bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial L-arginine pathway and relaxations to vasopressin in canine basilar artery
Authors: Cosentino F. , Sill J. C. , Katusic Z. S.
Published: December 2017

Experiments were designed to determine the role of the L-arginine pathway in endothelium-dependent relaxations to vasopressin. The effects of L-arginine analogues NG-nitro-L-arginine (L-NNA), NG-nitro-L-arginine methyl ester (L-NAME), and NG-monomethyl-L-arginine (L-NMMA) on basal and vasopressin-induced activity of nitric oxide synthase were studied in isolated canine basilar arteries. Rings with and without endothelium were suspended for isometric tension recording in Krebs-Ringer bicarbonate solution bubbled with 94% O2-6% CO2 (37 degrees C, pH 7.4). Radioimmunoassay was used to determine the level of guanosine 3',5'-cyclic monophosphate (cGMP). All experiments were performed in the presence of indomethacin, a cyclooxygenase inhibitor. L-NAME and L-NMMA caused endothelium-dependent contractions and inhibited basal production of cGMP. In contrast, L-NNA did not affect basal tone or basal production of cGMP. L-Arginine analogues inhibited relaxations to vasopressin but did not affect relaxations to a nitric oxide donor, molsidomine (SIN-1). The effects of L-NNA, L-NAME, and L-NMMA were reversed in the presence of L-arginine. The relaxations to vasopressin were associated with an increase of cGMP levels in the arterial wall. This effect of vasopressin was inhibited in the presence of L-NNA. These studies suggest that the relaxations to vasopressin are mediated by activation of the endothelial L-arginine pathway, leading to increased production of nitric oxide, with subsequent activation of guanylate cyclase in smooth muscle cells. In canine basilar artery, L-NAME and L-NMMA are nonselective inhibitors of both basal and stimulated production of nitric oxide, whereas L-NNA selectively inhibits vasopressin-induced activation of the L-arginine pathway.
Mechanoelectrical feedback effects of altering preload, afterload, and ventricular shortening
Authors: Hansen D. E.
Published: December 2017

Electrophysiological consequences of altering ventricular load (mechanoelectrical feedback) were characterized in an isolated canine heart preparation. A computerized servo pump system controlled left ventricular volume and allowed ventricular ejection against a simulated arterial load (3-element Windkessel model). In 12 ventricles, end-diastolic volume (Ved) was held constant (end-diastolic pressure 6-12 mmHg) as arterial resistance (R) was varied (0.5-12 mmHg.s.ml-1), but afterload-dependent changes in the monophasic action potential (MAP) were not observed despite a large stroke volume effect. In contrast, when R was held constant in eight ventricles while Ved was increased from 20 to 40 ml, the plateau phase of the MAP was abbreviated, the terminal portion of phase 3 repolarization was delayed, and MAP duration measured at 20, 70, and 90% repolarization decreased (P < 0.05). In six ventricles, immediate transitions from isovolumic to ejecting mode at constant Ved did not alter MAP duration, but the magnitude of early afterdepolarizations (EADs), observed during isovolumic beats at high Ved, was reduced with resumption of ventricular ejection. As stroke volume of the initial ejecting contraction was increased by stepwise reductions of R, the magnitude of the EADs decreased progressively. Thus altering ventricular afterload does not modulate action potential duration in ventricles subjected to elevated, physiological, or even greatly reduced levels of afterload, whereas diastolic filling to high Ved does. Under conditions that lead to reduced stroke volume and high end-systolic volume, EADs are produced that are virtually abolished when ventricular ejection fraction is normalized.
Regulation of adenosine receptor system in coronary artery: functional studies and cAMP
Authors: Hussain T. , Mustafa S. J.
Published: December 2017

Regulation of the adenosine receptor system was investigated using a new in vitro model of porcine coronary artery after exposure to an adenosine receptor agonist. Isolated coronary arteries were incubated in the absence (control) and presence (treated) of 2-chloroadenosine (CAD) in culture media (pH 7.4) at 37 degrees C with 92.5% O2-7.5% CO2. CAD treatment led to a significant rightward shift in the relaxation responses to the adenosine receptor agonists CAD, 5'-(N-ethylcarboxamido)adenosine, and R-phenylisopropyladenosine. The shift was both concentration and time dependent and was maximum at 100 microM at 3 days. The relaxation responses to isoproterenol and sodium nitroprusside were unaltered under identical conditions. Forskolin-mediated relaxation was also shifted rightward in the treated group. The shift in CAD- and forskolin-mediated relaxation in the treated group was endothelium independent. On the other hand, isoproterenol (10 microM, 3 days) treatment produced a rightward shift in the relaxation response to isoproterenol, while the response to CAD was unaltered. In a separate set of experiments, CAD did not stimulate adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in the treated arteries compared with control. However, NaF and forskolin stimulation of cAMP was markedly decreased in the treated group. Unlike these agonists, isoproterenol stimulation of cAMP was similar in both treated and control groups. The data suggest the desensitization of the adenosine receptor via regulation of stimulatory guanine nucleotide binding proteins without altering the beta-receptor-mediated responses in coronary artery.
Microvascular hemodynamics in the sickle red blood cell perfused isolated rat lung
Authors: Haynes J. , Taylor A. E. , Dixon D. , Voelkel N.
Published: December 2017

