bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated diaphragmatic blood flow during submaximal exercise in rats with chronic heart failure
Authors: Musch T. I.
Published: December 2017

The exercise blood flow response of muscles involved in respiration was determined in rats with a myocardial infarction (MI), which was produced by tying the left main coronary artery, and in rats that underwent sham operations (Sham). Arterial blood gases, acid-base parameters, and blood flow (ml/100 g of tissue) to the diaphragm, intercostals, and transverse abdominis muscles were measured during steady-state treadmill exercise (20% grade, 28 m/min). The responses of MI rats that were classified as having a small (MIS < 25%, n = 7), medium (25% < or = MIM < or = 35%, n = 8), and large (MIL > 35%, n = 7) infarct were compared with those of Sham (n = 12) rats using analysis of variance techniques. Results demonstrated that arterial PO2 and PCO2 were similar for all groups during exercise (PaO2 = 110-112 mmHg; PaCO2 = 28-29 mmHg) even though the MIM and MIL groups had developed a significant amount of pulmonary congestion, and the MIL group demonstrated indicators of severe left ventricular dysfunction. Blood flow to the diaphragm during exercise was significantly greater for the MIL group of rats, although blood flow to the intercostals and transverse abdominis muscles was similar across the different groups. Results from this study support the contention that MI rats (including rats with decompensated heart failure) will achieve the same effective alveolar ventilation during exercise as that found for Sham rats and in the process maintain arterial O2 saturation.(ABSTRACT TRUNCATED AT 250 WORDS)
Mathematical model of blood flow in a coronary capillary
Authors: Fibich G. , Lanir Y. , Liron N.
Published: December 2017

The coronary capillary flow is analyzed theoretically based on continuum mechanics. The capillary is a long, elastic, and permeable vessel loaded externally by tissue pressure, and it is subject to possible periodic length changes, together with adjacent myocytes. Capillary flow is driven by arteriolar-venular pressure difference. Ultrafiltration due to transmural hydrostatic and osmotic gradients is included, and consideration of mass conservation leads to a nonlinear flow equation. The results show that under physiological conditions ultrafiltration is of minor importance, and the analysis predicts regional differences in capillary flow. In regions with high tissue pressure (subendocardium), capillaries undergo significant periodic volume changes, giving rise to intramyocardial pumping. In those regions, capillary wall elasticity is of major importance. In regions with low tissue pressure (subepicardium), the possible periodic capillary length changes are predominant. The predicted flow patterns are in good qualitative agreement with measured epicardial phasic flow. In conclusion, the methodological advantage of a distributive analysis is demonstrated by its ability to elucidate and evaluate the role of flow determinants and their complex interactions.
Continuous pulmonary C-fiber stimulation produces sustained reflex cardiovascular depression
Authors: Schertel E. R. , Allen D. A.
Published: December 2017

We used an isolated perfused in situ left lung preparation to evaluate the hemodynamic response to specific pulmonary C-fiber stimulation with capsaicin in two groups of anesthetized dogs. In one group (n = 6), continuous administration of capsaicin at 5 micrograms.kg-1.min-1 into the isolated pulmonary circulation produced sustained (20 min) reflex decreases in mean arterial pressure, cardiac output, maximal left ventricular rate of pressure over time, and heart rate. These effects were abolished by vagotomy. In a second group (n = 5) of atropinized dogs, a mild hemorrhage was first performed in each dog during control conditions (capsaicin vehicle administration). The hemorrhage was performed by removing 10% of blood volume over 3 min and then replacing this blood 3 min later. After reinfusion and stabilization, the mild hemorrhage was repeated during continuous administration of capsaicin (6.0 +/- 1.0 microgram.kg-1.min-1) into the isolated pulmonary circulation. The decrease of mean arterial pressure in response to hemorrhage was significantly greater during capsaicin administration than during control conditions. Lung denervation prevented the effect of capsaicin administration on the response to hemorrhage. We concluded that continuous pulmonary C-fiber stimulation produces sustained cardiovascular depression and compromises the hemodynamic response to mild hemorrhage in dogs. This latter effect may represent a central alteration of baroreflex gain.
Role of L-arginine-derived nitric oxide in cholinergic dilation of gastric arterioles
Authors: Chen R. Y. , Ross G. , Chyu K. Y. , Guth P. H.
Published: December 2017

The role of L-arginine-derived nitric oxide (NO) in cholinergic vasodilation of resistance vessels was studied in the intact stomach of the rat, utilizing an in vivo microscopy technique. Two L-arginine analogues, NG-monomethyl-L-arginine (L-NMMA) and nitro-L-arginine methyl ester (L-NAME), were used to block NO synthesis. Cholinergic dilation of gastric submucosal arterioles was induced by topical application of various concentrations of acetylcholine (ACh) (10(-7)-10(-4) M). Intravenous but not topical administration of L-NMMA and L-NAME caused an increase in arterial pressure. Intravenous or topical L-NAME reduces resting arteriolar diameter. These findings support the contention that NO formation modulates basal vascular tone and suggest that NO release may play a significant role in the regulation of the gastric circulation. L-Arginine analogues attenuated the arteriolar dilating effect of ACh but not adenosine or nitroglycerin. Substantial arteriolar responses to ACh remained after systemic or topical treatment with either L-NMMA or L-NAME. These results indicate that the L-arginine-NO pathway accounts only in part for ACh-induced vasodilation in gastric resistance vessels in vivo.
Enhanced resistance artery sensitivity to agonists under isobaric compared with isometric conditions
Authors: Dunn W. R. , Wellman G. C. , Bevan J. A.
Published: December 2017

