bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-dose endothelin-1 potentiates volume-induced secretion of atrial natriuretic factor
Authors: Donckier J. , Hanet C. , Galanti L. , Stoleru L. , Van Mechelen H. , Robert A. , Ketelslegers J. M. , Pouleur H.
Published: December 2017

To evaluate the role of calcium in volume-induced secretion of atrial natriuretic factor (ANF), effects of verapamil and endothelin-1 (ET-1), both known to influence free intracellular calcium, were studied during saline infusion in seven conscious instrumented dogs. Fifteen minutes after intravenous injection of placebo or verapamil (0.25 mg/kg) or during continuous ET-1 infusion (at 5 ng.kg-1.min-1), saline (10% body wt) was infused during 40 min. Saline produced a rise (P less than 0.001) of plasma ANF from 28.1 +/- 6.3 to 50.4 +/- 12.9 pM after placebo, from 30.2 +/- 6.1 to 51.1 +/- 8.5 pM after verapamil, and from 31.2 +/- 6.1 to 81.0 +/- 12.9 pM with ET-1. This increase was comparable after placebo and verapamil, but was 80% greater with ET-1 (P less than 0.02). Plasma ET-1, unchanged after placebo, rose (P less than 0.001) from 1.7 +/- 0.5 to 38.3 +/- 9.2 pM with ET-1. In the three experiments, heart rate and left atrial pressure (LAP) increased (P less than 0.001) similarly. The linear relation between ANF and LAP was steeper with ET-1 than with saline or verapamil (both P less than 0.05), indicating that the enhanced ANF secretion with ET-1 was occurring at all levels of LAP. Thus volume-induced secretion of ANF is not suppressed by verapamil, but is directly enhanced by low-dose ET-1, known to activate the phosphoinositide pathway.
Dynamic intramyocardial blood volume: evaluation with a radiological opaque marker method
Authors: Liu Y. H. , Bahn R. C. , Ritman E. L.
Published: December 2017

In this study the change of intramyocardial blood volume within one cardiac cycle was deduced from the time sequence of the volume delineated by radiopaque markers attached to the left ventricular wall. These data were compared with the change in the volume of the same region of myocardium estimated from the change in angiographic opacification of the heart wall. Five dogs were anesthetized, and four pairs of 2-mm-diameter lead beads were attached to the epicardial and endocardial regions. Two scans using the dynamic spatial reconstructor (a high-speed computed tomographic scanner) were performed during aortograms, one under control conditions and the other during adenosine infusion. The results have shown that the increases of myocardial volume defined by the beads (delta Vbead, % of volume at control) were comparable to the increase of intramyocardial blood volumes estimated by the increase in wall opacity (delta Vblood, % of muscle); delta Vblood = 0.93 delta Vbead + 1.54%; r = 0.987.
Altered pressure-volume relation of right atrium and venoatrial junction in diabetic rats
Authors: Patel M. B. , Zhang P. L. , Patel A. C. , Patel K. P.
Published: December 2017

Previous studies have indicated a blunted volume reflex in diabetic rats. This alteration of the volume reflex may be due to differences in distensibility of the right atrium and venoatrial junction, which contain a large number of volume receptors. This study was designed to determine whether the distensibility of the right atrium and venoatrial junction is altered in the diabetic rat. The distensibility was assessed by measuring the stiffness constants [slope of pressure-volume (P-V) curve] of the right atrium and venoatrial junction in 2-wk streptozotocin-induced diabetic rats. The P-V data of the right atrium and venoatrial junction were measured in control and diabetic rats over a range of 0-10 mmHg by infusion of isotonic saline in KCl-arrested, in situ hearts. Similar P-V data also were determined in an additional group of diabetic rats under daily insulin treatment, which normalized plasma glucose. The mean slope of the P-V curve of the right atrium and venoatrial junction in the diabetic rats was significantly greater than the mean slope of the control and insulin-treated diabetic rats. The results indicate that diabetic rats have stiffer right atria and venoatrial junctions, which may reduce stimulation of the volume receptors to acute volume loading. In addition, the increased stiffness in the diabetic rats was prevented by chronic insulin treatment. An altered afferent limb of the volume reflex in diabetic rats contributing to blunted diuretic and natriuretic responses to volume loading may be due to these documented changes in the distensibility of the right atrium and venoatrial junction.
Transvascular albumin and IgG flux in skin after a continuous 3-h bradykinin infusion
Authors: Wallace J. R. , Bell D. R.
Published: December 2017

Bradykinin (1 microgram/min) was infused into the femoral artery of one hindleg of anesthetized rabbits for 3 h. Measurements of the initial extravascular uptake for labeled albumin and immunoglobulin (Ig) G were compared with measurements of the lymph protein flux for endogenous albumin and IgG. With bradykinin, the initial extravascular uptake for both albumin and IgG, calculated as the 1-h extravascular distribution space at plasma concentration divided by time and expressed as a plasma clearance, was 12 times the control values. For both proteins, the lymph fluxes were not significantly greater than the values for extravascular uptake, indicating that the sustained increase in lymph protein flux was not due to washout of interstitial protein. The extravascular uptake for IgG was approximately 80% of that for albumin in both control and bradykinin animals, suggesting that the sustained response did not change the selectivity between the two proteins. Changes in the extravascular masses of endogenous albumin and IgG suggest that the initial response to bradykinin was a transient formation of endothelial gaps that did not restrict transvascular IgG transport more than albumin.
Beneficial influence of vasoactive intestinal peptide on ventriculovascular coupling in closed-chest dogs
Authors: Colston J. T. , Freeman G. L.
Published: December 2017

