bluuebunny/crossref_metadata_2025 huggingface dataset:
Depolarization modulates endothelial cell calcium influx and microvessel permeability
Authors: He P. , Curry F. E.
Published: December 2017

We investigated the mechanisms whereby high-potassium (57.9 mM) Ringer solutions attenuate the increase in permeability caused when microvessels are exposed to the calcium ionophores ionomycin and A23187 (5 microM). In single perfused microvessels we measured cytoplasmic calcium concentration, [Ca2+]i, in the cells forming the microvessel wall and the hydraulic conductivity, Lp, to follow changes in the permeability of the microvessel walls. In normal Ringer solution, [Ca2+]i was increased to an initial peak value of 226 +/- 12 nM after exposure to calcium ionophores; the corresponding increase in microvessel Lp was 10.3 +/- 2.6 times control. With high-potassium solutions, the peak value of [Ca2+]i was 133 +/- 12 nM and Lp was increased to only 2.5 +/- 0.7 times control. Increasing extracellular calcium from 1.1 to 5 mM with high potassium restored the initial peak value of [Ca2+]i to 303 +/- 38 nM. The increases in both [Ca2+]i and Lp were abolished in calcium-free solutions. If high-potassium solutions depolarize the cells forming the microvessel wall as indicated by the membrane potential-sensitive dye bisoxonol, then the magnitude of the initial increase in [Ca2+]i could be accounted for by changes in the electrochemical driving force through conductive channels for calcium ion. Our results conform to the hypothesis that the permeability properties of microvessels are modulated by changes in the membrane potential of the endothelial cells and/or pericytes forming the microvessel wall.
Neural and humoral mechanisms of angiotensin-dependent hypertension
Authors: Cox B. F. , Bishop V. S.
Published: December 2017

We examined whether neural or humoral mechanisms mediate the acute versus chronic phases of angiotensin II (ANG II)-dependent hypertension in rabbits. ANG II was administered intravenously at 50 ng.kg-1.min-1 for 10 days. This dose of ANG II elevated mean arterial pressure (MAP) from 76 +/- 2 to 98 +/- 2 mmHg on day 1 and sustained the hypertension throughout the infusion period. Heart rate (226 +/- 7 beats/min) was not altered. The depressor response to ganglionic blockade (-38 +/- 2 mmHg) was significantly blunted on day 1 (-22 +/- 3 mmHg) and was significantly enhanced on days 5 (-52 +/- 4 mmHg) and 7 (-52 +/- 6 mmHg). In contrast, plasma norepinephrine (PNE) and renal sympathetic nerve activity (RSNA) levels were acutely reduced to approximately one-third of control (day 1 of ANG II) and chronically rose to an intermediate level (2-9 days of ANG II). However, the pressor effect of resetting PNE and RSNA may be magnified by an augmented pressor responsiveness to alpha-agonists after chronic ANG II. In animals with the area postrema removed, PNE, RSNA, and heart rate were acutely reduced and remained chronically depressed. In addition, area postrema lesion blocked the chronic, but not the acute hypertensive response, to infusing ANG II. Thus the direct vasoconstrictor actions of ANG II appear to acutely predominate, whereas neurogenic vasomotor tone appears to chronically predominate. This shift appears to be mediated by changes in vascular sensitivity, as well as the area postrema allowing resetting of the baroreflex.
Autonomic nervous system and cardiovascular variability in rats: a spectral analysis approach
Authors: Cerutti C. , Gustin M. P. , Paultre C. Z. , Lo M. , Julien C. , Vincent M. , Sassard J.
Published: December 2017

Mechanisms underlying systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) beat-to-beat variability were investigated using spectral analysis in conscious genetically normotensive (LN) and hypertensive (LH) adult rats from the Lyon strains. In LN rats, basal SBP, DBP, and HR spectra exhibited peaks in low (LF: 0.38-0.45 Hz) and high (HF: 1.04-1.13 Hz) frequencies. The LF peak of SBP, and even more of DBP, could be attributed to the influence of the sympathetic nervous system as it disappeared after destruction of the sympathetic nerves or a combined alpha- and beta-adrenoceptor blockade, whereas it was higher after blockade of the parasympathetic system. The HF peak of HR, linked to the respiratory rate, was abolished by the parasympathetic system blockade, whereas those of SBP and DBP were enhanced. In LH rats, which exhibit a lower sympathetic activity, the LF peaks of SBP and DBP were less distinct compared with LN controls. We conclude that the LF peak of DBP and the HF peak of HR are likely to represent useful estimates of the sympathetic vascular control and of the parasympathetic cardiac control, respectively.
Neuropeptide Y and 3,4-dihydroxyphenylglycol effluxes from artery are oxygen sensitive
Authors: Rorie D. K. , Hunter L. W. , Tyce G. M.
Published: December 2017

Neuropeptide Y-like immunoreactivity (NPY-LI), norepinephrine (NE), and 3,4-dihydroxyphenylglycol (DOPEG), the intraneuronal metabolite of NE, were measured in superfusate before, during, and after electrical stimulation (ES) of nerves and in the tissue extract of dog pulmonary artery after in vitro superfusion. Vessels were stimulated at 12, 6, or 1 Hz. NE and DOPEG were quantified by high-performance liquid chromatography with electrochemical detection, NPY-LI by radioimmunoassay. The Krebs-Ringer superfusate was maintained at a partial pressure of oxygen of either 472, 100, 50, or 20 mmHg. Mean DOPEG efflux was 0.17, 0.15, 0.13, and 0.07 pmol/min during basal conditions and 0.73, 0.39, 0.30, and 0.15 pmol/min, respectively, during 12-Hz continuous stimulation using these four oxygen pressures. Stimulation-evoked efflux of NPY-LI was 1.5, 1.1, 0.3, and 0.2 fmol/min during 12-Hz stimulation. These studies provide evidence that the production and subsequent efflux of DOPEG into superfusate under resting conditions, during ES, and following ES are oxygen sensitive. Additionally, the efflux of NPY-LI from dog pulmonary artery resulting from high frequencies of ES is oxygen sensitive.
Regional epicardial and endocardial two-dimensional finite deformations in canine left ventricle
Authors: Fann J. I. , Sarris G. E. , Ingels N. B. , Niczyporuk M. A. , Yun K. L. , Daughters G. T. , Derby G. C. , Miller D. C.
Published: December 2017

