bluuebunny/crossref_metadata_2025 huggingface dataset:
Augmented phosphoinositide metabolism in aortas from genetically hypertensive rats
Authors: Turla M. B. , Webb R. C.
Published: December 2017

Recent studies suggest that serotonergic receptor activation is coupled to phospholipase C-mediated phosphoinositide hydrolysis, which results in the release of intracellular second messengers. The purpose of this study was to determine whether altered phosphoinositide metabolism is the basis for augmented vascular responsiveness to serotonin in genetic hypertension. Thoracic aortic segments isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto normotensive rats (WKY) were labeled with myo-[3H]inositol and stimulated with serotonin in the presence of LiCl. Accumulation of [3H]inositol phosphates was then quantitated by column chromatography. Basal inositol phosphate accumulation and basal incorporation of myo-[3H]inositol into aortic cell membranes from SHRSP was not significantly different from WKY values. At 2.6 x 10(-7) to 2.6 x 10(-4) M serotonin, phosphoinositide metabolism was significantly augmented in aortae from SHRSP compared with WKY. Depolarization (100 mM KCl) did not increase phosphoinositide hydrolysis above basal levels in SHRSP or WKY. 2-Nitro-4-carboxyphenyl-N,N-diphenyl carbamate (NCDC), an inhibitor of phospholipase C, prevented the serotonin-induced phosphoinositide metabolism. NCDC also partially inhibited phasic contractions (responses in calcium-free solution) to serotonin in aortas from SHRSP and WKY. In conclusion, abnormal phosphoinositide metabolism may be one mechanism responsible for the characteristic increase in vascular reactivity to serotonin in hypertension.
Exercise training enhances cardiac afferent inhibition of baroreflex function
Authors: DiCarlo S. E. , Bishop V. S.
Published: December 2017

The influence of cardiac afferents on the arterial baroreflex regulation of renal sympathetic nerve activity (RSNA) was examined before and after an endurance training program. The 8-wk endurance exercise training program resulted in an exercise-induced bradycardia (decreased heart rates at rest and during a graded exercise test). At rest (210 +/- 6 vs. 242 +/- 10 beats/min) and during treadmill running at 15.0 m/min, 20% grade (287 +/- 5 vs. 390 +/- 5 beats/min) posttraining heart rates were lower than pretraining. In addition, when compared with a group of untrained rabbits, trained rabbits had a significantly higher heart weight-to-body weight ratio (1.9 +/- 0.02 vs. 2.8 +/- 0.017 g/kg). Rabbits were instrumented with a Doppler flow probe around the ascending aorta, Silastic catheter inserted into the pericardial sac, electrodes around the renal sympathetic nerves and catheters in the central ear artery and vein. Before training, cardiac afferent blockade (intrapericardial procainamide, 2%) did not significantly alter resting mean arterial pressure, cardiac index, systemic vascular resistance index or RSNA. After training, intrapericardial procainamide mean arterial pressure increased (P less than 0.05) resting (75 +/- 4 to 86 +/- 3 mmHg) and RSNA (100% to 175 +/- 15%). More importantly, cardiac afferent blockade did not alter the range (106 +/- 4 vs. 103 +/- 4%) or gain (4.1 +/- 0.3 vs. 3.4 +/- 0.3%/mmHg) of the baroreflex function curve in the untrained rabbit. However, after training, cardiac afferent blockade increased (P less than 0.05) the range (55 +/- 3 to 103 +/- 4%) and gain (1.5 +/- 0.07 to 3.9 +/- 0.2%/mmHg) of baroreflex regulation of RSNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Spinal noradrenergic pathways and pressor responses to central angiotensin II
Authors: Elghozi J. L. , Head G. A.
Published: December 2017