The effect of vasoactive intestinal peptide (VIP) on ventriculovascular coupling in the intact cardiovascular system has not been defined. We studied seven dogs chronically instrumented with left ventricular (LV) pressure manometers and three sets of diameter gauges before and after infusions of 0.02, 0.05, and 0.10 microgram.kg-1.min-1 VIP. The dogs were studied after autonomic blockade, anesthesia, and intubation, with a fixed heart rate of 160 beats/min. Contractility was assessed using LV elastance at end systole (Ees) and the slope of the stroke work-end-diastolic volume relation. The vascular influence of VIP was quantified by determining effective arterial elastance (Ea) under steady-state conditions. The overall effect on ventriculovascular coupling was assessed using the transfer of mechanical energy from LV to the arterial system (TransPVA) quantified as the percentage of pressure-volume area (PVA) expressed as stroke work. LV relaxation was measured using the time constant of LV pressure decay. The results showed that VIP increased contractility (Ees increased to 129, 156, and 181% of control; P < 0.01 for all vs. control) and decreased effective arterial elastance (Ea fell to 84, 68, and 64% of control; P < 0.0155 vs. control for the two higher doses). VIP had no consistent effects on LV relaxation. Thus, in addition to its positive ventricular effects (increased contractility), VIP has beneficial vascular effects (reduced Ea). These properties combine to improve ventriculovascular coupling, such that VIP enhances delivery of mechanical energy from the LV to the circulatory bed.
Maximal myocardial blood flow is enhanced by chronic hypoxemia in late gestation fetal sheep
Authors: Reller M. D. , Morton M. J. , Giraud G. D. , Wu D. E. , Thornburg K. L.
Published: December 2017

The measurement of maximal myocardial blood flow gives information about the total cross-sectional area of the coronary resistance vessels. During a continuous left atrial infusion of adenosine (60 micrograms.kg-1.min-1), maximal myocardial blood flow was measured in 4 fetuses hypoxemic for a minimum of 5-8 days (pH = 7.33 +/- 0.01, arterial PCO2 = 49.8 +/- 4.2 Torr, arterial PO2 = 16.1 +/- 1.3 Torr, and arterial concentration of O2 = 5.3 +/- 1.2 ml/dl). These data were compared with an identically instrumented group of normoxemic fetuses (n = 7) following the same study protocol (pH = 7.38 +/- 0.02, arterial PCO2 = 43.1 +/- 3.8 Torr, arterial PO2 = 19.8 +/- 2.0 Torr, and arterial concentration of O2 = 7.9 +/- 1.0 ml/dl) (P < 0.05). At comparable arterial pressures, the maximal myocardial flow (ml.min-1.100 g tissue-1) for hypoxemic vs. normoxemic fetuses was 974 +/- 273 and 630 +/- 181 for the total myocardium, 986 +/- 367 and 602 +/- 192 for the left ventricular free wall, 1,025 +/- 346 and 614 +/- 178 for the septum, and 1,231 +/- 274 and 757 +/- 269 for the right ventricular free wall, respectively (P < 0.01). These data suggest that hypoxemia in the fetus can significantly alter the coronary vascular bed, which, if confirmed, would represent an important adaptation in the developing fetus.
Role of ATP-sensitive potassium channels in ovine fetal pulmonary vascular tone
Authors: Cornfield D. N. , McQueston J. A. , McMurtry I. F. , Rodman D. M. , Abman S. H.
Published: December 2017

To study the potential role of ATP-sensitive K+ (K+ATP) channels in fetal pulmonary vasoregulation, we studied the effect of a K+ATP channel agonist, lemakalim, and antagonist, glibenclamide, on the fetal pulmonary circulation in nine chronically instrumented late-gestation fetal lambs. Left pulmonary artery (LPA) blood flow was measured with an electromagnetic flow transducer. Brief (10 min) infusions of lemakalim at 3, 10, and 30 micrograms/min into the LPA produced dose-dependent increases in flow from 68 +/- 7 to 96 +/- 11, 160 +/- 15, and 204 +/- 34 ml/min, respectively. The duration of pulmonary vasodilation after the 10-min infusions of lemakalim at 3, 10, and 30 micrograms/min was 20 +/- 3, 47 +/- 10, and 55 +/- 15 min, respectively. Pulmonary blood pressure and flow did not change with intrapulmonary infusion of glibenclamide (10 mg), a K+ATP channel antagonist. Lemakalim-induced pulmonary vasodilation was not affected by nitro-L-arginine (10 mg), a competitive inhibitor of endothelium-dependent relaxing factor, but was blocked by glibenclamide. Prolonged (2 h) intrapulmonary infusions of lemakalim (2-6 micrograms/min) increased pulmonary blood flow by 137%. The increase in pulmonary blood flow was sustained throughout the infusion. Systemic and pulmonary arterial pressures decreased during prolonged infusion. We conclude that K+ATP channels are present in the fetal pulmonary circulation, but do not participate in the regulation of basal pulmonary vascular tone. K+ATP channel activation produces sustained vasodilation that is not mediated by endothelium-derived relaxing factor. We speculate that birth-related stimuli activate K+ATP channels to enhance the pulmonary vasodilation that occurs at birth.
Attenuation of postischemic microvascular disturbances in striated muscle by hyperosmolar saline dextran
Authors: Nolte D. , Bayer M. , Lehr H. A. , Becker M. , Krombach F. , Kreimeier U. , Messmer K.
Published: December 2017

