bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial and nonendothelial cyclooxygenase mediate rabbit pial arteriole dilation by bradykinin
Authors: Copeland J. R. , Willoughby K. A. , Tynan T. M. , Moore S. F. , Ellis E. F.
Published: December 2017

Aspirin (acetylsalicylic acid, ASA) was administered to rabbits in an attempt to inhibit selectively endothelial cyclooxygenase activity and therefore to determine its role in bradykinin-induced radical-mediated dilation of cerebral arterioles. With the use of the cranial window technique in anesthetized rabbits, pial arteriolar diameters were recorded in response to topically applied bradykinin, acetylcholine, and ventilation with 10% O2-9% CO2 gas mixture. Prostaglandins were measured in isolated cerebral microvessels and cerebrospinal fluid (CSF) using radioimmunoassay. Microvessel prostaglandin production was reduced significantly by 90 mg/kg i.v. ASA, whereas acetylcholine-stimulated increases of CSF prostaglandins were not similarly affected. This treatment reduced bradykinin-induced dilation of pial arterioles by 47%. After concurrent 90 mg/kg i.v. ASA plus 300 microM ASA topically applied to the brain, stimulated increases of CSF prostaglandins were reduced by 79%, while bradykinin-induced dilation was reduced by 78%. ASA did not reduce the dilator activity of either acetylcholine or ventilation with 10% O2-9% CO2. Acetylcholine- but not bradykinin-induced dilation was reduced by NG-nitro-L-arginine methyl ester. These results indicate intravenous ASA produced a relatively selective inhibition of cerebral microvascular cyclooxygenase and partial inhibition of bradykinin-induced dilation. Further inhibition of dilation occurred following ASA administered both systemically and topically to the brain. This indicates two sources of cyclooxygenase, endothelial and nonendothelial, mediate the bradykinin-induced dilation of rabbit pial arterioles. Furthermore, systemic doses of ASA do not eliminate brain prostaglandin formation.
Origin of regional pressure gradients in the left ventricle during early diastole
Authors: Nikolic S. D. , Feneley M. P. , Pajaro O. E. , Rankin J. S. , Yellin E. L.
Published: December 2017

Left ventricular (LV) pressure (P)-diameter, LVP-area, or LVP-volume relationships used to evaluate LV diastolic function assume uniform LV wall motion and constant LVP. Contrary to these assumptions, there are significant differences in ventricular dynamic geometry and in LV pressures measured simultaneously in different parts of the LV, particularly during early diastole. We instrumented six anesthetized open-chest dogs with three pairs of orthogonal ultrasonic crystals (anterior-posterior and septal-free wall minor axes, and base-apex major axis) and two micromanometers (in the apex and in the LV base). The mitral valve occluder was implanted during standard cardiopulmonary bypass in the mitral annulus. Data were recorded during 11 transient vena caval occlusions. The mitral valve was occluded for 1 beat every 6–8 beats during each vena caval occlusion to produce nonfilling diastole. With the decrease of the LV end-systolic volume (Ves) below the equilibrium volume Veq (volume of the completely relaxed LV at LVP = 0); the minimum negative LVP in nonfilling beats increases, the shape of the ventricle is more ellipsoidal in both filling and nonfilling beats, and the base-to-apex pressure gradient at the time of LVP minimum increases regardless of the presence or absence of filling. Thus heterogeneous myocardial stresses during isovolumic relaxation and early diastole result in ventricular shape changes, intraventricular redistribution of chamber volume, local accelerations of blood, and associated intraventricular LVP gradients. The role of elastic recoil assumes greater importance at Ves smaller than Veq, when the left ventricle becomes more ellipsoidal in shape during isovolumic relaxation, leading, in turn, to greater shape changes and greater LVP gradient.
Thyroid status and potassium currents in rat ventricular myocytes
Authors: Shimoni Y. , Severson D. L.
Published: December 2017

The size and rate dependence of the transient (Ito) and steady-state (Iss) outward potassium currents were investigated in isolated rat ventricular myocytes obtained from euthyroid, hyperthyroid, and hypothyroid rats, using the whole cell, suction electrode voltage-clamp method. Under hypothyroid conditions Ito was reduced in size, with no significant change in Iss. In hypothyroid cells, the rate dependence of both currents was greatly enhanced, resulting in a much larger attenuation with increasing stimulation rates. A significant slowing of the recovery kinetics of Ito was observed. These effects of hypothyroidism were reversed by physiological triiodothyronine (T3) replacement. These current changes were reflected in an altered rate dependence of the action potential configuration in hypothyroid myocytes. Under hyperthyroid conditions no significant changes were observed in the amplitude or time course of recovery of Ito. Iss amplitude was increased, but no changes were found in its rate dependence. These results are discussed in terms of hormonal, long-term modulation of potassium currents, and in terms of cardiac pathology under conditions of altered thyroid status.
Chronic central potassium infusion prevents deoxycorticosterone-salt hypertension in rats
Authors: Klarr S. A. , Keep R. F. , Betz A. L.
Published: December 2017

