bluuebunny/crossref_metadata_2025 huggingface dataset:
Phosphorylation potential and adenosine release during norepinephrine infusion in guinea pig heart
Authors: He M. X. , Wangler R. D. , Dillon P. F. , Romig G. D. , Sparks H. V.
Published: December 2017

This study tested the hypothesis that adenosine released from isolated guinea pig hearts (n = 5) in response to norepinephrine is related to the cellular phosphorylation potential (PP; [ATP]/[ADP][Pi]), where Pi is inorganic phosphate. 31P-nuclear magnetic resonance (NMR) was used to measure the relative concentrations of Pi, phosphocreatine (PCr), and ATP. Hearts were Langendorff perfused with a physiological salt solution containing 0.1 mM Pi. The venous effluent was collected for measurement of adenosine and partial pressure of oxygen (PO2). After a control period, norepinephrine (6 X 10(-8) M) was infused for 20 min during which 31P-NMR spectra and samples of venous effluent were collected every minute. With norepinephrine infusion, PCr decreased rapidly to 72% of control (P less than 0.05) by 8 min and then recovered to 80% of control for the remaining 12 min. ATP fell slowly to 70% of control (P less than 0.01) over 20 min. Pi increased to a peak at 2 min (P less than 0.01), then declined slowly to a steady state (60% of the peak and 3.5 X control) from 8 to 20 min. Adenosine release increased from 11 +/- 6 to a peak of 250 +/- 68 pmol.min-1.g-1 (P less than 0.01) at 7 min and then slowly fell (P less than 0.05) to a steady state of approximately 110 pmol.min-1.g-1 (P less than 0.01 vs. control) from 10 to 20 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Platelet-collagen adhesion enhances platelet aggregation induced by binding of VWF to platelets
Authors: Laduca F. M. , Bell W. R. , Bettigole R. E.
Published: December 2017

Ristocetin-induced platelet aggregation (RIPA) was evaluated in the presence of platelet-collagen adhesion. RIPA of normal donor platelet-rich plasma (PRP) demonstrated a primary wave of aggregation mediated by the binding of von Willebrand factor (VWF) to platelets and a secondary aggregation wave, due to a platelet-release reaction, initiated by VWF-platelet binding and inhibitable by acetylsalicylic acid (ASA). An enhanced RIPA was observed in PRP samples to which collagen had been previously added. These subthreshold concentrations of collagen, which by themselves were insufficient to induce aggregation, caused measurable platelet-collagen adhesion. Subthreshold collagen did not cause microplatelet aggregation, platelet release of [3H]serotonin, or alter the dose-responsive binding of 125I-labeled VWF to platelets, which occurred with increasing ristocetin concentrations. However, ASA inhibition of the platelet release reaction prevented collagen-enhanced RIPA. These results demonstrate that platelet-collagen adhesion altered the platelet-release reaction induced by the binding of VWF to platelets causing a platelet-release reaction at a level of VWF-platelet binding not normally initiating a secondary aggregation. These findings suggest that platelet-collagen adhesion enhances platelet function mediated by VWF.
Interaction between cardiac chambers and thoracic pressure in intact circulation
Authors: Beyar R. , Hausknecht M. J. , Halperin H. R. , Yin F. C. , Weisfeldt M. L.
Published: December 2017

A comprehensive model that describes the interaction between the cardiovascular system (CVS) and the intrathoracic pressure (ITP) based on a lumped parameter vascular representation and a time-varying elastance concept for the four cardiac chambers is presented. Special attention is given to two possible mechanisms of interventricular interaction; the constraining effects of the pericardium and direct interventricular interaction that results from the fact that the two ventricles share a common interventricular septum. The response of the CVS to positive and negative perturbations in the ITP and to injection of fluid into the pericardium was simulated and compared with experimental literature data. The results show that 1) the total heart volume is relatively constant throughout the cycle both for ITP of 0 and +15 mmHg, which is consistent with experimental data in dogs, thus suggesting that intrinsic properties of the cardiac chambers rather than a restricting pericardium is the mechanism for that observation. 2) The pericardium has a major role in modifying the transient and steady-state response to a step decrease in the ITP with a transient decrease in left ventricle (LV) end-diastolic volume followed by gradual increase afterwards. 3) The response to sudden injection of fluid into the pericardial space is a larger transient decrease in right ventricle than LV volume, which is consistent with experimental data. 4) Transmission across the septum has a relatively minor role in modifying the response of the CVS to negative pressure. Thus the model reasonably predicts the effects of intrathoracic and pericardial pressures on the circulation in a reflex-blocked animal and provides a means for placing multiple potential mechanisms in proper hierarchial order with regard to contributions to LV and overall CVS function.
Ascorbic acid: a nonradioactive extracellular space marker in canine heart
Authors: Reil G. H. , Frombach R. , Kownatzki R. , Quante W. , Lichtlen P. R.
Published: December 2017