We have compared the responsiveness of rabbit mesenteric resistance arteries with agonists under isometric and isobaric conditions. When pressurized (60 mmHg), arteries spontaneously reduced their diameter by 18.1%. An equivalent isometric stress did not generate force in a “wire” myograph. Subsequently, much higher concentrations of norepinephrine (NE) and histamine were required to cause isometric contractions than were needed to reduce vascular diameter of pressurized vessels, whereas angiotensin II produced a maintained response only in pressurized arteries. Reducing transmural pressure to 20 mmHg abolished pressure-induced myogenic tone and decreased arterial sensitivity to NE. Under isometric conditions, partial depolarization with KCl increased sensitivity to NE and histamine to within the concentration range effective in pressurized vessels and also "revealed" responses to angiotensin II. The membrane potential of the vascular smooth muscle cells under partially depolarized conditions was similar to that found in vivo and in vessels studied isobarically. These observations demonstrate a fundamental interaction between pressure-induced myogenic tone and the sensitivity of resistance arteries to vasoactive stimuli. This influence was mimicked in isometrically mounted vessels by partial depolarization, indicating a possible pivotal role for membrane potential in determining the reactivity of the resistance vasculature.
Influence of neuropeptide Y on regional vascular capacitance in dogs
Authors: Deschamps A. , Fournier A. , Magder S.
Published: December 2017

To determine the effect of neuropeptide Y (NPY) on regional vascular capacitances, we measured the regional blood volume (Vb), unstressed volume (V0), blood flow distribution, venous compliance (Cv), venous resistance (Rv), and the time constant of venous drainage (tau v) in the splanchnic and extrasplanchnic circulation of 13 dogs anesthetized with chloralose. Cardiac output was kept constant with circulatory bypass. The extrasplanchnic region was further divided into superior vena caval (SVC) and inferior vena caval (IVC) regions. Vb was measured in the splanchnic and SVC regions using indicator dilution curves and the mean transit times. Changes in venous outflow pressures were used to change regional volumes, and a stop-flow procedure was used to obtain the regional venous filling pressures. This allowed construction of pressure-volume (P-V) curves and the calculation of Cv, Rv, and tau v. Hexamethonium chloride was infused throughout the experiment to prevent autonomic reflexes. Sham injections had no effects on four dogs. In nine dogs, NPY (bolus of 7.4 x 10(-8) or 14.8 x 10(-8) mol and 0.37 mol/min infusion) increased arterial blood pressure from 98.4 +/- 4.2 to 121.3 +/- 6.9 mmHg (P < 0.001), decreased splanchnic Vb from 31.6 +/- 2.1 to 24.9 +/- 1.8 ml/kg (P < 0.01), and decreased splanchnic V0 from 21.8 +/- 2.6 to 12.1 +/- 2.2 ml/kg (P < 0.001). SVC volumes were not affected by NPY. Extrasplanchnic Cv increased with NPY, but splanchnic Cv did not change. Thus exogenous NPY infusion decreases splanchnic capacitance, which could potentially increase venous return and cardiac output.
Platelets do not modulate leukocyte-mediated coronary microvascular damage during early reperfusion
Authors: Reynolds J. M. , McDonagh P. F.
Published: December 2017

Several studies indicate that leukocytes and platelets exacerbate the compromise of myocardial function that occurs after ischemia-reperfusion (I/R). However, it is unclear whether both leukocytes and platelets must be present to mediate coronary microvascular damage early during reperfusion after ischemia. To examine the effects of leukocytes and platelets on microvascular damage after I/R, we measured transcoronary albumin extravasation (O/I), perfused coronary capillary density (Caps), and transcoronary albumin extravasation per perfused capillary [(O/I)/Caps] in isolated rat hearts perfused with a Krebs-albumin-red blood cell solution [K(2)RBC], whole rat blood diluted with Krebs buffer (DWB), leukocyte-free, platelet-rich DWB (LFB), or leukocyte-rich, platelet-free DWB (LRB) before and after a 30-min period of global, no-flow ischemia. We found that in isolated hearts perfused with K(2)RBC before ischemia, O/I values were significantly increased (+68%, P < 0.01) and Caps values were significantly decreased (-25%, P < 0.05) after 25 min of reperfusion. A similar pattern of O/I values (+72%, P < 0.01) and Caps values (-40%, P < 0.05) was observed in hearts perfused with LFB. These effects were exacerbated in hearts perfused with DWB or LRB. O/I values were increased 90% (P < 0.01), and Caps values were decreased 62% (P < 0.01) in the DWB-perfused hearts. Similar increases in O/I values (+82%, P < 0.01) and decreases in Caps values (-65%, P < 0.01) were measured in the LRB-perfused hearts. Additionally, (O/I)/Caps values were significantly increased in the hearts perfused with DWB (+93%, P < 0.01) and LRB (+84%, P < 0.01) compared with the hearts perfused with K(2)RBC or LFB. These results suggest that interactions between leukocytes and platelets are not requisite for the development of coronary microvascular damage early during reperfusion after ischemia.
Does a general alteration in nitric oxide synthesis system occur in spontaneously hypertensive rats?
Authors: Xiao J. , Pang P. K.
Published: December 2017

