bluuebunny/crossref_metadata_2025 huggingface dataset:
pH and voltage dependence of INa recovery kinetics in atrial cells exposed to lidocaine
Authors: Courtney K. R.
Published: December 2017

Lidocaine blocks sodium channels during depolarizations. The rate of recovery (repriming) of drug-blocked channels between depolarizations is slowed by both membrane depolarization and by acidification. This modulation of recovery kinetics was studied using a single-electrode voltage clamp on atrial cells isolated from the bullfrog. The pH dependence of recovery from inactivation, in drug-free conditions, is opposite to that observed in myelinated nerves; recovery occurs faster at higher pH levels in these cardiac preparations. The combined pH dependence and voltage dependence of repriming kinetics during lidocaine treatment can be explained by assuming that channels occupied by neutral drug can reactivate most readily at a rate that appears to be coupled to recovery from channel inactivation.
Microvascular rarefaction and tissue vascular resistance in hypertension
Authors: Greene A. S. , Tonellato P. J. , Lui J. , Lombard J. H. , Cowley A. W.
Published: December 2017

The purpose of this study was to quantitatively estimate the relative contribution of arteriolar rarefaction (disappearance of microvessels) and arteriolar constriction to the increases in total peripheral resistance and changes in the patterns of flow distribution observed in hypertension. A mathematical model of the hamster cheek pouch intraluminal microcirculation was constructed based on data from the literature and observations from our own laboratory. Separate rarefaction and constriction of third-order (3A) and fourth-order (4A) arterioles were performed on the model, and the results were quantified based on the changes of the computed vascular resistance. The degree of increase in resistance depended both on the number and the order of vessels rarefied or constricted and also on the position of those vessels in the network. The maximum increases in resistance obtained in the model runs were 21% for rarefaction and 75% for constriction. Rarefaction, but not constriction, produced large increases in the degree of heterogeneity of blood flow in the various vessel orders. These results demonstrate that vessel rarefaction significantly influences tissue blood flow resistance to a degree comparable with vessel constriction; however, unlike constriction, microvascular rarefaction markedly altered blood flow distribution in our model of the hamster cheek pouch vascular bed. These findings conform with the hypothesis that a significant component of the increase in total peripheral resistance in hypertension may be due to vessel rarefaction.
Modulation of cardiac autonomic activity during and immediately after exercise
Authors: Arai Y. , Saul J. P. , Albrecht P. , Hartley L. H. , Lilly L. S. , Cohen R. J. , Colucci W. S.
Published: December 2017

Fluctuations in heart rate above 0.03 Hz reflect autonomic modulation of sinoatrial node activity. To assess the dynamics of autonomic nervous activity during and immediately after exercise, we determined the power spectrum of heart rate and respiratory fluctuations in 43 normal subjects without known cardiac disease, 8 patients with severe congestive heart failure, and 6 patients status-post cardiac transplantation before, during, and after graded-work load exercise on a cycle ergometer. Before exercise, heart rate fluctuations (spectral power) at both high (0.15-0.80 Hz) and low (0.03-0.15 Hz) frequencies were significantly higher in normal subjects than in either heart failure or transplant patients but were not different between the two groups with heart disease. During exercise, heart rate power at all frequencies rapidly and progressively decreased in normal subjects, until at peak exercise it was not different from the other two groups. During recovery, heart rate power increased in normal subjects but remained significantly below base line. The findings demonstrate a marked reduction of autonomic modulation of heart rate in patients with heart failure and after cardiac transplant and support a progressive withdrawal of vagal activity during exercise with a gradual increase during recovery in normal subjects.
Adrenergic receptors of adrenal medullary vasculature
Authors: Jordan D. A. , Breslow M. J. , Kubos K. L. , Traystman R. J.
Published: December 2017

The present study evaluates possible effects of adrenal catecholamines, released by splanchnic nerve stimulation, on adrenal medullary blood flow (MQ) and adrenal catecholamine secretion (CS). Twelve pentobarbital-anesthetized mongrel dogs were subjected to three identical splanchnic nerve stimulations (5 V, 20 Hz, for 3 min) at 30-min intervals, and MQ (radiolabeled microsphere technique) and CS (high-performance liquid chromatography) were measured before and during each nerve stimulation. Animals were assigned to one of three groups and administered either saline, pindolol (1 and 4 mg/kg), or prazosin (1 and 4 mg/kg) before the second and third nerve stimulation, respectively. In the saline control group, each nerve stimulation resulted in similar increases in MQ and CS. Pindolol attenuated nerve stimulation-induced increases in MQ and CS by 50%, but had no effect on medullary catecholamine concentration. Prazosin augmented nerve stimulation-induced MQ, CS, and medullary catecholamine concentration by 35%. These data suggest that adrenal adrenergic receptors modulate elicited CS and mediate changes in adrenal medullary vascular tone.
Hypoxic reperfusion attenuates postischemic microvascular injury
Authors: Korthuis R. J. , Smith J. K. , Carden D. L.
Published: December 2017