The distribution pattern of ascorbic acid and L-[14C]ascorbic acid in myocardial tissue was compared with those of the classical radioactive extracellular space markers [3H]-inulin, [3H]sucrose, and Na82Br. A new polarographic technique was developed for analogue registration of ascorbic acid concentration in coronary venous blood. The kinetic data of the markers were studied in an open-chest canine heart preparation (n = 17 dogs) during a constant tracer infusion of up to 9 min. Distribution volumes were calculated based on the mean transit time method of Zierler (K. L. Zierler, Circ. Res. 10:393-407, 1962). The distribution volume of ascorbic acid (23.6 ml/100 g wet wt) as well as of L-[14C]ascorbic acid (24.5 ml/100 g wet wt) in myocardial tissue agreed closely with those of [3H]inulin (18.6 ml/100 g wet wt) and [3H]sucrose (22.0 ml/100 g wet wt), as well as 82Br- (27.3 ml/100 g wet wt). The obtained kinetic data confirmed that ascorbic acid exhibits the physicochemical properties of an extracellular space marker, though this compound was shown to leak slowly into myocardial cells. Favorable attributes of this indicator are its low molecular weight, high diffusibility in interstitial fluid, low binding affinity to macromolecules, and high transcapillary (1.8 X 10(-5) cm/s) as well as low transplasmalemmal penetration rate (3.7 X 10(-8) cm/s). Therefore, this nonradioactive marker can be applied in a safe and simple fashion, and without untoward side effects in experimental animals as well as in patients.
Intracellular Ca2+ and protein kinase C modulate K+ current in guinea pig heart cells
Authors: Tohse N. , Kameyama M. , Irisawa H.
Published: December 2017

Effects of protein kinase C (PKC) and intracellular calcium ion (Cai2+) on the delayed rectifier K+ current (IK) were investigated in the single ventricular cells of guinea pig by use of an internal-dialysis method and a whole cell voltage-clamp technique. 12-O-tetradecanoylphorbol-13-acetate (TPA, 10(-9) M), an activator of PKC, increased the amplitude of IK in the presence of Cai2+ higher than 10(-10) M. This effect of TPA was mimicked by a synthetic diacylglycerol, 1-oleoyl-2-acetylglycerol (OAG), 50 micrograms/ml, 125 microM, and was blocked by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (10 microM). The above findings suggest that IK channels were phosphorylated by PKC and thereby the amplitude of IK was increased. IK was also increased by elevating the concentration of Cai2+ in the absence of TPA. It is thus indicated that IK channels are modulated by Cai2+ not only through activation of PKC but also directly. Our observation may provide a possible mechanism by which Cai2+ mediates the link between the Ca2+ transients during contraction and the action potential duration.
Hemodynamic monitoring for 24 h in unanesthetized rats
Authors: Smith T. L. , Coleman T. G. , Stanek K. A. , Murphy W. R.
Published: December 2017

A new technique is described that allows minute-to-minute recordings of cardiac output and arterial pressure in unanesthetized rats for periods of 24 h and longer. Rats were instrumented with electromagnetic flow probes and arterial catheters. An electrical and hydraulic swivel was interposed between the rat and recording apparatus to allow free range of movement. Data were collected and analyzed once each minute by computer. Average 24-h values (mean +/- SD) for the following hemodynamic variables were determined in eight rats [expressed where appropriate as a function of body weight (BW)]: cardiac output (98.1 +/- 14.7 ml/min), cardiac index (29.2 +/- 4.4 ml.min-1.100 g BW-1), mean arterial pressure (92.5 +/- 7.8 mmHg), heart rate (347 +/- 45 beats/min), peak aortic flow (403 +/- 32 ml/min), stroke volume (282 +/- 26 microliters), stroke volume index (84.4 +/- 8.1 microliters/100 g BW), and total peripheral resistance index (3.26 +/- 0.46 mmHg.ml-1.min.100 g BW). These results provide a data base of hemodynamic values for unanesthetized adult, Sprague-Dawley male rats, which has not been previously available. In addition, cardiac index, mean arterial pressure, and total peripheral resistance index demonstrated diurnal variation. Diurnal variation contributed substantially to the overall variance observed within these variables. Hourly variance was also substantial and indicates the use of continuous recordings for short-term experiments.
Decreased lymphatic pumping after intravenous endotoxin administration in sheep
Authors: Elias R. M. , Johnston M. G. , Hayashi A. , Nelson W.
Published: December 2017

The effects of endotoxin on the ability of lymphatic vessels to pump fluid in vivo have been assessed with the use of a sheep model system that permits analysis of lymph pumping in sheep without the complication of variable lymph inputs. This involved the isolation of intestinal lymphatic vessels from all lymph input, with saline or lymph provided from a reservoir. The blood and nerve supplies to the vessel were left intact. With no net driving pressure, but with a transmural pressure applied to the vessel to initiate spontaneous contractions and fluid pumping, the intravenous administration of endotoxin (3.3 micrograms/kg in anesthetized sheep and 33 micrograms/kg in nonanesthetized animals) reduced fluid propulsion in both groups of animals (P less than 0.02 and P less than 0.03, respectively). Comparisons with animals that did not receive endotoxin revealed maximum inhibition greater than 90% in anesthetized and 50% in nonanesthetized sheep. Normal pulsatile lymphatic pressures (produced from lymphatic contractions) were reduced in frequency and amplitude after endotoxin administration. Endotoxin itself had no effect on the vessels when added to the fluid in the reservoir, suggesting that the inhibition of the "lymph pump" was mediated through the interaction of endotoxin with cellular or humoral elements in the host. In addition to suppression of lymphatic contractile activity, the intravenous injection of endotoxin enhanced lymph formation as indicated by the 3- to 10-fold increases in lymph flow rates in the two groups. We conclude that, for a given transmural pressure, the systemic administration of endotoxin reduces lymphatic pumping activity. We speculate that this effect may be important in the pathogenesis of the edema associated with sepsis.
Simultaneous measurement of calcium transients and motion in cultured heart cells
Authors: Peeters G. A. , Hlady V. , Bridge J. H. , Barry W. H.
Published: December 2017