The underlying mechanisms of the beneficial therapeutic effects of small-volume resuscitation with hyperosmolar solutions for treatment of hypovolemic shock are still poorly understood. Using the dorsal skinfold chamber model and intravital fluorescence microscopy, we investigated the effects of hyperosmolar saline dextran on ischemia-reperfusion injury in striated skin muscle of awake normovolemic golden hamsters. Test solutions (4 ml/kg body wt i.v.) were administered 2 min before reperfusion after 4 h of pressure-induced ischemia. In animals receiving 0.9% saline (control), we observed a drastic enhancement of leukocyte rolling along and sticking to the endothelium of postcapillary venules 0.5 h after reperfusion. Postischemic leukocyte rolling and sticking were significantly reduced when animals were treated with 7.2% saline alone (HSS), 10% Dextran 60 in 0.9% saline (HDS), or 10% Dextran 60 in 7.2% saline (HHS). In control animals, capillary perfusion was reduced to approximately 60% of preischemic values 0.5 h after reperfusion. Concomitantly, leakage of the macromolecule fluorescein isothiocyanate-dextran (5 mg in 0.1 ml saline i.v., M(r) 150,000) into the perivascular space increased from 0% before ischemia to approximately 12% at 0.5 h reperfusion. In contrast, when animals were treated with HSS, HDS, or HHS before reperfusion, capillary perfusion decreased to a significantly minor extent of approximately 15%, and macromolecular leakage was slightly increased to approximately 5%. Our results suggest that hyperosmolar saline dextran effectively attenuates postischemic microvascular disturbances elicited by ischemia-reperfusion, presumably through reduction of postischemic leukocyte-endothelium interaction and capillary swelling.
Endothelin stimulates multiple responses in isolated adult ventricular cardiac myocytes
Authors: Jones L. G. , Rozich J. D. , Tsutsui H. , Cooper G.
Published: December 2017

We have examined the responses to endothelin (ET) in isolated adult cardiac myocytes from both rodent and feline species to assess whether endothelin may have a role in the induction or mediation of cardiac hypertrophy in the adult animal. We have evidence that ET acts by more than one mechanism to promote cell-signaling events believed important in growth regulation. In isolated adult cardiac ventricular myocytes labeled overnight with [3H]inositol, endothelin (ET) promoted a two- to fourfold increase in the accumulation of inositol polyphosphates in a dose-dependent manner with an half-maximal effective concentration (EC50) of approximately 5 nM. In contrast, picomolar concentrations of ET promoted an increase in both the extent and velocity of sarcomere shortening in electrically stimulated myocytes. Pretreatment of cells with pertussis toxin had no effect on the ET-stimulated phosphoinositide hydrolysis, but blocked the ET-stimulated positive inotropic effect. In addition to these early responses to ET, results obtained by Northern blot analysis demonstrate that exposure of isolated cardiac myocytes to 100 nM ET promoted the expression of c-fos and c-zif in both mammalian species. These data demonstrate that ET stimulates multiple cell-signaling pathways in adult mammalian cardiac myocytes. A paracrine mechanism of regulation of adult myocardium is suggested.
Glycogen depletion-induced lactate reductions attenuate reflex responses in exercising humans
Authors: Sinoway L. I. , Wroblewski K. J. , Prophet S. A. , Ettinger S. M. , Gray K. S. , Whisler S. K. , Miller G. , Moore R. L.
Published: December 2017

Post leg exercise circulatory arrest (PLE-CA) raises blood pressure (BP) and reduces peak forearm vascular conductance (C). This reflex is evoked by activation of muscle afferents that are often sensitive to lactic acid. We tested the hypothesis that lactic acid reductions induced by muscle glycogen depletion would attenuate the lower-limb metaboreceptor-mediated pressor and forearm vasoconstrictor responses. Eleven subjects had C measured (plethysmography) during post leg exercise circulatory arrest (PLE-CA) (supine bicycle exercise for 9 min, 10 s at 75% VO2max before and after undergoing a glycogen-depletion paradigm (24-h fast followed by 10 min of supine leg exercise at 75% VO2max). In six subjects with lower lactate values, C during PLE-CA was higher after glycogen depletion (0.39 +/- 0.05 vs. 0.21 +/- 0.01 ml.min-1.100 ml-1 x mmHg-1; P < 0.01) and BP was lower (113 +/- 6 vs. 128 +/- 6 mmHg, P < 0.01). In five subjects without attenuated lactate responses, C and BP during PLE-CA were not different. Muscle biopsies (n = 5) demonstrated that the paradigm lowered muscle glycogen concentrations. Thus glycogen depletion-induced reductions in muscle lactate are associated with reduced muscle metaboreceptor-mediated responses.
Sarcolemmal Na(+)-Ca2+ exchange activity and exchanger immunoreactivity in developing rabbit hearts
Authors: Artman M.
Published: December 2017

It has been postulated that as a consequence of an underdeveloped sarcoplasmic reticulum, sarcolemmal Na(+)-Ca2+ exchange assumes relatively greater importance in modulating Ca2+ fluxes in the developing heart. To explore this concept, cardiac sarcolemmal vesicles were prepared from late fetal (28-day gestation), newborn (24-48 h), immature (14-16 days), and adult New Zealand White rabbits. Na(+)-dependent Ca2+ uptake was measured by diluting Na(+)-loaded (140 mM) vesicles into Na(+)-free buffer and measuring 45Ca2+ uptake (40 microM Ca2+) by timed quenching and rapid filtration. Vesicles from all four age groups demonstrated Ca2+ uptake curves characteristic of Na(+)-Ca2+ exchange with stimulation by valinomycin and inhibition by amiloride. Initial uptake velocity (measured at 2 s and corrected for the fraction of competent vesicles) was significantly higher in fetal (23.2 +/- 5.5 nmol/mg) and newborn (26.2 +/- 5.9 nmol/mg) than in adult sarcolemmal preparations (7.3 +/- 1.2 nmol/mg). Uptake was intermediate in the 2-wk-old group (13.7 +/- 1.7 nmol/mg). The relative amounts of exchanger protein were compared by quantitating immunoreactivity using a polyclonal antibody to the Na(+)-Ca2+ exchanger. Densitometric scanning of protein slot blots demonstrated approximately 2.5 times more exchanger protein in fetal and newborn sarcolemma than in adult preparations. The relative amount of exchanger protein detected immunologically corresponded with the age-related differences observed in exchanger activity. Thus the cardiac sarcolemmal Na(+)-Ca2+ exchanger is abundant and functionally well-developed in the late fetal/early newborn rabbit heart and appears to decline postnatally.(ABSTRACT TRUNCATED AT 250 WORDS)
Development of cardiac innervation, ventricular fibrillation, and sudden infant death syndrome
Authors: Stramba-Badiale M. , Lazzarotti M. , Schwartz P. J.
Published: December 2017