The results of several recent studies have demonstrated that reactive oxygen metabolites are responsible for a major portion of ischemia/reperfusion (I/R) injury in skeletal muscle. Presumably, the cytotoxic oxidants are produced during reperfusion when molecular oxygen (the source of the reactive oxygen metabolites) is reintroduced to the tissues. The purpose of this study was to test the hypothesis that molecular oxygen must be provided at reperfusion to produce I/R injury in skeletal muscle. Isolated, maximally vasodilated (papaverine) canine gracilis muscles were reperfused, after 4 h of inflow occlusion, from reservoirs containing autologous blood equilibrated with either 95% O2-5% CO2 or 95% N2-5% CO2 gas mixtures. Arterial PO2 fell from approximately 120 mmHg to less than 3-5 mmHg, during the use of nitrogen. The solvent drag reflection coefficient for total plasma proteins (sigma f) and total vascular resistance was determined for the following conditions: control (no ischemia), reperfusion with oxygenated blood after 4 h ischemia; and reperfusion (after 4 h ischemia), first with anoxic blood and then oxygenated blood. Reperfusion with oxygenated blood, after 4 h of ischemia, significantly reduced solvent drag reflexion coefficient (sigma f) from 0.93 +/- 0.02 to 0.63 +/- 0.02, indicating a dramatic increase in vascular permeability. Total vascular resistance increased from 6.1 +/- 1.1 mmHg.ml-1.min.100 g during the preischemic period to 12.9 +/- 3.0 mmHg.ml-1.min.100 g during normoxic reperfusion. In muscles reperfused with anoxic blood, sigma f averaged 0.82 +/- 0.06, whereas vascular resistance increased by 56 +/- 13%.(ABSTRACT TRUNCATED AT 250 WORDS)
A rate-sensitive component to the myogenic response is absent from bat wing arterioles
Authors: Davis M. J. , Sikes P. J.
Published: December 2017

The responses of three sequential branching orders of arterioles in the bat wing to rapid and slow changes in transmural pressure were studied. Arterial and venous pressures to the wing were elevated simultaneously by pressurizing a box containing the body of the animal, while the wing was exposed to atmospheric pressure. Box pressure was elevated from 0 to +48 mmHg at two rates: 24 and 0.6 mmHg/s. During this time, continuous recordings of hydrostatic pressure and diameter were made in single arterioles using intravital microscopic techniques. Second-order arterioles and arcuate arterioles from skin and skeletal muscle constricted in response to elevated transmural pressure but did not show an enhanced response to rapid pressure changes. There was a trend for terminal arterioles to show a transient peak constriction during rapid stretch, but this response was always associated with a biphasic change in arteriolar pressure. These results suggest that the transient arteriolar resistance changes associated with rapid transmural pressure increases in previous experiments may be primarily a result of transient pressure changes in small arterioles. We find no evidence that arterioles in this preparation exhibit a rate-sensitive component to their myogenic response.
Anatomical determinants of O2 flux density at coronary capillaries
Authors: Honig C. R. , Frierson J. L. , Gayeski T. E.
Published: December 2017

Calculations indicate that the PO2 in plasma falls to zero approximately 3 microns from an erythrocyte at O2 consumption (VO2) characteristic of myocardium (Federspiel, W.A., and A. Popel, Microvasc. Res. 32: 164-189, 1986). We measured distances between individual red cells along capillaries in rat hearts rapidly frozen in situ. Cell spacing varied widely even in branches of the same capillary. Plasma gaps between red cells were divided into two populations, those less than 5 microns and those greater than 5 microns. Mean gap lengths were 2.1 and 16.5 microns, respectively. Although the number of long plasma gaps was underestimated, gaps greater than 5 microns accounted for one-third of observed capillary length. Frozen muscles were also viewed in cross section. Because the depth of penetration of light was approximately equal to 3 microns, counts of red cell-containing capillary profiles in cross section depend on cell spacing as well as on number of cell-containing flow paths. Counts varied markedly with arterial O2 partial pressure, indicating that the capillary surface area functional for O2 transport changes in response to stress. The adaptive role of change in O2 flux density (flux per area) is discussed in light of new knowledge of tissue O2 gradients.
Vasopressin contributes to maintenance of arterial blood pressure in dehydrated baboons
Authors: Ryan K. L. , Thornton R. M. , Proppe D. W.
Published: December 2017

This study primarily sought to determine whether the role of vasopressin (VP) in maintenance of arterial blood pressure is enhanced in awake, chronically instrumented baboons after 68-72 h of dehydration. This question was approached by pharmacologically blocking vasopressin V1-receptors in euhydrated and dehydrated baboons with or without a normally functioning renin-angiotensin system (RAS). VP blockade during dehydration produced a rapidly occurring (within 5 min), statistically significant (P less than 0.05) decrease in mean arterial pressure (MAP) of 5 +/- 1 mmHg in the RAS-intact condition and an identical decline in MAP (5 +/- 1 mmHg) during blockade of the RAS by captopril, an angiotensin I-converting enzyme inhibitor. At 15 min after induction of VP blockade, heart rate was elevated by 9 +/- 2 beats/min in the RAS-intact condition and by 20 +/- 5 beats/min in the RAS-blocked condition. In addition, VP blockade in the dehydrated state produced small and equal increases in hindlimb vascular conductance in RAS-intact and RAS-blocked conditions. None of these cardiovascular changes were produced by VP blockade in the euhydrated state. RAS blockade produced modest declines in MAP in both hydration states, but the fall was larger by 7 +/- 4 mmHg in the dehydrated state. Thus both VP and the RAS contribute to the maintenance of arterial blood pressure during dehydration in the conscious baboon.
Vascular capacitance and reversal of 2-kidney, 1-clip hypertension in rats
Authors: Edmunds M. E. , Russell G. I. , Swales J. D.
Published: December 2017