In this study the effects of alveolar hypoxia on pulmonary microvascular hemodynamics in sickle red blood cell (HbSS-RBC) perfused rat lungs were studied under conditions of high and low oxygen tensions and compared with lung perfused with rat (HbRat) and normal human (HbAA) RBC controls. Independent of the RBC suspension (hematocrit 5%) used, ventilation with the room air gas mixture did not result in any significant differences in the pulmonary arterial pressure (Ppa), capillary pressure (Ppc), total pulmonary vascular resistance (RT), or angiotensin II pressor response. Ventilation of HbSS-RBC perfused lungs with a hypoxic gas mixture significantly increased the Ppa, Ppc, and RT above that which was seen in HbRat and HbAA controls. The increase in RT occurred mainly in the pulmonary artery independent of RBC suspension. In addition, no significant accumulation of lung water occurred in HbSS-RBC perfused lungs compared with HbRat and HbAA controls, as indicated by the change in capillary filtration coefficient and wet-to-dry lung weight ratio. In conclusion, deoxygenation of the HbSS-RBC and hypoxic pulmonary vasoconstriction is additive in altering pulmonary microvascular hemodynamics.
Low baroreflex sensitivity predisposes to salt-sensitive hypertension in the rabbit
Authors: Weinstock M. , Borosh M.
Published: December 2017

The aim of this study was to determine the effect of an increase in dietary salt on blood pressure (BP), Na+ balance, and plasma renin activity (PRA) in normotensive rabbits bred for differences in cardiac baroreflex sensitivity (BRS). Food and fluid intake, BP, heart rate, body weight, PRA, hematocrit, and creatinine clearance were monitored weekly and Na+ balance daily for 3 wk each on normal NaCl (8 meq/day) and high salt (32 meq/day) in 27 rabbits of the second and third generation of animals bred for high BRS (group I, 6.1 +/- 0.3 beats.min-1.mmHg-1, n = 9) or low BRS (group II, 3.61 +/- 0.1 beats.min-1.mmHg-1, n = 18). BRS was assessed in each animal on normal salt and at the end of the high-salt period. Both systolic and diastolic BP rose by > 10 mmHg in 50% of group II and by < 5 mmHg in the remainder and in all group I. The rise in BP was associated with Na+ and fluid retention and weight gain during the first 2 wk, which returned to presalt levels by the 3rd wk, although BP continued to rise. The lack of effect on BP in the remaining nine group II was associated with a marked sensitization of their BRS by the high salt to 6 +/- 0.4 beats.min-1.mmHg-1. BRS remained unchanged in the other rabbits. A highly significant correlation (P < 0.001) was found between the increment of BP and BRS after 3 wk of raised salt intake.(ABSTRACT TRUNCATED AT 250 WORDS)
Vascular capacitance following preoptic recess lesions
Authors: Bealer S. L.
Published: December 2017

Vascular capacitance was studied in anesthetized control (CONT) animals and in rats after electrolytic ablation of the periventricular tissue surrounding the anteroventral third cerebral ventricle (AV3V-X). Blood volume (BV) was determined by use of radiolabeled serum albumin, and mean arterial pressure (MAP) and central venous pressure (CVP) were continuously measured. Mean circulatory filling pressure (MCFP) was calculated by use of MAP and CVP obtained during circulatory arrest induced by inflation of a right atrial balloon during BV expansion and contraction. MCFP-BV relationships were calculated to estimate vascular compliance. CONT and AV3V-X animals were tested after treatment with both vehicle and hexamethonium, a ganglionic blocking agent. BV, MAP, and CVP were similar between CONT and AV3V-X animals. However, MCFP was significantly lower in AV3V-X animals (4.6 +/- 0.3 mmHg) than in CONT rats (6.6 +/- 0.5 mmHg). Furthermore, AV3V ablation caused a significant shift of the MCFP-BV relationship toward the volume axis with no change in compliance, indicating decreased venous tone. Finally, hexamethonium treatment significantly reduced MCFP in CONT animals (3.8 +/- 0.7 mmHg) and shifted the MCFP-BV line toward the BV axis but had no effect on these measures in AV3V-X animals. These data indicate that electrolytic ablation of AV3V periventricular tissue significantly reduces venous tone by decreasing neurally mediated venoconstriction.
Microgravity and orthostatic intolerance: carotid hemodynamics and peripheral responses
Authors: Lacolley P. J. , Pannier B. M. , Cuche J. L. , Hermida J. S. , Laurent S. , Maisonblanche P. , Duchier J. L. , Levy B. I. , Safar M. E.
Published: December 2017

A ground-based model [24 h of bed rest (BR) with head-down tilt (HDT)] was used to investigate the cardiovascular deconditioning responsible for orthostatic intolerance, frequently observed after weightlessness flights. This experimental deconditioning is shown to be distinguished by an increase of mean blood pressure (P < 0.05), with increased total peripheral resistances (TPRs). Systolic tangential tension of the carotid arterial wall, cardiac output and frequency (spectral analysis), and plasma norepinephrine and epinephrine were not significantly altered, while plasma dopamine was increased (P < 0.05). Cardiovascular homeostasis was challenged before and after 24 h of BR with HDT through -40 mmHg lower body negative pressure (LBNP). Systolic tangential tension of the carotid wall was decreased, with a decrease of systolic pressure and cardiac output; increased heart rate was likely due to an increase of sympathetic drive with a decrease of vagal braking. The overall picture was not changed after 24 h of BR with HDT, except for a lack of increase of TPRs: their increase (+13.7%, P < 0.05) before was no longer observed after (-2.6%) 24 h of BR with HDT. This apparent deficiency cannot be explained. However, a heterogeneity in the response of TPR should be considered because the magnitude of the increase of blood pressure to cold pressor test was the same after 24 h of BR with HDT as it was before.(ABSTRACT TRUNCATED AT 250 WORDS)
M3 and M1 receptors in cerebral arterioles in vivo: evidence for downregulated or ineffective M1 when endothelium is intact
Authors: Shimizu T. , Rosenblum W. I. , Nelson G. H.
Published: December 2017