Although it has long been established that cerebrospinal fluid potassium concentration (CSF [K]) is very tightly regulated, it has been reported that rats made hypertensive by central infusions of aldosterone have significantly lower CSF [K] compared with normotensive controls. We investigated whether reduced CSF [K] is also present in another animal model of hypertension, the deoxycorticosterone acetate (DOCA)-salt rat, and we hypothesized that chronic intracerebroventricular (IVT) infusion of potassium with miniosmotic pumps might attenuate the rise in blood pressure observed in these rats. DOCA-salt rats without IVT infusions or with control CSF infusions (0.5 microliter/h of 2.9 mM K for 2 wk) had a significantly increased systolic blood pressure and a significantly lower CSF [K] compared with their respective sham groups. In contrast, DOCA-salt rats receiving IVT infusions with elevated [K] (10, 30, or 150 mM) had significantly lower blood pressures compared with those receiving control CSF. They also did not exhibit decreased CSF [K] compared with their respective sham groups. At 10 and 150 mM K, the blood pressure rise in DOCA-salt rats was not significantly different from shams. At 30 mM K, there was a slight, but significant, increase in blood pressure in the DOCA-salt rats compared with their shams, but this rise was still much less than in DOCA-salt rats infused with 2.9 mM K. Infusions with elevated [K] had no effect on blood pressure in the sham animals. These studies suggest that altered brain potassium homeostasis may play an important role in the development of DOCA-salt hypertension.
Immediate responses of endothelial cells to hypoxia and reoxygenation: an in vitro model of cellular dysfunction
Authors: Watkins M. T. , Haudenschild C. C. , al-Badawi H. , Velazquez F. R. , Larson D. M.
Published: December 2017

We have studied endothelial functions and integrity under clinically relevant levels of acute and profound hypoxia. Bovine aortic endothelial cells (EC) grown on microcarrier beads were exposed for 15-min intervals to normoxic (20% O2) or hypoxic (1–2% O2) medium. Control intervals were followed by four hypoxic and then four normoxic intervals for reoxygenation. Prostacyclin release from EC significantly decreased after only 15 min of hypoxia and remained low despite reoxygenation. This decrease in prostacyclin release was not coincident with decreased viable cells (Trypan blue exclusion) or with increased cell lysis (increased lactate dehydrogenase) after hypoxia or reoxygenation. When the medium was supplemented with 30 microM arachidonate (saturating concentration), prostacyclin release still significantly decreased after 30 min of hypoxia but returned to baseline levels by 30 min of reoxygenation. Similar results were obtained for thromboxane B2 release. These data suggest that 1) EC decrease prostacyclin release during acute, profound hypoxia, 2) EC decrease prostaglandin production during hypoxia despite abundant exogenous arachidonate, and 3) recovery of prostaglandin production is dependent on exogenous arachidonate during reoxygenation.
Effects of hypertrophy on left atrial and ventricular compliance and plasma ANF levels in conscious dogs
Authors: Hasebe N. , Hittinger L. , Kohin S. , Shen Y. T. , Graham R. M. , Vatner S. F.
Published: December 2017

Alterations in left atrial (LA) and left ventricular (LV) compliance and arterial and coronary sinus atrial natriuretic factor (ANF) concentrations at baseline and in response to both volume depletion and expansion were investigated in 15 conscious dogs with aortic banding-induced LV hypertrophy (LVH) (LV/body wt increased by 64%), which also induced LAH (LA/body wt increased by 61%). With volume expansion coronary sinus ANF increased more (P < 0.05) in dogs with LVH (+427 +/- 88 pg/ml) compared with control dogs (+146 +/- 45 pg/ml). Arterial ANF levels also rose more with volume expansion in LVH. In dogs with LVH, the LV end-diastolic pressure-diameter relationship was shifted to the left with a steeper slope with volume expansion, such that at any given diastolic dimension, diastolic pressure was higher. In contrast, the pressure-dimension relationship for the LA appendage was shifted in the opposite direction during both atrial systolic and diastolic phases, with a more shallow slope in hypertrophy compared with control dogs, resulting in an augmented pressure-dimension product during volume loading in LAH. In conclusion, in dogs with LVH and LAH, enhanced ANF was revealed in the coronary sinus and systemic circulation during volume expansion, which could be due, in part, to a more compliant, but hypertrophied, LA, which responded to equivalent volume loading with an augmented pressure-dimension product.
Regulation of coronary diameter by myogenic mechanisms in arterial microvessels greater than 100 microns in diameter
Authors: Rajagopalan S. , Dube S. , Canty J. M.
Published: December 2017

We performed the present study to determine the quantitative significance of transient and steady-state myogenic responses in isolated coronary resistance vessels greater than 100 microns in diameter. Small coronary arteries were isolated from freshly excised porcine hearts (n = 14) and were studied under static conditions in a superfused vessel chamber that allowed internal diameter to be assessed continuously using video microscopic techniques. At a mean distending pressure of 50 mmHg, the passive diameter of resistance arteries following sodium nitroprusside averaged 181 +/- 10 (SE) microns. Upon heating, vessels developed spontaneous tone and constricted to 72 +/- 3% of their maximum diameter. After a 30-mmHg step change in coronary pressure from 50 to 80 mmHg, there was an initial dilation from 131 +/- 9 to 149 +/- 11 microns, followed by myogenic constriction that returned diameter to the initial value over a period of several minutes (134 +/- 10 microns, P = NS). Directionally opposite peak transients were observed during reductions in pressure. Steady-state diameter remained relatively constant over a pressure range from 100 to 20 mmHg. Although these data demonstrate that myogenic responses are present in resistance arteries that are greater than 100 microns in diameter, their contribution to steady-state coronary resistance changes as pressure is varied is small. This suggests that additional mechanisms contribute to the phenomenon of coronary autoregulation in this class of resistance vessel.
Role of intracellular SOD in oxidant-induced injury to normal and copper-deficient cardiac myocytes
Authors: Sarvazyan N. , Askari A. , Klevay L. M. , Askari A. , Huang W. H.
Published: December 2017