Immune dysfunction has been reported in spontaneously hypertensive rats (SHR). The current study investigated interactions between macrophages or vascular smooth muscle cells (VSMC) and lymphocytes in SHR and examined the role of nitric oxide (NO) in this interaction. SHR macrophages significantly inhibited the proliferation of lymphocytes from SHR and the genetic control, Wistar-Kyoto rats (WKY). This inhibition was reversed by a NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA). SHR VSMC also significantly inhibited the proliferation responses of lymphocytes from SHR and WKY. The inhibition was cell density dependent. In addition, L-NMMA fully reversed the inhibition by SHR VSMC. Upon stimulation, the macrophages and VSMC from SHR produced a significantly higher amount of NO compared with those from WKY. These results suggest that the overproduction of NO was involved in the interaction between macrophages or VSMC and lymphocytes in SHR. Increased NO synthase activity in macrophages and VSMC may indicate a general activation of the NO synthesis system in SHR. The alteration of the NO synthesis system may be an important factor contributing to the lymphocyte depression in hypertension.
Characterization of E-selectin expression in vivo with use of a radiolabeled monoclonal antibody
Authors: Keelan E. T. M. , Licence S. T. , Peters A. M. , Binns R. M. , Haskard D. O.
Published: December 2017

We have studied endothelial luminal surface expression of E-selectin in vivo in the pig. Intravenous interleukin-1 (IL-1, 5-μg/kg bolus ± 50-ng·kg-1·min-1 infusion for 2 h) induced E-selectin expression in many organs, as shown by immunostaining and selective clearance of intravenous 111In- or 99mTc-labeled anti-E-selectin monoclonal antibody MAb 1.2B6) compared with radiolabeled immunoglobulin G1 control. Specific clearance of MAb 1.2B6 commenced 30­45 min after intravenous IL-1. Skin sites injected with IL-1, tumor necrosis factor, phytohemagglutinin, or phorbol myristate acetate at various times (45 min­24 h) before exsanguination showed specific accumulation of MAb 1.2B6 when 99mTc-MAb 1.2B6 and 111In-control immunoglobulin G1 were injected intravenously 10 min before exsanguination. This was maximal in 2-h IL-1 and tumor necrosis factor lesions and after 9 h in phytohemagglutinin and phorbol myristate acetate lesions. This novel approach has allowed us to quantify changes in vascular luminal expression of E-selectin in models of inflammation involving systemic and localized endothelial cell activation and has considerable potential for analyzing these changes in relation to leukocyte traffic and other manifestations of inflammatory responses in vivo.

endothelium; inflammation; radioimmunodetection

Submitted on February 25, 1993

Accepted on June 23, 1993
Mathematical model of acetylcholine kinetics in neuroeffector junctions
Authors: Dexter F. , Rudy Y. , Saidel G. M.
Published: December 2017

Acetylcholine (ACh) kinetics in neuroeffector junctions (NEJ) of the sinus node plays a key role in vagal control of heart rate. Prior studies have shown that the concentration of ACh ([ACh]) in NEJ appears to follow first-order linear kinetics. To find out the reason why, we examine mathematically diffusion, degradation, and receptor binding of ACh in NEJ. We identify seven conditions that potentially influence ACh kinetics. Because these conditions are satisfied for NEJ in the sinus node, 1) the nonlinearity of ACh binding to muscarinic receptors has little effect on [ACh]; 2) [ACh] does not depend on the distribution of acetylcholinesterase between the interstitial space and the pacemaker cells; 3) the interval from trough to subsequent peak [ACh] at the pacemaker cells is negligible; 4) the mean [ACh] at the pacemaker cells is proportional to the frequency of vagal activity multiplied by the amount of ACh released per vagal stimulus and divided by the rate coefficient of ACh degradation; and 5) [ACh] at pacemaker cells nearly follows first-order linear kinetics but does not at other sites in the NEJ. We conclude that earlier studies showed that [ACh] follows first-order linear kinetics, because they predicted [ACh] only at pacemaker cells. ACh kinetics at other sites in the NEJ, such as at nerve endings, is different.
Effect of low perfusate [Ca2+] and diltiazem on cardiac sarcoplasmic reticulum in myocardial stunning
Authors: Abdelmeguid A. E. , Feher J. J.
Published: December 2017

The ability of low perfusate Ca2+ concentration ([Ca2+]) or diltiazem to improve sarcoplasmic reticulum (SR) function and mechanical performance after ischemia-reperfusion was investigated using an isovolumic Langendorff preparation. SR function was evaluated by the oxalate-supported Ca2+ uptake rates of ventricular homogenates. Influx of Ca2+ was estimated from the rate of Ca2+ uptake in the presence of high concentrations of ryanodine (500 microM) to close the Ca2+ efflux channel. Ca2+ efflux under the assay conditions was estimated as the difference in Ca2+ uptake rate in the presence and absence of ryanodine. Ten and fifteen min of global, normothermic ischemia decreased the Ca2+ uptake rate in the presence of ryanodine, suggesting that Ca2+ influx was decreased. The effect of ischemia on Ca2+ influx was not altered by preperfusion with low [Ca2+] (0.2 mM) or with 1.0 microM diltiazem. Ischemia decreased SR Ca2+ uptake rate twice as much in the absence of ryanodine as in its presence, indicating an increased efflux of Ca2+. This increased efflux was reduced by preperfusion with either low [Ca2+] or diltiazem. The decreased Ca2+ influx was completely reversed by 15 min of reperfusion, whereas the increased Ca2+ efflux was only partially reversed. These results indicate that ischemia exerts independent effects on the SR Ca2+ influx and efflux pathways. The results also suggest that one site of cardiac protection by low [Ca2+] or diltiazem is the ryanodine-sensitive Ca2+ efflux pathway of the SR, rather than the Ca2+ influx pathway.
Conversion of big ET-1 in the rat lung: role of phosphoramidon-sensitive endothelin-1-converting enzyme
Authors: Hisaki K. , Matsumura Y. , Maekawa H. , Fujita K. , Takaoka M. , Morimoto S.
Published: December 2017