Pial arterioles of mice were monitored by intravital television microscopy. Responses to acetylcholine (ACh) and to McN-A-343, a selective M1 activator, were monitored before and after endothelial injury by a laser-dye technique in the presence or absence of different reference antagonists to the M1, M2, and M3 muscarinic receptors. ACh and McN-A-343 produced endothelium-dependent dilation that was blocked by 4-diphenyl-N-methyl-piperidine methiodide, an inhibitor of the M3 receptor. Dilations were not augmented by blocking the M1 receptor with pirenzepine. Endothelial injury unmasked a constricting effect of both ACh and McN-A-343. The constricting effect was blocked by pirenzepine. The results support the literature suggesting an action of McN-A-343 at more than one site. They indicate that ACh causes endothelium-dependent relaxation via the M3 receptor and directly constricts vascular smooth muscle via the M1 receptor. There does not appear to be continuous competition between endothelium-dependent relaxation and endothelium-independent constriction. Rather the M1 receptors mediating constriction in vascular smooth muscle appear downregulated and/or uncoupled from the contractile machinery as long as the overlying endothelium synthesizes/releases the mediator (endothelium-derived relaxing factor) of ACh's dilating action.
A factor released from coronary vascular endothelium inhibits myocardial contractile performance
Authors: Fort S. , Lewis M. J.
Published: December 2017

The effect of continuous intracoronary infusion of bradykinin (BK; 10(-6) M) on the myocardial contractile performance of isolated Langendorff-perfused ferret hearts was investigated. BK produced a transient but marked inhibition of contractile performance, the changes being fully resolved by 2-3 min. This effect of BK was blocked after disruption of the coronary vascular endothelium with Triton X-100 (0.5%). Prior infusion of the endothelium-derived relaxing factor (EDRF) synthesis inhibitor N omega-nitro-L-arginine (10(-4) M) failed to alter the mechanical effects induced by BK. These changes in contractile performance were reduced, however, by the K+ channel-blocking agent glibenclamide (10(-6) M) but were unaffected by tetrapentylammonium bromide (5 x 10(-5) M) or 4-aminopyridine (10(-3) M). These findings therefore indicate that BK inhibits myocardial contractile performance by opening myocardial ATP-sensitive K+ channels, probably via the release of an endothelium-derived factor unrelated to EDRF.
In vivo cerebrovascular reactivity in Wistar and Fischer 344 rat strains during aging
Authors: Lartaud I. , Bray-des-Boscs L. , Chillon J. M. , Atkinson J. , Capdeville-Atkinson C.
Published: December 2017

Basal cerebral blood flow (CBF) and CBF regulation after hypercapnia and hypotensive hemorrhage were investigated using H2 clearance in the frontal cortex of awake 2-, 14-, or 23-mo-old Wistar or Fischer 344 rats. Basal CBF decreased in old Wistar but not in mature Wistar (old 64.4 +/- 2.8, mature 87.6 +/- 2.6, young 79.6 +/- 2.2 ml.min-1 x 100 g-1) or in old Fischer 344 (old 71.9 +/- 2.9, young 73.3 +/- 1.6 ml.min-1 x 100 g-1) rats. Cerebrovascular reactivity to hypercapnia decreased in mature and old Wistar (old 2.1 +/- 0.3, mature 3.1 +/- 0.7, young 7.0 +/- 2.1 ml.min-1 x 100 g-1 x mmHg-1) but not in old Fischer 344 rats (old 4.6 +/- 1.4, young 4.9 +/- 0.9 ml.min-1 x 100 g-1 x mmHg-1). The lower limit of CBF autoregulation increased by 20 mmHg during maturation and/or aging in the two strains. Because blood gases and pH evolved similarly in both strains, we postulate that differences in cerebrovascular structure and/or function explain the differences in CBF regulation in the older representatives of the two strains.
Endothelium-dependent contractions to oxygen-derived free radicals in the canine basilar artery
Authors: Katusic Z. S. , Schugel J. , Cosentino F. , Vanhoutte P. M.
Published: December 2017

Experiments were designed to determine the effect of oxygen-derived free radicals in isolated canine basilar arteries. Rings with and without endothelium were suspended for isometric tension recording in modified Krebs-Ringer bicarbonate solution bubbled with 95% O2-5% CO2 (temperature = 37 degrees C; pH = 7.4). A radioimmunoassay technique was used to measure production of prostaglandins and thromboxane B2. Xanthine oxidase (1-9 mU/ml, in the presence of 10(-4) M xanthine) and hydrogen peroxide (10(-6) to 10(-4) M) caused concentration-dependent contractions. The removal of endothelium reversed these contractions into relaxations. Contractions to xanthine oxidase and hydrogen peroxide were inhibited in the presence of superoxide dismutase (150 U/ml), catalase (1,200 U/ml), indomethacin (10(-5) M), and SQ 29548 (10(-6) M) but not in the presence of deferoxamine (10(-4) to 10(-3) M) and dimethyl sulfoxide (10(-4) M). NG-monomethyl-L-arginine (3 x 10(-5) M) augmented the contractions to hydrogen peroxide. Xanthine oxidase stimulated production of 6-ketoprostaglandin F1 alpha, prostaglandin F2 alpha, prostaglandin E2, and thromboxane B2. The stimulatory effect was prevented by the removal of endothelial cells. These studies suggest that xanthine oxidase causes endothelium-dependent contractions mediated by: 1) hydrogen peroxide-induced stimulation of the endothelial metabolism of arachidonic acid via the cyclooxygenase pathway, leading to activation of prostaglandin H2-thromboxane A2 receptors, and 2) inactivation of basal production of nitric oxide by superoxide anions.
In vivo visualization of oxidative changes in microvessels during neutrophil activation
Authors: Suematsu M. , Schmid-Schonbein G. W. , Chavez-Chavez R. H. , Yee T. T. , Tamatani T. , Miyasaka M. , Delano F. A. , Zweifach B. W.
Published: December 2017