Previous studies have shown that susceptibilities of hepatocytes and endothelial cells to H2O(2)-induced injury are altered by changes in the intracellular activity of Cu,Zn-containing superoxide dismutase (CuZn-SOD). To evaluate the role of intracellular CuZn-SOD in oxidant-induced injury to rat cardiac myocytes, cells with reduced CuZn-SOD activity but normal ATP content were either isolated from the hearts of adult copper-deficient rats or obtained by treatment of normal isolated adult myocytes with diethyldithiocarbamate. These myocytes and controls with normal CuZn-SOD activity were exposed to either reagent H2O2 or oxidants generated by extracellular glucose oxidase plus glucose or xanthine oxidase plus xanthine. It was shown that myocytes with CuZn-SOD activities reduced by 70-90% were equally susceptible to H2O2 and the two oxidant-generating systems as the control myocytes. The findings suggest that in adult cardiac myocytes, in contrast to the situation in some other cells, intracellular CuZn-SOD may not have a significant defensive role against acute H2O(2)-induced injury. The possibility remains, however, that changes in the activity of this enzyme, e.g., in copper deficiency, may be relevant to the ability of myocytes to cope with chronic oxidative stress resulting from imbalance between intracellular oxygen radical-generating and -scavenging systems.
Static tension is associated with increased smooth muscle cell DNA synthesis in rat pulmonary arteries
Authors: Weiser M. C. , Majack R. A. , Tucker A. , Orton E. C.
Published: December 2017

During the development of pulmonary hypertension, vascular cell proliferation closely parallels the rise in pulmonary intravascular pressure. The possible direct physical effect that elevated pressures may have on inducing vascular cell proliferation in pulmonary hypertension is unclear. To address this question, static force (0, 1, 5, and 10 g) was applied to hilar pulmonary arterial rings cultured in a serum-free medium. Incorporation of the thymidine analogue, bromodeoxyuridine (BrdU), into medial and adventitial cells was analyzed by immunohistochemistry. Medial cell BrdU incorporation (%positive cells) was increased (P < 0.0001) at all levels of force compared with 0-g controls (unmounted and mounted, but without applied force) (unmounted: 0.65 +/- 0.08; mounted: 0 g, 1.8 +/- 0.39; 1 g, 3.7 +/- 0.35; 5 g, 5.2 +/- 0.43; 10 g, 2.8 +/- 0.17). Hypoxia exposure and endothelial denudation of arteries attenuated (P < 0.05) tension-induced medial cell BrdU labeling (2.5 +/- 0.96 and 3.3 +/- 0.63, respectively) compared with control arteries (6.0 +/- 0.54). Nifedipine reduced tension-induced medial cell BrdU incorporation (P < 0.05). There was no difference in DNA synthesis in adventitial cells at the various levels of force, although hypoxia decreased adventitial cell BrdU incorporation overall (P < 0.05). We conclude that static wall tension may be an important direct stimulus for medial cell DNA synthesis.
Reperfusion induces 5-lipoxygenase translocation and leukotriene C4 production in ischemic brain
Authors: Ohtsuki T. , Matsumoto M. , Hayashi Y. , Yamamoto K. , Kitagawa K. , Ogawa S. , Yamamoto S. , Kamada T.
Published: December 2017

5-Lipoxygenase (5-LO) converts arachidonic acid, released from membrane phospholipids upon external stimulation, to leukotriene C4 (LTC4), which induces various kinds of cellular and molecular responses. We examined the effects of 5 min of ischemia on brain 5-LO and LTC4 during reperfusion using the gerbil model of transient forebrain ischemia that develops neuronal necrosis selectively in the hippocampus. Neurons exhibited dense 5-LO immunoreactivity; 5-LO was partially redistributed from cytosolic to particulate fractions 3 min during reperfusion. LTC4 was generated in neurons and was increased in all forebrain regions during reperfusion. Postischemic increases in LTC4 were inhomogeneous; a greater increase was observed in the hippocampus (13.37 +/- 0.24 pmol/g tissue) than in the other regions (cerebral cortex: 3.29 +/- 1.09 pmol/g). Superoxide dismutase and dimethylthiourea, oxygen radical scavengers, attenuated the production of LTC4 and damage to the neurons in the hippocampus during reperfusion. Our findings indicated that reperfusion, which was associated with translocation of cytosolic 5-LO to membranes and generation of oxygen radicals, induced the production of LTC4 and suggested that excess LTC4 production may mediate irreversible reperfusion injuries in the hippocampal neurons.
Induction of NO synthase in rat cardiac microvascular endothelial cells by IL-1 beta and IFN-gamma
Authors: Balligand J. L. , Ungureanu-Longrois D. , Simmons W. W. , Kobzik L. , Lowenstein C. J. , Lamas S. , Kelly R. A. , Smith T. W. , Michel T.
Published: December 2017

There are important phenotypic differences between endothelial cells of large vessels and the microvasculature and among microvascular endothelial cells isolated from different tissues and organs. In contrast to most macrovascular endothelial cells, we demonstrate that cultured cardiac microvascular endothelial cells (CMEC) have no detectable constitutive NO synthase (NOS) activity but have a robust increase in NOS activity in response to specific inflammatory cytokines. To determine the identity of the inducible NOS (iNOS) isoform(s) induced by cytokines, we used reverse-transcription polymerase chain reaction techniques to clone and sequence a 217-bp cDNA fragment from CMEC cultures pretreated with interleukin-1 beta (IL-1 beta) and interferon-gamma (IFN-gamma) that was identical to the corresponding portion of the murine macrophage iNOS cDNA. By use of this CMEC iNOS cDNA as a probe in Northern analyses, IL-1 beta, but not IFN-gamma, increased iNOS mRNA content in CMEC, although IFN-gamma markedly potentiated iNOS induction in these cells. In IL-1 beta- and IFN-gamma-pretreated CMEC, dexamethasone only minimally suppressed the rise in iNOS mRNA, protein abundance, or maximal iNOS enzyme activity in whole cell lysates but suppressed nitrite production by 60% in intact CMEC. Dual labeling of cytokine-pretreated CMEC in primary culture with an anti-iNOS antiserum and a fluorescein-labeled lectin specific for the microvascular endothelium of rat heart (GS-1) confirmed the presence of iNOS expression in these cells. iNOS was also detected in microvascular endothelium in situ in ventricular muscle from lipopolysaccharide-, but not sham-injected, rat hearts.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine activates a glibenclamide-sensitive K+ current in cat atrial myocytes
Authors: Wang Y. G. , Lipsius S. L.
Published: December 2017

