bluuebunny/crossref_metadata_2025 huggingface dataset:
Reductions of myocardial Na-K-ATPase activity and ouabain binding sites in heart failure: prevention by nadolol
Authors: Fan T. H. , Frantz R. P. , Elam H. , Sakamoto S. , Imai N. , Liang C. S.
Published: December 2017

To study the changes in myocardial digitalis binding sites in heart failure, we measured myocardial ouabain binding sites, Na-K-adenosinetriphosphatase (ATPase) activity, and ventricular muscle mechanical responses to acetylstrophanthidin in dogs with right-heart failure (RHF) produced by tricuspid avulsion and pulmonary artery constriction. Sham-operated dogs were studied as the control. RHF produced a significant decrease in ouabain binding sites in the right and left ventricular myocardium, which was accompanied by a proportional decrease in Na-K-ATPase activity. However, RHF and sham-operated dogs did not differ in systemic hemodynamic or right ventricular trabeculate muscle isometric contractile responses to acetylstrophanthidin. To determine whether chronic beta-adrenergic stimulation contributed to the development of Na-K-ATPase downregulation, we administered nadolol (40 mg/day) to a separate group of dogs during an early stage of RHF development. Nadolol effectively prevented the reduction of myocardial ouabain binding sites that occurred in RHF. Thus we conclude that myocardial ouabain binding sites and Na-K-ATPase activity are reduced in dogs with experimental heart failure and that these changes probably occur as a result of the attendant heightened sympathetic activity.
Inhibition of platelet aggregation and the stimulation of prostacyclin synthesis by insulin in humans
Authors: Kahn N. N. , Bauman W. A. , Hatcher V. B. , Sinha A. K.
Published: December 2017

An intravenous bolus injection of insulin (35.5 microM) followed by an infusion of insulin (0.53 microM.kg-1.h-1) for 2.5 h (which maintained plasma levels between 0.71 nM to 1.4 nM) in normal fasting volunteers (n = 16), increased [3H]prostaglandin E1 (a probe for prostacyclin) binding to platelets by two- to threefold over the control. Scatchard analyses showed that the increased binding was due to the increase of both high and low affinity receptor numbers with little change in the receptor affinities. Similar results were obtained by using [3H]prostacyclin as the radioligand. The increased binding was associated with more than a twofold decrease of the minimum concentration of prostanoid needed to inhibit aggregation of platelets through the increased formation of adenosine 3',5'-cyclic monophosphate. Furthermore, the infusion increased the mean plasma prostacyclin level from 12.10 +/- 4.5 pM to 23.9 +/- 6.7 pM (n = 16; P < 0.001). These effects of insulin were at least partially direct, since the treatment of endothelial cells with insulin in tissue culture stimulated the production of the autacoid. Bolus injection of insulin (0.71 microM/kg) showed that the above effects of insulin could be demonstrated within 20 min after the injection, attained maximal ranges in approximately 60 min, and disappeared by 2–4 h.
Endothelin-1 enhances cross-bridge function of ferret myocardium: role of second messengers
Authors: Wang J. , Flemal K. , Morgan J. P.
Published: December 2017

To investigate postreceptor pathways of endothelin and the site of action responsible for enhancing myocardial contractility, studies were performed on ferret papillary muscles loaded with the Ca2+ indicator aequorin. Endothelin-1 (ET) and the alpha 1-adrenoceptor agonist, phenylephrine (PE) produced similar dose-dependent increases in tension development and peak intracellular Ca2+ concentration ([Ca2+]i); moreover, pretreatment with PE eliminated effects of ET, suggesting similar postreceptor pathways. Because alpha 1-adrenoceptor activation is thought to cause the hydrolysis of phosphatidylinositol and generate D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and 1,2-diacylglycerol (DAG), the protein kinase C (PKC) activator 4 beta-phorbol 12-myristate 13-acetate (PMA) was used to determine whether activation of PKC was responsible for the myocardial actions of ET. In contrast to ET, PMA decreased tension development and peak [Ca2+]i, and pretreatment with PMA attenuated the myocardial action of ET; however, intracellular Ins(1,4,5)P3 levels were greatly increased by ET stimulation, suggesting that rather than DAG, Ins(1,4,5)P3 might be the second messenger for the actions of ET. To determine whether ET produced actions on the contractile elements, thereby enhancing myocardial contractility, 2,3-butanedione monoxime (BDM) was used to interfere with the interaction of myosin and actin. Pretreatment with 6 mM BDM did not alter the half-maximum effective concentration (EC50) of the [Ca2+]o-tension relation, but, in contrast, shifted the ET dose-response curve to the right, and increased the EC50 by approximately 1.0 log unit. In addition, ET partially reversed the downward shift of the peak [Ca2+]i-peak tension curve induced by BDM.(ABSTRACT TRUNCATED AT 250 WORDS)
Substantial reductions in blood pressure after bilateral nephrectomy in fetal sheep
Authors: Anderson D. F. , Barbera A. , Faber J. J.
Published: December 2017

The role of the kidneys in the maintenance of arterial blood pressure was examined in fetal sheep. Surgery was performed on 11 pregnant sheep (8 twin pregnancies) at approximately 125 days. All 19 fetuses were instrumented with hindlimb arterial and venous catheters. Eleven of the fetuses (but only 1 of each twin) were also bilaterally nephrectomized. Fetal arterial blood pressure was measured several times between 2 and 14 days after surgery. Arterial blood pressure in the intact fetuses increased from 44 +/- 1 to 47 +/- 1 mmHg (SE) but gradually decreased from 37 +/- 4 to 25 +/- 3 mmHg in the nephrectomized group. Whereas the arterial blood pressures measured on the first day of the experiment were not statistically significantly different between the two groups, by the final day of the experiment the arterial blood pressure of the intact fetuses was much higher than that of the nephrectomized fetuses. Venous blood pressure was similar in the two groups. We conclude that bilateral nephrectomy in fetal sheep not only stops the normal gestational increase in arterial blood pressure but also leads to a progressive decline.
Adrenal blood flow and secretory effects of adrenergic receptor stimulation
Authors: Ligier B. , Breslow M. J. , Clarkson K. , Raff H. , Traystman R. J.
Published: December 2017