This study was designed to characterize temporal changes of oxidative metabolism in microvascular endothelium in vivo associated with neutrophil adhesion and diapedesis. The rat mesentery was loaded with dichlorofluorescein (DCFH) diacetate, a hydroperoxide-sensitive fluorescent probe that is trapped within viable cells as a nonfluorescent form and is converted to fluorescent dichlorofluorescein (DCF) by hydroperoxides. The fluorescent light emission was recorded with digital microscopy and its camera response was calibrated by superfusion of the mesentery with known concentrations of hydroperoxides. After rinsing with a precursor-free solution, it was possible to observe both the neutrophil adhesion and fluorescence changes in venular endothelium during superfusion with platelet-activating factor (PAF, 100 nM) by alternately changing light sources. In the PAF-treated animals, DCF fluorescence in the venular wall was markedly elevated concurrent with an increase in the number of adherent neutrophils. An onset of a significant DCF fluorescence was observed as early as 10 min after PAF application. The venular oxidative changes were co-localized with neutrophils adhering to the endothelium or migrating into the interstitium. The oxidative impact in the venular wall superfused with 100 nM PAF for 40 min was equivalent to that induced by the 10-min superfusion of 0.8 mM of tert-butyl hydroperoxide. Pretreatment with dipyridyl, an iron chelator, or dimethylthiourea, a hydroxyl radical scavenger, significantly attenuated the PAF-induced oxidative changes in the venule but had little effect on neutrophil adhesion. These findings suggest that an endothelial cell-dependent mechanism involving an iron-catalyzed reaction may have a role in enhancement of neutrophil-mediated oxidative stress in venular endothelium.
Compensatory downregulation of myocardial Ca channel in SR from dogs with heart failure
Authors: Cory C. R. , McCutcheon L. J. , O'Grady M. , Pang A. W. , Geiger J. D. , O'Brien P. J.
Published: December 2017

In this study we tested the hypothesis that the ryanodine-binding Ca-release channel activity and density of the sarcoplasmic reticulum (SR) terminal cisternae were decreased in congestive heart failure (CHF) that occurs spontaneously in doberman pinschers or experimentally with rapid ventricular pacing of mongrels. We used a novel, sensitive, and easy-to-perform microassay and demonstrated a 50% decrease in activity of the myocardial SR Ca pump and a 75% reduction in SR Ca-release channel activity in CHF. Decreases in Ca channel content were associated with increases in net Ca sequestration. 45Ca-release experiments from passively loaded SR terminal cisternae and ryanodine-binding studies confirmed a 53–68% downregulation of the Ca-release channel activity. As a consequence of release channel downregulation, there was partial restoration of net Ca sequestration activity in dogs with CHF and complete compensation in dogs with mild cardiac dysfunction. Deterioration of Ca cycling correlated with deterioration of myocardial performance, apparently due to decreased Ca-adenosinetriphosphatase (ATPase) pump and not Ca channel content. One-half the reduction in Ca-release activity could be attributed to decreased Ca sequestration and one-half to decreased Ca channel density. Downregulation of Ca channel content decreases the amplitude of the Ca cycle and maximizes the downregulation of Ca pumps that may occur. Although these adaptations may reduce cellular energy expenditure, they are likely to render the myocardium more susceptible to fatigue and failure.
Production of arachidonic acid metabolites in adult rat cardiac myocytes, endothelial cells, and fibroblast-like cells
Authors: Linssen M. C. , Engels W. , Lemmens P. J. , Heijnen V. V. , Van Bilsen M. , Reneman R. S. , van der Vusse G. J.
Published: December 2017

Cells were incubated in the presence of the Ca2+ ionophore A23187 (10 microM) and arachidonic acid (AA, 80 microM). The release of eicosanoids from subcultivated cardiac endothelial and fibroblast-like cells amounted to 23.3 +/- 4.5 and 2.0 +/- 0.4 nmol/mg cellular protein per 30 min, respectively. The release from isolated cardiomyocytes remained below the detection limit of the high-performance liquid chromatography assay (< 0.00015 nmol/assay). When a very sensitive radioimmunoassay was applied, cardiomyocytes released 0.002 +/- 0.0001 nmol prostacyclin per milligram cellular protein per 30 min. Prostaglandin (PG) E2 and PGF2 alpha, 12-hydroxyheptadecatrienoic acid, 11- and 15-hydroxyeicosatetraenoic acid, and thromboxane B2 were the main eicosanoids released by endothelial cells. The stable product of prostacyclin, 6-keto-PGF1 alpha, contributed relatively little to the total amount of eicosanoids formed by endothelial cells. Fibroblast-like cells released predominantly PGE2 and 6-keto-PGF1 alpha and, to a lesser extent, 12-hydroxyheptadecatrienoic and 15-hydroxyeicosatetraenoic acids. Neither endothelial cells nor fibroblast-like cells released leukotrienes. A23187 stimulated eicosanoid release from endothelial cells when exogenous AA was below 40 microM. Addition of albumin reduced the amount of eicosanoids produced. Histamine and bradykinin did not influence 6-keto-PGF1 alpha and PGE2 production in cardiomyocytes. Histamine only gave rise to a slight but significantly higher release of 6-keto-PGF1 alpha in endothelial cells.
Prostanoids promote pial arteriolar dilation and mask constriction to oxytocin in piglets
Authors: Busija D. W. , Khreis I. , Chen J.
Published: December 2017