Vascular capacitance was studied in conscious early-phase (less than 6 wk) 2-kidney, 1-clip (2K, 1C) hypertension and compared with sham-clipped control rats. Two other groups of 2K, 1C rats were studied before and 6 h after unclipping or a sham operation. Mean circulatory filling pressure (MCFP) was measured during a brief circulatory arrest caused by inflation of a right atrial balloon. Blood volume (BV) was determined from plasma volume (125I-labeled albumin) and hematocrit. MCFP was measured at resting BV and after rapid BV changes. Vascular compliance was derived from the MCFP-BV curve. Hypertensive 2K, 1C rats had an increase in hematocrit (46 +/- 1.3 vs. 42 +/- 0.4%, P less than 0.01) and no difference in BV compared with controls. MCFP was increased (8.6 +/- 1.0 vs. 7.2 +/- 0.2 mmHg, P less than 0.01) with no difference in compliance, indicating decreased unstressed vascular volume in the 2K, 1C group. After unclipping, there was a significant fall in mean arterial pressure to normal, with a fall in MCFP (8.14 +/- 0.32 to 6.78 +/- 0.11 mmHg, P less than 0.01), but there was no difference in BV or compliance compared with the 2K, 1C group, indicating an increase in unstressed vascular volume after unclipping. These studies for the first time show an important role for vascular capacitance in modulating the circulatory changes accompanying the fall in blood pressure in surgical reversal of 2K, 1C hypertension.
Stiffness and shortening changes in myofilament-extracted rat cardiac myocytes
Authors: Roos K. P. , Brady A. J.
Published: December 2017

Sarcomere lengths, cell widths, volumes, stiffness, and regional striation uniformity were determined from isolated adult cardiac myocytes. Single cells were examined in the control saline solution followed by a sequence of relaxing, membrane skinning, and myofilament extraction solutions. Cell size and shape parameters were determined from freely dispersed myocytes, whereas stiffness was measured from myocytes attached to a perturbator and tension transducer with micropipettes. There were small changes in cell appearance, size, shape, and stiffness in the relaxing and skinning solutions. However, in 0.17-0.56 M KCl myosin extraction media, cell length declined significantly to 1.19 microns, and stiffness fell to 5-10% of control. The rate of cell shortening and stiffness decline was dependent on KCl concentration and pH. Subsequent exposure to higher ionic strength 0.60 M KI thin filament extraction media elicited additional decreases in stiffness (less than 5% of control) and cell length (0.98 micron). Cell shortening and stiffness decline have similar time courses under the same conditions, and they appear to coincide with A-band disassembly as indicated by electron micrographs. These data suggest that cardiac myocyte stiffness, size, and shape are determined in part by a stressed cytoskeleton that is associated with the myofilament apparatus.
Polyethylene glycol-conjugated superoxide dismutase and catalase reduce ischemic brain injury
Authors: Liu T. H. , Beckman J. S. , Freeman B. A. , Hogan E. L. , Hsu C. Y.
Published: December 2017

Superoxide dismutase and catalase enzymatically scavenge superoxide and hydrogen peroxide, respectively. Conjugation of polyethylene glycol to superoxide dismutase (PEG-SOD) or catalase (PEG-CAT) prolongs the circulatory half-life of the native enzymes and enhances their intracellular access. We studied the protective effect of these free radical scavengers on ischemic brain injury using a rat model of focal cerebral ischemia, which is suitable for therapeutic trials. Intravenous administration of PEG-SOD (10,000 U/kg) and PEG-CAT (10,000 U/kg) before ischemia reduced the infarct volume (treatment, 139 +/- 9 mm3, means +/- SE, N = 38; placebo, 182 +/- 8 mm3, n = 37, P less than 0.002). This finding supports the concept that superoxide and hydrogen peroxide contribute to brain injury following focal cerebral ischemia.
Contractile properties of isolated vascular smooth muscle after photoradiation
Authors: Freas W. , Hart J. L. , Golightly D. , McClure H. , Muldoon S. M.
Published: December 2017

The purpose of this study was to characterize the responses of various types of vascular smooth muscle to conditions that would be encountered during photodynamic therapy, namely laser illumination of photosensitizer-pretreated tissue. Vascular smooth muscle obtained from representative canine, rodent, and rabbit vascular beds was cut into rings and placed in organ baths (37 degrees C, aerated with 95% O2-5% CO2). These vessels were pretreated for 30 min with the photosensitizer hematoporphyrin derivative (HpD, 3-30 micrograms/ml) washed, and then exposed to red laser light (633 nm, 1-3.5 mW) for up to 20 min. Under basal tension conditions laser illumination of HpD-pretreated vessels resulted in an increase in tension, whereas laser illumination of vessels not exposed to HpD did not contract. This sustained contraction was not reversed by washing the tissue with fresh Krebs-Ringer solution. Responses to norepinephrine, transmural electrical stimulation, and elevated concentrations of KCl were reduced in blood vessels tested after HpD laser illumination. Laser-induced contractions of canine carotid arteries did not require the presence of an intact vascular endothelium. Vascular effect of these photosensitizers appears to involve the formation of oxygen-derived radicals. This preparation could provide a good model for examining the effects of free radicals on vascular physiology.
Arterial vasodilators, cardiac volume load, and cardiac hypertrophy in normotensive rats
Authors: Tsoporis J. , Yuan B. X. , Leenen F. H.
Published: December 2017