We have investigated the contribution of spinal noradrenergic (NA) pathways to the central pressor effects of angiotensin II (ANG II) in conscious rabbits with intact baroreceptors and after sinoaortic denervation (SAD). Very low intracisternal (ic) doses of ANG II [half maximum dose (ED50) = 6 x 10(-15) mol] produced increases in mean arterial pressure (MAP) and decreases in heart rate. Pressor responses to intracisternal ANG II were markedly reduced by 100 pmol of the ANG II antagonist [( Sar1, Ile8] ANG II, ic) and by intravenous prazosin, suggesting that central activation of ANG II receptors increased sympathetic vasoconstrictor tone. After SAD, the rabbits exhibited a 900-fold increase in sensitivity to ANG II (i.e., responded to very much lower doses, ED50 = 5 x 10(-18) mol). Intraspinal 6-hydroxydopamine (6-OHDA) injections given 1 mo earlier did not alter dose-response curves in baroreceptor-intact rabbits. However, the SAD-induced increase in sensitivity to ANG II was not observed in rabbits with depletion of spinal NA pathways. The results suggest intracisternal administration of ANG II activates two functionally distinct pathways: 1) a very sensitive site that utilizes NA projections to the spinal cord, and 2) a less sensitive site that uses non-NA descending pathways. Under normal baroreceptor input the former pressor pathway is completely inhibited. Thus the role of the central renin-angiotensin system may be of greater physiological importance in conditions where the baroreflex is suppressed.
Negative shift of cardiac Na+ channel kinetics in cell-attached patch recordings
Authors: Kimitsuki T. , Mitsuiye T. , Noma A.
Published: December 2017

Na+ channel kinetics were studied by recording single-channel currents in the cell-attached patch configuration of the patch-clamp technique in single ventricular cells isolated from guinea pig hearts. The inactivation time course of ensemble currents was accelerated, and the peak amplitude increased temporarily and then decreased within a few minutes after the gigaohm seal formation. After reaching a new steady state, the inactivation-voltage relation was found to have shifted to more negative potentials. The potential of half-maximal inactivation was more negative by 20–31 mV from the resting potential or between -96 and -112 mV. The voltage dependency of the channel activation also shifted. Although the cell membrane was depolarized using the whole cell patch-clamp electrode and single-channel currents were recorded with an independent cell-attached electrode, the shift of the inactivation curve was also evident. Complete removal of Ca2+ using 5 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid in the pipette solution failed to prevent the shift. Increasing Ca2+ to 10 mM, however, reduced magnitude of the shift significantly. Involvement of an increased membrane fluidity and surface potential of the glass pipette to the shift is discussed.
Model-based analysis of transmural vessel impedance and myocardial circulation dynamics
Authors: Kresh J. Y. , Fox M. , Brockman S. K. , Noordergraaf A.
Published: December 2017

The basic structure of a model of the coronary circulation has been developed to explain the relationship between transmural perfusion dynamics and intramyocardial mechanics. The model is in the form of a topologically isomorphic network representation and incorporates experimentally measured time-varying perfusion and intramyocardial pressure sources as driving inputs to the model. The intramyocardial vessels are treated as nonlinear impedance elements possessing regional external pressure-dependent resistance and capacitance. Three circuit branches, perfusing the epicardial, subepicardial, and subendocardial muscle layers, are mathematically modeled and are used to predict time-dependent flow within the left ventricular myocardium. The phasic coronary blood flow characteristics predicted by the model exhibit waveform patterns that correlate qualitatively with those patterns measured experimentally. In addition, the pressure-dependent vascular capacitance induces a sustained (out of phase with arterial inflow) venous systolic flow. The model also exhibits retrograde systolic subendocardial flow and stop-flow pressure, which are dependent on coronary resistive and capacitive properties and on the perfusion pressure decay time constant. Furthermore, the results predict an abrupt decrease in subendocardial flow with perturbation of either arteriolar or capillary bed compliance. The model describes time-dependent intramyocardial properties that have been confusing and controversial in the understanding of coronary circulation dynamics. Several steps are identified that are expected to improve and refine the model significantly.
Changes in microvascular permeability with acceleration of edema in dog lungs
Authors: Butler B. D. , Drake R. E. , Sneider W. D. , Allen S. J. , Gabel J. C.
Published: December 2017