The fluorescent Ca2+ probe indo-1 is a new intracellular Ca2+ concentration [( Ca2+]i) indicator that may be suitable for measurement of [Ca2+]i transients in intact heart cells. We exposed spontaneously contracting cultured chick embryo ventricular cells (37 degrees C) to the membrane-permeable indo-1-acetoxymethyl ester (indo-1 AM). Indo-1 loading was associated with a decrease in the amplitude of contraction measured with a video motion detector, but contractility returned to control levels during a subsequent 30-min wash. Analysis of emission spectra of dye obtained by digitonin permeabilization of cells loaded in indo-1 AM showed that the active intracellular dye was not pure indo-1 but probably includes partially deesterified molecules. With the use of an inverted X40 objective epifluorescence system, washed cells containing indo-1 were excited at 360 nm, and fluorescence intensity was measured at 410 nm (increases with increasing [Ca2+]) and 480 nm (decreases with increasing [Ca2+]). Calibration of the [Ca2+]i signals, reflected by the ratio of 410 to 480 nm fluorescence, was achieved by use of ethylen-glycol-bis(beta-aminoethylether)-N,N'-tetraacetic acid (EGTA)-Ca2+ buffered solutions containing the nonfluorescent Ca2+ ionophore Bromo-A23187. Average end-diastolic and peak-systolic [Ca2+]i were 328 +/- 32 and 813 +/- 72 nM (means +/- SE, n = 8). The onset of the [Ca2+]i transient preceded motion by 27 +/- 5 ms (means +/- SE, n = 4), but generally resembled the motion signals in contour. These findings indicate that indo-1 may be used to detect [Ca2+]i transients in isolated ventricular cells without causing significant alterations in mechanical performance.
Control of arterial pressure in conscious, sinoaortic-denervated sheep in normoxia and hypoxia
Authors: Miki M. , Miki K. , Hajduczok G. , Curran-Everett D. , Krasney J. A.
Published: December 2017

The contribution of the sinoaortic reflexes to the control of both the mean level and variability of arterial pressure (Pa) and heart rate (HR) was studied in five adult ewes after chronic section of the carotid sinus and aortic depressor nerves (SAD). SAD group responses were compared with a sham-operated group (n = 6). Pa was 15% lower in the SAD group due to a reduction of total peripheral resistance. The standard deviations and coefficients of variation for both Pa and HR obtained by continuous 16-h monitoring (10-s intervals) in the SAD sheep were not significantly different from those of the sham group. Arterial hypoxia (arterial PO2 = 40 mmHg for 96 h) had no significant influence on the mean values or variability for Pa and HR for either group, although both groups spent more time lying down. Ventilation was unchanged in the SAD group. Thus mean Pa is lower after removal of baroreceptor and chemoreceptor inputs, but the variabilities of both HR and Pa are unaltered during both normoxia and hypoxia in this sedentary species.
Ca2+ signals obtained with multiple indicators in mammalian vascular muscle cells
Authors: DeFeo T. T. , Briggs G. M. , Morgan K. G.
Published: December 2017

Enzymatically isolated single cells from ferret portal vein were loaded with the fluorescent dyes fura-2 and chlortetracycline. Ferret portal vein intact strips were loaded with the luminescent indicator aequorin. At short loading times, fura-2 loading resulted in relatively homogeneous images of labeled cells. At longer loading times, extremely heterogeneous images were obtained that were similar to those produced by chlortetracycline, an indicator recognized to enter calcium-storage organelles. A significant effect of fura-2 on contractile function was detected at the long but not at the short loading time. Caffeine, which is known to deplete calcium from sarcoplasmic reticulum, decreased the fura-2 fluorescent intensity when cells were incubated for a long loading time but caused no statistically significant change at the short loading time. Caffeine caused no drop in the aequorin signal but did cause a drop in the chlortetracycline fluorescence. These results are consistent with the idea that aequorin reports cytoplasmic intracellular calcium concentration ([Ca2+]i), chlortetracycline reports stored calcium, and fura-2 reports a mixed signal from the cytoplasm and calcium-storage organelles depending on incubation time.
Preconditioning of ischemic myocardium: reperfusion-induced arrhythmias
Authors: Shiki K. , Hearse D. J.
Published: December 2017

Hearts of anesthetized rats (n = 12 in each of 7 groups) were subjected to 5 min of regional ischemia; on reperfusion, 100% exhibited ventricular tachycardia (VT), 83% ventricular fibrillation (VF), and the mean total number of premature ventricular complexes (PVC) was 681 +/- 220. Hearts were then reverted to sinus rhythm and allowed to "recover" for 10, 20, 30, 60, 120 min, 1 or 3 days; they were again subjected to 5 min of ischemia and reperfusion. With recovery periods of 10 and 20 min a second episode of ischemia and reperfusion resulted in very few arrhythmias: 0% VF in both instances, 17 and 8% VT, and only 4 +/- 3 and 9 +/- 5 PVC, respectively. As the recovery period increased to 3 days there was a progressive return of vulnerability to reperfusion-induced arrhythmias. However, this return was slow, such that with a recovery time of 60 min, only 33% of hearts fibrillated. In additional studies, hearts were subjected to 0.5, 1.0, 3.0, or 5 min of regional ischemia, 10 min of reperfusion, 5 min of ischemia, and a second period of reperfusion. The vulnerability to arrhythmias during the second period of reperfusion was found to correlate inversely with the incidence of arrhythmias elicited by the first episode of reperfusion. We propose that a very short period of ischemia and reperfusion "preconditions" the myocardium so as to influence the vulnerability of the heart to subsequent reperfusion-induced arrhythmias, and that "recovery" from this effect can take a substantial period of time.
Contractile function of isolated young and adult rat heart cells
Authors: Haworth R. A. , Griffin P. , Saleh B. , Goknur A. B. , Berkoff H. A.
Published: December 2017