To assess a possible involvement of cardiac volume overload in the development of cardiac hypertrophy during chronic arterial vasodilator treatment, changes in indexes of cardiac volume load in relation to changes in cardiac anatomy were evaluated during treatment of normotensive rats with 120 mg/l hydralazine or 120 mg/l minoxidil, with drinking water. Long-term treatment with hydralazine, but not minoxidil, caused small decreases in systolic blood pressure; neither vasodilator affected heart rate with chronic treatment. Arterial vasodilator treatment for 2 wk or more resulted in increases in plasma and blood volumes by 10-20%. Both arterial vasodilators increased right atrial pressure and left ventricular end-diastolic pressure in the initial weeks of treatment. Only the minoxidil group showed a persistent increase in right atrial pressure throughout the treatment period. These hemodynamic changes were associated with increases in left ventricular (LV) internal diameter and right ventricular (RV) weight, and with minoxidil these changes were also associated with increased LV weight. LV wall thickness did not increase. Cardiac volume overload therefore indeed occurs during treatment with arterial vasodilators and may contribute to their effects on cardiac anatomy (i.e., development of RV hypertrophy and, in the case of minoxidil, also, eccentric LV hypertrophy), which are consistent with cardiac volume overload.
Protein kinase inhibitor prevents pulmonary edema in response to H2O2
Authors: Johnson A. , Phillips P. , Hocking D. , Tsan M. F. , Ferro T.
Published: December 2017

We investigated the effect of H2O2 (92 microM) in isolated guinea pig lungs perfused with a buffered Ringer solution. Pulmonary arterial pressure (Ppa), pulmonary capillary pressure (Ppc), and change in lung weight (delta W) were recorded at 0 min and at 15, 30, and 60 min after the H2O2. The capillary filtration coefficient (Kfc) was measured at 0 and 30 min. The perfusion of H2O2 increased the Ppa, Ppc, delta W, and Kfc. The thromboxane synthetase inhibitor Dazoxiben, or the vasodilator papaverine, prevented the increases in Ppa and Ppc. The protein kinase C (PKC) inhibitor H7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride] prevented the increases in Ppa, Ppc, delta W, and Kfc, whereas the inactive isoquinoline HA1004 [N-(2-guanidinoethyl)-5-isoquinolinesulfonamide hydrochloride] had little effect on the H2O2 response. H2O2 increased the number of stress fibers and disrupted the peripheral band of cultured confluent endothelial cells, changes that were prevented with pretreatment with H7. PKC may mediate the increases in vascular permeability and pulmonary edema that occur in response to H2O2.
Effect of manipulations of Ca2+ environment on atrial natriuretic factor release
Authors: De Bold M. L. , De Bold A. J.
Published: December 2017

The effects of Ca2+ on the kinetics of atrial natriuretic factor (ANF) release [measured as immunoreactive cardionatrin (IRC)] were studied on an in vitro, spontaneously beating rat atrial preparation. It was found that ethylene glycolbis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) and Ca2+-free media induced a significant increase in the rate of basal IRC release. Reintroduction of Ca2+ reversed the augmented basal IRC release induced by EGTA and restored mechanical activity. It was also found that the stretch-induced IRC release was independent of extracellular Ca2+ and took place even in the presence of EGTA. The presence of absence of Ca2+ had no apparent effect on ANF processing. In all instances, cardionatrin I (ANF 99-126) was found to be the most abundant peptide released. Morphologically, no obvious differences were observed during either basal or stretch-induced IRC release. These results suggest that, unlike most other endocrine secretory systems, a reduction of cytosolic Ca2+ stimulates basal IRC release. These findings suggest an adaptation of atrial cardiocytes to accomplish their dual role as secretory and contractile cells.
Nodulus-uvula depressor response: central GABA-mediated inhibition of alpha-adrenergic outflow
Authors: Henry R. T. , Connor J. D. , Balaban C. D.
Published: December 2017

Electrical stimulation of a lateral region of the cerebellar nodulus-uvula transition zone in anesthetized albino rabbits decreases mean arterial blood pressure in direct proportion to stimulus intensity. The hypotension has an abrupt onset and is phasic; heart rate is unaffected. Neural pathways that might mediate the depressor response were studied using autonomic-blocking agents. Pretreatment with 2 mg/kg iv of either propranolol HCl or atropine methyl nitrate did not alter the onset or duration of the hypotensive response. However, pretreatment with 2 mg/kg iv phentolamine HCl abolished the depressor response, and 7 mg.kg-1.min-1 iv tetraethylammonium infusion decreased the response by more than 50%. Ipsilateral injections of 200 ng bicuculline methiodide into an area immediately dorsal to the superior cerebellar peduncle or the dorsal aspect of the superior vestibular nucleus reversibly attenuated the nodulus-uvula evoked depression. Anterograde horseradish peroxidase-wheat germ agglutinin (HRP-WGA) transport experiments revealed that both these regions receive direct inputs from the nodulus-uvula. These data suggest that hypotensive events elicited by lateral nodulus-uvula stimuli represent a central, alpha-aminobutyric acid-mediated, phasic inhibition of vasomotor drive mediated through autonomic ganglia to alpha-adrenoreceptors in the vasculature.
Pulmonary vascular permeability and resistance measurements in control and ANTU-injured dog lungs
Authors: Allison R. C. , Rippe B. , Prasad V. R. , Parker J. C. , Taylor A. E.
Published: December 2017