The preceding paper [Y. G. Wang and S. L. Lipsius, Am. J. Physiol. 268 (Heart Circ. Physiol. 37): H1313–H1321, 1995.] showed that when an atrial myocyte is treated with two consecutive exposures to acetylcholine (ACh) separated by a recovery interval, the second ACh exposure elicits a larger increase in K+ conductance than the first ACh exposure. In the present study a nystatin-perforated patch whole cell recording method was used to determine the mechanisms underlying the potentiating effect of ACh on ACh-induced K+ currents and the nature of the potentiated K+ current. The K+ current potentiated by the second ACh exposure was selectively abolished by 1) M1 muscarinic receptor block by 0.1 microM pirenzepine, 2) depletion of sarcoplasmic reticulum (SR) Ca2+ stores by 1 microM ryanodine or 10 mM caffeine, 3) intracellular dialysis with 10 mM ethylene glycolbis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), 4) omitting external Ca2+, 5) 50% external Na+, 6) inhibition of protein kinase C by 0.01 microM staurosporine or 0.1 microM calphostin C, or 7) inhibition of ATP-sensitive K+ channels with 10 microM glibenclamide (Glib). AFDX-116 (100 microM), an M2 muscarinic receptor antagonist, selectively abolished the conventional ACh-activated K+ current and revealed an ACh-activated Glib-sensitive K+ current. In addition, with K+ conductances blocked and zero external Ca2+, 10 microM ACh induced a small nonselective inward current carried by Na+.(ABSTRACT TRUNCATED AT 250 WORDS)
Substance P-induced calcium entry in endothelial cells is secondary to depletion of intracellular stores
Authors: Sharma N. R. , Davis M. J.
Published: December 2017

Substance P (SP) induces an elevation in cytosolic Ca2+ concentration ([Ca2+]i) in porcine coronary artery endothelial cells by way of Ca2+ influx and release from intracellular stores. We tested the hypothesis that SP-induced Ca2+ influx occurs due to activation of a Ca(2+)-permeable influx pathway coupled to depletion of intracellular stores. With the use of the perforated patch technique and fura 2 microfluorimetry, a fivefold greater increase in [Ca2+]i per unit decrease in membrane potential was obtained in the presence of SP (10 nM) compared with resting state, implying that SP increased Ca2+ conductance. When K+ channels were blocked, SP activated a net inward current with a reversal potential (2.5 +/- 1 mV) not significantly different from that (2 +/- 1 mV) for inward current recorded in response to store depletion by (2,5-di-tert-butylhydroquinone) (BHQ, 10 microM). Increasing bath [Ca2+] induced a similar shift in reversal potential for SP- and BHQ-induced currents. Inositol 1,4,5-trisphosphate (20 microM), applied through the patch pipette, activated an inward current with Ca2+ selectivity similar to SP- and BHQ-activated currents. Dialysis of cells with heparin (5 mg/ml) completely blocked SP-induced inward current but not BHQ-induced current. These results suggest that the SP-induced increase in Ca2+ conductance can be completely explained by activation of a Ca(2+)-permeable influx pathway coupled to depletion of intracellular stores.
Effects of age on intrinsic heart rate, heart rate variability, and AV conduction in healthy humans
Authors: Craft N. , Schwartz J. B.
Published: December 2017

Heart rate, heart rate variability, and atrioventricular (AV) conduction were studied in 20 young (30 +/- 5 yr) and 19 older (69 +/- 7 yr) healthy men and women before and after single and double autonomic blockade (randomized order: atropine, 0.04 mg/kg i.v.; propranolol, 0.2 mg/kg i.v.). Basal R-R intervals did not differ, but older age increased P-R intervals (177 +/- 24 vs. 149 +/- 17 ms, P < 0.001) and decreased SD of R-R (43 +/- 17 vs. 70 +/- 18 ms, P = 0.001) and heart rate spectral content (area under the power vs. frequency curve from 0.04 to 0.32 Hz: 3.01 +/- 2.1 vs. 7.82 +/- 4.8 beats/min2, P < 0.009), as well as postural responses (R-R decreases of 107 +/- 80 vs. 250 +/- 72 ms, P < 0.002). Atropine decreased R-R intervals, SD of R-R, and high-frequency (0.24-0.32 Hz) spectral content less in elderly subjects compared with younger subjects. Propranolol increased R-R and P-R intervals equally in old and young and abolished low-frequency (0.04-0.12 Hz) increases with standing (P < 0.0008). After double blockade, R-R, P-R, and paced AV intervals were longer in old subjects. Mean values were as follows: R-R intervals, 859 +/- 176 vs. 677 +/- 106 ms, P < 0.001; P-R intervals, 179 +/- 23 vs. 149 +/- 17 ms, P = 0.0002; paced P-R intervals (500 ms), 251 +/- 39 vs. 215 +/- 47 ms; and AV block cycle length, 413 +/- 51 vs. 385 +/- 69 ms (multivariate analysis of variance, P < 0.03). After double autonomic blockade, heart rate variability was nearly eliminated in young and old (reduced > 98%, P < 0.0001). We conclude that age differences in heart rate variability can be explained by autonomic influences, but heart rate and AV conduction differences exist independently of beta-adrenergic and/or parasympathetic influences.
Cardiopulmonary baroreceptors modulate carotid baroreflex control of heart rate during dynamic exercise in humans
Authors: Potts J. T. , Shi X. , Raven P. B.
Published: December 2017

