP and methoxamine, the decreases in heart rate (HR) and CO were significantly greater with AVP than with methoxamine. Pretreatment with atenolol and methscopolamine bromide abolished the decreases in HR after both AVP and methoxamine injections but attenuated the AVP-induced decreases in CO less than the methoxamine-induced CO decreases. In untreated rats and in rats receiving cardiac autonomic blockade, the reduction in MBF and the increases in mesenteric resistance were greater after AVP than after methoxamine. Furthermore, SpNA decreased to a greater extent with all doses of AVP than with methoxamine. We conclude that in the rat the exaggerated reduction in CO induced by circulating AVP is not because of a sensitization of neural mechanisms but rather to caridac actions of the peptide. In contrast, AVP sensitizes the sympathetic control of the mesenteric vascular bed to counterbalance its potent local vasoconstrictor effects.
A high density in vitro extracellular electrode array: description and implementation
Authors: Cohen M. L. , Hoyt R. H. , Saffitz J. E. , Corr P. B.
Published: December 2017

The detailed activation sequence in myocardium provides information critical to the understanding of the mechanisms of cardiac arrhythmias and the influence of interventions. Despite the pivotal role of activation mapping, the interpretation of isochronic maps and the correlation to detailed tissue morphology may be limited when the interelectrode distances are large with respect to cell dimensions. Additionally, dynamic beat-to-beat variations in the activation pattern or the effect of interventions such as single extra stimuli cannot be assessed adequately without recording from all sites simultaneously. To surmount these limitations, we have fabricated and tested an extracellular recording array consisting of 224 bipolar tungsten wire electrodes with a 350-microns interelectrode distance (140 microns edge-to-edge distance), and used signal processing equipment to record from all electrodes simultaneously at a 2-kHz sample rate. Stimulation can be performed sequentially from 12 different sites at 30 degree angles around the periphery of the recording array. Transarray bipoles can be recorded from any combination of eight radially oriented sites. Activation maps recorded in normal tissue after programmed stimulation and activation maps from an area of fixed anatomic block in the epicardial border zone of infarcted tissue are presented. The results demonstrate a lack of influence of the recording array on the electrophysiological properties of the tissue as verified with transmembrane action potential recordings and sequential extracellular maps. This electrode permits precise assessment of transient details of the activation sequence with unparalleled anatomic resolution.
Left atrial hypertension causes pleural effusion formation in unanesthetized sheep
Authors: Allen S. , Gabel J. , Drake R.
Published: December 2017

We studied the effect of left atrial pressure (LAP) elevation on the formation of pleural effusion in unanesthetized sheep. We prepared the animals by placing catheters in the left atrium, pulmonary artery, femoral artery, and vein. We also placed a balloon catheter in the left atrium. After a recovery period of at least 1 wk, we measured LAP, pulmonary artery pressure (PAP), systemic arterial pressure, systemic venous pressure, cardiac output, plasma protein concentration, and plasma colloid osmotic pressure (pi c). We calculated capillary pressure (Pc) as 0.5(PAP - LAP). We then elevated LAP such that Pc-pi c was between -10 and 19.5 mmHg for 6-24 h. At the end of the experiment, we killed the sheep and measured the volume and protein concentration of the right pleural effusion. We also determined the extravascular fluid to blood free dry weight of the right lung. We found that pleural effusions and pulmonary edema formed when Pc-pi c greater than 5 mmHg. We also found that the pleural effusion volume correlated with the amount of pulmonary edema. Our data show that elevated LAP may cause pleural effusions, but only after pulmonary edema has developed.
Single potassium channels recorded from vascular smooth muscle cells
Authors: Stuenkel E. L.
Published: December 2017

Single-channel activities were recorded from smooth muscle cells of vascular fragments isolated from rat pancreas. Three K-selective channel types were identified and characterized from cell-attached and inside-out membrane patches. Mean single-channel slope conductances of the three channel types, under conditions of symmetrical K (145 mM), were 43, 91, and 276 pS. The channel types exhibited differential sensitivity to tetraethylammonium (TEA) and intracellular Ca concentrations ([Ca2+]i). Intracellular TEA (10 mM) was effective in blocking the small conductance channel whereas the large conductance channel was found to be sensitive to [Ca2+]i. The properties of the large-conductance K channel are consistent with its identification as a calcium-activated maxi K channel described in a variety of tissues. Each of the channel types showed sensitivity to membrane potential, with increasing opening transitions at depolarizing membrane potentials. The small conductance channel type was observed to be active at resting membrane potentials. The generality of each of these channel types to other smooth muscle cell preparations and possible physiological implications are discussed.
Effect of leukotriene D4 on blood flow to cerebrum and choroid plexus
Authors: Mayhan W. G. , Faraci F. M. , Spector R. , Heistad D. D.
Published: December 2017