The stimulated contractile function of aerobic isolated adult rat heart cells was assessed by laser light diffraction. Cells were maintained for up to 8 h by attachment to a cover slip and continuous perfusion in a chamber on the microscope stage. On stimulation such cells beat as though unattached. Cells showed a negative staircase which was reduced by increasing Ca or isoproterenol. Ryanodine caused a positive staircase on stimulation, which was enhanced by increasing Ca or isoproterenol or by using cells from younger rats. For beats of constant contraction duration, there was a linear relationship between the magnitude of cell shortening and the velocity of shortening, independent of the concentration of extracellular Ca. We conclude the following. 1) The beat characteristics of isolated cells are very similar to those of papillary muscle. 2) Attachment of cells need not alter their unloaded shortening characteristics. 3) Cells appear to contract against an internal load, to an extent determined by the degree of myofilament activation. 4) Cells from young rats require less extracellular Ca than those from adult rats for the same beat magnitude.
Influence of intracellular acidosis on contractile function in the working rat heart
Authors: Jeffrey F. M. , Malloy C. R. , Radda G. K.
Published: December 2017

The decrease in myocardial contractility during ischemia, hypoxia, and extracellular acidosis has been attributed to intracellular acidosis. Previous studies of the relationship between pH and contractile state have utilized respiratory or metabolic acidosis to alter intracellular pH. We developed a model in the working perfused rat heart to study the effects of intracellular acidosis with normal external pH and optimal O2 delivery. Intracellular pH and high-energy phosphates were monitored by 31P nuclear magnetic resonance spectroscopy. Hearts were perfused to a steady state with a medium containing 10 mM NH4Cl (extracellular pH, 7.4). The subsequent washout of NH3 from the cytosol generated a slight acidosis (from intracellular pH 7.0 to 6.8) which was associated with little change in the determinants of O2 consumption (rate-pressure product) and O2 delivery (coronary flow). Acidosis induced a substantial decrease in aortic flow and stroke volume which was associated with little change in peak systolic pressure. Results were qualitatively similar at different external [Ca2+] (1.75, 2.5, 3.15 mM) and preload (12 or 21 cmH2O) but were most prominent at the lowest external [Ca2+] and left atrial pressure. In contrast to this model of isolated intracellular acidosis, hearts subject to a respiratory (extracellular plus intracellular) acidosis showed a marked reduction in pressure development. It was concluded that 1) for the same intracellular acidosis the influence on tension development was more pronounced with a combined extra- and intracellular acidosis than with an isolated intracellular acidosis, and 2) stroke volume at constant preload was impaired by intracellular acidosis even though changes in developed pressure were minimal. These observations suggest that isolated intracellular acidosis has adverse effects on diastolic compliance and/or relaxation.
Regulation of twitch tension in sheep cardiac Purkinje fibers during calcium overload
Authors: Berlin J. R. , Cannell M. B. , Lederer W. J.
Published: December 2017

The dependence of twitch tension on the interval (delta t) between depolarizations was examined in voltage-clamped sheep cardiac Purkinje fibers under conditions of calcium overload. During the development of calcium overload (produced by sodium-pump inhibition), twitch amplitude changes from a monotonic function of delta t to an oscillatory one. We investigated the cellular processes underlying this oscillatory relationship. Measurable calcium current was blocked by D 600 (25 microM), but neither the twitch nor the oscillatory dependence of twitch tension on delta t was abolished. Caffeine (2 mM), applied to modify sarcoplasmic reticulum function, decreased the oscillatory period of the twitch/interval relationship as it increased the frequency of spontaneous fluctuations of resting tension. Our results suggest that the oscillatory relationship between twitch amplitude and delta t is not caused by changes in the calcium current per se but rather by fluctuations in the amount of releasable calcium in the sarcoplasmic reticulum. Additionally, we conclude that the calcium current may not be a necessary prerequisite for depolarization to trigger calcium release from the sarcoplasmic reticulum under conditions of calcium overload.
Age-related changes in adrenergic vasoconstrictor responses of the rat hindlimb
Authors: Handa R. K. , Duckles S. P.
Published: December 2017

Vascular adrenergic responses were examined in the hindlimb perfused with blood at constant flow using pentobarbital-anesthetized male Fischer 344 rats aged 6, 12, 20, and 24 mo. The increase in hindlimb perfusion pressure to lumbar sympathetic nerve stimulation was significantly smaller in 20- and 24-mo-old rats than in younger animals, whereas vasoconstrictor responses to intraarterial administration of norepinephrine, L-phenylephrine, and methoxamine were reduced only in the 24-mo-old animals. Thus neurogenic vasoconstriction in the hindlimb is reduced at 20 mo of age, whereas there is a more generalized postjunctional loss of adrenergic responsiveness at 24 mo. In the presence of the beta-adrenoceptor antagonist, propranolol, vasoconstrictor responses to exogenous norepinephrine did not differ when 12- and 20-mo-old animals were compared. Furthermore, in the presence of propranolol the nerve-mediated rise in hindlimb perfusion pressure also did not differ in 12- and 20-mo-old rats. Blockade of neuronal norepinephrine uptake with cocaine produced a greater potentiation of vasoconstrictor responses to both nerve stimulation and exogenous norepinephrine in the older rats. Therefore, the reduced nerve-mediated vasoconstriction in 20-mo-old rats may be due to neuronal activation of beta-adrenoceptors as well as enhanced neuronal norepinephrine reuptake.
Modulation of macromolecular permeability by immune-complexes and a beta-adrenoceptor stimulant
Authors: Adamski S. W. , Langone J. J. , Grega G. J.
Published: December 2017