We evaluated subepicardial and subendocardial two-dimensional finite deformations in the left ventricular (LV) anterior, lateral, and posterior regions in the closed-chest, conscious dog heart. Eight dogs underwent placement of 22 radiopaque markers in the LV myocardium. Sets of three markers were implanted in the anterior, lateral, and posterior subepicardium and subendocardium at the mid-ventricular level; reference markers were placed at apical and basal sites. Eight hours later, biplane videofluoroscopy was performed. Finite deformations for each subepicardial and subendocardial region were analyzed during three consecutive beats at end expiration. Circumferential shortening occurred in all layers and regions; similarly, longitudinal shortening occurred in all layers except that of the posterior endocardium. Values of principal strain were -0.19 +/- 0.08 (SD) and -0.10 +/- 0.03 for the anterior subendocardium and subepicardium, -0.20 +/- 0.07 and -0.10 +/- 0.02 for the lateral subendocardium and subepicardium, and -0.13 +/- 0.02 and -0.10 +/- 0.03 for the posterior subendocardium and subepicardium respectively (P less than 0.05 subendocardium vs. subepicardium). Second principal strain tended to be near zero or positive (from -0.01 +/- 0.05 to 0.04 +/- 0.05) in all regions. The end-systolic direction of principal strain was -29 +/- 32 degrees and -34 +/- 29 degrees in the anterior subepicardium and subendocardium, -47 +/- 10 degrees and -30 +/- 37 degrees in the lateral subepicardium and subendocardium, and -4 +/- 29 degrees and +7 +/- 23 degrees in the posterior subepicardium and subendocardium. Anterior and lateral directions of principal strain were similar in the subepicardial and subendocardial layers and oriented along the epicardial fiber axis, but the posterior direction tended to be circumferentially oriented.(ABSTRACT TRUNCATED AT 250 WORDS)
Distribution of cardiac output during diurnal changes of activity in rats
Authors: Delp M. D. , Manning R. O. , Bruckner J. V. , Armstrong R. B.
Published: December 2017

Rat locomotor and feeding behavior varies on a diurnal basis; at night the animals actively forage and eat, whereas during the day they are more inactive and somnolent. At night, cardiac output is higher, presumably for enhanced perfusion of the active muscles to support increased metabolism and for enhanced perfusion of the digestive organs to support increased digestion and nutrient absorption. Conversely, it is hypothesized that during the daytime, blood flow to these two tissues is relatively low. The purpose of this study was to test these hypotheses by measuring cardiac output and the distribution of cardiac output in rats at various times in the diurnal cycle (8:00 A.M., 4:00 P.M., and 8:00 P.M.). The radiolabeled microsphere technique was used to measure cardiac output and distribution of blood flow to the tissues. Distribution of the total cardiac output was accounted for by complete dissection, weighing, and counting of organs and carcass. Cardiac output at 8:00 P.M. (136 +/- 9 ml/min) was elevated 13% (P less than 0.05) over that at 4:00 P.M. The proportion of the cardiac output distributed to the skeletal muscles (4:00 P.M.: 25%; 8:00 P.M.: 27%) and to the digestive tract (4:00 P.M.: 14%; 8:00 P.M.: 14%) did not change between the two time periods. Thus total muscle blood flow increased (P less than 0.05) from 31 +/- 2 at 4:00 P.M. to 36 +/- 4 ml/min at 8:00 P.M.; the only digestive organ to show a significant increase in blood flow from 4:00 P.M. to 8:00 P.M. was the stomach (133 +/- 17 to 166 +/- 19 ml/min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Muscle capillary-to-fiber perimeter ratio: morphometry
Authors: Mathieu-Costello O. , Ellis C. G. , Potter R. F. , MacDonald I. C. , Groom A. C.
Published: December 2017

It is known that a substantial amount of capillary tortuosity is found in shortened muscles. However, the increased capillary length and surface area contributed by tortuosity and branching are seldom taken into account when capillarity is estimated and/or blood-tissue exchange is modeled in muscles. In this paper, we sought morphometric estimates of capillarity in transverse sections that incorporated data on capillary geometry. We derived equations to estimate capillary perimeter per fiber perimeter (i.e., capillary-to-fiber perimeter ratio) in transverse sections. We show how capillary-to-fiber perimeter ratio is related to capillary surface per fiber surface, i.e., to the amount of capillary surface available for exchange per muscle fiber surface area, and how it can be obtained by morphometry. Because capillary tortuosity and fiber perimeter are both a function of sarcomere length, the degree of extension or shortening of muscle samples obviously needs to be taken into account when capillary-to-fiber perimeter ratio is compared between muscles and/or samples. Using data currently available on capillary length and diameter with fiber shortening and extension, we show that it is a feature of capillary-to-fiber perimeter ratio to change relatively little with sarcomere length. As sarcomere length decreases from 2.80 to 1.58 microns in perfusion-fixed hindlimb muscles of rats, capillary and fiber perimeters in transverse sections increase substantially, whereas the ratio between the two variables, capillary-to-fiber perimeter ratio, changes only less than or equal to 10-15%.(ABSTRACT TRUNCATED AT 250 WORDS)
Areas of rostral medulla providing tonic control of renal and splenic nerves
Authors: Beluli D. J. , Weaver L. C.
Published: December 2017