The effects of bilateral vagotomy and of right, left, and bilateral stellectomy on sinus node and on ventricular fibrillation threshold (VFT) were assessed in three groups of puppies (1, 3, and 5 wk old) and one group of adult dogs. Heart rate was increased by vagotomy and reduced by right stellectomy in all groups. After vagotomy, VFT did not change in the first week, while it decreased in the third week (-21%, P < 0.0001), in the fifth week (-20%, P < 0.001) and in the adults dogs (-18%, P < 0.005). VFT was not modified by right stellectomy in the first week and in the fifth week (0%, NS), while it decreased in the third week (-28%, P < 0.05) and in the adults (-32%, P < 0.001). Left stellectomy, performed after right stellectomy, increased VFT in the third week (+52%, P < 0.05), in the fifth week (+62%, P < 0.001), and in the adults (+45%, P < 0.01). Thus removal of either vagal or right cardiac sympathetic activity increases susceptibility to ventricular fibrillation already during the first weeks of life. By contrast, removal of left sympathetic nerves increases cardiac electrical stability. These findings are consistent with the hypothesis that a developmental abnormality in cardiac innervation may play a role in the genesis of some cases of sudden infant death syndrome.
Prostanoids modulate opioid-induced increases in cerebrospinal fluid vasopressin concentration
Authors: Armstead W. M. , Mirro R. , Shibata M. , Leffler C. W.
Published: December 2017

Topical dynorphin and beta-endorphin produce increases in both prostanoid and vasopressin concentrations in cortical periarachnoid fluid of newborn pigs. The present study, in anesthetized piglets with cranial windows implanted, investigated the role of these prostanoids in the mediation of this vasopressin release by opioids. Topical prostaglandin (PG) I2 (100 ng/ml) increased pial arteriolar diameter from 145 +/- 4 to 178 +/- 4 microns and also increased cerebrospinal fluid (CSF) vasopressin from 1.1 +/- 0.1 to 4.1 +/- 0.5 microU/ml, but CSF vasopressin was not changed by PGE2, PGF2 alpha, and U-46619. Therefore, it is possible that PGI2 causes the increase in CSF vasopressin produced by opioids. Consistent with this concept, indomethacin and aspirin blocked dynorphin- and beta-endorphin-induced vasopressin release. The present data indicate that PGI2 contributes to opioid-induced changes in CSF vasopressin concentration and, thereby, to vasopressinergic contributions to opioid-induced cerebral vascular responses.
Effect of afterload and beta-adrenergic blockade on nonischemic myocardial contraction pattern
Authors: Birkeland S. , Westby J. , Grong K. , Lekven J.
Published: December 2017

We studied how changes in afterload affect regional contraction in the anterior wall of the left ventricular after circumflex coronary arterial (CFX) occlusion and subsequent beta-adrenergic blockade in pentobarbital sodium-anesthetized cats. Regional function was determined by orthogonal sonomicrometry. CFX occlusion produced nonuniform hyperkinesis in the nonischemic anterior wall; shortening of circumferential segments increased from 10.1 to 14.1% (P < 0.001), whereas shortening of longitudinal segments increased from 3.0 to 9.6% (P < 0.001). Hyperkinesis of longitudinal segments was influenced neither by changes in afterload over a pressure range of +/- 30 mmHg nor by beta-adrenergic blockade, indicating that hyperkinesis of longitudinal segments does not rely on increased inotropic state or resistance to ventricular emptying. Hyperkinesis of longitudinal segments occurred at end-diastolic lengths equal to preocclusion conditions, whereas hyperkinesis of circumferential segments was dependent on activation of the Frank-Starling mechanism. Furthermore, shortening of circumferential segments decreased with increments in afterload, particularly after CFX occlusion and subsequent beta-adrenergic blockade. In conclusion, CFX occlusion alters the contraction pattern of the nonischemic anterior wall. The postocclusion contraction is sensitive to increased afterload in the cardiac minor axis direction. These initial alterations may well direct the following remodeling process in infarcted hearts.
Recruitment of myocardial work and metabolism in regionally stunned porcine myocardium
Authors: McFalls E. O. , Duncker D. J. , Krams R. , Sassen L. M. , Hoogendoorn A. , Verdouw P. D.
Published: December 2017

We characterized postischemic changes in myocardial metabolism and regional external work, as measured by the integral of left ventricular pressure-segment-length loops. In 12 anesthetized swine, the left anterior descending coronary artery (LAD) was occluded for 10 min and reperfused for 30 min for two successive cycles. Before ischemia, regional work was 16,920 +/- 5,630 mmHg-mm/min and after stunning, work was reduced to 50 +/- 14% (P < 0.05). At baseline, oxygen and lactate consumption were 4.80 +/- 1.40 and 1.02 +/- 0.46 mumol.min-1 x g-1, respectively, and after stunning they were reduced to 3.24 +/- 0.80 (P < 0.05) and 0.16 +/- 0.21 mumol.min-1 x g-1 (P < 0.05), respectively. The atria were then paced 50 beats/min higher than the reperfusion heart rate, during and without an infusion of dobutamine (2 micrograms.kg-1 x min-1). During dobutamine, both regional external work and oxygen consumption returned to 98% of preischemic values, but lactate utilization remained depressed. We conclude that regional external work and oxygen consumption remain coupled during inotropic stimulation after stunning, with a preferential shift toward nonlactate substrates.
Trophic effects of catecholamines and parathyroid hormone on adult ventricular cardiomyocytes
Authors: Schluter K. D. , Piper H. M.
Published: December 2017