To evaluate effects of adrenergic receptor stimulation on regional adrenal blood flow and secretion, pentobarbital-anesthetized dogs (n = 5–6/group) received the beta-agonist isoproterenol (group I), the alpha 1-agonist phenylephrine (group II), or the alpha 2-agonist dexmedetomidine (group III). Measurements of adrenal cortical (CQ) and medullary (MQ) blood flow (radiolabeled microspheres) and catecholamine secretion were made before and during agonist infusion. Isoproterenol increased catecholamine secretion but had no direct effect on MQ or CQ. In contrast, phenylephrine increased MQ and CQ four- and twofold, respectively. Dexmedetomidine had no effect on MQ or catecholamine secretion. To evaluate whether blood flow effects of phenylephrine were due to increases in mean arterial blood pressure (MAP) or related to activation of alpha 1-adrenergic receptors, two additional groups of animals received phenylephrine; group IV had MAP maintained at baseline by controlled hemorrhage into a pressurized bottle; group V received prazosin before phenylephrine. Prevention of MAP increase did not prevent the vasodilation response to phenylephrine, but it was completely blocked by prazosin. Canine adrenal homogenates incubated with the alpha 1-adrenoceptor ligand, 125I-labeled 2-[beta-(4-hydroxyphenyl)ethlaminomethyl]tetralone, demonstrated specific and saturable binding, supporting the presence of alpha 1-adrenergic receptors. We conclude that increases in MQ and CQ elicited by phenylephrine appear to be due to alpha 1-receptor stimulation. The mechanism responsible for this vasodilation is not known.
Baroreflex dysfunction in diabetes mellitus. I. Selective impairment of parasympathetic control of heart rate
Authors: McDowell T. S. , Chapleau M. W. , Hajduczok G. , Abboud F. M.
Published: December 2017

The purpose of this study was to determine the effect of diabetes mellitus on baroreflex control of heart rate. Diabetes (blood glucose = 378 +/- 21 mg/dl) was induced in rabbits by alloxan (n = 9). Alloxan-treated rabbits that remained normoglycemic (n = 9) and rabbits given saline instead of alloxan (n = 5) served as controls. Baroreflex control of heart rate was evaluated in conscious rabbits by measuring changes in heart rate during phenylephrine-induced increases and nitroglycerin-induced decreases in arterial pressure. In diabetic rabbits, the gain of the baroreflex-mediated bradycardia in response to increased pressure decreased significantly from -1.8 +/- 0.3 beats.min-1 x mmHg-1 before alloxan (n = 9) to -0.9 +/- 0.1 and -0.9 +/- 0.3 beats.min-1 x mmHg-1 after 12 and 24 wk of diabetes, respectively (n = 8; P < 0.05). There was no significant change in baroreflex gain in either alloxan-treated or saline-treated normoglycemic rabbits. Baroreflex-mediated bradycardia was not influenced significantly after beta-adrenergic blockade with propranolol (1 mg/kg) and was still impaired in diabetic vs. control rabbits after propranolol. The gain of the baroreflex-mediated tachycardia in response to decreased pressure was not altered in any of the three groups. Propranolol significantly decreased but did not abolish baroreflex-mediated tachycardia. Neither the vagal nor the sympathetic component of the tachycardia was altered significantly by diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)
L-NAME antagonizes vasopressin V2-induced vasodilatation in dogs
Authors: Liard J. F.
Published: December 2017

Experiments were performed in conscious chronically instrumented dogs to study the mechanism of hemodynamic effects mediated by selective vasopressin V2 agonists. In one group of dogs (n = 5) instrumented for the measurement of arterial pressure and cardiac output (electromagnetic flowmeter), the infusion of NG-nitro-L-arginine methyl ester (L-NAME; 20 or 40 micrograms.kg-1 x min-1) prevented or significantly inhibited the increase in cardiac output, heart rate and systemic conductance induced by injections of 1-desamino-8-D-arginine vasopressin (DDAVP, desmopressin) and 4-valine-8-D-arginine vasopressin (VDAVP), two selective V2 agonists. L-NAME infusion did not modify the aortic adenosine 3',5'-cyclic monophosphate increase induced by DDAVP infusion. In a second group of dogs similarly prepared (n = 4), the administration of L-arginine (10 mg.kg-1 x min-1) at the same time as that of L-NAME (20 micrograms.kg-1 x min-1) completely prevented the hemodynamic effects of L-NAME and restored the response to DDAVP administration. In a third group of dogs (n = 4), the infusion of a bradykinin B2 antagonist, at a rate that significantly inhibited the cardiac output, heart rate, and blood pressure responses to bradykinin, did not modify the hemodynamic response to DDAVP infusion. We conclude that the hemodynamic effects of selective V2 agonists in dogs are not mediated by bradykinin release but instead via a V2-like receptor on endothelial cells that triggers the release of nitric oxide.
Effect of endogenous vasopressin on blood flow to choroid plexus during hypoxia and intracranial hypertension
Authors: Faraci F. M. , Kinzenbaw D. , Heistad D. D.
Published: December 2017