The objective of this study was to determine whether nonuniform control of tonic discharge of renal and splenic nerves by the rostral ventrolateral medulla (RVLM) is dependent on viscerotopic representation of the kidney and the spleen in this region. Small (15 nl, 13 pmol) injections of the potent tau-aminobutyric acid agonist muscimol were used to map the RVLM of anesthetized rats, searching for areas that selectively provided tonic excitation of renal or splenic nerves. Most of the muscimol microinjections produced depressor responses and inhibition of sympathetic nerve activity. Activity of renal nerves was inhibited significantly more than that of splenic nerves, but we found no evidence for topographical organization of RVLM influences on tonic activity of these two nerves. However, this investigation did yield an important new observation, since approximately 10% of the injections caused pressor responses and increases in sympathetic discharge. The unexpected increases must have been caused by blockade of small groups of tonically active sympathoinhibitory neurons located throughout the RVLM. This disinhibition was not evoked from any specific region of the RVLM. In conclusion, the RVLM neurons and putative interneurons that tonically control the discharge of postganglionic renal and splenic neurons appear to be distributed homogeneously throughout this area. Neither excitatory nor inhibitory elements were organized topographically to specifically influence the renal or the splenic nerve. The neural organization responsible for the preferential effect on renal nerves may exist in the local microcircuitry within the RVLM and will be revealed only by an even more discrete analysis of these circuits.
Positive and negative contractile effects of neuropeptide Y on ventricular cardiomyocytes
Authors: Millar B. C. , Weis T. , Piper H. M. , Weber M. , Borchard U. , McDermott B. J. , Balasubramaniam A.
Published: December 2017

The potency of neuropeptide Y (NPY) to cause negative and positive contractile responses in rat ventricular cardiomyocytes was investigated. In these cells, NPY was found to activate the transient outward K+ current (Ito) and the slow inward Ca2+ current (Isi). As reported before (H. M. Piper, B. C. Millar, and J. R. McDermott, Naunyn Schmiedeberg's Arch. Pharmacol. 340: 333-337, 1989), NPY attenuated the increase in the contractile response induced by isoprenaline (10(-7) M). This effect of NPY could be abolished by 1) the presence of the inhibitor of Ito, 4-aminopyridine (4-AP, 0.5 mM); 2) pretreatment of the cells with pertussis toxin (1 microgram/ml for 6 h); and 3) the presence of the 19-amino acid COOH-terminal fragment of NPY, NPY-(18-36) (10(-6) M). In the absence of isoprenaline, but in the presence of 4-AP, NPY exerted a stimulatory effect on the cardiomyocytes. This effect could be abolished 1) by using the inhibitor of the Isi, verapamil (10(-8) M), but not 2) by pretreatment with pertussis toxin, nor 3) by coincubation with NPY-(18-36). The results indicate that in the rat the antiadrenergic negative contractile effect of NPY results from its action on the Ito. Blockade of this current by 4-AP unmasks a positive contractile effect of NPY that is related to activation of the Isi.
Abnormal Cai2+ handling is the primary cause of mechanical alternans: study in ferret ventricular muscles
Authors: Kihara Y. , Morgan J. P.
Published: December 2017

We tested the hypothesis that mechanical alternans of the heart is due to alternations in intracellular calcium (Cai2+) levels. Eight papillary muscles were isolated from the right ventricles of male ferrets and were chemically loaded with aequorin to record cytoplasmic Cai2+. To produce a steady-state mechanical alternans, the preparations were perfused with a physiological salt solution containing a low calcium concentration (0.25 mM), at 22 degrees C, and stimulated at 0.5-1.0 Hz in the presence of carbachol and propranolol. The aequorin signal (Cai2+) and isometric contraction were simultaneously recorded. In each muscle, the strong beats (beats with higher peak tension) were associated with larger Ca2+ transients than the weak beats. The relationships between peak Cai2+ and peak tension, both during strong and weak beats, were similarly modified by short-term frequency responses. On the other hand, the time courses of the isometric contractions and Ca2+ transients during strong beats and weak beats were superimposable. These data indicate that mechanical alternans is caused by an alternate change of Cai2+ available for activation of the myofilaments. Prolongation of the time for recycling Ca2+ by the sarcoplasmic reticulum, i.e., a depressed uptake function of the Ca2+ pump with concomitant slow transportation of Ca2+ from the uptake compartment to the release compartment in the sarcoplasmic reticulum, is suggested as a cause of the abnormal Cai2+ handling during mechanical alternans.
Regulation of single calcium channels in cerebral arteries by voltage, serotonin, and dihydropyridines
Authors: Worley J. F. , Quayle J. M. , Standen N. B. , Nelson M. T.
Published: December 2017

Unitary currents through Ca channels were measured from cell-attached patches on smooth muscle cells isolated from rabbit cerebral (basilar) arteries. Barium (80 and 10 mM) and calcium (80 and 10 mM) were used as the charge carriers. The dihydropyridine Ca channel agonist BAY R 5417 was used to increase open-state probability (Popen), with 500 nM BAY R 5417 increasing Popen 10-fold at 0 mV. Barium currents through single Ca channels were greater than calcium currents at any voltage, with single-channel conductances negative to -20 mV of 24.6 pS (80 mM barium), 15.1 pS (80 mM calcium), 17.2 pS (10 mM barium), and 5.8 pS (10 mM calcium). The single-channel Popen increased 2.7-fold per 5- to 7-mV membrane depolarization (negative to 0 mV) and was half maximal at +0.4 mV (80 mM calcium) and +13.5 mV (80 mM barium). Ca channels with calcium but not with barium as the charge carrier exhibited pronounced inactivation positive to -20 mV (half time, 112 ms at 0 mV). The dihydropyridine nimodipine (2 nM) inhibited average currents through Ca channels. The cerebral artery constrictor serotonin increased Popen of single Ca channels by as much as 200-fold without an effect on single-channel conductance. A second distinct amplitude of unitary currents was often observed, corresponding to a channel conductance of about one-half the more commonly observed level. The small-conductance-level channel was voltage dependent, did not inactivate over 0.5-s test pulses (with barium), and could be activated by serotonin.
Regulation of K+ and Ca2+ channels in experimental cardiac failure
Authors: Gopalakrishnan M. , Triggle D. J. , Rutledge A. , Kwon Y. W. , Bauer J. A. , Fung H. L.
Published: December 2017