Elevation of left atrial pressure to 25–40 mmHg causes continuous pulmonary edema formation in dog lungs. However, after 5–120 min, the rate of edema formation often increases (acceleration of edema). Acceleration of edema could be associated with an increase in microvascular membrane permeability because an increase in permeability would cause fluid to filter through the microvascular membrane more rapidly. To test the hypothesis that acceleration is associated with increased permeability, we used the continuous weight-gain technique to estimate the pulmonary microvascular membrane filtration coefficient (Kf) before and after acceleration of edema in 10 dogs. Acceleration occurred 36 +/- 38 (SD) min after elevation of left atrial pressure to 35.2 +/- 5.4 mmHg. Rate of weight gain increased from 0.47 +/- 0.17 g/min before acceleration to 0.88 +/- 0.26 g/min (P less than 0.05) after acceleration of pulmonary edema. Kf was increased from initial values of 0.058 +/- 0.027 to 0.075 +/- 0.029 ml.min-1.mmHg-1 (P less than 0.05) after acceleration. In five additional dogs we cannulated lung lymphatics and determined the lymph to plasma protein concentration ratio (CL/CP) before and after acceleration. CL/CP increased from base-line values of 0.37 +/- 0.07 to 0.44 +/- 0.06 (P less than 0.05) after acceleration. Both the increase in Kf and CL/CP data support the hypothesis that acceleration of edema is due, in part, to a slight increase in microvascular membrane permeability. However, the findings could also have been caused by an increase in interstitial conductance, washout of interstitial proteins, or alveolar flooding.
Vasopressin and prostanoid mechanisms in control of cerebral blood flow in hypotensive newborn pigs
Authors: Armstead W. M. , Leffler C. W. , Busija D. W. , Mirro R.
Published: December 2017

The interaction between vasopressinergic and prostanoid mechanisms in the control of cerebral hemodynamics in the conscious hypotensive newborn pig was investigated. Indomethacin treatment (5 mg/kg) of hypotensive piglets caused a significant decrease in blood flow to all brain regions within 20 min. This decrease in cerebral blood flow resulted from increased cerebral vascular resistances of 52 and 198% 20 and 40 min after treatment, respectively. Cerebral oxygen consumption was reduced from 2.58 +/- 0.32 ml.100 g-1.min-1 to 1.01 +/- 0.12 and 0.29 +/- 0.08 ml.100 g-1.min-1 20 and 40 min after indomethacin, respectively, in hemorrhaged piglets. Treatment with the putative vascular (V1) receptor antagonist [1-(beta-mercapto-beta, beta-cyclopentamethylene propionic acid-2-(O-methyl)tyrosine]arginine vasopressin (MEAVP) had no effect on regional cerebral blood flow, calculated cerebral vascular resistance, or cerebral metabolic rate either before or during hemorrhagic hypotension. However, decreases in cerebral blood flow and metabolic rate and increases in vascular resistance on treatment with indomethacin were blunted markedly in animals treated with MEAVP. These data are consistent with the hypothesis that the prostanoid system contributes to the maintenance of cerebral blood flow and cerebral metabolic rate during hypotension in the newborn pig, as reported previously, and implicate removal of vasopressinergic modulation by prostanoids as a potential mechanism for indomethacin-induced cerebral vasoconstriction in hypotensive newborn piglets.
Lack of an effect of atrial natriuretic peptide on myogenic contraction of microvascular smooth muscle
Authors: Faber J. E.
Published: December 2017