Because questions have arisen regarding pulmonary vascular permeability and resistance measurements in isolated, perfused lungs, we sought to determine the 1) stability of repeated measurements of permeability and resistance in control lungs; and 2) magnitude of change in these measurements when permeability was greatly increased. Using blood-perfused dog lungs, we measured filtration coefficient (Kf) and isogravimetric capillary pressure (Pci) as indexes of vascular permeability, and we also determined total vascular resistance (Rt) as well as the segmental resistances using the double-occlusion pressure (Pdo). In a control group (n = 8), the base-line measurement of Kf (0.21 +/- 0.02 ml.min-1.cmH2O-1.100 g-1) and Pci (10.2 +/- 0.9 cmH2O) did not change over 4 h, indicating no changes in endothelial barrier function. Base-line Rt (13.9 +/- 2.6 cmH2O.l-1.min.100 g) also did not significantly increase. In a second group (n = 5), alpha-naphthylthiourea (ANTU) increased the initial Kf more than eight times (from 0.17 +/- 0.03 to 1.40 +/- 0.32 ml.min-1.cmH2O-1.100 g-1) and decreased Pci by 56% (from 9.4 +/- 0.6 to 4.1 +/- 0.4 cmH2O) at 1 h, indicating severely damaged endothelium. In addition, the Pdo determined during isogravimetric conditions correlated very well with Pci not only in control lungs (observed previously) but also in very permeable lungs (not previously reported). We conclude that this experimental model provides an excellent means of assessing changes in pulmonary microvascular permeability, with a spectrum ranging from no changes in hourly measurements for 4 h to obvious changes in permeability by 1 h.
Negative intrathoracic pressure decreases independently left ventricular filling and emptying
Authors: Peters J. , Fraser C. , Stuart R. S. , Baumgartner W. , Robotham J. L.
Published: December 2017

The mechanism for the fall in left ventricular (LV) stroke volume with normal and obstructed inspiration is controversial with changes proposed in LV preload and afterload. During respiration extending over several cardiac cycles, changes in both LV filling and emptying could occur, rendering demonstration of any responsible mechanism difficult. To evaluate the independent effects of negative intrathoracic pressure (NITP) on LV filling and emptying, we have analyzed the effects of NITP confined to either diastole or systole using electrocardiogram (ECG)-triggered phrenic nerve stimulation in six anesthetized closed-chest dogs. Lung volume was either maintained by completely obstructing the airway or allowed to increase during NITP. With diastolic NITP and the airway obstructed during phrenic nerve stimulation, LV filling volume (integrated mitral flow) significantly decreased (-37 +/- 6.1% SE) associated with increases in LV and right atrial filling pressures at end diastole relative to both atmospheric and esophageal pressures. Right atrial pressure relative to either atmospheric or esophageal pressure increased significantly more than left atrial pressure. The ensuing LV stroke volume (integrated ascending aortic flow) decreased significantly (-30.8 +/- 5.9%). With NITP confined to systole and at constant LV preload, LV stroke volume also decreased (-12.9 +/- 2.5%) associated with an increase in LV systolic pressure relative to esophageal pressure. Similar significant changes were observed despite a smaller fall in esophageal pressure when lung volume was allowed to increase during either diastolic or systolic NITP. We conclude that 1) NITP confined to diastole decreases LV filling and the ensuing LV stroke volume, most likely by ventricular interdependence; 2) NITP confined to systole also decreases LV stroke volume, presumptively by imposing an increased afterload on the LV; 3) both diastolic and systolic mechanisms should contribute to a decreased LV stroke volume during normal and obstructed inspiration; and 4) if the effects of intrathoracic pressure changes were to extend over several cardiac cycles, mechanisms exist to account for either increases or decreases in LV volumes.
Mechanisms of hypoxia-induced atrial natriuretic factor release from rat hearts
Authors: Lew R. A. , Baertschi A. J.
Published: December 2017

Potential mechanisms of hypoxia-induced atrial natriuretic factor (ANF) release [A.J. Baertschi, J.M. Adams, and M.P. Sullivan. Am. J. Physiol. 255 (Heart Circ. Physiol. 24): H295-H300, 1988] were investigated in Langendorff-perfused rat hearts. The ANF release was graded with stimulus intensity; 10 min of perfusion with Krebs-Henseleit solution equilibrated with 95, 20, 10, 5, and 0% oxygen led to peak ANF levels of 140 +/- 31 (SE), 202 +/- 20, 407 +/- 76, 659 +/- 119, and 516 +/- 83% of base-line ANF (159 +/- 14 pg/ml), respectively. Hypoxia-induced release of lactate dehydrogenase and creatine kinase did not correlate with ANF release; this finding, along with other experiments, rules out tissue damage as a significant factor. Phentolamine (1.3 microM) and propranolol (0.1 microM) each reduced peak hypoxia-induced (0% O2) ANF release to 333 and 310%, respectively, whereas atropine sulfate (15 microM) had no inhibitory effect. The three antagonists combined reduced the peak hypoxia-induced ANF release to the same extent (307%) as either phentolamine or propranolol alone. Earlier (24 h) catecholamine depletion of rats with 100 mg/kg 6-hydroxydopamine also significantly reduced peak hypoxia-induced ANF release to 330%. Neither the reduction of the ANF secretory responses by these interventions nor the remaining ANF response could be attributed to changes in atrial mechanics. Therefore, these studies demonstrate that alpha- and beta-adrenergic stimulation is responsible for approximately half the hypoxia-induced ANF release from the isolated heart, whereas an as yet undefined mechanism accounts for the remainder of the response.
Distribution of alpha 1-adrenergic receptors in myocytic regions and vasculature of feline myocardium
Authors: Saffitz J. E.
Published: December 2017