To examine the status of ATP-sensitive K+ (K+ATP) channels and 1,4-dihydropyridine-sensitive Ca2+ (Ca2+DHP) channels during experimental cardiac failure, we have measured the radioligand binding properties of [3H]glyburide and [3H]PN 200 110, respectively, in tissue homogenates from the rat cardiac left ventricle, right ventricle, and brain 4 wk after myocardial infarction induced by left coronary artery ligation. The maximal values (Bmax) for [3H]glyburide and [3H]PN 200 110 binding were reduced by 39 and 40%, respectively, in the left ventricle, and these reductions showed a good correlation with the right ventricle-to-body weight ratio in heart-failure rats. The ligand binding affinities were not altered. In the hypertrophied right ventricle, Bmax values for both the ligands were not significantly different when data were normalized to DNA content or right ventricle weights but showed an apparent reduction when normalized to unit protein or tissue weight. Moderate reductions in channel densities were observed also in whole brain homogenates from heart failure rats. Assessment of muscarinic receptors, beta-adrenoceptors and alpha 1-adrenoceptors by [3H]quinuclidinyl benzilate, [3H]dihydroalprenolol, and [3H]prazosin showed reductions in left ventricular muscarinic and beta-adrenoceptor densities but not in alpha 1-adrenoceptor densities, consistent with earlier observations. It is suggested that these changes may in part contribute to the pathology of cardiac failure.
Synergistic nonuniform shortening of atrial refractory period induced by autonomic stimulation
Authors: Takei M. , Furukawa Y. , Narita M. , Ren L. M. , Karasawa Y. , Murakami M. , Chiba S.
Published: December 2017

We investigated the nonuniform effects of autonomic nerve stimulation of the effective refractory period (ERP) of the right atrium in the anesthetized dog. Stimulation of the discrete intracardiac sympathetic nerves to the sinoatrial (SA) nodal region uniformly shortened ERPs at three sites in the right atrium after administration of atropine. Right ansa subclavia (RS) stimulation similarly shortened ERPs in the absence of atropine. Stimulation of the discrete intracardiac parasympathetic nerves to the SA nodal region (SAP stimulation) shortened ERPs of the right atrium in a nonuniform manner. Simultaneous RS and SAP stimulation additively shortened ERPs at each site and decreased sinus rate much more than SAP stimulation alone. Shortening of ERP induced by SAP stimulation was greater than that induced by RS stimulation at similar absolute changes in heart rate. These results suggest that simultaneous activation of sympathetic and parasympathetic nerves nonuniformly shortens the ERP in the right atrium as the algebraic sum of the individual responses to each stimulation. However, parasympathetics exert the principal neural control over atrial ERP.
1H-nuclear magnetic resonance deoxymyoglobin signal as indicator of intracellular oxygenation in myocardium
Authors: Kreutzer U. , Jue T.
Published: December 2017

We report in this study that the intracellular oxygenation state is measurable with the 1H nuclear magnetic resonance signal of the proximal histidine N delta H proton of deoxymyoglobin. The signal appears in a clear spectral region of the 1H spectrum and is sensitive to various hypoxic and ischemic conditions. In perfused heart, the deoxymyoglobin's response to tissue oxygenation precedes the one reflected in the 31P phosphocreatine or ATP signals, suggesting that oxidative energy metabolism is still sufficient even when the myoglobin is partially saturated with oxygen. Our method offers then a unique way to observe tissue oxygenation and its interaction in localized tissue region in vivo.
Halothane anesthesia abolishes pulmonary vascular responses to neural antagonists
Authors: Chen B. B. , Nyhan D. P. , Fehr D. M. , Murray P. A.
Published: December 2017

We investigated the effects of the inhalational anesthetic halothane on autonomic nervous system (ANS) regulation of the baseline pulmonary vascular pressure-flow (P/Q) relationship compared with that measured in the conscious state. Multipoint pulmonary vascular P/Q plots were constructed by stepwise constriction of the thoracic inferior vena cava to decrease venous return and Q. P/Q plots were generated in the same dogs in the conscious state and during halothane anesthesia (approximately 1.2% end tidal) in the intact (no drug) condition and after administration of selective ANS antagonists. In conscious dogs, sympathetic alpha 1-adrenoreceptor block with prazosin decreased (P less than 0.01) the pulmonary vascular pressure gradient [pulmonary arterial pressure-pulmonary arterial wedge pressure (PAP-PAWP)] over the entire range of Q studied; i.e., inhibition of endogenous alpha 1-adrenoreceptor activity caused pulmonary vasodilation. In contrast, alpha 1-adrenoreceptor block had no effect on PAP-PAWP at any value of Q during halothane anesthesia. In conscious dogs, sympathetic beta-adrenoreceptor block with propranolol increased (P less than 0.01) PAP-PAWP over the entire range of Q studied; i.e., inhibition of endogenous beta-adrenoreceptor activity resulted in pulmonary vasoconstriction. However, beta-adrenoreceptor block had no effect on PAP-PAWP at any value of Q during halothane anesthesia. Finally, cholinergic receptor block with atropine decreased (P less than 0.05) PAP-PAWP at values of Q greater than 100 ml.min-1.kg-1 in conscious dogs but had no effect on PAP-PAWP at any value of Q during halothane anesthesia. These results indicate that endogenous ANS regulation of the baseline pulmonary vascular P/Q relationship observed in conscious dogs is abolished during halothane anesthesia.
Reflex control of fetal arterial pressure and hormonal responses to slow hemorrhage
Authors: Chen H. G. , Wood C. E.
Published: December 2017