The purpose of this study was to examine effects of leukotriene D4 on blood flow to the cerebrum and choroid plexus. Blood flow was measured with microspheres in anesthetized rabbits. Under control conditions, blood flow to the cerebrum was 37 +/- 4 ml. min-1.100 g-1 (mean +/- SE) and blood flow to the choroid plexus was 428 +/- 52 ml.min-1.100 g-1. Intra-atrial infusion of leukotriene D4 at 0.1 and 1.0 microgram.kg-1.min-1 did not alter blood flow to the brain or choroid plexus, but produced a 49 +/- 3% and 69 +/- 5% decrease in blood flow to the bowel. We also examined effects of intracerebroventricular administration of leukotriene D4. Intraventricular injection of 1.0 microgram of leukotriene D4 did not affect blood flow to the cerebrum or choroid plexus. In contrast, intraventricular injection of 1.0 microgram of angiotensin II produced a 42 +/- 4% decrease in blood flow to the choroid plexus. In summary, neither intravascular nor intraventricular administration of leukotriene D4 affects blood flow to the brain or choroid plexus.
Transformation of neutrophils as indicator of irreversibility in hemorrhagic shock
Authors: Barroso-Aranda J. , Schmid-Schonbein G. W.
Published: December 2017

Recent evidence shows that the presence of circulating neutrophils (PMNs) influences the lethal course and extent of ischemic injury associated with hemorrhagic shock. The objective of this study was to use the Wiggers shock model to investigate the correlation between the appearance of activated circulating PMNs as measured by the spontaneous reduction of nitro blue tetrazolium [(NBT)-positive PMNs] and survival rate. Rats were maintained at 35-mmHg arterial pressure for 90 min and then observed over 24 h for survival. This protocol resulted in 50% mortality. In all animals in which levels of circulating NBT-positive PMNs before bleeding were greater than 225 cells/mm3, the experimental procedure was lethal. Animals that initially had low numbers of NBT-positive PMNs (to approximately 135 cells/mm3) and maintained low counts during the hypotensive period consistently survived. Animals, which before bleeding had low NBT-positive PMN counts but during the course of hypotension significantly elevated their circulating count, have low probability for survival. In those cases in which high NBT-positive PMN counts occurred only later in the course of the hypotensive period, the rats survived. These results suggest that the number of circulating NBT-positive PMNs is a singular index for the trend toward irreversibility in this shock model.
Wall motion asynchrony prolongs time constant of left ventricular relaxation
Authors: Aoyagi T. , Iizuka M. , Takahashi T. , Ohya T. , Serizawa T. , Momomura S. , Sato H. , Mochizuki T. , Matsui H. , Ikenouchi H. , et al.
Published: December 2017

To evaluate the effects of wall motion asynchrony on left ventricular (LV) relaxation, we performed atrioventricular sequential pacing with the second stimulation at six epicardial sites in open-chest anesthetized dogs. Myocardial segment lengths in the basal, mid, and apical LV free wall were measured by ultrasonic crystals. The standard deviation of interval from the onset of the QRS complex to that of elongation in each segment length was used as a quantitative index for asynchrony (asynchrony index, AI). The AI increased significantly in all sequential pacing modes compared with the control right atrial pacing. The time constant (T) of LV relaxation derived from exponential fit with zero-asymptote was prolonged significantly in all sequential pacing modes except for pacing at the LV base. In each dog there was a good correlation between changes in AI and T [r = 0.61 - 0.98 (mean = 0.84)]. Since the regional inactivation process of the myocardium is considered to be unchanged during these interventions, we concluded that asynchronous wall motion plays an important role in the impairment of LV relaxation.
Oral vanadyl sulfate in treatment of diabetes mellitus in rats
Authors: Ramanadham S. , Mongold J. J. , Brownsey R. W. , Cros G. H. , McNeill J. H.
Published: December 2017