We examined conversion of Big endothelin-1 (ET-1) to mature ET-1 and pressor action during perfusion of the isolated perfused rat lung with Big ET-1. Big ET-1 caused a concentration-related increase in perfusion pressure and the pressor molar potency of the peptide was fivefold less than that of ET-1. Pressor responses to Big ET-1 were accompanied by an increase in immunoreactive-ET (IR-ET) levels in the perfusate and in the lung tissues. Pretreatment with phosphoramidon (10(-4) M), a metalloproteinase inhibitor, markedly suppressed the pressor action and increment in IR-ET in the tissues. Unexpectedly, the amount of IR-ET in the perfusate during perfusion of Big ET-1 was not influenced by phosphoramidon treatment. On the other hand, chymostatin, an inhibitor of chymotrypsin-like enzymes, effectively suppressed IR-ET levels in the perfusate; however, this enzyme inhibitor was without effect on the pressor action of Big ET-1 or on the increase in IR-ET levels in lung tissues. We tentatively conclude that the phosphoramidon-sensitive conversion of Big ET-T to ET-1 is linked to the pressor action of Big ET-1 in the isolated perfused rat lung. In addition, it seems likely that chymostatin-sensitive conversion of Big ET-1 to ET-1 does not play a major role in the conversion of the precursor to the mature form. We propose that IR-ET present in the tissues rather than that in the perfusate is a better indicator of the functional conversion of Big ET-1 in the rat lung.
Effects of beta-blockade on neurohumoral responses and neurochemical markers in pacing-induced heart failure
Authors: Levett J. M. , Marinelli C. C. , Lund D. D. , Pardini B. J. , Nader S. , Scott B. D. , Augelli N. V. , Kerber R. E. , Schmid P. G.
Published: December 2017

We investigated neurohumoral profiles and transmitter and neuroenzyme markers of cardiac autonomic innervation in control (unpaced) dogs and three groups of dogs with pacing-induced heart failure (paced, paced + beta-adrenergic blockade, and paced + cardiac denervation). Left ventricular ejection fraction decreased significantly and to a comparable extent in all paced groups. Pacing increased plasma norepinephrine (NE); increases in NE were not attenuated but instead tended to be exaggerated by treatment with propranolol or cardiac denervation. Atrial hypertrophy occurred in all paced groups compared with the control group. However, atrial and right ventricular hypertrophy were not as pronounced in the paced plus cardiac denervation group as in the paced and paced plus propranolol groups. Pacing also depleted neuropeptide Y and NE from all heart chambers; propranolol treatment did not modify these local tissue changes. Pacing caused selective depletion of neuroenzymes predominantly in the left ventricle; again, propranolol did little to modify these changes. In this study of paced animals with experimentally maintained cardiac dysfunction, failure to modify noradrenergic responses with intrapericardial cardiac denervation suggests that noncardiac sources contribute predominantly to high plasma NE. Failure to modify neurohumoral, neuropeptide, and neuroenzyme responses with beta-antagonist suggests this treatment has little practical direct influence on sympathetic vasomotor activity or neuronal function in heart failure.
Potassium channels are not involved in vasopressin-induced vasodilation in the rat lung
Authors: Eichinger M. R. , Russ R. D. , Walker B. R.
Published: December 2017

We have previously observed that arginine vasopressin (AVP)-induced pulmonary vasodilation is attenuated by nitric oxide (NO) synthesis inhibition; however, blockade of the response is incomplete even at very high doses of the inhibitor. Thus it was hypothesized that the remaining vasodilation might be due to release of an endothelium-derived hyperpolarizing factor acting to open vascular smooth muscle K+ channels. Lungs were isolated from male Sprague-Dawley rats and perfused at constant flow with physiological saline solution containing 4% albumin. After equilibration, lungs were treated with either glibenclamide (50 microM), Ba2+ (100 microM), tetraethylammonium (10 mM), or the respective vehicle and were then constricted with the thromboxane mimetic U-46619. Upon development of a stable degree of vasoconstriction, AVP (2.5 x 10(-9) M) was administered and its vasodilator action noted. AVP caused an approximately 60% reversal of U-46619 vasoconstriction in control lungs, and this response was not affected by any of the K+ channel blockers. In contrast, administration of the NO synthesis inhibitor N omega-nitro-L-arginine (L-NNA; 300 microM) significantly attenuated AVP-induced dilation to approximately 25%. The addition of K+ channel blockers did not further diminish the vasodilatory response in L-NNA-treated lungs. In conclusion, these results suggest that ATP- and Ca(2+)-sensitive K+ channels are not involved in the pulmonary vasodilatory response to AVP.
Regulation of [Na+]i and [Ca2+]i in guinea pig myocytes: dual loading of fluorescent indicators SBFI and fluo 3
Authors: Satoh H. , Hayashi H. , Noda N. , Terada H. , Kobayashi A. , Hirano M. , Yamashita Y. , Yamazaki N.
Published: December 2017