Late-gestation fetal sheep respond to slow hemorrhage with increases in plasma concentrations of adrenocorticotropic hormone (ACTH), hydrocortisone, arginine vasopressin (AVP), and plasma renin activity (PRA) that correlate to the acidemia and hypercapnia also produced by hemorrhage. This study was designed to investigate the role of peripheral chemoreceptors in the mediation of these responses. Chronically catheterized fetal sheep were left intact or were subjected to bilateral section of cervical vagosympathetic trunks and carotid sinus nerves. At least 5 days after surgical preparation (between 121 and 138 days of gestation) fetuses were bled at a rate of 11 ml/10 min for 2 h. Denervated fetuses were studied with or without simultaneous infusion of phenylephrine. Denervation exaggerated the decrease in mean arterial pressure and arterial pH and the increase in arterial PCO2 during hemorrhage. Infusion of phenylephrine in the denervated fetuses prevented the decrease in blood pressure and reduced the magnitudes of changes in blood gases. Fetal plasma ACTH, hydrocortisone, and PRA responses to the hemorrhage were exaggerated in the denervated fetuses (not infused with phenylephrine) compared with the intact fetuses. Phenylephrine infusion attenuated the ACTH response and inhibited the AVP response but did not alter the PRA response. We conclude that the sectioned fibers are important for the maintenance of blood pressure and blood gases during hemorrhage and that the PRA, AVP, and ACTH responses to slow hemorrhage are not mediated by peripheral chemoreceptors.
Effects of physiological aging on cardiac electrophysiology in perfused Fischer 344 rat hearts
Authors: Schmidlin O. , Bharati S. , Lev M. , Schwartz J. B.
Published: December 2017

Aging effects on heart rate and atrioventricular (AV) conduction were studied in Langendorff-perfused hearts from 18 mature (4-6 mo), 12 middle-aged (12-14 mo), and 18 senescent (24-26 mo) Fischer 344 rats. Heart rate decreased with increasing age from 218 +/- 18 in mature to 196 +/- 27 (mean +/- SD) beats/min in middle-aged rats to 183 +/- 22 beats/min in senescent rats (analysis of variance, P less than 0.001). Spontaneous AV conduction time increased from 43 +/- 7 to 49 +/- 5 to 62 +/- 9 ms with aging (P less than 0.0001). Paced AV conduction time also lengthened with aging, and AV Wenckebach block cycle length increased from 122 +/- 10 to 133 +/- 9 to 152 +/- 16 ms (P less than 0.005). Intra-atrial conduction time was unaffected by age. Age differences in heart rate and AV conduction responses to isoproterenol (0.5 x 10(-9) to 1 x 10(-7) M) were noted with greater sensitivity at lower doses in hearts from younger rats. In separate experiments, 18 mature and 19 senescent Fischer 344 rats received reserpine (0.25 mg.kg-1.day-1 ip) for 6 days before study. Age differences in heart rate and AV conduction persisted (P less than 0.0001). Histopathological examination of AV nodal and His-bundle tissues in three hearts from each age group showed increased intercellular collagen with advancing age.(ABSTRACT TRUNCATED AT 250 WORDS)
Depletion of brain glutathione by buthionine sulfoximine enhances cerebral ischemic injury in rats
Authors: Mizui T. , Kinouchi H. , Chan P. H.
Published: December 2017

Oxygen free radicals have been implicated in the pathogenesis of brain injury induced by ischemia/reperfusion. We studied the role of endogenous reduced glutathione (GSH) in brain infarction associated with focal cerebral ischemia caused by permanent ligation of the right middle cerebral artery (MCA) and the right common carotid artery (CCA) plus temporary occlusion of the left CCA. GSH levels in the ischemic side of cortex decreased with time after ischemia and preceded cortical infarction estimated by the staining of mitochondrial respiratory enzymes with 2,3,5-triphenyltetrazolium chloride. GSH levels in the contralateral cortex were unchanged through the experimental periods. The extent of decrease of GSH levels and the severity of infarction in the ischemic cortex at 24 h after ischemia depended on the duration of occlusion of the left CCA. Depletion of brain GSH with buthionine sulfoximine, a selective inhibitor for gamma-glutamylcysteine synthetase, exacerbated cortical infarction and edema after ischemia. These results suggest that the endogenous brain GSH is an important determinant in the defense mechanisms against lesion formation after ischemia and support the possible role of oxygen radicals in the pathogenesis of ischemic brain injury.
Fructose-1,6-bisphosphate improves efficiency of work in isolated perfused rat hearts
Authors: Starnes J. W. , Seiler K. S. , Bowles D. K. , Giardina B. , Lazzarino G.
Published: December 2017

The purpose of this study was to determine whether exogenous fructose-1,6-bisphosphate (F-1,6-P2) directly affects myocardial hemodynamics and certain metabolic parameters. Isolated working rat hearts were perfused for 30 min with 10 mM glucose (+insulin) as the exclusive exogenous substrate followed by 15 min with glucose plus one of the following concentrations (in mM) of F-1,6-P2: 1.25, 2.5, 5, or 10, and finally returned to the glucose only buffer. Additions of 2.5 and 5 mM F-1,6-P2 decreased (P less than 0.01) oxygen consumption (VO2) by 10.8 and 17.0% and coronary flow by 8.3 and 10.3%, respectively. No changes were observed in lactate release, cardiac output (CO), peak systolic pressure, heart rate, or pressure work (PW). Efficiency, expressed as PW divided by VO2, increased with F-1,6-P2 by 8.6% with 1.25 mM (P less than 0.05), 13.2% with 2.5 mM (P less than 0.01), and 16.9% with 5 mM (P less than 0.01). F-1,6-P2 at 10 mM produced no further improvements in VO2 or efficiency but was associated with declines (P less than 0.05) in CO and PW. Glucose plus 10 mM fructose had no effects on any of the above parameters, indicating that the F-1,6-P2-induced changes were not due to changes in osmolarity or to end products of F-1,6-P2 hydrolysis. Some chelation of buffer calcium by F-1,6-P2 occurred, but when free calcium was equalized in glucose and glucose plus 5 mM F-1,6-P2 buffers, the decline in VO2 (11.5%) was still far greater than could be explained by exogenous F-1,6-P2 metabolism in the glycolytic pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine increases pulmonary blood flow in intact fetuses via endothelium-dependent vasodilation
Authors: Tiktinsky M. H. , Cummings J. J. , Morin F. C.
Published: December 2017