Numerous studies have reported that, at rest, maximal carotid baroreflex gain is modulated by cardiopulmonary baroreceptors. The purpose of this study was to measure the maximal gain for carotid baroreflex control of heart rate (HR) and blood pressure [mean arterial pressure (MAP)] during dynamic exercise alone and when exercise was accompanied by two levels of cardiopulmonary baroreceptor unloading. Lower body negative pressure (LBNP) produced similar reductions in central venous pressure (CVP) at rest and during exercise. Baroreflex gain for HR at rest was not affected by low-level LBNP but was significantly increased by high-level LBNP [-0.31 +/- 0.05 to -0.57 +/- 0.23 beats.min-1.mmHg-1 carotid sinus pressure (CSP), no LBNP vs. high-level LBNP, P < 0.05]. Exercise combined with low- and high-level LBNP resulted in reflex HR gains (-0.83 +/- 0.44 and -0.83 +/- 0.17 beats.min-1.mmHg-1 CSP, low- vs. high-level LBNP, P < 0.05) that were significantly greater than the algebraic sum of the HR gain measured during exercise and LBNP alone. Neither exercise nor the two levels of LBNP significantly altered baroreflex gain for MAP. The slope relating HR gain to CVP at rest was significant (0.07 +/- 0.02 beats.min-1.mmHg CSP-1.mmHg CVP-1, P < 0.01) and increased 114% during exercise (P < 0.05). A similar analysis of MAP gain found no difference in slope between rest and exercise (P > 0.05). Together these data indicate 1) a tonic inhibitory interaction between cardiopulmonary baroreceptors and carotid baroreflex control of HR during exercise, and 2) a nonlinear relationship between deactivation of cardiopulmonary baroreceptors and changes in carotid baroreflex gain. This interaction may improve overall cardiovascular regulation when central blood volume and/or CVP is reduced, as has been reported during prolonged exercise in the heat.
Modulation of reflex pressor response to contraction and effect on substance P release by spinal 5-HT1A receptors
Authors: Nobrega A. C. , Meintjes A. F. , Ally A. , Wilson L. B.
Published: December 2017

This study investigated whether activation of serotonin1A [5-hydroxytryptamine (5-HT)1A] receptors in the dorsal horn of the spinal cord attenuates the reflex pressor response to static contraction and passive muscle stretch. In addition, we determined if the attenuation of the response to contraction is mediated by inhibiting substance P (SP) release in the dorsal horn. Static contractions of the triceps surae muscle of chloralose-anesthetized cats were induced by stimulating the cut L7 and S1 ventral roots. Microdialysis (10 mM) of a selective 5-HT1A agonist [8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT)] into the L7 dorsal horn region produced a reversible attenuation of the reflex pressor response to a 1-min contraction (in mmHg: control = 36 +/- 3; 8-OH-DPAT = 17 +/- 3; recovery = 31 +/- 8; P = 0.013; n = 6) or passive stretch (in mmHg: control = 36 +/- 6; 8-OH-DPAT = 15 +/- 2; recovery = 32 +/- 6; P = 0.002; n = 6). However, a 5-HT1B agonist, 1-[3-(trifluoromethyl)-phenyl]piperazine, had no effect on the reflex pressor response. During 5-min contractions (n = 8), 8-OH-DPAT (10 mM) also blunted the pressor response but had no effect on the levels of SP-like immunoreactivity (in fmol/100 microliters: control = 0.492 +/- 0.026; 8-OH-DPAT = 0.501 +/- 0.034). These results suggest that activation of 5-HT1A receptors in the dorsal horn attenuates the reflex pressor response to contraction through a mechanism other than inhibition of SP release.
Effects of aging on 24-h dynamic baroreceptor control of heart rate in ambulant subjects
Authors: Parati G. , Frattola A. , Di Rienzo M. , Castiglioni P. , Pedotti A. , Mancia G.
Published: December 2017

The effects of aging on the dynamic modulation of baroreflex sensitivity over 24 h was assessed in eight elderly (mean age +/- SD, 63.9 +/- 3.2 yr) and in eight young (23.9 +/- 6.1 yr) mild or moderate essential hypertensive patients, who were subject to a 24-h intra-arterial (Oxford technique) blood pressure recording in ambulatory conditions. The sensitivity of baroreflex control of the heart rate was dynamically assessed by quantifying 1) the slope of the regression line between pulse interval (the reciprocal of heart rate) and systolic blood pressure changes over spontaneously occurring hypertension-bradycardia or hypotension-tachycardia sequences (time domain analysis) and 2) the ratio between spectral-powers of pulse interval and systolic blood pressure around 0.1 Hz (alpha-coefficient: frequency domain analysis). The 24-h average sequence slope was lower in old than in young individuals (4.4 +/- 0.5 vs. 9.9 +/- 1.3 and 4.8 +/- 0.7 vs. 8.4 +/- 1.4 ms/mmHg for hypertension-bradycardia and hypotension-tachycardia sequences, respectively; P < 0.05 for both). Similar results were obtained by using the alpha-coefficient approach. The marked nighttime increase in baroreflex sensitivity observed in young individuals was much less evident in the elderly. Thus 24-h baroreflex sensitivity is markedly impaired by aging. The impairment becomes manifest also as an inability to increase baroreflex sensitivity at night.
Change in phase relationship between SBP and R-R interval during lower body negative pressure
Authors: Blaber A. P. , Yamamoto Y. , Hughson R. L.
Published: December 2017