The physiological and pathophysiological roles of myocardial alpha 1-adrenergic receptors are not clearly defined. To delineate the distribution of alpha 1-receptors in myocytic and vascular components of the heart, we characterized the binding of [3H]prazosin to alpha 1-receptors in unfixed, transmural slices of feline left ventricle. Specific binding ratios greater than 95% were achieved at radioligand concentrations near the dissociation constant (Kd). Binding of radioligand to receptors in transmural slices was rapid, reversible, saturable, stereoselective, and displaceable by subtype-selective antagonists with a rank order of potency characteristic of alpha 1-receptors. Analysis of binding isotherms indicated a Bmax of 9.1 +/- 1.9 fmol/mg protein and a Kd of 36.9 +/- 6.3 pM. Results of light microscopic autoradiography indicated that regions composed of closely arranged cardiac myocytes contained three to fourfold more alpha 1-receptors per unit section area than the resistance microvasculature, which in turn contained approximately twice the density of alpha 1-receptors observed in the medial smooth muscle of large conductance arteries. No differences in the density of alpha 1-receptors between subepicardial and subendocardial regions were observed for either myocytic regions or coronary arterioles. These results indicate that myocytic regions of the cat ventricle contain a high density of alpha 1-adrenergic receptors. The methods developed should be of value in characterizing the distribution and function of alpha 1-receptors and mechanisms of regulation of adrenergic responsiveness in intact myocyardium.
Uterine and nonuterine vascular responses to angiotensin II in ovine pregnancy
Authors: Rosenfeld C. R. , Naden R. P.
Published: December 2017

The uteroplacental vasculature is more refractory to angiotensin II (ANG II) than the systemic vasculature as a whole. To ascertain the differences in responses between reproductive and nonreproductive tissues that account for this, we infused ANG II (0.573, 5.73, and 11.5 micrograms/min) in pregnant sheep (137 +/- 5 days of gestation) and monitored arterial pressure (MAP), heart rate, and uterine blood flow (UBF); cardiac output and regional blood flows were measured with radiolabeled microspheres. Dose-dependent changes in MAP, UBF, and systemic (SVR) and uterine (UVR) vascular resistance occurred (P less than 0.05); systemic responses exceeded uterine (P less than 0.05), except with 11.5 micrograms/min, when % delta UVR = % delta SVR, % delta UVR greater than % delta MAP, and UBF fell 29%. Although a dose-dependent rise in placental resistance occurred, blood flow was unaffected except at 11.5 micrograms ANG II/min, falling 16.8 +/- 3.5% (P = 0.059). In contrast, endometrial perfusion decreased 68 +/- 4.2 and 81 +/- 1.8% (P less than 0.01) with 5.73 and 11.5 micrograms ANG II/min, respectively. Myometrial responses were intermediate, thus placental flow increased from 75 to greater than 90% of total UBF. Adipose, renal, and adrenal glands were extremely sensitive to ANG II, with blood flows decreasing maximally at 0.573 micrograms/min (P less than 0.05). Maximum adipose vascular resistance occurred at 0.573 micrograms/min, greater than 400% (P less than 0.001), exceeding responses in all tissues (P less than 0.05). The placenta is less responsive to ANG II than other uterine and most nonreproductive tissues, resulting in preferential maintenance of uteroplacental perfusion and protecting the fetus from the effects of this vasoconstrictor.
Role of calcium in caffeine-norepinephrine interactions in cardiac Purkinje fibers
Authors: Satoh H. , Vassalle M.
Published: December 2017

Caffeine-norepinephrine interactions were studied in canine cardiac Purkinje fibers perfused in vitro. Caffeine (0.5-1 mM) or theophylline (0.5-1 mM) increased and then decreased contractile force in the absence and presence of 0.5-10 microM norepinephrine (NE) [in high extracellular calcium concentration ([Ca]o) caffeine only decreases force]. Occasionally, caffeine only decreased force in the presence of NE. In the presence of NE and 12 mM (sometimes even 4 mM) extracellular potassium concentration, caffeine did not decrease force below the precaffeine level. Reciprocally, in 0.5-2 mM caffeine NE increased force, although less than in the absence of caffeine. Even in 9 mM caffeine, NE increased force but slowed the final phase three repolarization of the action potential. Both NE and 8.1 mM [Ca]o increased force, but NE decreased force in the presence of high [Ca]o. In NE and propranolol (or propranolol alone), caffeine only increased force, whereas it had the usual effects in the presence of methoxamine or phenotolamine. In the presence of iodoacetic acid and 2-deoxy-D-glucose, NE caused contracture and caffeine exaggerated it. In contrast, in NE and 2 mM Mn, caffeine only increased force. It is concluded that initially NE diminishes the cytoplasmic calcium overload induced by caffeine (by promoting Ca uptake into the sarcoplasmic reticulum) and subsequently enhances it (by increasing the slow inward current).
Left ventricular systolic resistance in rats with hypertension and hypertrophy
Authors: Shroff S. G. , Motz W.
Published: December 2017

Traditional indexes of ventricular performance often fail to identify differences between the normal and hypertrophied ventricle. This may not be the case for load-independent mechanical properties, elastance, and resistance. Accordingly, we derived these properties of the intact left ventricle (LV) in 25-wk-old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto controls (WKY) using in-situ and isolated hearts. We found that 1) pump performance was similar in SHR and WKY, both at base line and after dextran; 2) the peak systolic elastance (Emax) was higher and theoretical maximum flow (Qmax, inverse of ventricular resistance) was lower in SHR; (3) slopes of peak isovolumetric pressure-volume and stress-strain relations were significantly higher in SHR; and 4) although end-diastolic pressure-volume relation for SHR was shifted to the right, there was no difference in end-diastolic stress-strain relations. Thus elastance in hypertrophied LV is augmented due to both an increase in muscle mass and the force-generating capacity of the myocardium. Furthermore, we propose that the decrease in Qmax seen in SHR reflects a change in certain velocity-dependent properties of the myocardium, whereas the preservation of pump performance is a result of the opposing effects of increased Emax and decreased Qmax. These observations underscore the importance of quantifying systolic resistance, together with elastance, for a better assessment of the LV as a mechanical pump.
Steroids during development of genetic hypertension in rats of Lyon strain
Authors: Vincent M. , Gomez-Sanchez C. E. , Bataillard A. , Sassard J.
Published: December 2017