In previous studies we demonstrated that constriction of cremaster microvessels by occupation of alpha 1- but not alpha 2-adrenoceptors is inhibited by atrial natriuretic factor (ANF) at physiological concentrations (10(-11) to 10(-9) M). The present study examined the effect of ANF on “myogenic” constriction of arterioles induced by elevation of intravascular pressure. The cremaster skeletal muscle of anesthetized rats was denervated and extended with intact circulation into a tissue bath. Intravital microscopy was used to measure diameters of first- and second-order arterioles (80-150 microns diam). In group 1, propranolol and phentolamine (both at 10(-6) M) were added to the cremaster bath to block beta- and alpha-adrenoceptors, respectively. Norepinephrine was infused (3.51 micrograms.kg-1.min-1 iv) to raise arterial pressure by 30-35 mmHg. This induced a 30 +/- 3% (means +/- SE) decrease in arteriolar diameter (myogenic constriction). Thereafter, cumulative addition of ANF (10(-11) to 10(-7) M) to the tissue bath had no effect on microvessel diameter, except at the highest concentration wherein the myogenic constriction was reduced by approximately 40%. In a second study the rat's body, excluding the cremaster, was enclosed in an airtight Plexiglas box. Cremaster intravascular pressure was increased by elevating box (ambient) pressure by 10 and 20 mmHg, which caused arteriolar diameter to decrease to 81 +/- 5 and 73 +/- 8% control diameter, respectively, in the absence, and similar amounts 72 +/- 4 and 69 +/- 5%, in the presence of 10(-8) M ANF.(ABSTRACT TRUNCATED AT 250 WORDS)
Impaired endothelium-dependent relaxations in hypertensive resistance arteries involve cyclooxygenase pathway
Authors: Diederich D. , Yang Z. H. , Buhler F. R. , Luscher T. F.
Published: December 2017

Endothelial cells modulate vascular tone by releasing endothelium-derived relaxing (EDRF) and contracting factors. An imbalance of these factors in hypertension could contribute to increased peripheral vascular resistance. Mesenteric resistance arteries of Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) were suspended in a myograph filled with physiological salt solution (37 degrees C; 95% O2–5% CO2). In WKY rings contracted with norepinephrine, acetylcholine (10(-9)-10(-4) M) evoked endothelium-dependent relaxations (88 +/- 2%, IC50 7.3 +/- 0.1; n = 31). Hemoglobin (10(-5) M) but not meclofenamate (10(-5) M) reversed the relaxations delineating EDRF as the mediator. Nitric oxide (3 X 10(-9)-10(-5) M) induced comparable relaxations as acetylcholine. In SHRSP, relaxations to acetylcholine but not those to nitric oxide were impaired (61 +/- 5%, IC50 greater than 6.6 +/- 0.4; n = 24; P less than 0.005). In SHRSP, meclofenamate but not the thromboxane synthetase inhibitor CGS 13080 normalized endothelium-dependent relaxations. Relaxations to sodium nitroprusside were enhanced in SHRSP both in rings with and without endothelium. Thus our results are compatible with the concept that endothelium-dependent relaxations in resistance arteries are mediated by nitric oxide. In SHRSP, endothelium-dependent relaxations are impaired because of a cyclooxygenase-dependent substance interfering with the release and/or action of EDRF.
Epicardial serotonin receptors in circulatory control in conscious Sprague-Dawley rats
Authors: Veelken R. , Sawin L. L. , DiBona G. F.
Published: December 2017

To investigate cardiac chemoreceptors in rats a catheter was chronically implanted into the pericardial sac via the thymus. Intrapericardial (ipc) injection of 200 microliters isotonic saline vehicle did not alter arterial blood pressure, heart rate, right atrial pressure, or respiratory rate. Phenyl biguanide (PBG) and nicotine (NIC) were injected into the pericardial sac. In intact rats anesthetized with methohexital sodium, 90 micrograms PBG ipc decreased blood pressure (BP), heart rate (HR), and renal nerve activity (RNA), whereas 300 micrograms NIC ipc increased BP and decreased HR and RNA. Sinoaortic baroreceptor denervation (SAD) did not affect the responses to PBG and abolished only the HR response to NIC. When vagotomy was added to SAD, all responses to intrapericardial PBG were abolished, but the increase in BP and decrease in RNA resulting from intrapericardial NIC persisted. In SAD rats anesthetized with methohexital, PBG produced dose-dependent decreases in BP and RNA, whereas NIC produced dose-dependent increases in BP and decreases in RNA; the serotonin (5-HT3) antagonist MDL 72222 (80 micrograms ipc) abolished the responses to PBG but not to NIC. MDL 72222 inhibited BP and RNA responses to PBG to a similar extent in conscious and anesthetized SAD rats. Anesthesia attenuated the magnitude and time course of BP and RNA responses to PBG compared with the conscious state. In conclusion, 1) sympathoinhibitory responses to intrapericardial PBG and NIC are mediated by epicardial receptors with different afferent neural pathways, PBG by cardiac vagal afferents and NIC by nonvagal, possibly cardiac sympathetic afferents; 2) PBG exerts its effects via epicardial 5-HT3 receptors; 3) anesthesia attenuates the responses to PBG.
Simultaneous measurement of Ca2+, contraction, and potential in cardiac myocytes
Authors: Spurgeon H. A. , Stern M. D. , Baartz G. , Raffaeli S. , Hansford R. G. , Talo A. , Lakatta E. G. , Capogrossi M. C.
Published: December 2017