The suffused, noneverted cheek pouch of ovalbumin (OA)-immunized hamsters was employed to study changes in vascular permeability utilizing intravital light microscopy and direct measurements of plasma to suffusate tracer efflux. Suffusion of the cheek pouches of immunized animals with OA for 10 min stimulated the formation of focal venular fluorescein isothiocyanate dextran (FITC-D, 70,000 Da) leakage sites and produced increases in the plasma to suffusate FITC-D efflux resulting in marked increases in concentration of FITC-D in suffusate ([FITC-D]s). The intravenous injection of the FITC-D 15 to 60 min after the start of the OA suffusion failed to reveal the formation of vascular FITC-D leakage sites or increases in [FITC-D]s. In contrast, the intravenous injection of the tracer at the start or 10 min after the start of the OA suffusion revealed the formation of venular FITC-D leakage sites and marked increases in [FITC-D]s. Treatment with diphenhydramine or isoproterenol completely inhibited the antigen-stimulated formation of venular FITC-D leakage sites and increases in [FITC-D]s. It is concluded that antigen-antibody reactions resulting in the production of immune complexes trigger immediate increases in the plasma to suffusate FITC-D clearance via the formation of venular FITC-D leakage sites subsequent to the release of endogenous histamine. The increase in venular permeability is marked but transient, lasting approximately 10 min, and is subject to inhibition by either diphenhydramine or isoproterenol.
Effect of cyclosporin on blood pressure and renin-aldosterone axis in rats
Authors: Lustig S. , Stern N. , Eggena P. , Tuck M. L. , Lee D. B.
Published: December 2017

Although hypertension is a frequent complication of cyclosporin A (CSA) therapy in clinical practice, little experimental information is available on the nature and the mechanism of this form of hypertension. We studied the effect of currently recommended therapeutic dosages of CSA, i.e., 5 (CSA5) and 20 (CSA20) mg.kg-1.day-1, on blood pressure and the renin-aldosterone system (RAS) in spontaneously hypertensive rats (SHR). Influence of in vivo CSA treatment on in vitro angiotensin II (ANG II)-stimulated aldosterone secretion by isolated adrenal glomerulosa cells (AGC) was also measured. CSA treatment in SHR resulted in a consistent increase in systolic blood pressure. This increase in blood pressure occurred in the absence of significant changes in creatinine clearance in CSA5 rats, whereas in CSA20 rats a significant reduction in creatinine clearance was observed. Sodium balance and serum calcium and magnesium concentrations were not different between the control group and either of the two CSA-treated groups of rats. Plasma renin concentration (PRC) and inactive renin (IR) were markedly elevated, but plasma renin substrate remained unchanged with CSA administration. Despite the presence of hyperreninemia, plasma aldosterone was not elevated, suggesting that CSA may induce relative adrenal resistance to ANG II. This possibility was tested using AGC isolated from CSA-treated rats. ANG II-stimulated aldosterone secretion in AGC was diminished by low dose and aborted by high dose CSA-treatment. Thus CSA administration in SHR induces a predictable increase in blood pressure in association with "hyperreninemic hypoaldosteronism."
Calmodulin antagonists depress calcium and potassium currents in ventricular and vascular myocytes
Authors: Klockner U. , Isenberg G.
Published: December 2017

Myocytes isolated from guinea pig ventricles or bovine portal veins were voltage clamped with a single patch electrode. The calmodulin antagonists (CaM-A) calmidazolium, trifluoperazine (TFP), and chlorpromazine acted as Ca antagonists; they reduced the calcium inward current ICa in a voltage- and use-dependent way. For ventricular myocytes, 50% effective concentration (EC50) of calmidazolium was 1 microM, and the EC50 for TFP was 2.5 microM. For vascular myocytes, these numbers were 0.3 and 1 microM, respectively. CaM-A moderately retarded the inactivation time course and shifted the ICa availability curve to more negative potentials. CaM-A were not selective Ca antagonists; other membrane currents such as sodium currents and inwardly and delayed potassium currents were reduced as well (EC50 between 5 and 10 microM). It is unlikely that the above effects require binding of CaM-A to Ca-calmodulin, since reduction of ICa or potassium current (IK) was not modified when 1) the cells were loaded with 100 microM exogenous calmodulin or 2) Ca ions were removed from the extra- and intracellular space. Instead, the unspecific reduction of membrane currents may result from a change in the lipids of the sarcolemma into which CaM-A partition and accumulate.
Influence of vasoconstrictor systems on leg vasodilation during heating of dehydrated baboons
Authors: Thornton R. M. , Proppe D. W.
Published: December 2017

This study, carried out in two parts, sought to determine the importance of vasopressin (VP), the renin-angiotensin system (RAS), and the sympathetic nervous system in the dehydration-produced attenuation of hindlimb (cutaneous) vasodilation during environmental heating (EH). Baboons, chronically instrumented for blood sampling and for measurement of mean iliac blood flow (MIBF), arterial pressure, and core temperature (Tc), were subjected to EH while in euhydrated and dehydrated (64–72 h of water deprivation) states. EH consisted of exposure to an elevated ambient temperature (40–42 degrees C) until Tc reached 39.5 degrees C. In part I, indexes of the above vasoconstrictor systems were measured. Base-line plasma renin activity (PRA) and VP and norepinephrine concentrations were all significantly elevated by dehydration. In addition, the increase in PRA during EH was accentuated by dehydration. In part II, the effects of blockades of the RAS, the pressor action of VP, and the innervation of the hindlimb on hindlimb vasodilation during EH were assessed. None of these blockades, singly or together, reversed the dehydration-produced attenuation of the increase in MIBF during EH. Thus we conclude that other mechanisms are responsible for the dehydration-produced attenuation of cutaneous vasodilation in baboons during EH.
Specificity of FPL 57231 for leukotriene D4 receptors in fetal pulmonary circulation
Authors: Gause G. E. , Baker R. , Cassin S.
Published: December 2017