We determined effects of oxytocin on piglet pial arterioles and the role of prostanoids in mediating arteriolar responses. Anesthetized piglets were equipped with closed cranial windows, and arteriolar diameter was measured using intravital microscopy. Pial arterioles were exposed to 10(-10) to 10(-4) M oxytocin. Cerebrospinal fluid (CSF) levels of prostaglandin E2 (PGE2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were determined using radioimmunoassay. Baseline diameter was 110 +/- 4 microns and increased to 120 +/- 6 microns at 10(-8) M (9 +/- 3%, n = 20). CSF levels of PGE2 were 697 pg/ml during baseline and increased to 1,685 +/- 316 pg/ml during 10(-6) M, 2,243 +/- 327 pg/ml during 10(-5) M, and 2,941 +/- 500 pg/ml during 10(-4) (n = 6). CSF levels of 6-keto-PGF1 alpha were 354 +/- 73 pg/ml during baseline and increased to 734 +/- 168 pg/ml at 10(-5) M and to 836 +/- 167 pg/ml at 10(-4) M (n = 5). After inhibition of prostaglandin synthesis by indomethacin (5 mg/kg i.v.), oxytocin constricted at all doses, starting at 10(-10) M (5 +/- 2%) and continuing to constrict at 10(-4) M (24 +/- 2%, n = 14). We conclude that: 1) piglet pial arterioles respond to relatively low levels of oxytocin, 2) local presence and/or production of prostanoids promotes dilation, and 3) endogenous prostanoids prevent constriction of pial arterioles to oxytocin. Our results suggest that oxytocin could play a role in the regulation of cerebral hemodynamics.
Propionyl-L-carnitine limits chronic ventricular dilation after myocardial infarction in rats
Authors: Micheletti R. , Di Paola E. D. , Schiavone A. , English E. , Benatti P. , Capasso J. M. , Anversa P. , Bianchi G.
Published: December 2017

To determine whether propionyl-L-carnitine (PLC) administration ameliorates ventricular remodeling after myocardial infarction, we performed coronary occlusion in rats and examined the long-term effects of the drug 19-24 wk after surgery. In view of the well-established role of angiotensin-converting enzyme (ACE) inhibitors in the reduction of ventricular dilation after infarction, the therapeutic impact of oral PLC (60 mg/kg) was compared with that of enalapril (1 mg/kg). Infarct size measured planimetrically was found to be comparable in untreated, PLC-treated, and enalapril-treated rats, averaging 40-46% of the left ventricular free wall. Heart weight was increased 14, 16, and 11% with no treatment, with PLC, and with enalapril, respectively. The relationship between left ventricular filling pressure and chamber volume demonstrated that PLC and enalapril significantly prevented the expansion in cavitary size after infarction. These protective influences were observed throughout the range of filling pressures measured, from 0 to 30 mmHg. At a uniform reference point of filling pressure of 4 mmHg, untreated infarcted hearts showed an expansion in ventricular volume of 2.17-fold (P < 0.0001). Corresponding increases in this parameter after PLC and enalapril were 36 and 43%, respectively, both not statistically significant. Moreover, PLC was capable of reducing the alterations in myocardial compliance associated with myocardial infarction. In conclusion, PLC reduces the magnitude of decompensated eccentric hypertrophy produced by myocardial infarction in a manner similar to that found with ACE inhibition.
Effects of corticotropin-releasing factor on isolated rat heart activity
Authors: Grunt M. , Glaser J. , Schmidhuber H. , Pauschinger P. , Born J.
Published: December 2017

We investigated effects of bolus administration of corticotropin-releasing factor (CRF) on parameters of cardiac activity in isolated working rat hearts. Effects at a dose of 5 micrograms of CRF were compared in hearts perfused with Krebs-Henseleit solution, norepinephrine (NE, 10(-9) M), propranolol (3 x 10(-6) M), NG-nitro-L-arginine (L-NNA, 3 x 10(-5) M), or indomethacin (3 x 10(-5) M). CRF increased coronary flow for > 30 min (P < 0.01) with maximum increases of 31.7%, suggesting a prolonged vasodilatory action of the peptide. CRF, in addition, induced transient (lasting < 10 min) increases in maximum aortic pressure and oxygen consumption (P < 0.01), suggesting an inotropic action of the peptide. Perfusions of NE and propranolol did not change the cardiac response to CRF. L-NNA, inhibiting release of endothelium-derived relaxant factor (EDRF), and indomethacin diminished the vasodilatory response to CRF, as indicated by significantly shortened increases in coronary flow after CRF (P < 0.05). Indomethacin also enhanced peak increases in maximum aortic pressure after CRF (P < 0.01). The data confirm direct effects of CRF on cardiac activity. They also suggest that the mediation of coronary vasodilation by CRF involves the endothelial release of prostacyclin and EDRF.
Recovery of myocardial function after repetitive episodes of reversible ischemia
Authors: Gall S. A. , Maier G. W. , Glower D. D. , Gaynor J. W. , Cobb F. R. , Sabiston D. C. , Rankin J. S.
Published: December 2017

The question of whether recovery of regional myocardial function after repetitive, reversible ischemia differs from recovery after a single episode of myocardial ischemia remains controversial. Therefore, eight conscious dogs were instrumented with ultrasonic dimension transducers and left ventricular micromanometers. Each animal underwent (in random sequence, 72 h apart) a single 15-min left anterior descending coronary arterial (LAD) occlusion and two 15-min LAD occlusions separated by 1 h of reperfusion. The preload recruitable work area (PRWA; the area beneath the regional stroke work vs. end-diastolic length relationship) quantified regional myocardial performance. Repetitive ischemia significantly delayed recovery of PRWA over the first 24 h (P < 0.05). Although postischemic myocardial creep resolved rapidly after single occlusion, double occlusion prevented recovery of creep during the first 4 h of reperfusion. The recovery time course of PRWA paralleled the resolution of myocardial creep, suggesting that creep contributed significantly to delayed functional recovery and that myocardial "stunning" after repetitive ischemia may result in part from interaction between postischemic diastolic properties and systolic dysfunction.
Endothelium-derived relaxing factor inhibits norepinephrine contraction of fetal guinea pig arteries
Authors: Thompson L. P. , Weiner C. P.
Published: December 2017