To investigate the mechanisms regulating intracellular Na+ and Ca2+ concentrations ([Na+]i and [Ca2+]i, respectively), we monitored both ion concentrations simultaneously using fluorescent probes, Na(+)-binding benzofuran isophthalate (SBFI) and fluo 3, in unstimulated guinea pig ventricular myocytes. After the addition of 500 microM strophanthidin, [Na+]i increased gradually from 6.6 +/- 0.6 to 20.1 +/- 1.6 mM (mean +/- SE) at 50 min. [Ca2+]i, expressed as the percentage change of corrected fluo 3 fluorescence, was kept at the low level during the first 20 min and then began to increase to 447 +/- 81% of the control at 50 min. The addition of 1 microM hexamethylene amiloride prevented the increases in both [Na+]i and [Ca2+]i. The perfusion of Ca(2+)-free solution or 5 mM Ni(2+)-containing solution suppressed the increase in [Ca2+]i. In cells that exhibited spontaneous contractile activities, [Ca2+]i increased further than that in quiescent cells, whereas [Na+]i levels were similar. In the presence of 1 microM ryanodine, both the spontaneous contractile activities and the further increase in [Ca2+]i were eliminated. These findings indicated that 1) the pathway of Na+ entry was mainly through Na(+)-H+ exchange and that the elevated [Na+]i induced Ca2+ entry mediated by the reverse mode of Na(+)-Ca2+ exchange, and 2) the entered Ca2+ triggered the ryanodine-sensitive Ca2+ release from the sarcoplasmic reticulum, causing the dissociation in the relationship between [Na+]i and [Ca2+]i.
Hypercapnic acidosis increases oxygen cost of contractility in the dog left ventricle
Authors: Hata K. , Goto Y. , Kawaguchi O. , Takasago T. , Saeki A. , Nishioka T. , Suga H.
Published: December 2017

The effect of acidosis on left ventricular (LV) mechanoenergetics was assessed in seven excised, cross-circulated dog hearts with the use of the frameworks of the contractility index (Emax) and the relationship between myocardial oxygen consumption (VO2) and pressure-volume area (PVA; a measure of the LV total mechanical energy). Acidosis was stably maintained without hypoxia by appropriately mixing CO2 and air in a membrane oxygenator in the coronary arterial perfusion circuit. Acidosis [pH: 6.98 +/- 0.09 (SD), PCO2: 91 +/- 25 mmHg in the coronary arterial blood] decreased Emax by 45 +/- 12% (P < 0.01) and PVA by 47 +/- 12% (P < 0.01) at a fixed LV volume. When the preacidosis Emax level was restored by Ca2+ infusion during acidosis, unloaded VO2 (the VO2 intercept of the VO2-PVA relation) exceeded the control value by 19 +/- 17% (P < 0.05), indicating that acidosis required higher VO2 for nonmechanical activities at a matched Emax. Moreover, the oxygen cost of enhanced contractility (the incremental ratio of unloaded VO2 to Emax) was 1.53 +/- 0.40 times higher (P < 0.01) during acidosis than preacidosis. We conclude that acidosis results in LV contractile dysfunction accompanied by an increased oxygen cost of contractility. This increased energy cost of the excitation-contraction coupling can be accounted for by a decreased Ca2+ sensitivity of the contractile proteins during acidosis.
Diminished effect of cAMP on Ca2+ accumulation in skinned fibers of hypertrophied rat heart
Authors: Tomita F. , Bassett A. L. , Myerburg R. J. , Kimura S.
Published: December 2017

Sarcoplasmic reticulum (SR) Ca2+ uptake is reduced in the hypertrophied ventricle. To determine whether events initiated by beta-adrenergic stimulation are involved, we compared the effects of adenosine 3',5'-cyclic monophosphate (cAMP) on SR Ca2+ uptake between normal and pressure-overloaded hypertrophied hearts using saponin-skinned rat left ventricular muscles. Left ventricular pressure overload was induced by partial ligation of the abdominal aorta for 4–6 wk before study. Age-matched normal rats served as controls. Pressure overload increased the left ventricular weight-to-body weight ratio 60.8%. The SR was loaded by exposing the muscles to 10(-6) M Ca2+ solution; SR Ca2+ release was induced by 5 or 25 mM caffeine, and the amount of Ca2+ released from the SR was estimated by the area under the caffeine-induced transient contraction. Concomitant exposure to 10(-4) M cAMP did not influence caffeine-induced Ca2+ release in either normal or hypertrophied fibers. When 10(-4) M cAMP was applied during the Ca(2+)-loading periods, the amount of Ca2+ accumulated by the SR increased in both normal and hypertrophied fibers. However, the extent of increase was significantly smaller in hypertrophied fibers than in normal fibers [10.9 +/- 1.7 and 27.4 +/- 5.3% in 1 min of Ca2+ loading (P < 0.05), 12.2 +/- 3.2 and 24.7 +/- 3.8% in 4 min of Ca2+ loading (P < 0.05), respectively]. cAMP (10(-4) M) shifted the force-pCa relationship to the right similarly in normal and hypertrophied muscles, and there was no difference in the force-pCa relationship between the two groups either with or without cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of inhibition of nitric oxide synthesis on vasopressin secretion in conscious rabbits
Authors: Goyer M. , Bui H. , Chou L. , Evans J. , Keil L. C. , Reid I. A.
Published: December 2017

NO synthase is present in magnocellular neurons of supraoptic and paraventricular nuclei as well as in the posterior pituitary gland and may participate in control of vasopressin secretion. To test this possibility, experiments were performed in conscious, chronically prepared rabbits to determine the effect of NO synthesis inhibition with NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) on basal vasopressin secretion and vasopressin responses to increased plasma osmolality (hypertonic saline infusion; P osm) and decreased blood pressure (nitroprusside infusion). L-NAME infusion (0.5 mg.kg-1 x min-1 i.v.) increased mean arterial pressure [MAP; 82.6 +/- 3.4 to 93.0 +/- 3.0 mmHg (P < 0.02)], decreased heart rate [HR; 242 +/- 12 to 209 +/- 9 beats/min (P < 0.02)], decreased plasma renin activity [PRA; 3.1 +/- 0.6 to 2.0 +/- 0.6 ng.ml-.2 h-1 (P < 0.001)], and increased plasma vasopressin concentration [P AVP; 2.2 +/- 0.3 to 4.5 +/- 1.0 pg/ml (P < 0.05)]. P(osm) did not change. Hypertonic saline infusion did not change MAP or HR but decreased PRA [4.3 +/- 0.8 to 0.9 +/- 0.2 ng.ml-1 x 2 h-1 (P < 0.01)], increased P(osm) [284 +/- 1 to 305 +/- 2 mosmol/kg H2O (P < 0.001)], and increased PAVP [2.8 +/- 0.3 to 12.7 +/- 2.7 pg/ml (P < 0.01)].(ABSTRACT TRUNCATED AT 250 WORDS)
Preload does not influence nonmechanical O2 consumption in isolated rabbit heart
Authors: Higashiyama A. , Watkins M. W. , Chen Z. , LeWinter M. M.
Published: December 2017