Exogenous vasopressin decreases blood flow to the choroid plexus and production of cerebrospinal fluid. Some studies indicate that hypoxia and increases in intracranial pressure (ICP) produce increases in circulating vasopressin. We examined the hypothesis that endogenous release of vasopressin decreases blood flow to the choroid plexus during hypoxia and increased ICP. Blood flow to the choroid plexus was measured in anesthetized rabbits using microspheres. Hypoxia increased cerebral blood flow more than twofold but had little effect on blood flow to the choroid plexus. In contrast, hypoxia produced a marked increase in blood flow to the choroid plexus in the presence of a vasopressin V1-antagonist, [d(CH2)5Tyr(Me)]AVP. During intracranial hypertension, blood flow to the choroid plexus decreased from 409 +/- 42 to 295 +/- 25 ml.min-1 x 100 g-1 (means +/- SE; P < 0.05 vs. control) when ICP was increased from 1 to 40 mmHg. The vasopressin antagonist inhibited the decrease in blood flow to the choroid plexus in response to increased ICP. Thus release of vasopressin during hypoxia and increased ICP have a constrictor effect on blood vessels of the choroid plexus. Plasma levels of vasopressin increased minimally during hypoxia and increased ICP, which suggests that sources of vasopressin other than plasma affect blood vessels of the choroid plexus. We propose that endogenous vasopressin may play a protective role during hypoxia and intracranial hypertension by a negative feedback mechanism to reduce blood flow to the choroid plexus.
Steady-state catecholamine stimulation does not increase cytosolic adenosine in canine hearts
Authors: Kroll K. , Martin G. V.
Published: December 2017

Myocardial adenosine production increases transiently during the onset of catecholamine stimulation; however, there is conflicting evidence regarding whether cytosolic adenosine concentrations are increased during sustained steady-state stimulation. If cytosolic adenosine is not elevated during steady-state stimulation, then adenosine produced in the cytosol does not play a role in mediating the sustained increase in myocardial blood flow. The purpose of the present study was to determine whether cytosolic adenosine concentrations in the anesthetized dog heart are increased during steady-state stimulation with norepinephrine, epinephrine, and atrial pacing. Regional cytosolic adenosine concentrations were assessed by measuring myocardial content of S-adenosyl-L-homocysteine (SAH) after 20 min of intravenous administration of L-homocysteine thiolactone. Excess homocysteine causes myocardial accumulation of SAH at a rate dependent on the cytosolic concentration of adenosine. Steady-state metabolic stimulation caused more than twofold increases in myocardial blood flow and oxygen consumption, but there was no increase in left ventricular content of SAH in the stimulation group [6.3 +/- 0.9 nmol/g (SE); n = 6] relative to a parallel unstimulated control group (6.4 +/- 0.9 nmol/g; n = 6). The transmural distribution of SAH was nearly uniform, and there was no correlation between regional measurements of blood flow and myocardial content of SAH or ATP either during metabolic stimulation or under control conditions. In separate experiments, myocardial ischemia caused fivefold increases in SAH content, confirming the sensitivity of the SAH method for increased cytosolic adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
Resetting of 24-h sodium and water balance during 4 days of servo-controlled reduction of renal perfusion pressure
Authors: Reinhardt H. W. , Corea M. , Boemke W. , Pettker R. , Rothermund L. , Scholz A. , Schwietzer G. , Persson P. B.
Published: December 2017

This study examines whether an increase in renal perfusion pressure (RPP) is necessary to escape endogenously stimulated Na- and water-retaining mechanisms. In seven dogs stimulation was accomplished by a servo-controlled reduction of RPP (rRPP) below the threshold for pressure-dependent renin release for 4 days. Oral intake was standardized. Plasma renin activity (PRA) rose from 2.5 in controls to approximately 5 ng ANG I.ml-1 x h-1 during rRPP days. Plasma aldosterone concentration (PAC) increased by approximately 50% only on day 1 of rRPP but fell at or below control levels thereafter. The PAC-to-PRA ratio decreased during rRPP days. Atrial natriuretic factor (ANF) rose to values three times higher than in controls. Mean systemic blood pressure (MABP) rose from 111 +/- 12 in controls to 142 +/- 14 mmHg on day 4 of rRPP. On day 1 of rRPP 60% of the Na and 24% of the water intake were retained. However, after 2–3 days the input-output balance was restored but on a higher level of total body Na and total body water (new “set point”). Because elevated systemic MABP could not exert direct pressure effects on the kidneys due to servo control of rRPP, there must be other factors, e.g., fall in PAC, increase in ANF, and changes in intrarenal hemodynamics and physical factors that may have contributed to the resetting of input-output balances during rRPP.
Metformin improves cardiac function in isolated streptozotocin-diabetic rat hearts
Authors: Verma S. , McNeill J. H.
Published: December 2017

The effects of metformin administration were studied in isolated perfused working hearts from control and diabetic rats. Control and streptozotocin-treated diabetic rats were treated for 8 wk with metformin hydrochloride. Treatment was initiated at 350 mg.kg-1 x day-1 and was gradually increased to a dose of 650 mg.kg-1 x day-1, which was maintained over a 6-wk period. Isolated heart performance was assessed under conditions of increasing preload to evaluate the performance of each heart to “stress.” Hearts from untreated diabetic rats exhibited a depressed response to increases in left atrial filling pressures from 17.5 to 22.5 cmH2O in terms of left ventricular developed pressure, ventricular contractility, and ventricular relaxation compared with age-matched untreated controls. The diabetic hearts also exhibited a delayed half time to relaxation at filling pressures from 15 to 22.5 cmH2O. The function curves were performed at a constant heart rate of 300 beats/min. These responses were restored to control values in diabetic rats treated with metformin. Metformin treatment did not affect the ventricular responses in control rats. Metformin reduced plasma glucose levels in the diabetic rats from 24.3 to 14.4 mM without any increase in the plasma insulin levels. The diabetic group had higher triglycerides than age-matched untreated control rats, and metformin administration in diabetic rats reduced triglyceride levels to control values but had no effect in control rats. In conclusion, metformin administration improves cardiac performance in streptozotocin-diabetic rats under conditions of increasing preload.
Flow pulsation and network structure in mesenteric microvasculature of rats
Authors: Seki J.
Published: December 2017