As in the adult circulation, the endothelium may play an important role in determining fetal vascular tone. The purpose of this study was to determine the influence of the endothelium on norepinephrine- and phenylephrine-induced contraction of pulmonary and carotid arteries from near-term fetal guinea pigs. Isometric contractions of isolated rings to the cumulative addition of norepinephrine (10(-9)-10(-5) M) were measured before and after 1) endothelium removal, 2) NG-monomethyl-L-arginine (L-NMMA; 10(-4) M) to inhibit endothelium-derived relaxing factor (EDRF), 3) methylene blue (10(-5) M) to inhibit guanylate cyclase, 4) oxyhemoglobin (3 x 10(-6) M) to bind EDRF, and 5) indomethacin (10(-5) M) to inhibit cyclooxygenase. All treatment effects were measured in endothelium-intact segments. The maximal norepinephrine contraction of fetal pulmonary (40 +/- 8% KCl, n = 7) and carotid (13 +/- 7% KCl, n = 7) arteries was much less (P < 0.05) than the maximal contraction to 120 mM KCl. Treatments that inhibit the action of EDRF increased contraction of both fetal pulmonary and carotid arteries. L-NMMA also increased contraction to phenylephrine. Indomethacin had no effect on the contractile responses to norepinephrine of either artery. Thus EDRF inhibits alpha-adrenoceptor-stimulated contraction of fetal pulmonary and carotid arteries and may attenuate the constrictor responsiveness of the fetal circulation in vivo.
TNF-alpha release in endotoxemia contributes to neutrophil-dependent pulmonary edema
Authors: Horgan M. J. , Palace G. P. , Everitt J. E. , Malik A. B.
Published: December 2017

We examined whether the generation of tumor necrosis factor (TNF-alpha) after lipopolysaccharide (LPS) challenge contributes to increases in lung vascular permeability and water content. Guinea pig lungs perfused at constant flow with Ringer-albumin solution (0.5 g/100 ml) were challenged for 120 min with LPS (Escherichia coli; final concentration 33 ng/ml; n = 5). Lung effluent samples were assayed for TNF-alpha activity using the modified L-929 fibroblast cytolytic assay. TNF-alpha concentrations increased in a time-dependent manner with a peak value of 100 +/- 20 pg/ml noted 90-120 min after LPS. Human neutrophils [polymorphonuclear leukocytes (PMN; 2 x 10(7)] added to the perfusion solution after endotoxin challenge (n = 5) produced a threefold increase in lung tissue myeloperoxidase (MPO) activity over control values. PMN, added after LPS and activated using phorbol 12-myristate 13-acetate (PMA; 5 x 10(-9) M; n = 6), produced three- to sixfold increases in mean pulmonary arterial pressure (Ppa) and pulmonary capillary pressure (Pcap), wet weight-to-dry weight ratio (W/D), and the pulmonary capillary filtration coefficient (Kf,c) over control values (P < 0.05). Activation of PMN with PMA in non-LPS-challenged lungs produced only threefold increases in Ppa and Pcap and did not change W/D and Kf,c. Infusion of an anti-TNF-alpha antibody before the LPS challenge reduced by approximately 50% the increases in Ppa, Pcap, MPO content, Kf,c, and lung wet weight gain (P < 0.05). Therefore, endotoxin-induced TNF-alpha generation in lungs significantly contributes to pulmonary sequestration of PMN. Activation of the sequestered PMN increases pulmonary vascular permeability and tissue water content.
L-arginine analogues blunt prostaglandin-related dilation of arterioles
Authors: Koller A. , Sun D. , Messina E. J. , Kaley G.
Published: December 2017

The effects of arginine analogues, inhibitors of endothelium-derived nitric oxide synthesis, on dilation of arterioles in response to various vasoactive substances were studied. At 65 mmHg intravascular pressure, isolated arterioles of rat cremaster muscle developed tone spontaneously and achieved control diameters similar to those observed in vivo (84.1 +/- 2.0 microns vs. passive diameter: 161.3 +/- 3.4 microns). Acetylcholine (ACh, 5 x 10(-8) M), sodium nitroprusside (SNP, 5 x 10(-8) M), arachidonic acid (AA, 10(-7) M), prostaglandin E2 (PGE2, 10(-9) M), and adenosine (ADO, 10(-6) M) were added to the Krebs bicarbonate buffer solution, suffusing the vessels. The peak vasodilator effects of all agents were studied before and after the administration of various doses of N omega-nitro-L-arginine (L-NNA; 10(-5), 10(-4), and 10(-3) M), which significantly reduced, in a dose-dependent manner, the basal diameter of arterioles by 3.6, 15.2, and 18.9%, respectively. The lowest concentration of L-NNA significantly inhibited arteriolar dilations to ACh by approximately 26%. Higher concentrations of L-NNA and N omega-monomethyl-L-arginine (L-NMMA; 10(-4) M) caused a further significant reduction in the dilation to ACh (to approximately 47%) and also significantly reduced dilator responses to AA and PGE2. In the presence of the highest concentration of L-NNA (10(-3) M), dilation to SNP and ADO were also significantly reduced. Removal of endothelium abolished dilation to ACh and AA but did not alter that to SNP, PGE2, or ADO.(ABSTRACT TRUNCATED AT 250 WORDS)
ATP depletion causes a reversible decrease in Na+ pump density in cultured ventricular myocytes
Authors: Ikenouchi H. , Zhao L. , McMillan M. , Hammond E. M. , Barry W. H.
Published: December 2017

To examine factors contributing to impaired K+ homeostasis induced by prolonged but sublethal ATP depletion, we subjected cultured chick ventricular myocytes to metabolic inhibition with 20 mM 2-deoxy-D-glucose plus 1 mM NaCN for 2 h and then allowed myocytes to recover for 5 days in medium containing 6% fetal calf serum (FCS) or in hormone-supplemented serum-free medium. We measured spontaneous contractions (with a video motion detector), K+ content, K+ uptake, membrane potential, and Na+ pump density ([3H]ouabain binding). Exposure to metabolic inhibition for 2 h caused an acute decrease in Na+ pump site density [8.2 +/- 1.1 to 3.8 +/- 0.8 (SE) pmol/mg protein; n = 9, P < 0.02]. Compared with control cells (no metabolic inhibition, cultured for 5 days in serum-free medium), Na+ pump density remained depressed in cells recovered from metabolic inhibition in serum-free medium (3.0 +/- 0.7 pmol/mg), and this was associated with persistently depressed K+ uptake (54% of control), K+ content (67% of control), and membrane depolarization (-19 +/- 2 mV), a significant decrease in cell number (79% of control), and failure to resume spontaneous contractions. Exposure of cells inhibited for 2 h to culture medium containing 6% FCS resulted in a return of Na+ pump site density toward normal levels by 5 days, associated with recovery of K+ uptake and K+ content, preservation of cell number, and resumption of contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
Modulation of cerebral arterial tone by endothelium-derived relaxing factor
Authors: Brian J. E. , Kennedy R. H.
Published: December 2017