Myocardial energy consumption for nonmechanical activity (excitation-contraction coupling) has been shown to be length dependent in isolated muscle studies but no more than minimally affected by preload in the whole heart. However, unloaded O2 consumption (VO2, which is used to estimate nonmechanical VO2 in whole heart) may not be accurate for quantifying nonmechanical energy consumption, because it contains VO2 for residual cross-bridge cycling. To more accurately determine the influence of left ventricular (LV) diastolic volume on nonmechanical VO2 in whole heart, we employed a new method for quantifying nonmechanical VO2, using the drug 2,3-butanedione monoxime (BDM). We measured VO2 and force-time integral during infusion of BDM (< or = 5 mM) at high (VH) and low LV volumes (VL) in 16 excised isovolumically contracting red blood cell-perfused rabbit ventricles. LV end-diastolic pressure was 9.7 +/- 4.6 and 3.8 +/- 2.8 (SD) mmHg at VH and VL, respectively. Nonmechanical VO2, estimated as the VO2-axis intercept of the linear VO2-force-time integral relation obtained during BDM infusion, did not differ significantly between VH and VL (0.0137 +/- 0.0083 and 0.0132 +/- 0.0090 ml O2.beat-1 x 100 gLV-1, P = 0.702). A multiple linear regression analysis for the pooled data confirmed this finding (P = 0.361). We conclude that, in the rabbit heart, LV diastolic volume does not importantly affect nonmechanical energy consumption over a physiological range of LV end-diastolic pressure. This indicates that length-dependent activation does not have an energetic cost in whole rabbit heart and suggests that its predominant mechanism is increased Ca2+ affinity for the contractile proteins.
Influences of neural mechanisms on heart period and arterial pressure variabilities in quadriplegic patients
Authors: Guzzetti S. , Cogliati C. , Broggi C. , Carozzi C. , Caldiroli D. , Lombardi F. , Malliani A.
Published: December 2017

The heart period (R-R) variability power spectrum presents two components, at low (LF; approximately 0.10 Hz) and high (approximately 0.25 Hz) frequencies, whose reciprocal powers appear to furnish an index of sympathovagal interaction modulating heart rate. In addition, the LF component of the systolic arterial pressure variability spectrum furnishes a marker of sympathetic modulation of vasomotor activity. The contribution of spinal and supraspinal neural circuits to the genesis of these rhythmic oscillatory components remains largely unsettled. Therefore we performed spectral analysis of R-R and systolic arterial pressure variabilities in 15 chronic neurologically complete quadriplegic patients (QP) and in 15 control subjects during resting conditions, controlled respiration, and head-up tilt. At rest, in seven QP the LF component was undetectable in both cardiovascular variability spectra; in two QP this component was present only in R-R variability spectrum, whereas the remaining six showed a significantly reduced LF in both signals. In QP, the LF component, when present, underwent paradoxical changes with respect to controls, decreasing during tilt and increasing during controlled respiration. In five QP in whom the recording session was repeated after 6 mo, a significant increase in LF was observed in both variability spectra. These data confirm the finding that a disconnection of sympathetic outflow from supraspinal centers can cause the disappearance of the LF spectral component. However, LF presence in some QP supports the hypothesis of a spinal rhythmicity likely to be modulated by the afferent sympathetic activity.
Inhibitory effect of interleukin-6 on vascular smooth muscle contraction
Authors: Ohkawa F. , Ikeda U. , Kawasaki K. , Kusano E. , Igarashi M. , Shimada K.
Published: December 2017

Our objective was to investigate the direct effect of interleukin-6 (IL-6) on the vascular smooth muscle contraction. We measured the contraction of endothelium-denuded aortic rings isolated from Sprague-Dawley rats. We also investigated the involvement of vasodilator prostaglandin and guanosine 3',5'-cyclic monophosphate (cGMP) productions in the effect of IL-6 using cultured rat vascular smooth muscle cells (VSMC). Exposing the aortic rings to recombinant murine IL-6 (50 U/ml) for 180 min significantly suppressed the phenylephrine (10(-9)-10(-5) M)-induced contraction. This inhibitory effect of IL-6 on the contraction tended to exhibit a dose-dependent relationship (0.5-50 U/ml). The effect of IL-6 was totally eliminated in the presence of indomethacin (10(-5) M). The release of immunoreactive 6-ketoprostaglandin F1 alpha from cultured rat VSMC was significantly increased by exposure to IL-6. Intracellular cGMP concentration in VSMC was not affected by IL-6. In conclusion, IL-6 is a potent inhibitor of the alpha-adrenergic-stimulated contraction of vascular smooth muscle. Its action is endothelium independent and mediated by the increased synthesis of prostacyclin in VSMC.
Regulation of G proteins by adenosine receptor agonist in coronary artery
Authors: Hussain T. , Mustafa S. J.
Published: December 2017