Red cell velocity was measured by a fiber-optic laser-Doppler anemometer microscope in microvessels of the mesentery of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto control rats (WKY) with high temporal resolution. Based on the velocity data, the propagation velocity of flow pulse along single microvessels as well as the arteriovenous distributions of the mean volumetric flow, the amplitude of flow pulsation, and the phase lag of the flow relative to the systemic pressure were analyzed in relationship to the vessel wall rheology and the network topology. The propagation velocity was 3.5–134 cm/s in arterioles of 12–43 microns in diameter, and it increased with increasing diameter. The mean volumetric flow exhibited a power law relationship to the vessel diameter, in which the exponents were 3.16 and 3.30 for arterioles and 3.03 and 2.85 for venules in SHR and WKY, respectively. The exponents for arterioles were > 3 (P < 0.1) and different between SHR and WKY (P < 0.12). The amplitude of the flow pulsation also varied in a power law with the vessel diameter, whose exponents for arterioles were 3.41 and 3.52 for SHR and WKY, respectively. The flow phase lag increased gradually with decreasing vessel diameter in arterioles and increased comparatively rapidly with increasing vessel diameter in venules, which suggests more compliant vessel walls for venules than arterioles. The slope of the increase in the flow phase lag with the vessel diameter in arterioles of SHR was larger than that for WKY (P < 0.05). This difference in the flow phase lag distribution and the difference in the exponent of the mean flow rate vs. diameter relationship may reflect that the number of small arterioles relative to large ones is reduced in SHR microvasculature compared with that in WKY.
Serotonin relaxes porcine pial veins
Authors: Lee T. J. , Ueno M. , Sunagane N. , Sun M. H.
Published: December 2017

The effect of serotonin [5-hydroxytryptamine (5-HT)] on pial venous tone of the pig was examined using in vitro tissue bath techniques. Isolated pial venous rings exhibited spontaneous rhythmic contractions (SRC) on mechanical stretching and/or applications of several vasoactive substances, including norepinephrine. On the other hand, KCl induced sustained active muscle tone (SAT) without SRC. The SRC induced by mechanical stretching were not affected by tetrodotoxin, nitro-L-arginine, alpha- and beta-adrenergic, histaminergic, and muscarinic receptor antagonists, indicating that the SRC in porcine pial veins are of myogenic origin. The SRC induced by stretching or applications of vasoactive substances and SAT induced by KCl were inhibited by 5-HT in a concentration-dependent manner. The inhibition was prevented by methysergide and methiothepin but not by ketanserin, propranolol, 3 alpha-tropanyl-1H-indole-3-carboxylic acid ester, hemoglobin, or nitro-L-arginine. The SRC and SAT were inhibited by 5-carboxamidotryptamine (5-CT), 8-hydroxy-2-di-N-propylaminotetralin HBr (8-OHDPAT), 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP), and 5-methoxytryptamine (5-MT), but not by sumatriptan, alpha-methylserotonin, or 2-methylserotonin. On the other hand, 5-CT, 8-OHDPAT, TFMPP, 5-MT, and sumatriptan constricted the porcine pial arteries exclusively. In 15% of pial venous preparations examined, 5-HT at low concentrations induced ketanserin-sensitive constrictions. These results indicate that the porcine pial venous smooth muscle contains multiple subtypes of 5-HT receptors. The 5-HT inhibition of SRC and SAT is predominant and is mediated by 5-HT1-like receptors, which, however, do not seem to correspond to 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT1E, or 5-HT1F receptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)
Metabolic inhibition of ICa,L and IK differs in feline left ventricular hypertrophy
Authors: Furukawa T. , Myerburg R. J. , Furukawa N. , Kimura S. , Bassett A. L.
Published: December 2017

To determine the intrinsic responsiveness of hypertrophied myocardium, electrophysiological properties of endocardial myocytes enzymatically dissociated from normal and hypertrophied feline left ventricle (LV) were compared during metabolic inhibition by 1 mM CN-. Chronic pressure overload was induced under surgical anesthesia. A single-pipette, whole cell clamp method was used to record action potential and membrane currents. Before CN-, action potential duration (APD) values at 90% repolarization (APD90) and at 0 mV (APD0mV) were significantly longer in hypertrophied cells. The current density of L-type Ca2+ currents (ICa,L) was not significantly different, whereas the time constant of the slow component (tau s) of ICa,L inactivation was significantly longer in hypertrophied cells. The current density of delayed rectifier K+ current (IK) was significantly smaller, the fast component (tau f) and tau s of IK activation were delayed, and those of IK deactivation were enhanced in hypertrophied cells. During exposure to CN-, APD shortened significantly more in hypertrophied cells; amplitude of ICa,L decreased, and the tau f and tau s of ICa,L inactivation shortened only in hypertrophied cells. However, IK showed no significant differences in changes in amplitude or kinetics during CN- exposure between normal and hypertrophied cells. Thus enhanced APD responsiveness to CN- is an intrinsic property of hypertrophied LV cells and ICa,L appears to be particularly affected by metabolic perturbation in such cells.
Endothelial dysfunction in mesenteric resistance arteries of diabetic rats: role of free radicals
Authors: Diederich D. , Skopec J. , Diederich A. , Dai F. X.
Published: December 2017