In vitro, acetylcholine causes vasodilation by releasing endothelium-derived relaxing factor (EDRF) from endothelial cells. EDRF may be nitric oxide, derived from the amino acid L-arginine (L-Arg), by a process that is inhibited by NG-monomethyl-L-arginine (L-NMMA) and restored by L-Arg. We studied the effect of L-NMMA and L-Arg on the increase in pulmonary blood flow caused by acetylcholine in unanesthetized intrauterine near-term fetal lambs. Three protocols were employed. In each protocol, acetylcholine (0.48 +/- 0.15 micrograms/kg) was injected at 15-min intervals for 120 min. In the control protocol, nothing else was given. In the second protocol, L-NMMA (14 +/- 5 mg/kg) was given at 35 min. In the third protocol, L-NMMA was given at 35 min followed by L-Arg (138 +/- 73 mg/kg) at 80 min. In the control protocol, acetylcholine increased pulmonary blood flow 179 +/- 17% while it decreased pulmonary arterial pressure 15 +/- 1% and did not affect left atrial pressure. The response to each injection lasted less than 1 min and did not change throughout the experiment. L-NMMA completely blocked, whereas L-Arg completely restored, the effect of acetylcholine on pulmonary blood flow. We conclude that acetylcholine increases pulmonary blood flow in the fetal lamb via the release of EDRF derived from L-Arg. We speculate that endothelium-dependent vasodilation may play a role in the increase in pulmonary blood flow at birth.
Characterization of coronary vasoconstriction produced by rostral ventrolateral medulla stimulation in rats
Authors: Jones L. F. , Brody M. J.
Published: December 2017

Previous studies have demonstrated that coronary vasoconstriction can be produced by activation of specific central nervous system sites in the cat. The present study was undertaken 1) to develop a rat model for studying central influences on coronary circulation and 2) to utilize this model for characterization of the changes in coronary blood flow (CBF) produced by stimulation of rostral ventrolateral medulla (RVLM). Electrical stimulation of right RVLM in chloralose-anesthetized rats with bilateral vagotomy produced a transient decrease in CBF followed by an increase in CBF concomitant with a decrease in hindquarter blood flow, a pressor response, and tachycardia. After atenolol the tachycardia and increase in CBF were abolished, whereas the decrease in CBF was enhanced and prolonged. Phentolamine (1 mg/kg iv) or removal of the stellate ganglia inhibited the decrease in CBF but did not totally abolish the increase in coronary vascular resistance. Inhibition of nitric oxide synthesis with N-nitro-L-arginine (10 microM/kg iv) enhanced the decrease in CBF produced by stimulation in RVLM. These results indicate that, in rat model, the centrally induced decrease in CBF is 1) mediated by cardiac sympathetic innervation but only partially through alpha-adrenoceptors and 2) enhanced by removal of the inhibitory effect of the endothelium.
Comparison of the effects of BAY K 8644 on cardiac Ca2+ current and Ca2+ channel gating current
Authors: Hadley R. W. , Lederer W. J.
Published: December 2017

Effects of (-)-BAY K 8644 on Ca2+ channel function were studied in guinea pig ventricular myocytes. It was found that the compound has both voltage-dependent stimulatory and inhibitory effects on the Ca2+ current (ICa), in agreement with prior studies. The basis for these effects was studied by evaluating the effects of (-)-BAY K 8644 on the Ca2+ channel gating current. It was found that the voltage-dependent inhibitory effects of the drug on ICa could be well explained by similar reductions in the amount of gating charge moved. However, the stimulatory effect of (-)-BAY K 8644 on ICa could not be simply correlated with changes in the amount of gating charge moved. Although the drug produced a shift of the charge-voltage relationship to more negative potentials, the drug actually reduced the total amount of movable gating charge. Thus it could be demonstrated that there are membrane potentials where (-)-BAY K 8644 reduced the Ca2+ channel gating current while enhancing ICa. In addition, the drug was found to slow the decay of the gating current during repolarization. It seems likely that (-)-BAY K 8644 has a dual effect on Ca2+ channels: affecting both the voltage dependence of gating charge and the relationship between open probability and charge movement.
Spontaneous vasomotion in hamster cheek pouch arterioles in varying experimental conditions
Authors: Bouskela E. , Grampp W.
Published: December 2017

The spontaneous rhythmic motor activity (vasomotion) of arterioles was studied in vivo in the hamster cheek pouch by means of intravital microscopy. In control conditions, arteriolar vasomotion was regularly present in healthy preparations, independent of anesthesia (pentobarbital sodium or alpha-chloralose), composition of the superfusate [tris(hydroxymethyl)aminomethane-buffered or N-2-hydroxy-ethylpiperazine-N'-2-ethanesulfonic acid-supported HCO3(-)-buffered saline solutions) or a combined nerve, alpha- and beta- receptor blockade. In arterioles with internal diameters between 13 and 52 microns, the vasomotion frequency (3-15 cycles/min) and amplitude (2-10 microns) were not significantly correlated to vessel size. The frequency and amplitude of the spontaneous arteriolar vasomotion could be modified by changes in the physical and chemical environment of the preparation. Thus, addition of pinacidil, a K+ channel activator, to the superfusate dose dependently decreased and finally suppressed vasomotion, in combination with an increase of the vessel diameter. These effects could be counteracted if glibenclamide (10(-6) M), a K+ channel blocker, was added to the superfusing solution. In the absence of any major changes in vessel diameter, vasomotion was also abolished by increasing the PO2 (from approximately 15 to 30 mmHg), varying the pH (from 7.40 to 7.22 or 7.65), and lowering the temperature to 15 degrees C in the superfusion solution. The abolition of vasomotion observed because of increased PO2 and changes in pH could be reversed by addition of glibenclamide (10(-6) M) or tetraethylammonium chloride (TEA, 5 x 10(-3) M), another K+ channel blocker, to the superfusion solution; in the case of lowered temperature only glibenclamide was effective.(ABSTRACT TRUNCATED AT 250 WORDS)
Intestinal lymphatic vessels release endothelial-dependent vasodilators
Authors: Bohlen H. G. , Lash J. M.
Published: December 2017