Trophic effects of isoproterenol (Iso), norepinephrine (NE), phenylephrine (PE), and biologically active fragments of parathyroid hormone (PTH), PTH-(1–34) and PTH-(28–48), were investigated in mechanically quiescent, isolated ventricular cardiomyocytes from adult rat. In 24-h incubations in modified serum-free medium 199 incorporation of [14C]phenylalanine, changes in total protein and specific activities of cytosolic enzymes, creatine kinase (CK) and lactate dehydrogenase (LDH) were monitored. NE and PE (10 microM), but not Iso, distinctly increased phenylalanine incorporation, total cell protein, and specific activity of CK but not LDH. Induction of CK, but not LDH, was also produced by phorbol 12-myristate 13-acetate (10 nM) but not dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP, 1 mM). It was abolished by copresence of cycloheximide (35 microM) or actinomycin D (5 microM). CK-BB was the only induced isoform of CK, as shown for PE incubations. PTH-(1'34) and PTH-(28–48) (30–300 nM) had effects comparable to NE and PE. They increased phenylalanine incorporation and total protein content and induced CK but not LDH. In summary, distinct trophic effects on adult cardiomyocytes were found with alpha 1-adrenergic agonists, fragments of PTH containing the midregional amino acids 28–34, and direct activation of protein kinase C but neither beta-adrenergic agonists nor DBcAMP.
2,3-Butanedione monoxime increases contractile efficiency in the rabbit ventricle
Authors: Watkins M. W. , Slinker B. K. , Goto Y. , LeWinter M. M.
Published: December 2017

The efficiency of chemomechanical energy transduction (contractile efficiency) of the left ventricle (LV) has been calculated from the linear correlation of the systolic pressure-volume area (PVA) of the LV and its O2 consumption (VO2). Thus far, a wide range of acute interventions, including adrenergic agents, Ca(2+)-sensitizing drugs, and Ca2+ channel blockers have not altered contractile efficiency. In contrast, hyperthyroidism has been reported to decrease contractile efficiency, an effect attributed at the cross-bridge level to an increase in the V1/V3 myosin isoenzyme ratio. We hypothesized that an acute intervention which directly alters cross-bridge cycling would also change contractile efficiency. Accordingly, 2,3-butanedione monoxime (BDM), a negative inotropic agent that is thought to directly inhibit cross-bridge formation, was administered to seven excised, red blood cell-perfused, isovolumically beating rabbit LVs. At 3-4 mM perfusate concentration, BDM resulted in the following reversible mechanical and energetic effects compared with control. Contractility, assessed by the slope (Emax) of the end-systolic pressure-volume relation, decreased by 11% (196.6 +/- 25.9 vs. 222 +/- 28 mmHg/ml). Both the time to end systole (Tmax) and relaxation half time (T1/2) decreased. The slope of the VO2-PVA relation decreased by 20% (1.55 +/- 0.44 x 10(-5) vs. 1.95 +/- 0.52 x 10(-5) ml O2 x mmHg-1 x ml-1), equivalent to an increase in contractile efficiency from 36.5 +/- 10.4 to 46.4 +/- 14.4%, while the O2 costs of the mechanically unloaded LV decreased by 12% (0.0258 +/- 0.0060 vs. 0.0292 +/- 0.0064 ml O2 x beat-1 x 100 g-1). Finally, BDM also produced coronary vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypocapnic-hypoglycemic interactions on cerebral high-energy phosphates and pH in dogs
Authors: Sieber F. E. , Derrer S. A. , Eleff S. M. , Koehler R. C. , Traystman R. J.
Published: December 2017

With a level of hypoglycemia (1–1.5 mM) that does not alter cerebral O2 uptake and glucose uptake in dogs, induction of hypocapnia may cause severe electroencephalographic (EEG) abnormalities. The aim of this study was to determine the effect of hypoglycemia (blood glucose = 1.1 +/- 0.1 mM) and hypocapnia (arterial PCO2 = 15 +/- 1 mmHg) on cerebral ATP, phosphocreatine, and intracellular pH (pHi; 31P magnetic resonance spectroscopy), cerebral blood flow (CBF; radiolabeled microspheres), global O2 uptake, and glucose uptake in anesthetized dogs. Neither hypoglycemia nor hypocapnia alone altered brain high-energy phosphates, pHi, O2 or glucose uptake or caused major EEG abnormalities. Hypocapnia alone decreased CBF to 62 +/- 4% of control. The combination of hypoglycemia and hypocapnia did not decrease CBF (85 +/- 6% of control), and O2 and glucose uptake were unchanged. During hypocapnic hypoglycemia, isoelectric EEG was seen in 40% of animals, ATP and phosphocreatine decreased to 38 +/- 12 and 43 +/- 12% of control, respectively, while pHi increased from 7.13 +/- 0.05 to 7.43 +/- 0.09. The increase in pHi was related reciprocally to the decrease in venous PCO2, indicating little change in intracellular bicarbonate concentration ([HCO3-]i). With normoglycemic hypocapnia, in contrast, estimated [HCO3-]i decreased 57 +/- 1%. These data suggest that active regulation of pHi during normoglycemic hypocapnia is impaired during hypoglycemic hypocapnia associated with decreased ATP.
Evaluation of hypercholesterol diet-induced changes in viscoelastic properties of carotid circulation in pigs
Authors: Burattini R. , Montanari L. , Mulligan L. J. , Cannon M. S. , Gross D. R.
Published: December 2017