A system is described that can simultaneously record cytosolic Ca2+ concentration ([Ca2+]i), cell length, and either membrane potential or current in single cardiac myocytes loaded with the fluorescent Ca2+ indicator indo-1. Fluorescence is excited by epi-illumination with 3.8-microsecond flashes of 350 +/- 5 nm light from a xenon arc. Indo-1 fluoresence is measured simultaneously in spectral windows of 391-434 nm and 457-507 nm, and the ratio of indo-1 emission in the two bands is computed as a measure of [Ca2+]i for each flash. With cells loaded with the permeant acetoxymethyl ester of indo-1, quantitation of [Ca2+]i is not precise, owing to subcellular compartmentation of indo-1; however, the instrument would allow full quantitation if indo-1 free acid was introduced by microinjection. Simultaneously, cell length is measured on-line from the bright-field image of the cell. Because fluorescence collection is time gated during the brief flash, and red light (650-750 nm) is used for the bright-field image, cell length and [Ca2+]i measurements are obtained simultaneously without cross talk. Membrane potential or current can be recorded simultaneously with indo-1 fluorescence and cell length via standard patch-clamping techniques.
Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses
Authors: Tolins J. P. , Palmer R. M. , Moncada S. , Raij L.
Published: December 2017

An endothelium-derived relaxing factor (EDRF) has recently been identified as nitric oxide (NO), originating from endothelial cell metabolism of L-arginine. In vitro studies suggest that EDRF/NO stimulates soluble guanylate cyclase and increases guanosine 3',5'-cyclic monophosphate (cGMP) levels in vascular smooth muscle cells, resulting in the vasorelaxant effects of endothelium-dependent vasodilators such as acetylcholine (ACh). The importance of EDRF/NO in normal physiology or disease states remains uncertain. We therefore investigated the relationship between ACh-induced hemodynamic responses, synthesis of EDRF/NO, and changes in the rate of urinary cGMP excretion in the anesthetized rat in vivo. Intravenous infusion of ACh resulted in hypotension, maintenance of glomerular filtration rate, and renal vasodilatation. ACh induced a dose-dependent increase in urinary cGMP excretion, an effect that was not observed with equihypotensive doses of the endothelium-independent vasodilator, prostacyclin. Rates of cGMP excretion were significantly correlated with the fall in systemic blood pressure induced by ACh. Treatment with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of enzymatic synthesis of nitric oxide from L-arginine, prevented the ACh-induced increase in urinary cGMP excretion as well as the systemic and renal hemodynamic effects of ACh. Plasma levels of atrial natriuretic peptide were unchanged by ACh infusion. Intravenous infusion of L-NMMA was associated with increased blood pressure and decreased basal rates of urinary cGMP excretion. This hypertensive effect was reversed by administration of L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of increased splenic arterial flow and venous pressure on splenic red cell accumulation
Authors: Thorvaldson J. , Stokland O. , Ilebekk A.
Published: December 2017