We have investigated the hypothesis that beat-by-beat interaction of systolic blood pressure (SBP) to R-R interval (the spontaneous baroreflex) is dependent on the length of the R-R interval. Data were collected from eight healthy men while heart rate was slow (R-R interval 1,043 +/- 34 ms) and accelerated (R-R interval 804 +/- 18 ms) by application of lower body negative pressure (LBNP greater than or equal to -40 mmHg). Time series data of SBP and R-R interval were searched for spontaneous baroreflex sequences in which R-R interval changed in the same (lag 0), next (lag 1), or next following (lag 2) beat as SBP. This phase relationship was also quantified by cross-spectral analysis. At rest, 85% of all spontaneous baroreflex sequences occurred with no lag (lag 0). With LBNP, there was a significant reduction in the number of lag 0 sequences (26%), whereas lag 1 and lag 2 sequences increased (10–26% and 5–29%, respectively). Cross-spectral phase also changed significantly from -2.3 +/- 6.3 degrees at rest to 70.5 +/- 7.4 degrees during LBNP. These data supported the hypothesis that the lag of a baroreflex event was dependent on the prevailing R-R interval.
Inhibitory effect of indomethacin on prostacyclin receptor-mediated cerebral vascular responses
Authors: Parfenova H. , Zuckerman S. , Leffler C. W.
Published: December 2017

The present study addresses the hypothesis that indomethacin, in addition to blocking prostaglandin synthesis, directly inhibits prostacyclin receptor-mediated cerebral vascular responses. To test this hypothesis, the effects of indomethacin on pial arteriolar dilation in response to the prostacyclin receptor agonist iloprost were investigated using a cranial window technique in newborn pigs. Topically applied iloprost resulted in dose-dependent pial arteriolar dilation and concomitant increases in cortical adenosine 3',5'-cyclic monophosphate (cAMP). Indomethacin (5 mg/kg iv + 10(-4) M topically) greatly reduced both the vasodilation and the increase in cortical cAMP in response to iloprost. In contrast, indomethacin did not attenuate beta-adrenoreceptor-mediated vasodilation and the increase in cortical cAMP in response to isoproterenol. Aspirin (50 mg/kg iv + 10(-3) M topically) did not affect pial arteriolar dilation or the increase in cortical cAMP in response to iloprost. Unlike indomethacin, aspirin was not effective in inhibiting prostanoid-associated cerebral vasodilation and increase in cortical cAMP in response to hypercapnia. The present data suggest that indomethacin selectively inhibits prostacyclin receptor-mediated responses in the newborn pig cerebral circulation. The combination of highly effective inhibition of prostaglandin H synthase and prostacyclin receptor-mediated vasodilation may contribute to the increased efficacy of indomethacin compared with other prostaglandin H synthase inhibitors in blocking certain vasodilator responses associated with prostanoids.
Effects of repetitive vagal stimulation on heart rate and on cardiac vasoactive intestinal polypeptide efflux
Authors: Hill M. R. , Wallick D. W. , Martin P. J. , Levy M. N.
Published: December 2017

In dogs anesthetized with alpha-chloralose, we assessed the "vagally induced tachycardia" elicited by successive 2-min periods of intense vagal stimulation (0.5 ms, 10 mA, 20 Hz) after we had blocked the animals' muscarinic and beta-adrenergic receptors with atropine and propranolol, respectively. We found that the tachycardia produced by the successive vagal stimulations progressively decreased to < 20% of the initial tachycardia response within 84 min. We also observed that the chronotropic response to vasoactive intestinal polypeptide (VIP) injected into the sinus node artery after the vagal stimulation regimen did not differ significantly from the response to the same dose of VIP injected prior to vagal stimulation. This finding indicates that the postjunctional responsiveness of the cardiac pacemaker cells had not diminished over the course of the vagal stimulation regimen. In isolated, perfused right atrial preparations, we observed a close correlation between the efflux of VIP from the atrial tissues and the chronotropic responses to vagal stimulation. Our results support the hypotheses that 1) VIP is a mediator of vagally induced tachycardia, 2) the reduction in VIP efflux is associated with a diminished vagally induced tachycardia, and 3) the reduced efflux of VIP probably reflects a diminution in neuronal release, perhaps by depletion of this peptide from the vagus nerve endings consequent to the prolonged neural stimulation.
Episodic hypertension due to autonomic dysreflexia in acute and chronic spinal cord-injured rats
Authors: Krassioukov A. V. , Weaver L. C.
Published: December 2017

Spinal cord injury results in abnormal sympathetic control of the cardiovascular system, consisting of exaggerated reflexes with resulting hypertension and bradycardia that has been termed autonomic dysreflexia. We studied changes in arterial pressure and heart rate caused by colon or urinary bladder distension in unanesthetized acute (7 day) and chronic (30 day) spinal cord-injured rats to evaluate the time course of these responses in an animal model of spinal cord injury. In conscious control rats colon and bladder distension caused brief (2-10 s) pressor responses of 10 mmHg associated with tachycardia and escape reactions. Colon distension in spinal cord-injured rats increased arterial pressure by 41 +/- 2, 22 +/- 3; and 49 +/- 5 mmHg at 24 h and 7 and 30 days after cord transection, respectively. These responses lasted 30 s-5 min and were accompanied by bradycardia. Distension of the urinary bladder caused similar responses in spinal rats after 24 h and 30 days of cord transection. We propose that the initial responses may be related to loss of descending inhibition of spinal reflexes but that plastic changes in the spinal cord is one of the mechanisms for the autonomic dysreflexia occurring 1 mo after injury.
Left ventricular mechanics in arrested dog heart: effects of ventricular interaction and vascular volumes
Authors: Manor D. , Williams S. , Ator R. , Bryant K. , Scheel K. W.
Published: December 2017