We have previously reported that prolonged exposure of coronary artery to 2-chloroadenosine (CAD) desensitizes the adenosine receptor without altering the beta-receptor-mediated response (Am. J. Physiol. 264 (Heart Circ. Physiol. 33): H441-H447, 1993). In the present study, alpha-subunits of guanine nucleotide binding proteins, stimulatory (Gs) and inhibitory (Gi), were measured using bacterial toxin-catalyzed ADP ribosylation along with a functional response to Gi protein (through muscarinic receptor activation) in the arteries treated with CAD. Isolated coronary arteries were incubated with and without CAD in culture media. CAD treatment (10(-4) M) resulted in a time-dependent (1, 3, and 7 days) attenuation in the cholera- and pertussis toxin-catalyzed ADP ribosylation of 45- and 41-kDa membrane proteins, respectively. Similarly, the 3-day treatment of the arteries with CAD (10(-8)-10(-4) M) produced a concentration-dependent decrease in cholera toxin-catalyzed ADP ribosylation of 45-kDa protein. Unlike cholera toxin, the alterations in ADP ribosylation of 41-kDa protein catalyzed by pertussis toxin was biphasic, an increase at lower concentration of CAD (10(-8)-10(-6) M) followed by a decrease at higher concentration of CAD (10(-5)-10(-4) M). The contraction-response curve to methacholine, a muscarinic receptor agonist, was significantly shifted to the left in the vascular rings treated with a low concentration of CAD (10(-6) M) while without an effect at high concentration (10(-4) M) of CAD. The data suggest that CAD exposure regulates the alpha-subunits of both Gs and Gi in coronary artery.(ABSTRACT TRUNCATED AT 250 WORDS)
Repeated endothelial removal augments intimal thickening and attenuates EDRF release
Authors: Niimi Y. , Azuma H. , Hirakawa K.
Published: December 2017

To evaluate the significance of repeated denudation injury in progression of atherosclerosis, we performed a single and then a second balloon denudation on the rabbit carotid arteries. Morphological examinations and organ chamber experiments were performed, and the results were compared. On morphological examinations, reendothelialization was almost completed in 2 wk after redenudation, whereas it required 6 wk after a single denudation. Intimal thickening progressed after redenudation. Organ chamber experiments showed that contractile responses and endothelium-independent relaxation remained unchanged after redenudation. Endothelium-dependent relaxations to acetylcholine, ADP, and substance P decreased progressively by repeating denudation. These relaxation responses were inhibited by NG-nitro-L-arginine, hemoglobin, and methylene blue and were considered to be associated with the production and/or release of endothelium-derived relaxing factor-nitric oxide (EDRF-NO). The diffusion barrier mechanism for the decreased endothelium-dependent relaxations was ruled out using sandwich experiments. In conclusion, repeated endothelial denudation caused progression of intimal thickening and acceleration of endothelial regeneration, and repeated endothelial regeneration resulted in progressively less production and/or release of EDRF-NO.
Acute reductions in PO2 depolarize pulmonary artery endothelial cells and decrease [Ca2+]i
Authors: Stevens T. , Cornfield D. N. , McMurtry I. F. , Rodman D. M.
Published: December 2017

Whereas pulmonary artery endothelial cells (PAECs) are sensitive to oxygen, neither the effect of an acute reduction in PO2 on PAEC membrane potential nor its effect on intracellular free Ca2+ ([Ca2+]i) is known. We hypothesized that in confluent primary cultures of PAECs, an acute decrease in PO2 would depolarize the cell membrane, inhibit Ca2+ influx, and reduce [Ca2+]i. To test this hypothesis, the membrane-sensitive fluorophore bis (1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC4, 1 microM) and [Ca2+]i-sensitive probe fura 2 (3 microM) were used. A decrease in PO2 from 125 to 35 mmHg caused membrane depolarization and a 60 +/- 8% (data are means +/- SE) reduction in Ca2+ influx, estimated by manganese quenching of fura 2 fluorescence. While basal [Ca2+]i was 79 +/- 5 nM in normoxic cells, it decreased to 31 +/- 2 nM after 15 min of hypoxia. Decreasing the electrochemical gradient for Ca2+ entry with either low extracellular Ca2+, the K+ channel blockers tetraethylammonium or charybdotoxin, or blockade of Ca2+ entry with lanthanum decreased [Ca2+]i by 54-71% of that observed during an acute reduction in PO2. These results demonstrate that an acute reduction in PO2 1) depolarizes PAECs, 2) reduces Ca2+ influx, and 3) decreases [Ca2+]i, and that a similar reduction in [Ca2+]i was observed with interventions designed to reduce the electrochemical driving force for Ca2+ entry.
Bidirectional electrical communication between smooth muscle and endothelial cells in the pig coronary artery
Authors: Beny J. L. , Pacicca C.
Published: December 2017

Using strips of the left descending branch of the pig coronary artery in vitro, we show that smooth muscle cells are hyperpolarized by isoproterenol, a beta-agonist, independently of the presence or absence of intact endothelium. This hyperpolarization is transmitted to the lining endothelial cells in intact coronary strips. On the contrary, the cultured endothelial cells, without contact with smooth muscles, are not hyperpolarized by the beta-agonist. This shows that, in addition to the hyperpolarizations that flow from the endothelium to the media in response to kinins, electrical signals are also transmitted in the opposite direction, from the smooth muscles to the lining endothelial cells. In an attempt to test whether electrical coupling through gap junctions is implicated in the transmission of hyperpolarizations between the endothelial and the smooth muscle cells, we used halothane, a gap junction uncoupler. We observed that halothane does not inhibit the transmission of kinin hyperpolarizations from the endothelium to the smooth muscles, whereas it inhibits the transmission of isoproterenol hyperpolarization in the reverse direction.
Microcirculatory structure-function relationships in skeletal muscle of diabetic rats
Authors: Sexton W. L. , Poole D. C. , Mathieu-Costello O.
Published: December 2017