Recent reports have suggested that vanadium in the form of vanadyl (+IV) possesses insulin-like activity. Therefore, in the present study we examined the effects of administering oral vanadyl to diabetic animals. Wistar rats made diabetic with streptozotocin and age-matched controls were maintained for 10 wk in the absence and presence of vanadyl sulfate trihydrate in the drinking water. In the presence of vanadyl, decreases in rate of growth and circulating levels of insulin were the only significant alterations recorded in control animals. In contrast, diabetic animals treated with vanadyl, despite having lower body weights and insulin levels, had normal plasma concentrations of glucose, lipid, creatinine, and thyroid hormone. In addition, abnormalities in isolated working heart function and glycerol output from adipose tissue of diabetic animals were also corrected after vanadyl treatment. These results suggest that vanadium when used in the vanadyl form is effective in diminishing the diabetic state in the rat by substituting for and replacing insulin or possibly by enhancing the effects of endogenous insulin.
Atrial natriuretic factor gene expression in rat ventricle during experimental hypertension
Authors: Mercadier J. J. , Samuel J. L. , Michel J. B. , Zongazo M. A. , de la Bastie D. , Lompre A. M. , Wisnewsky C. , Rappaport L. , Levy B. , Schwartz K.
Published: December 2017

Activation of atrial natriuretic factor (ANF) gene expression has been reported in the rat ventricle in several models of hemodynamic overload, including hypertension. However, nothing is known about the potential trigger(s) and the time course of this activation during the development of hypertension. We measured aortic blood pressure, left ventricular hypertrophy (LVH), and left ventricular ANF mRNA concentration (LV ANF mRNA) in a first group of rats (study A) killed at 5 and 18 h and 2, 4, 6, 9, 15, and 30 days after suprarenal coarctation of the abdominal aorta. Coarctation induced a progressive rise in aortic blood pressure and left ventricular mass. We observed a biphasic accumulation of ANF mRNA in the left ventricle with a peak at day 4 averaging 20 times the control value long before stable hypertension and hypertrophy were achieved, followed by a decrease until day 9. This decrease was followed by a new rise, which stabilized around 10 times the control value seen during stable hypertension and hypertrophy. In a second group of rats killed at days 4 and 30 (study B), we determined, in addition to the previous parameters, left ventricular end-diastolic pressure (LVEDP), plasma renin (PRC), and plasma ANF concentrations. LVEDP and PRC were markedly increased at day 4, but at day 30, during stable hypertension and hypertrophy, these parameters returned to control values, whereas plasma ANF was increased. Using immunocytochemistry, we looked in a third group of rats (study C) for the presence of the immunoreactive peptide at days 4 and 30.(ABSTRACT TRUNCATED AT 250 WORDS)
Phasic pressures and diameters in small epicardial veins of the unrestrained heart
Authors: Nellis S. H. , Whitesell L.
Published: December 2017

Previous data from this laboratory have revealed a large pressure pulse in small veins on the epicardial surface of the right ventricle of the rabbit. The phasic relationship between venule pressures and venule diameters in a beating heart was examined. Luminal pressures were measured in 39 different veins on the epicardial surface of the rabbit right ventricle. The venous luminal pressures averaged 12.6 mmHg maximum and 1.0 mmHg minimum. Pressures in 23 different small veins were also obtained at different right ventricular afterloads. Peak venous pressures increased with peak right ventricular pressure. The phasic diameter changes of 119 different vessels were examined. Vessel diameters decreased as luminal pressures increased. The average change in vessel diameter through a cardiac cycle was 20%, with a range from 0 to 60%. The large pulse pressures found in small veins appear to be related to decreasing vessel diameters and probably result from the displacement of blood as the vessels narrow.
Oxygen requirements of the dyskinetic myocardial segment
Authors: Gayheart P. A. , Vinten-Johansen J. , Johnston W. E. , Hester T. O. , Cordell A. R.
Published: December 2017