This study evaluated the possibility that the endothelial cells of microscopic lymphatic vessels can release vasoactive agents which affect the lymphatic vessels and nearby arterioles. Microinotophoresis of acetylcholine (ACh) or bradykinin (BK) onto the wall of quiescent submucosal lymphatic vessels in the rat small intestine had no discernible effects on their diameters but caused spontaneously active mesenteric lymphatic vessels to constrict. Application of ACh or BK to the arteriolar wall caused significant vasodilation. Release of either drug onto the wall of a nearby lymphatic produced arteriolar dilation that was approximately 80% of that observed with direct application to the arteriolar wall; drug application into parenchymal tissue produced a dilation less than 25% of that observed during application to the lymphatic. NG-monomethyl-L-arginine application to the lymphatic blocked all ACh-induced lymphatic-mediated responses but had no effect on the response to direct ACh application to the arteriolar wall or any of the responses to BK application. These results are consistent with the hypothesis that lymphatic endothelial cells are capable of releasing agents that dilate nearby arterioles and cause spontaneously active lymphatic vessels to constrict.
Serial reproducibility of conductance catheter volumetry of left ventricle in conscious dogs
Authors: Asanoi H. , Ishizaka S. , Kameyama T. , Nozawa T. , Miyagi K. , Sasayama S.
Published: December 2017

Although the conductance catheter technique has been currently applied to in situ measurement of left ventricular volume, reproducibility of this method has not been examined within the same subject on separate days. Accordingly, serial catheter volumetries (mean 5 days apart) were performed in 10 normal conscious dogs, which were chronically instrumented with the conductance catheter, a micromanometer, and caval cuff occluders. Left ventricular end-systolic pressure-volume relationship was also determined during transient caval occlusion. All hemodynamic variables were compared at the same heart rate. There were no significant changes in blood resistivity (10 +/- 7 omega cm, 8%) and the parallel conductance of the surrounding tissues (7 +/- 6 ml, 10%). The mean difference was 3 +/- 2 ml (7%) for end-diastolic volume and 3 +/- 2 ml (11%) for end-systolic volume. Stroke volume and ejection fraction were also reproducible with mean difference of 2 +/- 1 ml (9%) and 3 +/- 2% (8%) respectively. The end-systolic pressure-volume relationships were nearly superimposable with the slope being 6.05 +/- 1.82 mmHg/ml on day 1 and 6.13 +/- 2.22 mmHg/ml on day 2. The difference averaged 0.63 +/- 0.42 mmHg/ml (11%). These results suggest that highly reproducible volume estimates by conductance catheter offer its feasibility of serial assessment of ventricular performance in vivo.
Mechanisms of signal transduction for adenosine and ATP in pulmonary vascular bed
Authors: Lippton H. L. , Hao Q. , Hauth T. , Hyman A.
Published: December 2017

The purpose of the present study was to investigate the contribution of pertussis toxin (PTX)-sensitive guanine nucleotide (G) proteins in the pulmonary vascular response to adenosine and ATP in the intact cat under conditions of controlled pulmonary blood flow and left atrial pressure. Adenosine, ATP, and beta-tau-ATP increased lobar arterial pressure in a dose-dependent manner. The pulmonary vasoconstrictor response to adenosine was abolished by BW 1433U, a specific purinergic receptor (P1) inhibitor, PTX pretreatment, indomethacin, and ONO 3708, a thromboxane A2 (TxA2) receptor antagonist. These data suggest that the pulmonary vasoconstrictor response to adenosine depends on activation of P1 purinergic receptors coupled to PTX-sensitive G proteins and subsequent metabolism of liberated arachidonic acid to form TxA2. Because each blocking agent studied produced similar reductions in the pulmonary vasoconstrictor response to ATP without altering the pulmonary vasoconstrictor response to beta-tau-ATP, the present data suggest that ATP constricts the pulmonary vascular bed, in part, by hydrolysis to adenosine. Moreover, the present study suggests that both A1 purinoceptors that are linked to PTX-sensitive G proteins as well as P2x purinoceptors receptors that are independent of PTX-insensitive G proteins mediate the pulmonary vasoconstrictor response to ATP in vivo.
Estimation of heart mitochondrial creatine kinase flux using magnetization transfer NMR spectroscopy
Authors: Zahler R. , Ingwall J. S.
Published: December 2017