Diabetes was induced in rats by an injection of streptozotocin (55 mg/kg). Endothelium-dependent relaxations in mesenteric resistance arteries (luminal diameter 210 +/- 20 microns) of control and diabetic rats were compared in myographs. Acetylcholine induced endothelium-dependent relaxations that were mediated by nitric oxide (EDNO). EDNO-mediated relaxations were impaired in diabetic arteries; concentrations of acetylcholine required to produce 50% relaxation (ED50) of activated arteries were 5 nM in control and 13.5 nM in arteries from diabetic rats studied after 6 wk (P < 0.05). The impairment in relaxation worsened with duration of the diabetes; ED50 for acetylcholine increased to 63 and 100 nM in diabetic arteries studied after 16 and 24 wk of diabetes, respectively. NG-nitro-L-arginine produced 5.5- and 16-fold decreases in sensitivity of control and diabetic arteries to acetylcholine. NG-nitro-L-arginine produced at least as much inhibition of acetylcholine relaxations in diabetic arteries, indicating that the impaired relaxation noted in diabetic arteries does not result from decreased production of EDNO. EDNO-mediated relaxations in diabetic arteries were impaired by increased production of endothelium-derived free radicals. Superoxide dismutase, a scavenger of superoxide anion, and dimethylthiourea, a scavenger of hydroxyl radicals, normalized EDNO-mediated relaxations in diabetic arteries. The ED50 values for acetylcholine were 13.5, 5.5, and 4 nM for untreated and SOD- and DMTU-treated diabetic arteries, respectively (P < 0.05 for treated vs. untreated arteries). Superoxide anion and hydroxyl radicals appear to block EDNO-mediated relaxation by inactivating EDNO.(ABSTRACT TRUNCATED AT 250 WORDS)
Abnormal clot retraction, altered fibrin structure, and normal platelet function in multiple myeloma
Authors: Carr M. E. , Zekert S. L.
Published: December 2017

Clot retraction, measured by serum expression, is absent in some cases of multiple myeloma. Decreased clot retraction has been attributed to platelet dysfunction. A new instrument allows simultaneous measurement of platelet-mediated force development during clot retraction and of clot elastic modulus. We report 10 patients with immunoglobulin (Ig) G myeloma in whom the abnormalities of fibrin structure were quantitatively defined and platelet-fibrin interactions were assessed. Fiber mass-to-length ratios were calculated from gel turbidity. Platelet force development and clot elastic modula were measured in platelet-rich plasma gels. Fiber mass-to-length ratios for IgG myeloma patients were smaller (means +/- SE) (0.98 +/- 0.19 x 10(13) Da/cm) than for normal controls (1.36 +/- 0.06 x 10(13) Da/cm), indicating thinner fiber formation. Elastic modula of myeloma clots (51,013 +/- 14,660 dyn/cm2) were strikingly larger than modula for normal controls (23,355 +/- 1,887 dyn/cm2), indicating that such clots are mechanically less flexible. Platelet force development 1,200 s after thrombin addition was not diminished in myeloma patients (8,315 +/- 1,155 dyn) vs. controls (6,906 +/- 606 dyn). Abnormal clot retraction in myeloma appears to be primarily due to altered clot structure rather than platelet dysfunction.
Inotropic effects of ejection are myocardial properties
Authors: De Tombe P. P. , Little W. C.
Published: December 2017

Recent studies in isolated and in vivo canine hearts have suggested that the left ventricular end-systolic pressure (LVPes) of ejecting beats is the net result of a balance between positive and negative effects of ejection. At present, it is unknown whether these ejection effects are merely a ventricular chamber property or represent a fundamental myocardial property. Accordingly, we examined the effects of ejection in eight isolated rat cardiac trabeculae at the sarcomere level. We approximated in situ sarcomere shortening patterns using an iterative computer loading system. Six isovolumic contractions were compared with four ejecting contractions. The superfusing solution contained either 0.7 mM Ca2+ or 0.65 mM Sr2+ plus 0.15 mM Ca2+. With Ca2+, simulated LVPes ("LVP"es) of ejecting contractions was significantly lower than isovolumic "LVP"es (-5.3 +/- 5.6%), whereas with Sr2+, ejecting "LVP"es was significantly higher than isovolumic "LVP"es (+4.5 +/- 7.5%). Contraction duration and time to end systole were markedly prolonged in ejecting vs. isovolumic contractions with either Ca2+ or Sr2+. As a consequence, comparison of simulated LVP between ejecting and isovolumic beats throughout the contraction, i.e., at the same simulated LVV and time, revealed only a positive effect of ejection with either Ca2+ (+18.8 +/- 5.5%) or Sr2+ (+23.4 +/-9.3%). We conclude that both positive and negative effects of ejection are basic myocardial properties.
Coupling calcium binding to troponin C and cross-bridge cycling in skinned cardiac cells
Authors: Landesberg A. , Sideman S.
Published: December 2017

This study examines the coupling of calcium binding to troponin with the force developed by the cross bridges in the skinned cardiac muscle. It emphasizes the key role of the troponin complex in regulating cross-bridge cycling and defines four distinct states of the troponin complex in the single-overlap region. These include a "loose-coupling" state, wherein cross bridges can exist in the strong conformation without having calcium bound to the neighbor troponin C. Published simultaneous measurements of the force and the bound calcium are used to calculate the apparent calcium binding coefficients. The force-length relationships at different free calcium concentrations are used to evaluate the cooperative mechanism. The dependence of the affinity of troponin for calcium on the number of force-generating cross bridges is the dominant cooperative mechanism. The proposed loose-coupling model, with a positive feedback of force on calcium binding, describes the role of calcium in force regulation and the force-length relationship in skinned cardiac muscle. The ability to simulate the rate of force development is demonstrated.
Inhibition of alpha 2-adrenergic vasoconstriction during contraction of glycolytic, not oxidative, rat hindlimb muscle
Authors: Thomas G. D. , Hansen J. , Victor R. G.
Published: December 2017