The effects of leukotriene D4 and the putative leukotriene receptor antagonist FPL 57231 were studied on the pulmonary circulation of alpha-chloralose-anesthetized fetal lambs close to term. At constant pulmonary inflow leukotriene D4 (LTD4, 0.1-10 micrograms), as bolus injections, caused dose-dependent increases in pulmonary vascular resistance. FPL 57231 (1.0-10 mg/kg) not only blocked the pressor responses to LTD4 but also lowered the normal pulmonary vascular resistance in a dose-dependent fashion. However, FPL 57231 also decreased the pulmonary pressor response to U 46619, a thromboxane A2 mimic, as well as the pressor response to phenylephrine HCl. Furthermore, the pressor responses to LTD4 were markedly reduced by cyclooxygenase inhibition. In preliminary experiments we demonstrated that the phenidone derivative, BW755C, which is a dual inhibitor of both cyclooxygenase and 5-lipoxygenase enzymes, did not block the pressor response to hypoxia. We conclude that FPL 57231 decreases fetal pulmonary vascular resistance by nonspecific mechanisms. Also the action of LTD4, is indirect and by way of the cyclooxygenase system. Although exogenous leukotrienes are able to produce a marked pulmonary pressor response, endogenous leukotrienes are probably not responsible for the hypoxic pulmonary pressor response of the fetal lung or its normally high pulmonary vascular resistance.
Blood flow through new microvessels: factors that affect regrowth of vasa vasorum
Authors: Williams J. K. , Armstrong M. L. , Heistad D. D.
Published: December 2017

A segment of abdominal aorta in dogs was transplanted to its original position (high PO2) or to the femoral vein (low PO2), and a segment of thoracic aorta was transplanted to its original position. Two days after grafting to each location, there was no blood flow (measured with microspheres) through vasa vasorum. After 2 and 4 wk, blood flow through vasa was restored to normal, or above normal, levels in all grafts. Vasa in grafts did not have smooth muscle, and they were not responsive to adenosine. Medial necrosis occurred in grafts of thoracic aorta but not in grafts of abdominal aorta. There was cellular degeneration and medial atrophy in grafts of abdominal aorta to the femoral vein. We conclude that 1) revascularization of the aorta by vasa vasorum is rapid; 2) new vasa do not have smooth muscle, and they are not responsive to vasoactive stimuli; and 3) medial necrosis occurs in grafts in which delivery of oxygen to media is compromised, either by low luminal PO2 or by interruption of medial vasa (in thoracic aorta), but not when the abdominal aorta is excised and reanastomosed. Absence of medial necrosis in grafts of abdominal aorta indicates that diffusion from the lumen of the vessel is adequate to nourish the vessel. This finding provides evidence that adventitial vasa, in contrast to medial vasa, are not essential for nourishment of the vessel wall.
Effects of dihydropyridine calcium channel modulators on cardiac sodium channels
Authors: Yatani A. , Kunze D. L. , Brown A. M.
Published: December 2017

To investigate whether cardiac sodium channels have dihydropyridine (DHP) receptors we studied the effects of the optically pure (greater than 95%) enantiomers of the DHPs PN200–110 and BAY-K 8644 and the racemic DHP nitrendipine (NTD). Whole cell and single-channel sodium currents were recorded from cultured ventricular cells of neonatal rats using the patch-clamp method. NTD reduced cardiac sodium currents in a voltage-dependent manner. Inhibitory effects were due to an increase in traces without activity. The unit conductance remained unchanged. At negative holding potentials, NTD transiently increased the probability of channel opening. Both (+) and (-) PN 200–110 blocked sodium channels, although the (-) isomer was about one order of magnitude less effective. The blocking effects were voltage dependent. (+) BAY-K 8644 had similar blocking effects. (-) BAY-K 8644 produced an increase in sodium currents due to an increased frequency of channel openings and a marked prolongation of open time without any significant change in unit conductance. The DHPs have effects on cardiac sodium whole cell and single-channel currents that appear identical to and are as stereospecific as their effects on cardiac calcium currents, although the concentrations required are larger. In contrast the inwardly rectifying potassium channel (IK1) is unaffected by these DHPs. We conclude that functionally equivalent DHP receptors are present in cardiac sodium and calcium channels but not potassium channels and take this as evidence of the homology between sodium and calcium channels.
Effect of intracarotid administration of ouabain in dogs
Authors: Lopez J. A. , Timmis A. D. , Garan H. , Homcy C. J. , Powell W. J.
Published: December 2017

Recent work has documented both centrally mediated vasoconstriction and, paradoxically, a withdrawal of sympathetic activity in response to cardiac glycosides. In the present study the possibility that these different neurogenic responses might be dose related was investigated by infusing ouabain (5, 10, and 20 micrograms) for 5 min into the right common carotid artery of 51 anesthetized mongrel dogs. Effects on vascular resistance in the isolated, separately perfused but innervated gracilis muscle were measured. A 5-microgram infusion of ouabain (n = 6) produced a prolonged decrease in gracilis vascular resistance (GVR) of 19.4 +/- 5.4% (SE) from 43.4 +/- 6.7 (SE) to 33.7 +/- 4.2 mmHg.ml-1.100 g muscle.min (resistance units, RU). This vasodilatory response was not present in nine additional dogs following denervation of the carotid bifurcation. A 10-microgram infusion had no significant effect on GVR (n = 5), but the 20-microgram infusion of ouabain (n = 8) caused a rapid increase in GVR from 42.1 +/- 5.0 to 47.6 +/- 5.7 RU, an increase of 14.4 +/- 5.6%, which was not influenced by denervation of the carotid bifurcation (n = 8). This vasoconstriction was transient returning toward the control levels by 20 min following the infusion. These data indicate important dose-related differences in vascular responses to ouabain that are directionally opposite and mediated by separate neurogenic mechanisms. At high doses a centrally mediated vasoconstriction dominates, whereas at low doses carotid bifurcation mediated vascular dilatation occurs.
Improved techniques for cardiovascular monitoring in rats as applied during endotoxemia
Authors: Biber B. , Schaefer C. F. , Smolik M. J. , Lerner M. R. , Brackett D. J. , Wilson M. F. , Fagraeus L.
Published: December 2017