In heart, both enzyme and substrate of the creatine kinase (CK) reaction are compartmentalized: 0-25% of total CK activity is associated with the mitochondrial CK isoenzyme (mito-CK); 2-30% of the total ATP pool is in the mitochondria. Because most ATP is produced by oxidative phosphorylation, this ATP may be the preferred substrate for the mito-CK reaction. Thus flux through the mito-CK reaction should increase in proportion to the amount of mito-CK, until the enzyme becomes saturated. We previously developed a model of saturation-transfer nuclear magnetic resonance (NMR) spectroscopy that permits calculation of mito-CK flux. Here, we test the model for consistency in two ways: 1) we compare fluxes in rabbit hearts with 0% mito-CK and with 6% mito-CK at two rates of ATP synthesis and 2) we analyze six groups of rat and rabbit hearts with differing amounts of mito-CK and differing work loads. Hearts with no detectable mito-CK activity do not increase their baseline low level of mito-CK flux in response to the increased demand of contraction, but mito-CK flux increases with increased work in hearts with measurable amounts of mito-CK. Furthermore, mito-CK flux increases monotonically with increasing ATP synthesis rates but increases and then saturates with increasing mito-CK activity. Calculated mito-CK flux is of the same order of magnitude as ATP synthesis rate, as would be expected from the coupling of the mito-CK reaction to adenine nucleotide translocase. Thus the model predicts the appropriate relationship between mito-CK activity and mito-CK flux.
Expression of vascular escape: conductance or resistance?
Authors: D'Almeida Mark S. , Lautt W. Wayne
Published: December 2017

Vascular escape is that phenomenon whereby a tachyphylaxis occurs in the vasoconstriction of an arteriole to a constant sympathetic stimulation. Vascular escape, in vivo, is primarily a blood flow event. Calculated resistance, as an index of vascular tone, does not consistently describe the responses of the arterioles undergoing vascular escape. Conductance, which is the inverse of resistance, obviates several of the errors produced by the use of resistance. In this study, we illustrate this issue using hypothetical and experimental data. Escape responses were calculated in terms of resistance and conductance and plotted against blood flow escape responses. Resistance escape responses were nonlinearly related to blood flow escapes and overestimated vascular escape with both hypothetical and experimental data. Conductance escape responses were linearly related to flow escape responses and consistently described vascular escape. We therefore conclude that conductance is a better index of vascular tone to express vascular escape.

arterial vascular tone; vasoconstriction; autoregulatory escape; blood flow; blood pressure

Submitted on July 18, 1991

Accepted on November 11, 1991
Pressure of lymphatic capillaries in human skin
Authors: Spiegel M. , Vesti B. , Shore A. , Franzeck U. K. , Becker F. , Bollinger A.
Published: December 2017

The network of lymphatic capillaries of the human skin was depicted at the distal part of the tibial plateau by fluorescence microlymphography (fluorescein isothiocyanate-dextran 150,000). Intralymphatic pressure was determined in 28 lymphatic capillaries of 21 healthy volunteers (mean diameter 56.0 +/- 10.0 microns) by a servo-nulling pressure system. It averaged 4.0 +/- 4.5 mmHg (range: -6.8 to +10.7 mmHg). These are the first measurements of pressure in the initial lymphatics of human skin and form a basis with which to compare measurements made in patients with different forms of edema.
End-systolic pressure-volume and MVO2-pressure-volume area relations of isolated rat hearts
Authors: Wannenburg T. , Schulman S. P. , Burkhoff D.
Published: December 2017

We tested the utility of a standard isolated, crystalloid-perfused, isovolumic rat heart preparation for studying ventricular metabolism in terms of the myocardial oxygen consumption-pressure-volume area (MVO2-PVA) relations. The end-systolic pressure-volume relations (ESPVRs) determined between volumes of 0.15 and 0.65 ml were fit equally well by linear and nonlinear regression analysis within the data range but predicted widely differing volume-intercept (Vo) values. Linear regression analysis of the ESPVRs provided a mean slope (Ees) of 419 +/- 186 mmHg.g.ml-1 and Vo of 0 +/- 0.12 ml, respectively (n = 6). The MVO2-PVA relations were linear with a slope and MVO2 intercept of 1.30 +/- 0.31 x 10(-5) ml O2.mmHg-1.ml-1 and 0.38 +/- 0.09 x 10(-3) ml O2-beat-1.g-1, respectively. These MVO2-PVA parameters were not significantly different from those obtained when nonlinear regression analysis was applied to the ESPVR. Decreasing perfusate calcium concentration ([Ca2+]) (n = 7) resulted in a downward shift in the ESPVR, a decrease in the MVO2-PVA intercept (0.52 +/- 0.26 vs. 0.34 +/- 0.20 x 10(-3) ml O2.beat-1.g-1, P less than 0.01), and no significant change in the MVO2-PVA slope (1.33 +/- 0.47 vs. 1.57 +/- 0.69 x 10(-5) ml O2.mmHg-1.ml-1, NS). We conclude that this preparation may be a useful alternative to more expensive preparations for selected experiments in cardiac energetics.
Role of calcitonin gene-related peptide in capsaicin-induced gastric submucosal arteriolar dilation
Authors: Chen R. Y. , Li D. S. , Guth P. H.
Published: December 2017

The response of gastric submucosal arterioles to topical (submucosal) application of calcitonin-gene-related peptide (CGRP) or capsaicin with and without the human CGRP antagonist, hCGRP-(8-37), was studied using in vivo microscopy. CGRP (10(-11) to 10(-8) M) induced dose-dependent dilation. Topical treatment with hCGRP(8-37) (10(-6) M, for 10 min) caused a significant decrease in basal arteriolar diameter from 33 +/- 2 to 27 +/- 2 microns. hCGRP(8-37) did not alter acetylcholine- or adenosine-induced vasodilation but did significantly reduce CGRP 10(-8) M vasodilation from 97.3 +/- 10.1 to 15.9 +/- 4.4% of the maximal response. Topical capsaicin (10(-9) M to 5 x 10(-7) M) induced dose-dependent arteriolar dilation. This vasodilation was markedly attenuated by hCGRP(8-37). Selective ablation of capsaicin-sensitive sensory neurons nearly completely inhibited capsaicin-induced vasodilation, suggesting that this vasodilation is primarily neurogenic in origin. We conclude that 1) topical application of capsaicin stimulates capsaicin-sensitive sensory neurons and induces dose-dependent arteriolar dilation; 2) this vasodilation is mediated in part by CGRP; and 3) CGRP may be involved in modulating the basal tone of gastric resistance vessels.