Previous studies have produced conflicting evidence as to whether sympathetic vasoconstriction is impaired in active skeletal muscle. Because alpha 2-, not alpha 1-, adrenergic vasoconstriction is attenuated by mild acidosis, we hypothesized that alpha 2-mediated sympathetic vasoconstriction would be attenuated in contracting glycolytic muscle, which produces more acidosis than oxidative muscle. We compared effects of lumbar sympathetic nerve stimulation and alpha-adrenergic agonists on arterial pressure, femoral blood flow, and force output during contractions of oxidative or glycolytic muscles in anesthetized rats. We found that 1) sympathetic vasoconstriction was preserved during contractions of oxidative soleus muscle and during low-intensity contractions of glycolytic gastrocnemiusplantaris muscles but was abolished during maximal contractions of these glycolytic muscles; 2) this sympatholytic effect was caused by impaired alpha 2-, not alpha 1-, vasoconstriction; and 3) the increased muscle blood flow resulting from a combination of impaired vasconstriction and increased arterial pressure was paralleled by increased force of gastrocnemius-plantaris muscle contraction. Thus contraction-induced impairment of alpha 2-vasoconstriction can augment muscle blood flow and muscle contraction, but the degree of impairment depends on fiber type and intensity of muscle contraction.
Validation of a model for [1-11C]acetate as a tracer of cardiac oxidative metabolism
Authors: Ng C. K. , Huang S. C. , Schelbert H. R. , Buxton D. B.
Published: December 2017

To develop a compartmental model for estimating myocardial oxygen consumption rate (MVO2) with [1-11C]acetate, the metabolic fate of radiolabeled acetate was determined in normoxic and ischemic conditions in isolated perfused rat hearts. Glutamate composed 63 +/- 1 and 44 +/- 7% of the total tissue radioactivity 2 min postinjection in normoxic and ischemic myocardium, respectively, and radiolabeled glutamate remained the largest fraction throughout 40 min of perfusion. Based on the biochemical pathway of the tracer and the temporal distribution of 14C-labeled metabolites, a six-compartment model was formulated. Studies using [1-11C]acetate and a pair of NaI detectors were then performed in the same perfused heart system to validate the model. Consistency between the model predictions and biochemical measurements of tissue and effluent metabolites supported the validity of the kinetic model in normoxic and ischemic conditions. Model-estimated MVO2 correlated well with experimentally measured MVO2 for normoxic, hypoxic, and ischemic conditions, with a slope of 0.97 (r = 0.95). In addition, the model-estimated rate constant, k42, which corresponded to the oxidative flux, correlated strongly with the myocardial clearance rate (k1 or kmono) determined from the tissue kinetics. These findings provide a mechanistic basis for the use of k1 or kmono as an index of MVO2 in both normoxic and ischemic myocardium studied with [1-11C]acetate and positron emission tomography.
P-selectin and ICAM-1-dependent adherence reactions: role in the genesis of postischemic no-reflow
Authors: Jerome S. N. , Dore M. , Paulson J. C. , Smith C. W. , Korthuis R. J.
Published: December 2017

The aim of this study was to determine whether immunoneutralization of P-selectin or intercellular adhesion molecule-1 (ICAM-1) (endothelial cell adhesion molecules involved in leukocyte rolling and firm adhesion, respectively) would attenuate the development of postischemic capillary no-reflow. Microvascular patency was assessed in vascularly isolated canine gracilis muscles by perfusion with contrast media (India ink) at the end of the experimental protocol. Computerized video imaging was used to quantitate the number of ink-containing microvessels (< 10 microns diam) per muscle fiber in histological samples 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 (I-R), I-R + P-selectin monoclonal antibodies (MAbs) (MD6 or PB1.3), and I-R + ICAM-1 MAbs (CL18/6C7 or R6.5). The efficacy of a P-selectin MAb (MD3) that binds to a nonfunctional epitope was also evaluated. I-R was associated with a marked reduction in the number of patent capillaries per fiber (3.1 +/- 0.2 vs. 1.1 +/- 0.2 patent capillaries/fiber for control and I-R, respectively). Immunoneutralization with MAbs directed against functional epitopes on P-selectin (MD6 or PB1.3) significantly improved capillary perfusion (2.3 +/- 0.3 and 3.6 +/- 0.6 patent capillaries/fiber, respectively). On the other hand, MAb MD3, which binds to nonfunctional epitopes on P-selectin, failed to limit the development of postischemic no-reflow (1.0 +/- 0.2 patent capillaries/fiber). Immunoneutralization of ICAM-1 with CL18/6C7 and R6.5 increased the number of patent capillaries per fiber to 1.8 +/- 0.1 and 2.5 +/- 0.3, respectively. These data indicate that P-selectin and ICAM-1-dependent adherence reactions play an important role in the development of the no-reflow phenomenon in postischemic skeletal muscle.
Mediation of lung neutrophil uptake after endotoxin by CD18-integrin-dependent and -independent mechanisms
Authors: McCandless B. K. , Kaufman R. P. , Cooper J. A. , Neumann P. H. , Malik A. B.
Published: December 2017