We describe a new combination of techniques for measurements of systemic blood pressure, central venous pressure, pulmonary arterial (PA) pressure, PA wedge pressure, and cardiac output in the rat. Application of the method to the conscious rat in a septic shock (Escherichia coli endotoxin iv injection) model demonstrated a response pattern of decreased cardiac output and stroke volume, increased total peripheral vascular resistance and heart rate, and transiently decreased systemic arterial pressure. In the pulmonary circulation, a very brief hypertension and a sustained increase in pulmonary vascular resistance were observed, but changes in PA wedge pressure were small. The soft PA catheter (0.3 mm ID, 0.6 mm OD) had no undue effects on cardiovascular function. We suggest that this combined technique could be useful for many cardiovascular studies in the rat, not only as related to shock research.
An electronic, negative feedback device to control arterial pressure
Authors: Pardini B. J. , Lund D. D. , Wurster R. D. , Anderson R. H.
Published: December 2017

Cardiovascular investigations frequently require manipulation of the arterial pressure for assessment of neural reflexes. This has largely been accomplished in the past by a bolus injection or constant infusion of a vasoactive drug. The purpose of the present investigation was to develop a proportional, integrative, negative feedback device capable of controlling arterial pressure in rats by modulating the infusion rate of the vasoconstrictor, phenylephrine. The device was designed to 1) maintain arterial pressure at a constant plateau level above the prevailing control pressure and 2) create linear ramp increases in arterial pressure. We have validated this system with conscious and urethan-anesthetized rats instrumented with arterial cannulas for arterial pressure measurement and aortic or venous cannulas for phenylephrine infusion. When used to create steady-state changes in blood pressure at 150 mmHg, the device maintained arterial pressure within +/- 7 mmHg of the desired level for the 20-min experimental periods. When used to create rising arterial pressure ramps (duration: 60 s; magnitude: 30 mmHg), regression analysis of the pressure vs. time relationship indicated that the correlation coefficient was greater than 0.99 in 90% of the trials, indicating a linear ramp. This device will aid in future cardiovascular protocols, especially in the analysis of baroreflex sensitivity.
Oxygen-saving effect of negative work in dog left ventricle
Authors: Suga H. , Goto Y. , Yasumura Y. , Nozawa T. , Futaki S. , Tanaka N. , Uenishi M.
Published: December 2017

We compared left ventricular oxygen consumptions (VO2) of contractions performing negative external work (EW less than 0) and positive external work (EW greater than 0) that developed comparable peak systolic pressures in the excised cross-circulated dog hearts. We changed the polarity of ventricular work with volume servo-pump and measured both left ventricular VO2 and systolic pressure-volume area (PVA). PVA represents the total mechanical energy generated by contraction and is equal to the area circumscribed by the end-systolic and end-diastolic pressure-volume (PV) relation curves and the systolic PV trajectory. For comparable peak systolic pressures of approximately 90 mmHg, contractions performing negative EW of -834 +/- 327 mmHg.ml.100 g left ventricle-1 had 27 +/- 11% smaller VO2 and 62 +/- 12% smaller PVA than those performing positive EW of 851 +/- 329 mmHg.ml.100 g-1. The smaller VO2 for negative EW could be accounted for by the linear VO2-PVA relation regardless of the polarity and magnitude of work. The results indicate that negative work can save VO2 of contractions to develop a given peak systolic pressure.
Hypoxemia and hypercapnia in conscious dogs: opioid modulation of catecholamines
Authors: Rose C. E. , Latham L. B. , Brashers V. L. , Rose K. Y. , Sandridge M. P. , Carey R. M. , Althaus J. S. , Miller E. D.
Published: December 2017

The role of endogenous opioids in systemic and renal circulatory changes during combined acute hypoxemia and hypercapnic acidosis was evaluated in seven conscious female mongrel dogs in rigid sodium balance. Animals were studied 2 wk apart in separate protocols of combined acute hypoxemia (arterial O2 tension = 33 +/- 1 mmHg) and hypercapnic acidosis (arterial CO2 tension = 56 +/- 1 mmHg, pH = 7.19 +/- 0.01) of 40 min duration during 1) naloxone, 5 mg/kg iv bolus followed by an intravenous infusion of 5 mg.kg-1.h-1, and 2) vehicle (5% dextrose in water) alone. Systemic circulatory changes during the combined acute blood-gas derangement including increased mean arterial pressure, heart rate, and cardiac output and decreased total peripheral resistance were comparable between naloxone and vehicle treatments. However, in striking contrast to the brief fall in renal hemodynamic function during combined acute hypoxemia and hypercapnic acidosis with vehicle, naloxone administration during the combined acute blood-gas derangement resulted in a sustained decrease in effective renal plasma flow, glomerular filtration rate, and filtered sodium load and enhanced rise in circulating norepinephrine and epinephrine. Changes in plasma renin activity were comparable between vehicle and naloxone protocols except that plasma renin activity increased from the first to the second 20-min periods of combined hypoxemia and hypercapnic acidosis with naloxone. These observations suggest that endogenous opioids may contribute to preservation of renal hemodynamic function during acute blood-gas derangements, possibly through attenuation of sympathetic nervous system and renin-angiotension activation.
Cerebral blood flow, glucose use, and CSF ionic regulation in potassium-depleted rats
Authors: Schrock H. , Kuschinsky W.
Published: December 2017