The urinary excretion and the plasma concentration of deoxycorticosterone (DOC), corticosterone, 18-hydroxy-DOC (18-OH-DOC), aldosterone, and 19-nor-DOC were measured by specific radioimmunoassays in genetically hypertensive (LH), normotensive (LN), and low blood pressure (LL) male rats of the Lyon strains at two ages that characterize the development of their systolic blood pressure (SBP). When compared with both LN and LL controls, 5-wk-old LH rats exhibited an increased urinary DOC and decreased urinary corticosterone excretions, which were significantly related to the SBP level (r' = 0.618 and -0.520; n = 23; P less than 0.01 for DOC and corticosterone, respectively). In addition, the adrenal synthesis of LH rats was found to rely on an increased 18-hydroxylase activity as indicated by elevated urinary 18-OH-DOC/corticosterone and aldosterone/corticosterone associated with a lower 11-beta-hydroxylase activity shown by the decreased urinary corticosterone/DOC. Twenty-wk-old LH rats with fully developed hypertension exhibited normal urinary excretion of steroids and a decrease in plasma DOC concentration, which negatively correlated with the SBP level (r' = -0.574; n = 25; P less than 0.01). In conclusion, the present study demonstrates that in the Lyon model of genetically hypertensive rats, compared with two genetically different control strains and maintained under physiological unstressed conditions, the development of hypertension is associated with an increased urinary excretion of DOC. After the full development of their hypertension, the mineralocorticoid synthesis in LH rats returns to normal or low levels which could, however, remain inappropriately high for their sodium body content.
Aortic impedance and compliance in hypertensive rats
Authors: Zuckerman B. D. , Yin F. C.
Published: December 2017

We compared aortic impedance and compliance in normotensive control and hypertensive Wistar rats. Hypertension was induced by unilateral nephrectomy plus steroid and salt water administration. After at least 8 wk of sustained hypertension (tail-cuff systolic pressures greater than 172 mmHg), open-chest ascending aortic micromanometric pressures and electromagnetic flows were measured. We used a frequency-modulated pacing method to enhance the energy content of the pressure and flow signals at specific low frequencies and their multiples. Impedance spectra were calculated using both Fourier series and spectral analysis methods. Compliance was calculated from the low-frequency impedance moduli, assuming a windkessel model for the arterial system. During pentobarbital sodium anesthesia under baseline conditions, the hypertensive rats had higher total resistance (219,000 vs. 126,000 dyn.s.cm-5), higher characteristic impedance (7,334 vs. 5,377 dyn.s.cm-5), larger first zero crossing of impedance phase angle (13.9 vs. 10 Hz), larger ratio of backward to forward pressure waves (0.67 vs. 0.48), and lower compliance (0.00498 vs. 0.00720 ml/mmHg) than controls. The differences between the groups were eliminated when the blood pressures of the hypertensive rats were normalized by vasodilation with nitroprusside or when the control rats were made hypertensive by vasoconstriction with phenylephrine. Thus the hemodynamic alterations appear to be secondary to the increased blood pressure. These base-line differences and the responses to vasoactive drugs are similar to findings in humans, suggesting that this rat model is a good hemodynamic model of human hypertension.
Robin Fahraeus: evolution of his concepts in cardiovascular physiology
Authors: Goldsmith H. L. , Cokelet G. R. , Gaehtgens P.
Published: December 2017

We give an account of the work of Robin Fahraeus over the years 1917–1938, his contribution to our understanding of blood rheology, and its relevance to circulatory physiology. Fahraeus published few original papers on this subject, yet he clearly understood the phenomena occurring in the tube flow of mammalian blood. 1) The concentration of cells in a tube less than 0.3 mm in diameter differs from that in the larger feed tube or reservoir, the Fahraeus effect. This is due to a difference in the mean velocity of cells and plasma in the smaller vessel associated with a nonuniform distribution of the cells. 2) In tubes less than 0.3 mm in diameter, the resistance to blood flow decreases with decreasing tube diameter, the Fahraeus-Lindqvist effect. We define and generalize the two effects and describe how red cell aggregation at low shear rates affects cell vessel concentration and resistance to flow. The fluid mechanical principles underlying blood cell lateral migration in tube flow and its application to Fahraeus' work are discussed. Experimental data on the Fahraeus and Fahraeus-Lindqvist effects are given for red cells, white cells, and platelets. Finally, the extension of the classical Fahraeus effect to microcirculatory beds, the Fahraeus Network effect, is described. One of the explanations for the observed, very low average capillary hematocrits is that the low values are due to a combination of the repeated phase separation of red cells and plasma at capillary bifurcations (network effect) and the single-vessel Fahraeus effect.
Brief vagal stimuli and AV conduction in dogs: effects on retrograde exceed antegrade
Authors: Martin P. J.
Published: December 2017