This study was designed to further elucidate the role of the endothelium in regulation of cerebral vascular smooth muscle tone. Dose-dependent vasoconstrictive effects of serotonin (5-HT) were examined in endothelium-intact and endothelium-denuded ring segments prepared from canine basilar and middle cerebral arteries. Some preparations were pretreated with 10(-5) M N omega-nitro-L-arginine (L-NNA), an agent that inhibits the production of L-arginine-derived nitric oxide, one of the compounds proposed to be endothelium-derived relaxing factor. L-NNA alone elicited marked dose-dependent increases in tension in endothelium-intact preparations; a significantly smaller response was seen in endothelium-denuded preparations. The effects of L-NNA on endothelium-intact preparations were partially reversed by washing and treatment with L-arginine. The maximum tension induced by 5-HT was approximately doubled by removal of the endothelium as well as by L-NNA treatment of endothelium-intact preparations; a slight increase in maximum tension occurred in endothelium-denuded preparations treated with L-NNA. The concentration of 5-HT producing half-maximal contraction (ED50) was not affected by L-NNA. These data suggest that L-arginine-derived nitric oxide modulates canine cerebral arterial tone in both the resting state and during contraction with 5-HT.
Ibutilide: enhanced defibrillation via plateau sodium current activation
Authors: Wesley R. C. , Farkhani F. , Morgan D. , Zimmerman D.
Published: December 2017

Reductions in current and energy requirements for defibrillation have previously been ascribed to type III antiarrhythmic agents that block outward potassium conductance. This study investigated the effect on defibrillation of ibutilide, a type III antiarrhythmic agent that prolongs action potential duration by activating the sodium component of the plateau inward current. Pentobarbital-anesthetized dogs were subjected to serial episodes of ventricular fibrillation lasting 10 s. In protocol I, current and energy defibrillation requirements were determined via an interactive approach after bolus injections of saline placebo and ibutilide (0.1 mg/kg i.v.). In protocol II, a current dose-response method was utilized in which four shocks each at current doses of 0.7, 0.8, 0.9, and 1.0 x an estimated defibrillation threshold were administered before and after ibutilide (0.075 mg/kg bolus; 0.00125 mg.kg-1 x min-1 i.v.). In protocol I, current and energy values associated with defibrillation measured 10.9 +/- 4.5 A and 16.0 +/- 11.9 J for ibutilide compared with 14.1 +/- 5.6 A and 27.7 +/- 17.7 J for placebo, respectively (n = 9, P < 0.005). In protocol II, ibutilide significantly shifted the current doses associated with 50% successful defibrillation from 14.8 +/- 3.7 to 8.9 +/- 2.0 A (n = 6, P < 0.05). Eight of 15 animals given ibutilide exhibited one or more episodes of spontaneous defibrillation. Ibutilide significantly (P < 0.05) increased ventricular effective refractory period (+23.4%), and both preventricular fibrillation and postdefibrillation monophasic action potential duration at 90% repolarization (+21.7% and +23.3%, n = 9, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Differential effects of putative protein kinase C inhibitors on contraction of rat aortic smooth muscle
Authors: Shimamoto Y. , Shimamoto H. , Kwan C. Y. , Daniel E. E.
Published: December 2017

We investigated effects of three kinds of putative protein kinase C (PKC) inhibitors, calphostin C, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), and stauro-sporine, on aortic muscle contractions induced by KCl, phenylephrine, 12-O-tetradecanoylphorbol-13-acetate (TPA), and phorbol 12, 13-dibutyrate (PDBu). Calphostin C noncompetitively inhibited TPA-induced contractions in a concentration-dependent manner. At 10(-6) M, calphostin C completely abolished responses to TPA and also effectively inhibited PDBu-induced contractions. Such a concentration of calphostin C had no effect on KCl-induced contractions but decreased the maximal tension of phenylephrine-induced response curve by 35.3 +/- 6.6% H-7 (10(-5) M had little effect on TPA-induced contraction but significantly inhibited contractile responses to phenylephrine and KCl. Staurosporine (10(-8) M, 3 x 10(-8) M) inhibited contractile responses to KCl, phenylephrine, and TPA. We suggest that staurosporine and H-7, which are known to act on the catalytic domain of PKC carrying high degree of sequence homology with other protein kinases, are relatively nonselective for PKC. On the other hand, calphostin C acting on the regulatory domain of PKC, which is distinct from other protein kinases, may serve as a relatively more selective PKC inhibitor.
Enhanced single-channel K+ current in arterial membranes from genetically hypertensive rats
Authors: England S. K. , Wooldridge T. A. , Stekiel W. J. , Rusch N. J.
Published: December 2017