We studied polymorphonuclear neutrophil (PMN) uptake in lungs of endotoxemic rabbits using 111In-labeled PMN and isotope imaging by gamma scintigraphy. Rabbits were challenged intravenously with 100 micrograms Escherichia coli endotoxin either 4 or 24 h before an intravenous injection of 111In-labeled PMN, which was obtained from donor rabbits. The contribution of CD18 glycoprotein (beta 2-integrin) on PMN was examined using an anti-CD18 monoclonal antibody (MAb) IB4 infused 20 min before 111In-labeled PMN injection. In control rabbits, 111In-labeled PMN uptake in lungs was maximal within 5 min [36 +/- 2% increase above baseline (+/- SE)] and then fell exponentially with a disappearance half-time (t1/2) of 10 +/- 2 min. In rabbits challenged with endotoxin for either 4 or 24 h, maximum 111In-labeled PMN lung uptake and t1/2 values increased to 52 +/- 3 and 56 +/- 3% and to 26 +/- 2 and 31 +/- 6 min, respectively. Pretreatment with MAb IB4 (0.5 mg/kg iv) did not alter the PMN uptake response and t1/2 values in the 4-h endotoxin-challenged rabbits (i.e., maximum uptake of 52 +/- 3% above baseline and t1/2 of 26 +/- 2 min), whereas MAb IB4 prevented the increases in lung PMN uptake and t1/2 in 24-h endotoxin-challenged rabbits (maximum PMN uptake of 26 +/- 5% and t1/2 of 7 +/- 3 min; P < 0.001). In contrast, the control MAb OKM-1 did not prevent lung PMN uptake and the disappearance of PMN from lungs at either times.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of carotid sinus baroreceptor reflex on hepatic and splenic vascular capacitance in vagotomized dogs
Authors: Risoe C. , Tan W. , Smiseth O. A.
Published: December 2017

Mechanisms of how baroreflex activation changes splanchnic vascular volumes were studied in eight vagotomized dogs, anesthetized by chloralose/urethan. Hepatic and splenic vascular volume changes were determined from organ dimensions by sonomicrometry. Pulsatile carotid sinus pressure (CSP) in isolated and separately perfused carotid sinuses was changed among 200, 120, and 40 mmHg. Lowering CSP from 120 to 40 mmHg significantly decreased both hepatic and splenic vascular volume (at similar portal pressure) by 1.9 +/- 0.5 and 1.8 +/- 0.6 ml/kg body wt, respectively. Increasing CSP from 120 to 200 mmHg tended to increase regional vascular volumes (P = NS). The combined volume change of liver and spleen between CSP 40 and 200 mmHg was 4.2 +/- 0.6 ml/kg body wt (P < 0.001). Pressure-volume (dimension) curves at high, low, and baseline CSP were determined to separate active and passive mechanisms of vascular volume changes. Changes in CSP did not change regional vascular compliance. Low CSP significantly decreased unstressed liver and unstressed splenic volume by 3.3 +/- 0.9 and 1.9 +/- 0.5 ml/kg body wt, respectively. These results indicate that liver and spleen both contribute to blood volume mobilization by vasoconstriction during low CSP and that the carotid sinus baroreceptor reflex modulates hepatic and splenic vascular capacitance by changing unstressed volume rather than by changing vascular compliance.
N omega-nitro-L-arginine constricts cerebral arterioles without increasing intracellular calcium levels
Authors: Dietrich H. H. , Kimura M. , Dacey R. G.
Published: December 2017

The coupling between intracellular Ca2+ concentration ([Ca2+]i) and smooth muscle cell (SMC) contractility is well known, but recent reports suggest that SMCs can contract without an increase in [Ca2+]i. Penetrating arterioles were isolated from rat cortex, cannulated, and loaded extraluminally with fura 2. We used ratio imaging of corresponding vessel wall areas to estimate and correlate [Ca2+]i to the vessel diameter during various extraluminal treatments. Control diameter was 45.6 +/- 3.9 (SE) microns with an estimated [Ca2+]i of 181 +/- 18 nM. Extraluminal papaverine or pH of 6.8 dilated the vessels to 61.0 +/- 6.6 and 57.8 +/- 5.8 microns and decreased [Ca2+]i to 108 +/- 33 and 155 +/- 8 nM, respectively. Alkaline pH of 7.65 or the Ca2+ ionophore ionomycin constricted the arterioles to 34.8 +/- 3.9 and 30.0 +/- 5.8 microns and increased [Ca2+]i to 273 +/- 47 and 853 +/- 155 nM, respectively. These results show an inverse relationship between vessel diameter and [Ca2+]i. Blocking the production of endothelium-derived nitric oxide (EDNO) with N omega-nitro-L-arginine constricted the vessels to 34.4 +/- 3.5 microns without raising but lowering [Ca2+]i to 157 +/- 44 nM. The dissociation of vessel tone and estimated [Ca2+]i after EDNO blocking has not been reported before in cerebral arterioles and may indicate that EDNO regulates vascular tone in a Ca(2+)-independent manner.
Cerebrovascular responsiveness to CO2 in Haemophilus influenzae type b meningitis in rabbits
Authors: Slater A. J. , Berkowitz I. D. , Wilson D. A. , Traystman R. J.
Published: December 2017

The effect of experimental meningitis on regional cerebral blood flow (rCBF), cerebral metabolic rate for oxygen (CMRO2), and cerebrovascular responsiveness to CO2 was determined in pentobarbital-anesthetized rabbits. The animals were inoculated intracisternally with saline (control) or log-phase Haemophilus influenzae type b (Hib). Eighteen hours later rCBF was determined with radiolabeled microspheres at normocapnia, hypocapnia, and hypercapnia. Cerebrovascular responses to hypocapnia and hypercapnia were assessed by calculating the change in cerebrovascular resistance per millimeter mercury change in PaCO2. At all CO2 levels, meningitis (M) was associated with elevated CBF compared with control (C: 47.5 +/- 3.0, M: 60.9 +/- 4.5 ml.100 g-1.min-1 at normocapnia, P < 0.01). Regional differences were present. In forebrain, the hyperemia in meningitis was confined to the superficial cortical grey matter. When compared with control, meningitis was not associated with altered vasoreactivity during hypocapnia (C: -0.026 +/- 0.006, M: -0.026 +/- 0.008 mmHg.ml-1 x 100 g-1.min-1.mmHg PaCO2(-1)) or hypercapnia (C: -0.037 +/- 0.004, M: -0.026 +/- 0.008 mmHg.ml-1 x 100 g.min.mmHg PaCO2(-1)). CMRO2 in meningitis was not significantly different from control (C: 3.53 +/- 0.29, M: 3.51 +/- 0.22 ml O2.100 g-1.min-1). These findings indicate that cerebrovascular responsiveness to CO2 is preserved in experimental Hib meningitis. Furthermore, enhanced CBF together with unchanged CMRO2 indicates that "luxury" cerebral perfusion is present in this model of bacterial meningitis.
Heart rate variability in two models of cardiac hypertrophy in rats in relation to the new molecular phenotype
Authors: Carre F. , Maison-Blanche P. , Ollivier L. , Mansier P. , Chevalier B. , Vicuna R. , Lessard Y. , Coumel P. , Swynghedauw B.
Published: December 2017