We opened the chests of 20 mongrel dogs (16–28 kg) that were anesthetized with pentobarbital sodium (22 mg/kg), given propranolol (1 mg/kg), and bipolar catheters placed into the right atrium and ventricle. We crushed the sinoatrial (SA) node and paced the heart to produce either an antegrade (A-V) or a retrograde (V-A) conduction (where A is atrial activation and V is ventricular activation). Both cervical vagosympathetic trunks were ligated and connected to electrodes that were driven by a computer-controlled, isolated stimulators. Three brief vagal stimulus bursts (at the same intensity but at different times in the cardiac cycle) were given at least 1 min apart, the pacing site was changed, and the identical three-stimulus bursts were again applied. This procedure was continued until the phase of the stimulus had scanned the entire cardiac cycle. Forty-four sets of vagal effect curves were generated. The composite data indicate that brief vagal stimuli have about twice the effect on the peak amplitude of the change in retrograde than in antegrade AV nodal conduction in the dog. Unexpectedly, the duration of the parasympathetic effect is also considerably greater (approximately 40%) and the decay is slower (approximately 48%) for retrograde than for antegrade conduction, even when the vagal effect curves have been normalized to the same amplitude. This latter result suggests that some factor other than diffusion and inactivation of ACh determines the duration of the A-V conduction response to a brief vagal stimulus.
Influence of sympathetic discharge pattern on norepinephrine and neuropeptide Y release
Authors: Pernow J. , Schwieler J. , Kahan T. , Hjemdahl P. , Oberle J. , Wallin B. G. , Lundberg J. M.
Published: December 2017

The effects of sympathetic nerve stimulation on vasoconstrictor responses and overflow of norepinephrine (NE) and neuropeptide Y-like immunoreactivity (NPY-LI) were studied in the dog gracilis muscle and pig spleen in vivo. A continuous regular impulse activity was compared with irregular human sympathetic and regular bursting patterns. During control conditions, stimulation with the irregular activity induced larger peak vasoconstriction than the regular activity at 0.59 Hz, but not at higher frequencies in the muscle, at 0.59 and 2.0 Hz in the spleen. The nerve stimulation-evoked overflow of NE and NPY-LI from the muscle were not influenced by the pattern of stimulation. The overflow of NPY-LI, but not that of NE, from the spleen was enhanced by the irregular activity at 0.59 and 2.0 Hz, and both NPY-LI and NE overflows were enhanced by regular burst activity at 2.0 Hz. After blockade of alpha- and beta-adrenoceptors by phenoxybenzamine and propranolol, respectively, which enhanced nerve stimulation-evoked overflow of both NE and NPY-LI, the NE overflow from the muscle evoked by the irregular activity was slightly larger at 0.59 Hz but smaller at higher frequencies compared with that evoked by regular activity, whereas the detectable overflow of NPY-LI was not largely influenced by the stimulation pattern. In conclusion, both the vasoconstrictor response and the overflow of NPY-LI and NE seem to be influenced by the pattern and frequency of sympathetic nerve stimulation.
Arterial hemodynamics in a rabbit model of atherosclerosis
Authors: Zuckerman B. D. , Weisman H. F. , Yin F. C.
Published: December 2017

Although atherosclerosis significantly alters the structural characteristics of the arterial tree, its effect on arterial impedance, which is a means of quantifying the functional characteristics of the arterial system, has not been characterized. To assess how one type of atherosclerosis affects impedance, we studied arterial impedance in New Zealand White rabbits after 11 wk on a 2% cholesterol diet. From open-chest aortic pressures and flows, impedance data were obtained from spectral analysis of randomly paced and Fourier analysis of nonpaced beats. Compliance was calculated from the low-frequency impedance moduli by assuming a windkessel model for the arterial system. Under base-line conditions, the atherosclerotic impedance phase spectrum in the low-frequency range remained negative for higher values of frequency than in controls. There was no difference between the groups in mean arterial blood pressure, impedance modulus spectrum, characteristic impedance, compliance, or total peripheral resistance. Wave reflections were, however, increased in the atherosclerotic animals. The differences between the two groups in phase and wave reflection were completely abolished after phenylephrine (3 micrograms.kg-1.min-1). Thus this study demonstrates that under base-line conditions atherosclerosis increases wave reflection at the input to the arterial system in the absence of an alteration in global arterial compliance, total peripheral resistance, or mean blood pressure. This increase is presumably secondary to atherosclerotic changes at arterial sites, which produce local impedance mismatching.
Coronary constriction due to neuropeptide Y: alleviation with cyclooxygenase blockers
Authors: Martin S. E. , Patterson R. E.
Published: December 2017

Intra-arterial administration of neuropeptide Y (NPY), a peptide endogenous to sympathetic nerves, increases coronary vascular resistance by 30-40%. To test whether blockade of prostaglandin synthesis altered the severity of the NPY-induced coronary vasoconstriction, dogs (n = 25) were anesthetized and instrumented to record hemodynamic parameters. In control animals (n = 11) paired infusions of NPY (42 nmol/3 min) were given at 0 and 120 min. NPY produced similar increases in coronary resistance by 10 min, 31 +/- 7% (mean +/- SD) with the first dose vs. 32 +/- 12% with the second dose. The increases in resistance were due to an initial decrease in coronary flow (10 +/- 6%) followed by a prolonged increase in aortic pressure (15-20% over 20 min). Each infusion of NPY decreased heart rate (-10 +/- 7%) but did not alter left ventricular dP/dt. The effects of NPY lasted 40–60 min. In a separate group, a cyclooxygenase inhibitor (COI), indomethacin (n = 6) or ibuprofen (n = 8), was given 1 h before the second dose of NPY. The increases in coronary resistance were blunted significantly after cyclooxygenase blockade from a predrug value of 36 +/- 13 to 19 +/- 12%. In these treated animals, the decrease (-12 +/- 6%) in coronary blood flow seen with the first dose of NPY was prevented (4 +/- 14%) during the second dose (P less than 0.05). Of the two drugs, ibuprofen appeared to restore coronary flow more than did indomethacin. Neither drug affected the base line or the NPY-elicited changes in aortic pressure, heart rate, dP/dt, or myocardial oxygen demands.(ABSTRACT TRUNCATED AT 250 WORDS)