Rats were kept on a low-K+ diet for 25 or 70 days. Local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCGU) were measured in 31 different structures of the brain by means of the [14C]iodoantipyrine and [14C]2-deoxy-D-glucose method. After 25 and 70 days of K+ depletion LCBF was decreased significantly in 27 and 30 structures, respectively, the average decrease being 19 and 25%. In contrast, average LCGU was not changed. Cisternal cerebrospinal fluid (CSF) K+ concentration decreased significantly from 2.65 +/- 0.02 mM in controls to 2.55 +/- 0.02 mM and 2.47 +/- 0.02 mM in the two treated groups (P less than 0.01). CSF [HCO3-], pH, and PCO2 were increased in K+-depleted animals. These data show that K+ depletion induces an increase in CSF pH and a decrease in CSF K+ concentration, both of which cause a reduction in cerebral blood flow. The increased CSF PCO2 is secondary to the reduction of blood flow, since brain metabolism and arterial PCO2 remained constant.
Effects of vasoactive stimuli on blood flow to choroid plexus
Authors: Faraci F. M. , Mayhan W. G. , Williams J. K. , Heistad D. D.
Published: December 2017

The goal of this study was to examine effects of vasoactive stimuli on blood flow to choroid plexus. We used microspheres to measure blood flow to choroid plexus and cerebrum in anesthetized dogs and rabbits. A critical assumption of the microsphere method is that microspheres do not pass through arteriovenous shunts. Blood flow values obtained with simultaneous injection of 15- and 50-micron microspheres were similar, which suggests that shunting of 15-micron microspheres was minimal. Blood flow to choroid plexus under control conditions was 287 +/- 26 (means +/- SE) ml.min-1.100 g-1 in dogs and 385 +/- 73 ml.min-1.100 g-1 in rabbits. Consecutive measurements under control conditions indicated that values for blood flow are reproducible. Adenosine (5 microM.kg-1. min-1 iv) did not alter blood flow to cerebrum but increased blood flow to choroid plexus two- to threefold in dogs and rabbits. Norepinephrine (0.5 micrograms.kg-1.min-1) and phenylephrine (25 micrograms.kg-1.min-1) did not affect blood flow to cerebrum but decreased blood flow to choroid plexus by approximately 50%. We suggest that 1) the microsphere method provides reproducible valid measurements of blood flow to the choroid plexus in dogs and rabbits and 2) vasoactive stimuli may have profoundly different effects on blood flow to choroid plexus and cerebrum.
Autonomic modulation of atrioventricular conduction in ouabain-treated dogs
Authors: Wallick D. W. , Stuesse S. L. , Martin P. J.
Published: December 2017

There is a pronounced interaction between the two autonomic divisions in the control of some cardiac variables, e.g., heart rate and contractility; usually parasympathetic activation suppresses the sympathetic effects. There is controversy about whether a similar interaction occurs for atrioventricular (AV) conduction. We have previously been unable to describe such an interaction in adult dogs, although others found a sympathetic-parasympathetic interaction when the dog heart was paced at very short intervals (200-240 ms). We reasoned that a cardiac glycoside (ouabain 20 micrograms/kg iv), which accentuates the parasympathetic effect, might expose any autonomic interaction. The atrial and ventricular electrograms, heart period, and atrioventricular conduction time (A-A and A-V intervals) were measured in 18 anesthetized, open-chest adult dogs. The sinoatrial (SA) node was suppressed by injection of Nembutal (pentobarbital sodium) through the SA nodal artery, and the hearts were paced at 500- to 700-ms intervals. The sympathetic and vagus nerves were stimulated bilaterally at three levels before and after ouabain or a diluent was given. Data were analyzed by analysis of variance. We found that there was no significant sympathetic-parasympathetic interaction (P greater than 0.05) even after ouabain had potentiated the vagal effect by up to 100%. Thus, in dogs, control of AV conduction time by either autonomic division is independent of activity of the other divisions when the cycle length is not abbreviated.
Effects of age and training status on heart rate recovery after peak exercise
Authors: Darr K. C. , Bassett D. R. , Morgan B. J. , Thomas D. P.
Published: December 2017

Previous studies have shown that the kinetics of heart rate (HR) recovery are delayed in older individuals after exercise. This study was designed to determine whether this observation held when the variables of physical fitness and work intensity were controlled. Twenty male subjects were categorized into four groups (n = 5) according to age and fitness level (peak O2 consumption ml. kg-1.min-1): young trained (YT) 24 +/- 2 yr, 63 +/- 3 ml.kg-1. min-1; old trained (OT) 51 +/- 2 yr, 57 +/- 3 ml.kg-1.min-1; young untrained (YU) 25 +/- 3 yr, 44 +/- 2 ml.kg-1.min-1; old untrained (OU) 57 +/- 4 yr, 36 +/- 4 ml.kg-1.min-1. Bicycle ergometry exercise was performed in incremental stages to a maximally tolerated level of exertion, and HR was monitored continuously postexercise. Regression analysis of the fast (15-120 s) and initial slow (120-240 s) phases of recovery showed no effect of age on HR recovery when comparing YT vs. OT and YU vs. OU. Trained subjects, irrespective of age, demonstrated a significantly faster HR recovery than untrained subjects which was particularly marked during fast-phase recovery (P less than 0.005). These results indicate that the slower HR recovery previously reported in older subjects may be due to a failure to control for variables that influence recovery HR.