The analysis of heart rate variability (HRV) provides information on neural control of the heart. We investigated HRV in normal rats and in models of experimental cardiac hypertrophy using the Holter monitoring and peak/trough method. In normal rats, two heart rate oscillations with different wavelengths, high frequency (HF) and low frequency (LF) oscillations, were detected. The HF oscillations were insensitive to propranolol and suppressed by atropine. The LF oscillations were sensitive to both antagonists. Thyrotoxicosis resulted in cardiac hypertrophy (+20%) and tachycardia. The HF oscillations were unchanged, whereas LF oscillations were hampered at low heart rate in this group. Aortic stenosis resulted in cardiac hypertrophy (+53%), but heart rate oscillations were unchanged. The (number x amplitude) product for both types of oscillations correlated with heart rate in controls but not in the thyrotoxicosis or aortic stenosis models. Alterations of HRV in cardiac hypertrophy occur in rats as in humans. They may reflect the changes in the molecular components of the adrenergic/muscarinic system, which defines the new myocardial phenotype.
Effects of intra-atrial injection of colored microspheres on systemic hemodynamics and regional blood flow in rats
Authors: Kobayashi N. , Kobayashi K. , Kouno K. , Horinaka S. , Yagi S.
Published: December 2017

The hemodynamic effects of various numbers of colored nonradioactive microspheres (CMS) and those of accumulation of CMS caused by multiple sequential injection were evaluated in 51 Sprague-Dawley male rats. CMS (15 microns) were injected into the left atrium. Regional blood flow and cardiac output were evaluated using the reference blood sample technique. Ficoll-70 was given after each blood sample withdrawal as a fluid replacement. A bolus injection of < or = 1,000,000 CMS caused no significant hemodynamic disturbances. Amounts of 500,000 CMS can be repeatedly injected up to four times (cumulative dose of 2,000,000 CMS) without producing any adverse hemodynamic effects. The values of cardiac output obtained with the CMS technique were correlated well (r = 0.971, P < 0.0001) with those obtained with electromagnetic flow probes. An excellent reproducibility of organ blood flow was observed after four sequential injections of 500,000 CMS. This study establishes the limits of CMS that can be injected into the rat without inducing hemodynamic changes and also suggests that the CMS technique can be employed to evaluate cardiac output and regional blood flow precisely and repeatedly.
Reflex control of active cutaneous vasodilation by skin temperature in humans
Authors: Pergola P. E. , Kellogg D. L. , Johnson J. M. , Kosiba W. A.
Published: December 2017

The purpose of this study was to examine whether reflex effects of changes in whole body skin temperature (Tsk) on cutaneous vasculature are mediated through the vasoconstrictor or the active vasodilator arm of the sympathetic nervous system. In six subjects, reflex responses in forearm skin blood flow (SkBF) to changes in Tsk were monitored by laser-Doppler flowmetry. SkBF was monitored at a control site and at a 0.6-cm2 site where bretylium (BT) had been iontophoretically applied to abolish sympathetic vasoconstrictor control. Reflex control of SkBF at BT-treated sites is solely through active vasodilator activity. An index of cutaneous vascular conductance (CVC) was calculated from the blood flow signal and mean arterial pressure, measured noninvasively. Data are expressed relative to maximum CVC (CVCmax) achieved by local warming of measurement sites to 42 degrees C at the end of each study. Tsk was controlled with a water-perfused suit covering the entire body except for the head and arms. Esophageal temperature (Tes) was measured as an index of internal temperature. In part A (rest), raising Tsk at rest from 31.9 +/- 0.3 to 36.7 +/- 0.2 degrees C increased CVC at control sites from 3 +/- 0.2 to 5 +/- 0.6% of CVCmax. CVC did not change at BT-treated sites, suggesting that at rest, with a normal internal temperature, reflex effects of raising Tsk on SkBF are mediated through vasoconstrictor withdrawal. In part B (exercise), exercise at a low Tsk increased Tes to 37.49 +/- 0.1 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)
Attenuation of blood flow-induced dilation in arterioles after muscle contraction
Authors: Cabel M. , Smiesko V. , Johnson P. C.
Published: December 2017

The response of third-order arterioles (n = 15) in rat cremaster muscle to increased luminal flow was studied after brief (20-30 s) occlusion of a neighboring arteriole in pentobarbital-anesthetized rats. Red cell velocity increased almost fivefold (485 +/- 54% of control) during occlusion, and vessel diameter increased 63 +/- 11%. Initially, the calculated wall shear rate increased to 430 +/- 40% of control during occlusion but then decreased to 308 +/- 35% of control as a consequence of arteriolar dilation. The muscle was subsequently stimulated to contract for 1 min, and the occlusion procedure was repeated after arteriolar diameter and red cell velocity had returned to control levels. In this instance the vessel dilation was 34 +/- 10% or about one-half of that seen during the previous occlusion, although velocity and shear rate rose to a similar degree (474 +/- 54 and 397 +/- 35%, respectively). Dilation during a third occlusion 2-7 min after the vessel recovered from the second occlusion was as great as during the first occlusion (77 +/- 20%). The results indicate that flow-induced dilation in arterioles of rat cremaster muscle is transiently attenuated after muscle contraction.