Arterial smooth muscle from hypertensive rats shows an increased membrane permeability to K+ that depends on Ca2+ influx. To define the mechanism of this membrane alteration, we tested the hypothesis that Ca(2+)-dependent K+ current (IK(Ca)) is increased in arterial muscle membranes from genetically hypertensive rats. Single-channel K+ currents measured in cell-attached and inside-out aortic membrane patches from spontaneously hypertensive rats (SHR) were compared with those from normotensive Wistar-Kyoto rats (WKY). Inside-out patches from both rat strains showed a predominant 225 pS, Ca(2+)- and voltage-dependent K+ channel in symmetrical 145 mM KCl solutions, which was blocked by tetraethylammonium [concentration for half-maximal block (IC50) < or = 0.3 mM]. In cell-attached patches of aortic muscle cells bathed in physiological salt solution, this channel [IK(Ca) channel] showed a fivefold higher open-state probability (NPo) in SHR as compared with WKY. This increased NPo of SHR IK(Ca) channels in membranes of intact aortic muscle cells was not correlated with an altered membrane potential in current-clamped SHR myocytes or with changes in cytosolic free Ca2+ concentration in fura-2-loaded aortic muscle cells. However, inside-out aortic membrane patches from SHR showed more detected IK(Ca) channels per patch, a higher IK(Ca) channel NPo, and a greater total patch current than their WKY counterparts. Further analysis revealed a greater Ca2+ sensitivity of SHR than WKY IK(Ca) channels. These results suggest that IK(Ca) channel function is altered in isolated membrane patches of arterial muscle from genetically hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Muscle metaboreflex control of vasopressin and renin release
Authors: O'Leary D. S. , Rossi N. F. , Churchill P. C.
Published: December 2017

Dynamic exercise causes an increase in circulating blood levels of renin and vasopressin (AVP), yet the afferent mechanisms responsible for release of renin and AVP during exercise are poorly understood. Partial ischemia of active skeletal muscle induces a reflex pressor response, termed the muscle metaboreflex. Does muscle metaboreflex activation induce release of renin and AVP? The muscle metaboreflex was activated in conscious, chronically instrumented dogs during mild treadmill exercise (3.2 km/h, 0% grade) via graded partial occlusion of terminal aortic blood flow. Decreasing hindlimb perfusion to 40% of the control level during exercise significantly increased systemic arterial pressure (SAP) and heart rate (HR) from 103.4 +/- 2.4 to 166.7 +/- 4.2 mmHg and from 111.6 +/- 9.9 to 141.9 +/- 3.9 beats/min, respectively. However, only small nonsignificant changes in arterial plasma renin activity and AVP concentration occurred [control: renin = 0.46 +/- 0.8 ng angiotensin I (ANG I).ml-1.h-1, AVP = 0.53 +/- 0.17 pg/ml; metaboreflex activation: renin = 0.77 +/- 0.33 ng ANG I.ml-1.h-1, AVP = 1.09 +/- 0.34 pg/ml]. The experiments were repeated after ganglionic blockade (hexamethonium 10 mg/ml and atropine 0.2 mg/ml iv) to attenuate the reflex increase in SAP. In this setting, metaboreflex activation caused SAP to increase from 91.6 +/- 4.3 to only 114.7 +/- 6.8 mmHg and the reflex tachycardia was abolished (153.7 +/- 5.8 to 159.3 +/- 6.1 beats/min, P > 0.05). With the reflex pressor response markedly attenuated, AVP increased from 2.53 +/- 0.81 to 34.38 +/- 6.59 pg/ml with muscle metaboreflex activation, whereas no significant changes in renin activity occurred.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine regulates coronary blood flow during increased work and decreased supply
Authors: Martin S. E. , Lenhard S. D. , Schmarkey L. S. , Offenbacher S. , Odle B. M.
Published: December 2017

Adenosine may mediate coronary vasodilation during work-related hyperemia and during ischemia. We tested whether adenosine blockade with 8-p-sulfophenyltheophylline (PSPT) prevented dobutamine-induced hyperemia or magnified the reductions in flow due to vasopressin. Control (n = 8) and test (n = 7) dogs received paired infusions of dobutamine (70 micrograms/min iv for 5 min). Test dogs received PSPT (10 mg/kg iv) between doses. In both groups, paired infusions elicited comparable increases in oxygen consumption. However, in test dogs, the hyperemia was reduced significantly. Thus adenosine mediates the hyperemia of dobutamine. Separately, control dogs (n = 9) received vasopressin (0.6 microgram ic over 5 min); test dogs (n = 7) received PSPT before vasopressin. Vasopressin maximally increased coronary resistance by 3 min; effects were gone by 10 min. With PSPT, coronary resistance was increased further and remained high beyond 10 min. Thus adenosine-mediated vasodilation moderates the severity and duration of ischemia. These results indicate the importance of adenosine in mediating coronary flow during increased demand and reduced supply.
Increased mechanical extraction of T-tubule/junctional SR from cardiomyopathic hamster heart
Authors: Tawada-Iwata Y. , Imagawa T. , Yoshida A. , Takahashi M. , Nakamura H. , Shigekawa M.
Published: December 2017

We determined the contents of L-type calcium channels (LCC) and other membrane proteins in ventricular homogenates and microsomes prepared from hearts of 30- to 70-day-old Syrian cardiomyopathic (Bio 14.6) and normal hamsters. Quantitative immunoblot assay revealed that myopathic microsomes, as compared with normal controls, were enriched about twofold with the alpha 1-subunit of LCC, the ryanodine receptor calsequestrin, and Na(+)-K(+)-adenosinetriphosphatase (ATPase), whereas the contents of these proteins in ventricular homogenates were not different. In contrast, Na(+)-H+ antiporter and sarcoplasmic reticulum (SR) Ca(2+)-ATPase showed no difference in their contents in both homogenates and microsomes. Radioligand binding assay further showed no significant difference in the number of binding sites for [3H]prazosin, [125I]iodocyanopindolol, and [3H]saxitoxin between myopathic and normal microsomes. These result suggest that whereas membrane densities of LCC and the other proteins examined are not increased in myopathic cardiomyocytes, T-tubule/junctional SR membranes are more easily extracted from them by mechanical disruption. This, together with 1.5-fold higher yield of microsomal fractions from myopathic heart muscle, shows that abnormality exists in the mechanical property of cell membrane in the myopathic heart.