Measurements of pulsatile pressure and flow at the input of the left and right carotid arteries and a new lumped parameter model were used to quantify changes in the overall dynamic mechanical properties of the carotid circulation between five control diet-fed pigs and five pigs fed a hyperlipidemic diet for 16 wk. The model represents the portion of the circulation supplied by either the left or the right carotid artery and is characterized by five parameters: peripheral resistance (Rp), an overall inertance (L), and an overall frequency-dependent compliance constituted by a capacitor C (static compliance) in series with a Maxwell section, i.e., a capacitor Cd, in parallel with a resistor Rd. Rp was calculated as the ratio between mean pressure (P) and mean flow (Q). The other four parameters were estimated by fitting measured to model predicted flows. The average static compliance was reduced by 40% (P = 0.01) between normal (P = 62.0 +/- 4.3 mmHg) and hyperlipidemic diet-fed pigs (P = 62.7 +/- 4.7 mmHg). A significant reduction in the overall cross-sectional area was inferred from a 53% increase (P = 0.05) in L, whereas resistance vessel tone was unchanged as judged from estimates of Rp. No signs of occlusive disease were found in any of the animals.
Role of angiotensin and adrenoceptors in hemodynamic response to aortic cross-clamping
Authors: Gelman S. , Curtis S. E. , Bradley W. E. , Henderson C. T. , Parks D. A. , Cain S. M.
Published: December 2017

An earlier study has shown that angiotensin and catecholamines were responsible for the vasoconstriction observed in the isolated hindlimb preparation during aortic cross-clamping. That study also demonstrated that when vasoconstriction was blocked with an alpha-adrenergic antagonist, phenoxybenzamine, vasodilation was elicited by aortic cross-clamping. The present study tested the hypothesis that this vasodilation was mediated via beta-adrenergic receptors. Eighteen dogs had their hindlimb denervated, vascularly isolated, and pump perfused with blood drained from the inferior vena cava, after passing through a gas-exchanging membrane where oxygen and carbon dioxide tensions were normalized. Left and right thoracotomies were performed, and the aorta and inferior vena cava were cross-clamped. The cross-clamping was associated with 29-37% increase in limb vascular resistance in control dogs (n = 6), in animals pretreated with propranolol (2 mg/kg, n = 6), and in dogs pretreated with a combination of phenoxybenzamine (3 mg/kg) and propranolol (2 mg/kg, n = 6). In animals pretreated with a combination of phenoxybenzamine, propranolol, and enalaprilat (2 mg/kg, n = 6), an angiotensin-converting enzyme inhibitor, limb vascular resistance did not change. This study has confirmed that aortic cross-clamping is associated with vasoconstriction induced by angiotensin and activation of alpha-adrenoceptors and has further demonstrated that vasodilation is attributable to beta-adrenoceptor activation.
Role of tachycardia and V wave wall stress in the release of ANF during volume loading
Authors: Stewart J. M. , Wang J. , Zeballos G. A. , Ochoa M. , Schustek M. , Hintze T. H.
Published: December 2017

Heart rate is believed to be a primary determinant of atrial natriuretic factor (ANF) release; however, we postulated that V wave wall stress is the main signal for ANF release during volume loading. Conscious dogs were volume loaded with 1,000 ml of saline while the heart rate was allowed to vary and on another day while the heart was paced at 240 beats/min. During volume loading, plasma ANF increased from 58 +/- 10 to 221 +/- 31 pg/ml (P < 0.05), and heart rate increased from 97 +/- 3 to 182 +/- 9 beats/min. During pacing, plasma ANF increased from 42 +/- 8 to 85 +/- 10 pg/ml. A wave atrial pressures were increased during pacing and were fixed due to contraction against a closed atrioventricular valve. Volume loading increased plasma ANF to 180 +/- 25 pg/ml. V wave atrial pressure increased markedly, and V wave atrial wall stress increased from 25 +/- 10 to 131 +/- 44 and from 7 +/- 4 to 116 +/- 25 g/cm2, respectively. A wave pressure and wall stress were not increased by volume loading. V wave wall stress and ANF were significantly correlated. V wave atrial wall stress accounts for the majority of change in plasma ANF (60%), while tachycardia and A wave wall stress account for a smaller fraction (40%) of change.
Myocardial adenosine, flow, and metabolism during adenosine antagonism and adrenergic stimulation
Authors: Headrick J. P. , Ely S. W. , Matherne G. P. , Berne R. M.
Published: December 2017

Relationships between interstitial transudate adenosine and coronary flow and between global adenosine formation and cytosolic metabolism were examined in constant-pressure perfused guinea pig hearts during norepinephrine (NE) stimulation and adenosine antagonism with 10 microM 8-phenyltheophylline. Basal coronary flow was 5.7 ml.min-1 x g-1, and transudate and venous adenosine levels were approximately 0.26 and 0.06 microM, respectively. During 10 min of NE stimulation (15 nM), coronary flow and adenosine levels increased, the phosphocreatine-to-inorganic phosphate ratio ([PCr]/[Pi]) declined, and ATP and pH remained stable. Despite phasic release of adenosine, coronary flow correlated dose dependently with transudate adenosine, and adenosine release was inversely related to [PCr]/[Pi] under all conditions. 8-Phenyltheophylline infusion attenuated functional hyperemia by approximately 40%, enhanced the fall in [PCr]/[Pi], and potentiated elevations in transudate and venous adenosine. Similar results and correlations were obtained in hearts perfused at a constant-flow of 5.7 ml.min-1 x g-1, although stimulated adenosine levels and metabolic changes were greater and contractile responses smaller. These data indicate that: 1) endogenous adenosine plays a primary role in functional hyperemia in perfused guinea pig heart; 2) global adenosine formation appears related to phosphorylation status; and 3) adenosine receptor antagonism enhances metabolic disturbances during adrenergic stimulation and markedly potentiates adenosine release, indicating that the functional effects of antagonists may significantly underestimate the dilatory role of endogenous adenosine.
Action of C-type natriuretic peptide in isolated canine arteries and veins
Authors: Wei C. M. , Aarhus L. L. , Miller V. M. , Burnett J. C.
Published: December 2017