The effects of streptozotocin-induced diabetes on microcirculatory structure-function relationships in skeletal muscle were studied in control (C) and diabetic (D; 65 mg/kg streptozotocin ip) rats 6-8 wk after injection. Capillary exchange capacity was determined from measurements of capillary filtration coefficient (CFC) and permeability-surface area product (PS) for 51Cr-labeled EDTA in maximally vasodilated (papaverine), isolated hindquarters of C (n = 9) and D (n = 12) rats. Capillary numerical density, length, surface area, capillary geometry, and muscle fiber cross-sectional area were determined using morphometric methods in perfusion-fixed plantaris muscles from a second series of C (n = 5) and D (n = 6) rats. Hindquarters of D rats (61 +/- 3 g) weighed less than C rats (90 +/- 3 g) because of marked muscle atrophy. Minimal total vascular resistance was lower in D rats (P < or = 0.05), indicating an increased flow capacity. CFC was not different in C and D rats (0.0282 +/- 0.0020 vs. 0.0330 +/- 0.0025 ml.min-1.mmHg-1 x 100 g-1, respectively). The relationship between PS and flow was depressed in D rats (P < or = 0.05) compared with C rats, which indicated a reduced capillary diffusing capacity. Plantaris muscle weight was 41% less in D rats (174 +/- 9 vs. 293 +/- 11 mg; P < or = 0.001). Morphometric analysis revealed that muscle fiber cross-sectional area was reduced 39% in D rats, which, despite a lower capillary-to-fiber ratio (1.59 +/- 0.04 vs. 2.12 +/- 0.13; P < or = 0.001), resulted in a 27% increase in capillary density in D rats. Capillary diameter was less in D rats (3.58 +/- 0.12 vs. 4.51 +/- 0.23 microns; P < or = 0.005). Total capillary surface area was reduced 42% in D rats; however, capillary surface area per muscle fiber volume was unchanged in D rats (231 +/- 34 vs. 237 +/- 16 cm-1). These data indicate that there is remodeling of the capillary bed in skeletal muscle of D rats, resulting in a reduction in total microvascular surface area. The reduction in capillary surface area is proportional to the degree of muscle atrophy in D rats such that functional microvascular surface area per tissue mass (e.g., CFC) is unchanged. The lower diffusing capacity (PS) in D rats suggests that either small solute permeability is reduced and/or there is greater perfusion heterogeneity in D rat skeletal muscle.
Interaction of human platelets and leukocytes in modulation of vascular tone
Authors: Kaul S. , Waack B. J. , Padgett R. C. , Brooks R. M. , Heistad D. D.
Published: December 2017

We tested the hypothesis that the vasodilator response to human platelets is modulated by polymorphonuclear leukocytes (PMNs). Responses to platelets activated with thrombin, as well as PMNs activated with N-formylmethionyl-leucyl-phenylalanine (FMLP), were examined in perfused rabbit carotid arteries in vitro. Activation of platelets produced marked dilatation, and activation of PMNs produced modest constriction in arteries preconstricted with phenylephrine. Vasodilator responses to platelets were greatly impaired during infusion of activated PMNs. Pretreatment of PMNs with superoxide dismutase (SOD) partially restored dilator responses to platelets. Because SOD only partially restored vasodilator responses to platelets, we tested the possibility that adenosine-diphosphatase (ADPase) activity of PMNs may degrade ADP released by platelets and thus reduce vasodilator responses. After incubation with PMNs, dilator responses to ADP, but not acetylcholine, were significantly impaired. These findings indicate that vasodilatation produced by activated human platelets is profoundly impaired by activated leukocytes. We conclude that two mechanisms may account for this effect: 1) endothelium-derived relaxing factor, released in response to platelet-derived ADP, is inactivated by superoxide anion generated by activated PMNs and 2) ADP is degraded by ADPase activity of PMNs. We speculate that platelet-leukocyte interaction may have important effects on vasomotor tone.
Fluctuations in microvascular blood flow parameters caused by hemodynamic mechanisms
Authors: Kiani M. F. , Pries A. R. , Hsu L. L. , Sarelius I. H. , Cokelet G. R.
Published: December 2017

We have developed a mathematical model of microvascular network blood flow in which the nonlinear flow properties of blood and the nonuniform axial distribution of red blood cells in each vessel, as well as disproportionate cell partitioning at bifurcations, are all accounted for. The movements of red blood cells in the network are tracked; hence, the model is able to simulate temporal variations in local flow parameters in the network due to hemodynamic mechanisms. The model was applied to four rat mesenteric networks for which the topology, boundary conditions, blood velocity, and discharge hematocrit (Hctd) had been measured for each branch. Temporal variations in Hctd and blood velocity after simulation convergence were predicted. In some cases of the three vessels connected to a node, Hctd of one vessel fluctuates in a simple periodic form, Hctd of the second one oscillates in a more complex periodic form, whereas the Hctd of the third one does not oscillate at all. These variations were obtained with constant flow boundary conditions and, therefore, are due to hemodynamic factors alone. The temporal variations in flow parameters predicted by the model simulations are caused by hemorheological mechanisms and would be superimposed on variations caused by other mechanisms (e.g., vasomotion). The frequencies of the predicted fluctuations in blood velocity are in qualitative agreement with observed in vivo variations in dual-slit velocity in the arterioles of the cremaster muscle of anesthetized Golden hamster.