The present study was designed to determine the effects of right heart pressure on the compliance of the left ventricle (LV). The studies were conducted on isolated, blood-perfused, potassium-arrested dog hearts with vasomotor tone either present (n = 5) or absent (n = 8). A balloon was used to control LV volume, whereas right heart (RHP) or coronary sinus (CSP) pressures were controlled via a column placed in the right heart or coronary sinus, respectively. Control of CSP independently of RHP allowed us to assess the relative contribution of coronary venous pressure to changes in LV compliance under conditions of elevated RHP. LV volume and compliance at a LV pressure of 15 mmHg (V15 and C15, respectively) were calculated to quantify the shift and slope changes of the LV pressure-volume (P-V) relationships. V15 and C15 decreased with vasomotor tone present from 52.8 +/- 1.4 ml and 1.7 +/- 0.1 ml/mmHg at control, to 43.3 +/- 2.1 ml and 1.4 +/- 0.1 ml/mmHg (P < 0.05) with RHP = 0 and 20 mmHg, respectively. Similar effects were obtained with vasodilation, but C15 was significantly lower relative to autoregulation but C15 was significantly lower relative to autoregulation (1.0 +/- 0.1 at control RHP, P < 0.05). Elevation of CSP with vasomotor tone resulted in an upward shift in the LV P-V relationship: V15 decreased from 53.4 +/- 2.1 at CSP = 0 mmHg to 50.9 +/- 1.6 ml at CSP = 20 mmHg (P < 0.05). After vasodilation there was no detectable shift in the LV P-V relationship with elevation of CSP.
A chemoreflex model of relation between blood pressure and heart rate in sleep apnea syndrome
Authors: Van den Aardweg J. G. , van Steenwijk R. P. , Karemaker J. M.
Published: December 2017

In obstructive sleep apnea syndrome (OSAS), pronounced low-frequency (LF) oscillations of blood pressure and interbeat interval (I) occur during recurrent apneas. We investigated the time relations between LF oscillations of diastolic pressure (D) and I in 12 patients with OSAS by means of spectral analysis. A high coherency between I and D was found, allowing a description of the relation by gain and phase. Oscillations in I and D were almost in counterphase in the LF range. Simple physiological models were implemented to interpret the observed features of LF oscillations. Model 1 describes the vagal and sympathetic influence by the carotid body chemoreflex on the circulation. From derivation of the frequency response of this model, gain and phase relations were obtained as would be expected from the action of the chemoreflex. We found that a range of phase relations can be induced by this reflex, depending on the relative vagal and sympathetic efferent influence on the circulation. This range of phase relations was indeed observed in 10 patients. Extended models that also included the orienting reflex (model 1a) or the baroreflex and a mechanical influence of breathing on the circulation (model 2) could not fit the data without a major contribution of the chemoreflex. We conclude that the relation between LF oscillations in I and D in OSAS can be explained by assuming that stimulation of the carotid body chemoreflex is the main source of these oscillations.
Influence of O2 deprivation, reduced flow, and temperature on release of ANP from rabbit hearts
Authors: Focaccio A. , Ambrosio G. , Enea I. , Russo R. , Balestrieri P. , Chiariello M. , Volpe M.
Published: December 2017

The separate effects of hypoxia and ischemia on atrial natriuretic peptide (ANP) release were evaluated in Langendorff-perfused rabbit hearts. Heart rate, coronary flow, and atrial and ventricular volumes were kept constant. Hypoxia was induced for 20 min at room temperature in seven hearts and at 37 degrees C in a second group of seven hearts. A third group of eight hearts was subjected to global ischemia for 20 min by reducing coronary flow to 1 ml/min at room temperature. All hearts were reoxygenated/reperfused at 37 degrees C for 30 min. Hypoxia at 37 degrees C induced a significant increase in ANP release. In contrast, both room temperature hypoxia and ischemia were characterized by a significant decrease in ANP release, despite hemodynamic alterations similar to those recorded during hypoxia at 37 degrees C. Both reoxygenation and reperfusion induced a prompt reversal of the changes of ANP release observed during the period of oxygen deprivation. These data demonstrate that decreased oxygen availability and reduced coronary flow are not the primary factors affecting release of ANP during ischemia and that alterations of myocardial temperature may play a major role in this phenomenon.
cGMP prevents delayed relaxation at reoxygenation after brief hypoxia in isolated cardiac myocytes
Authors: Shah A. M. , Silverman H. S. , Griffiths E. J. , Spurgeon H. A. , Lakatta E. G.
Published: December 2017

Previous studies in isolated cardiac myocytes suggest that impaired relaxation during reoxygenation after brief hypoxia results from abnormal Ca(2+)-myofilament interaction. Recent studies indicate that guanosine 3',5'-cyclic monophosphate (cGMP)-elevating interventions selectively enhance myocardial relaxation. We investigated the effect of 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP) on posthypoxic relaxation in single rat myocytes, with simultaneous measurement of contraction and intracellular Ca2+ (indo 1 fluorescence). In control myocytes (n = 11), reoxygenation after 10 min of hypoxia markedly prolonged time to peak shortening (+36.5 +/- 4.2%) and half-relaxation time (+75.7 +/- 11.3% cf. normoxic values; both P < 0.001) and reduced diastolic length but did not change cytosolic Ca2+. Under normoxic conditions, 50 microM 8-BrcGMP slightly reduced time to peak shortening and half-relaxation time and increased diastolic length but did not alter cytosolic Ca2+. In the presence of 8-BrcGMP, there was no posthypoxic delay in twitch relaxation nor was there a decrease in diastolic length (half-relaxation time -5.8 +/- 3.3% cf. normoxic values; P < 0.05 cf. control group; n = 11). Cytosolic Ca2+ remained unaltered. Thus, 8-BrcGMP fully prevents impaired posthypoxic relaxation in isolated cardiac myocytes, probably by altering Ca(2+)-myofilament interaction.
Time- and voltage-dependent modulation of a Kv1.4 channel by a beta-subunit (Kv beta 3) cloned from ferret ventricle
Authors: Castellino R. C. , Morales M. J. , Strauss H. C. , Rasmusson R. L.
Published: December 2017