C-type natriuretic peptide (CNP) is a hormone that shares structural homology to atrial natriuretic peptide (ANP); however, distinct receptors have been found for each in cultured aortic endothelial and smooth muscle cells. CNP in vivo reduces arterial pressure, atrial pressures, and cardiac output. These actions are consistent with a decrease in cardiac preload. Therefore, the current studies were designed to test the hypothesis that CNP is a vasodilator distinct from ANP. Rings of canine renal and saphenous arteries and renal, saphenous, and femoral veins with and without endothelium were suspended to measure isometric force in an organ chamber. CNP caused significant concentration-dependent relaxations in veins with and without endothelium contracted with phenylephrine (10(-6) log M). In marked contrast, ANP caused no significant relaxation in veins either with or without endothelium. In arterial rings, responses to the peptides were heterogeneous. ANP caused relaxation in renal but not saphenous arteries. CNP induced modest and comparable relaxation in rings of saphenous but not renal arteries with and without endothelium. These results demonstrate that: 1) CNP and not ANP is a relaxing factor of isolated peripheral canine veins, and 2) the responses of arteries to ANP and CNP are heterogeneous. These findings support a distinct biological role for CNP in the regulation of cardiovascular tone.
Capillary filling kinetics in the rabbit heart during normoxemia and hypoxemia
Authors: Vetterlein F. , Keitel U. , Schmidt G.
Published: December 2017

In experiments on anesthetized rabbits the kinetics of capillary plasma filling in the heart during normoxemia and hypoxemia were studied. Three gamma globulins originating from three different species were infused into the left atrium for various periods of time. The hearts were shock frozen, and the respective globulins were immunohistochemically identified in parallel sections. The anatomic capillary density was determined by staining the capillary basement membrane. During normoxemia 69 and 66% (subepicardium and subendocardium, respectively) of the capillaries were labeled within 2 s, 84 and 78% within 5 s, and 96 and 92% within 10 s. Labeling was complete after 20 s. Hypoxemia (arterial PO2 27 mmHg, 5 min) led to a significant acceleration of capillary filling kinetics: 93 and 95% within 2 s, 98 and 99% within 5 s, 100 and 99% within 10 s. During hypoxemic conditions the entire left coronary flow was found increased by a factor of 2.3. The data may best be explained by the fact that hypoxemia does not lead to mobilization of previously nonperfused capillaries but induces either an amplification of capillary flow velocities or an increased frequency of periods with high capillary blood flow.
Heterogeneity of the hypoxic state in rat heart is determined at capillary level
Authors: Ince C. , Ashruf J. F. , Avontuur J. A. , Wieringa P. A. , Spaan J. A. , Bruining H. A.
Published: December 2017

Heterogeneity in the hypoxic state of Tyrode-perfused rat hearts was studied using NADH and Pd-porphine videofluorometry. Ischemic as well as high-flow anoxia resulted in a homogeneous rise of tissue NADH fluorescence, whereas normoxic recovery from both types of anoxia caused transiently persisting patchy fluorescent areas. Patterns were always the same for a given heart. PO2 distribution in the vasculature measured by Pd-porphine phosphorescence showed patterns similar to the NADH fluorescence patterns. Microsphere embolization of the capillaries, but not of arterioles, elicited identical NADH fluorescence patterns as seen during recovery from anoxia without microspheres. High heartbeat rates also caused patchy fluorescent areas but not in the presence of adenosine. Patterns corresponded to those seen during normoxic recovery from anoxia under low beat rates. It is concluded that there are circulatory units in the rat heart at the capillary level that result in the temporary persistence of anoxic areas during recovery from anoxia. These vulnerable areas are the first to be compromised during high heartbeat rates.
Maturational changes in endothelium-derived relaxations in newborn piglet pulmonary circulation
Authors: Perreault T. , De Marte J.
Published: December 2017

It is accepted knowledge that the endothelium can profoundly affect vascular tone through the release of vasoactive substances. The maturational changes in the role of the endothelium-derived relaxing factor (EDRF) and ATP-dependent K+ channels in the neonatal pulmonary circulation were investigated in isolated perfused lungs from 1- and 7-day-old piglets. The EDRF inhibitor, N omega-nitro-L-arginine (L-NNA), had potent dose-dependent constrictor effects on the pulmonary vasculature with normal and raised tone. The constrictor effect of L-NNA was greater (P < 0.05) in the 1-day-old than in the 7-day-old lungs and was significantly (P < 0.005) attenuated by pretreatment with the EDRF precursor, L-arginine. Furthermore, we studied the possibility of developmental changes in the sensitivity of smooth muscle cells to EDRF by testing sodium nitroprusside, nitric oxide, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP). All caused a decrease in perfusion pressure, but only sodium nitroprusside elicited a greater (P < 0.01) effect in the 1-day-old. Endothelin-1 (ET-1) and bradykinin (BK) elicited dilator responses that were significantly (P < 0.05) reduced in the presence of L-NNA. Interestingly, the dilator response to ET-1 was more marked (P < 0.001) in the younger group, whereas no age difference was noted with BK. Finally, lemakalim, a K+ channel activator, caused a vasodilation of equal magnitude at both ages. In summary, EDRF and ATP-dependent K+ channels appear to play a role in the control of the newborn piglet pulmonary vasculature.(ABSTRACT TRUNCATED AT 250 WORDS)
Complement C5a-mediated myocardial ischemia and neutrophil sequestration: two independent phenomena
Authors: Del Balzo U. , Engler R. L. , Ito B. R.
Published: December 2017