Oxygen requirements of a noncontracting myocardial segment subjected to passive systolic stretch (dyskinesis) have not been well described. The purpose of this study was to measure oxygen consumption (MVO2) of a myocardial segment made dyskinetic by intracoronary infusion of lidocaine. In 12 anesthetized open-chest dogs, segmental shortening was measured sonomicrometrically in regions perfused by the left anterior descending (LAD) and circumflex (Cfx) coronary arteries. MVO2 was measured by arterial-venous oxygen content differences and transmural blood flow. Dose-response curves to intracoronary lidocaine showed that complete dyskinesis was achieved by a 0.25-mg/ml dose of lidocaine, whereas the Cfx region maintained a constant level of segmental shortening. MVO2 of the LAD segment was similar to that of the Cfx segment under control conditions. With lidocaine-induced dyskinesis, MVO2 in the arrested segment was reduced by 33% (P less than 0.05), despite the loss of contractile function. When bulging was prevented by ventricular unloading, MVO2 in the arrested segment decreased to 2.65 ml O2.min-1.100 g-1 (i.e., basal oxygen requirements). In conclusion, MVO2 in a pharmacologically arrested myocardial segment undergoing systolic bulging is paradoxically high relative to both basal requirements and MVO2 in the normally contracting segment.
Cerebrospinal fluid ionic regulation, cerebral blood flow, and glucose use during chronic metabolic alkalosis
Authors: Schrock H. , Kuschinsky W.
Published: December 2017

Chronic metabolic alkalosis was induced in rats by combining a low K+ diet with a 0.2 M NaHCO3 solution as drinking fluid for either 15 or 27 days. Local cerebral blood flow and local cerebral glucose utilization were measured in 31 different structures of the brain in conscious animals by means of the iodo-[14C]antipyrine and 2-[14C]deoxy-D-glucose method. The treatment induced moderate [15 days, base excess (BE) 16 mM] to severe (27 days, BE 25 mM) hypochloremic metabolic alkalosis and K+ depletion. During moderate metabolic alkalosis no change in cerebral glucose utilization and blood flow was detectable in most brain structures when compared with controls. Cerebrospinal fluid (CSF) K+ and H+ concentrations were significantly decreased. During severe hypochloremic alkalosis, cerebral blood flow was decreased by 19% and cerebral glucose utilization by 24% when compared with the control values. The decrease in cerebral blood flow during severe metabolic alkalosis is attributed mainly to the decreased cerebral metabolism and to a lesser extent to a further decrease of the CSF H+ concentration. CSF K+ concentration was not further decreased. The results show an unaltered cerebral blood flow and glucose utilization together with a decrease in CSF H+ and K+ concentrations at moderate metabolic alkalosis and a decrease in cerebral blood flow and glucose utilization together with a further decreased CSF H+ concentration at severe metabolic alkalosis.
Contraction of diabetic rabbit aorta caused by endothelium-derived PGH2-TxA2
Authors: Tesfamariam B. , Jakubowski J. A. , Cohen R. A.
Published: December 2017

Endothelium-dependent relaxations and vasoactive prostanoid production caused by acetylcholine were determined in the aortas of rabbits with diabetes mellitus induced by alloxan. Aortas of diabetic rabbits, contracted submaximally by phenylephrine, showed significantly decreased endothelium-dependent relaxations induced by acetylcholine compared with the aortas of normal rabbits. Indomethacin, a cyclooxygenase inhibitor, and SQ 29548, a prostaglandin H2-thromboxane A2 (PGH2-TxA2) receptor antagonist, normalized the sensitivity of diabetic aortas to acetylcholine, whereas these agents had no effect on the response of normal aortas. The relaxations in response to a nonreceptor-mediated endothelium-dependent vasodilator, A23187, and an endothelium-independent vasodilator, sodium nitroprusside, were not different between normal and diabetic aortas. Acetylcholine also caused contractions of resting aortic rings with endothelium from diabetic, but not normal rabbits; these contractions were inhibited by indomethacin. Synthesis of TxA2, measured as immunoreactive TxB2, was significantly increased in diabetic aortic segments only when the endothelium was present. These results suggest that in the diabetic state, the endothelium releases a major vasoconstrictor cyclooxygenase product that either directly counteracts the relaxation caused by or selectively interferes with the release of endothelium-derived relaxing factor(s) induced by cholinergic receptor stimulation. The vasoconstrictor is most likely TxA2 or possibly its precursor, PGH2.