In mammals, voltage-gated K+ channels can be made of complexes containing alpha-subunits similar to the Shaker K+ channel and smaller cytoplasmic beta-subunits. Recent studies have suggested that these ancillary beta-subunits can modulate K+ channel gating properties. We studied the effects of a K+ channel beta-subunit, Kv beta 3, coexpressed with a Kv1.4 alpha-subunit, FK1, on the time and voltage dependence of channel activation, inactivation, recovery from inactivation, and deactivation, using an oocyte expression system. Kv beta 3 was found to accelerate both the fast and the slow component of Kv1.4 inactivation. Kv beta 3 also altered the relative contributions of the two components of inactivation by increasing the contribution of the slow component to the inactivation process. Kv beta 3 slowed recovery from inactivation for Kv1.4, but not for a Kv1.4 deletion mutant lacking N-type inactivation. Finally, steady-state activation and the time course of Kv1.4 current activation were not strongly influenced by Kv beta 3; however, deactivation was slowed in the presence of Kv beta 3. This study suggests that Kv beta 3 alters channel states which follow activation.
Preconditioning reduces infarct size but accelerates time to ventricular fibrillation in ischemic pig heart
Authors: Ovize M. , Aupetit J. F. , Rioufol G. , Loufoua J. , Andre-Fouet X. , Minaire Y. , Faucon G.
Published: December 2017

Preconditioning protects the rat heart from ventricular arrhythmias. However, the mechanism of this beneficial effect and its existence in large animal models remain unknown. We submitted 49 pigs to 40 min of left anterior descending coronary occlusion and 2 h of reperfusion and assessed the incidence of ventricular fibrillation (VF) and time to VF. Monophasic action potential duration (MAPD) and ventricular fibrillation threshold (VFT) were measured throughout the experiment. Preconditioning significantly reduced infarct size but failed to reduce the incidence of VF either during the 40-min ischemic insult or the following reperfusion. Moreover, preconditioning accelerated the onset of VF during the prolonged ischemia; time to VF averaged 8 +/- 2 min in the preconditioned group vs. 18 +/- 2 min in the control group (P < 0.05). This premature peak of VF in preconditioned hearts was associated with a significant decrease of VFT and shortening of MAPD. This suggests that preconditioning does not limit the incidence of VF in the pig model. Rather, preconditioning decreases the time to VF in this species, likely through lowering of the VFT and shortening of the action potential duration.
Differential effect of 5- and 15-lipoxygenase products on ischemically sensitive abdominal visceral afferents
Authors: Pan H. L. , Stahl G. L. , Longhurst J. C.
Published: December 2017

The effects of 5- and 15-lipoxygenase products, leukotriene B4 (LTB4) and (8R,15S)-dihydroxyeicosa(5E-9,11,13Z)tetraenoic acid (8R,15S-diHETE), on ischemically sensitive abdominal visceral C fiber afferents were evaluated, because this system is important in sensitizing cutaneous afferents. Single-unit activity of abdominal visceral C fiber afferents was recorded from the right thoracic sympathetic chain of anesthetized cats during 5 min of ischemia. Inhibition of 5-lipoxygenase with WY-50295 tromethamine (5 mg/kg iv) augmented the impulse activity from 0.48 +/- 0.15 to 0.79 +/- 0.24 impulses/s (P < 0.05) in seven ischemically sensitive afferents. Conversely, topical application of LTB4 (125 ng) directly onto the receptive field attenuated impulse activity of 10 ischemically sensitive C fiber afferents from 0.82 +/- 0.23 to 0.42 +/- 0.10 impulses/s (P < 0.05). In additional cats, application of 8R,15S-diHETE (125 ng) onto the receptive field augmented the impulse activity of nine ischemically sensitive C fiber afferents (from 0.48 +/- 0.15 to 0.70 +/- 0.15 impulses/s, P < 0.05) and significantly decreased the mechanical threshold of these nine afferents, whereas application of 8S,15S-diHETE (125 ng), a stereoisomer of 8R,15S-diHETE, attenuated the impulse activity from 0.77 +/- 0.48 to 0.45 +/- 0.13 impulses/s (P < 0.05) in six additional ischemically sensitive C fiber afferents. In animals pretreated with aspirin (50 mg/kg iv, n = 6) or 8S,15S-diHETE (125 ng, n = 6), WY-50295 tromethamine (5 mg/kg iv) still potentiated the impulse activity of ischemically sensitive C fiber afferents. These data indicate that 8R,15S-diHETE interacts with stereospecific receptors to sensitize, whereas LTB4 reduces, the response of abdominal visceral afferents to ischemia. Furthermore the data suggest that the augmented response of afferents to abdominal ischemia after inhibition of 5-lipoxygenase is, at least in part, independent of shunting to the cyclooxygenase or 15-lipoxygenase system.
Double-exponential curve fitting of isometric relaxation: a new measure for myocardial lusitropism
Authors: Tamiya K. , Beppu T. , Ishihara K.
Published: December 2017

New indexes for evaluation of isometric myocardial relaxation were proposed. In fully isometric and physiologically sequenced twitches, the time course of isometric force decline fitted well with Gompertz's double-exponential curve (r > or = 0.9995). We conformed the original equation to suit myocardial mechanics, i.e., F(t) = gamma 0 - gamma.exp [-alpha.exp (-beta t)] (t = 1, 2, ..., n), where F(t) denotes force as a function of time t. The gamma 0 and gamma relate to upper asymptote and force amplitude, respectively. Phase-plane analysis of F(t) revealed that alpha [3.56 +/- 0.67 (SD)] related to the phasic delay of relaxation onset but did not affect the F(t) vs. dF(t)/dt relation. The beta (0.127 +/- 0.021) and gamma were linearly related to negative dF(t)/dtmax; however, the terminal slope of the phase-plane diagram was governed by beta alone. The tau beta (0.081 +/- 0.017 s), a reciprocal of beta multiplied by sampling time, was practically independent of preload, total load, and muscle shortening. In isometric twitches, tau beta was substantially decreased by global ischemia, isoproterenol, and CaCl2 but increased by reperfusion. The alpha was independent of inotropic interventions but fell significantly during ischemia and was increased by reperfusion.