The intracoronary infusion of complement C5a causes a decrease in coronary blood flow and contractile dysfunction mediated by thromboxane (TxA2) and leukotrienes. Although these effects are accompanied by polymorphonuclear leukocyte (PMN) sequestration, the role of PMNs and the source of these eicosanoids remain unknown. To assess the contribution of PMNs to the C5a-induced myocardial ischemic response, the left anterior descending (LAD) coronary artery of pigs (n = 13) was cannulated and pump perfused at constant pressure with either normal arterial blood or neutropenic arterial blood (PMN count 0.02 x 10(3) cells/microliters) obtained from animals treated with cyclophosphamide (50 mg/kg iv, given 4 days before). The coronary vein draining the LAD region was cannulated for measurement of leukocyte count and TxB2 levels. Two groups of animals were studied: group 1 (n = 7) neutropenic animals were instrumented and normal animals served as blood donors and group 2 (n = 6) normal animals were instrumented and neutropenic animals served as blood donors. The myocardial response to intracoronary C5a (500 ng) was determined in each animal during coronary perfusion with normal arterial blood and also with neutropenic arterial blood. During perfusion with normal arterial blood, C5a decreased coronary flow to 52.3% and contractile function to 58.8% of preinfusion values. This was accompanied by a transient myocardial accumulation of PMNs (arterial-coronary venous gradient of 5.4 x 10(3) cells/microliters) and increased TxB2 levels in coronary venous blood (from 0.31 to 17.5 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)
CD18-dependent adherence reactions play an important role in the development of the no-reflow phenomenon
Authors: Jerome S. N. , Smith C. W. , Korthuis R. J.
Published: December 2017

The aim of this study was to determine whether immunoneutralization of the common beta-subunit of the neutrophil CD11/CD18 glycoprotein adherence complex with monoclonal antibody IB4 (mAb IB4) or neutrophil depletion with a specific canine polyclonal antineutrophil serum (ANS) would reduce the extent of no-reflow in postischemic skeletal muscle. Microvascular patency was assessed by infusion of india ink contrast media and quantified by counting ink-containing microvessels < 15 microns diameter in histological sections obtained from isolated canine gracilis muscles subjected to 4.5 h of continuous perfusion (nonischemic control), 4 h of ischemia and 30 min of reperfusion [ischemia/reperfusion (I/R)] alone, I/R plus ANS, and I/R plus mAb IB4. I/R was associated with a marked reduction in microvascular patency compared with nonischemic controls (0.9 +/- 0.1 vs. 2.3 +/- 0.1 ink-containing microvessels per muscle fiber, respectively). Neutrophil depletion or prevention of neutrophil adherence attenuated the I/R-induced reduction in the number of ink-containing capillaries (1.6 +/- 0.1 and 2.2 +/- 0.2 ink-containing microvessels per muscle fiber, respectively). These data indicate that neutrophils play an important role in the genesis of no-reflow in postischemic skeletal muscle by a mechanism that appears to involve CD18-dependent neutrophil adhesion to the endothelium.
Sympathetic denervation of resistance arteries increases contraction and decreases relaxation to flow
Authors: Bevan R. D. , Clementson A. , Joyce E. , Bevan J. A.
Published: December 2017

The effect of chronic sympathetic and possibly sensory denervation on flow-induced changes in smooth muscle tone was examined in a branch of the rabbit ear artery (200-400 microns ID). The superior cervical ganglion and 1-cm portions of the greater and anterior auricular nerves were removed from 4-wk-old rabbits while under general anesthesia, and arterial segments were studied 21 days later. Efficacy of denervation was assessed by catecholamine histochemistry and by absence of a constrictor response to transmural electrical field stimulation. Intraluminal flow of physiological saline solution was made through a pipette into matched-innervated and -denervated segments. Flow-induced contraction was increased in the denervated compared with the contralateral innervated segments. At the lowest flow rate studied (1 microliters/min), the contraction increased more than six times. This is consistent with the previously described nonspecific, nondeviational hypersensitivity of denervated vascular smooth muscle to constrictor influences. By contrast flow-related dilation at 10 and 20 microliters/min was significantly diminished. An intraluminal flow rate could be found that resulted in dilation in innervated but not the matched-denervated segments. Endothelial-mediated dilation to acetylcholine was also impaired. Chronic sympathetic denervation increased the magnitude of flow contraction and decreased that of flow relaxation.
Endothelium dependence of effects of high PCO2 on agonist-induced contractility of rat aorta
Authors: Fukuda S. , Morioka M. , Tanaka T. , Taga K. , Shimoji K.
Published: December 2017

To investigate the modulation of CO2 and endothelium of vascular contraction induced by various agonists, we studied the influence of high PCO2 (PCO2 = 91 mmHg, pH = 6.99) on the response of endothelium-intact and -rubbed rat aortic preparations to KCl, phenylephrine (PE), and human-porcine endothelin-1 (ET-1). Response of endothelium-intact aortic preparations to KCl was not influenced by both high PCO2 and the pH-matched acidotic solution (7.00) with normal PCO2, whereas that of endothelium-rubbed preparations was attenuated solely by high PCO2. With cyclooxygenase inhibitors or a thromboxane A2 receptor antagonist, high PCO2 attenuated the respose of both preparations to KCl. The dose-response curve of endothelium-intact and -rubbed preparations to PE was shifted to the right by both high PCO2 and the pH-matched acidotic solution with normal PCO2. The maximal response of endothelium-intact preparation to PE was attenuated by high PCO2. Indomethacin augmented the inhibitory action of high PCO2 on the PE-induced contraction. Contractile responses of endothelium-intact and -rubbed preparations to ET-1 were not influenced by high PCO2. With indomethacin, high PCO2 also had no influence on the ET-1-induced contraction of endothelium-intact preparations. Endothelium modified the high PCO2 effects on the time-contraction responses to the three agonists. CO2 and endothelium may variously modify the responses of rat aorta to different agonists. Cyclooxygenase-related eicosanoid(s) may be involved in the effects of high PCO2 on the response of rat aortic smooth muscle cells to KCl and PE.