The importance of increments in splenic venous pressure (SVP) and splenic arterial flow (SAF) for splenic red cell accumulation was estimated in 14 anesthetized dogs with the spleen in situ by arterial and splenic venous hematocrit measurements and continuous ultrasonic recording of splenic diameter (SD). A 10-mmHg increase in SVP by 4 min of splenic venous constriction reduced SAF by 32 +/- 5%, increased SD by 5.1 +/- 0.8%, and transiently reduced splenic venous hematocrit, measured every 10 s, from 35.4 +/- 1.4 to a minimum of 29.2 +/- 1.8%. A 10-mmHg rise in SVP by 4 min of saline infusion increased SAF by 178 +/- 25% and SD by 16.1 +/- 3.0%, and splenic venous hematocrit declined more rapidly and to a lower value than arterial hematocrit. Blood volume expansion with saline or blood at constant, 10-mmHg elevated SVP confirmed that splenic red cell accumulation was greater during blood volume expansion than during splenic venous constriction. We conclude that the spleen accumulates red cells when SVP is raised. At constant, elevated SVP splenic red cell accumulation is flow dependent.
Intramural coronary collateral flow in dogs
Authors: Scheel K. W. , Daulat G. , Mass H. J. , Williams S. E.
Published: December 2017

The objective of this study was to determine whether intramural collaterals contribute significantly to total retrograde flow (index of collateral flow). The left circumflex, left anterior descending, right, and septal coronary arteries were separately cannulated, and blood flows through these vessels were monitored on an isolated, blood-perfused beating heart preparation. Epicardial collaterals between the borders of the circumflex and right coronary perfusion territories were cauterized, and retrograde flow from the circumflex coronary artery was determined before and after cauterization. This procedure unmasked the intramural collateral flow component to retrograde flow. By occluding and unoccluding the coronary flows from the right, septal, and left anterior descending coronary arteries during these measurements, we were able to determine their contribution to epicardial and intramural collateral flow. We found that, after cauterization, an average of 58 +/- 3.6% of the total retrograde flow remained. The septal and left anterior descending coronary arteries contributed almost equally to this retrograde flow. We concluded that, because the epicardial collaterals were cauterized, the source of retrograde flow was from intramural collaterals and constituted about one-half of the measured retrograde flow in dogs with a native collateral circulation.
Arginine vasopressin increases apparent whole body capacity in anesthetized cats
Authors: Martin D. S. , McNeill J. R.
Published: December 2017

The effects of arginine vasopressin (AVP) on capacitance function were assessed in anesthetized cats by draining blood from the superior and inferior venae cavae into an external reservoir and then returning blood to the right atrium at a constant rate. Under these conditions, changes in reservoir volume were assumed to reflect reciprocal changes in whole body capacity. Intravenous infusions of AVP (1, 10, and 100 ng.kg-1.min-1) that elevated plasma AVP concentrations by approximately 30, 400, and 4,000 fmol/ml were associated with concentration-dependent increases in whole body capacity that ranged between 1.6 and 8 ml/kg. In contrast to AVP, intravenous infusions of angiotensin II (5, 10, and 50 ng.kg-1.min-1) had relatively little influence on capacity, whereas norepinephrine administration (300, 1,000, and 3,000 ng.kg-1.min-1) was associated with dose-dependent decreases in capacity of 4.5-10.3 ml/kg. Virtually the entire increase in whole body capacity to AVP can be accounted for by summation of the predicted contributions of an active reflex venodilatatory component and those of a passive component (arterial and cardiopulmonary compartments). Because systemic compliance (delta reservoir volume/delta venous pressure) was not changed by AVP administration, the contribution of a reflex venodilatatory component must be the result of increases in unstressed vascular volume (contained volume at 0 transmural pressure) as opposed to changes in compliance. These results may explain why AVP decreases cardiac output to a greater extent than either angiotensin II or sympathomimetics and, thus, why AVP is a weaker pressor agent in animals with intact autonomic function.
Pulmonary embolism: emboli and fibrinolysis inhibition in isolated canine lungs
Authors: Townsley M. I. , Barman S. A. , Taylor A. E.
Published: December 2017

The effect of fibrinolysis inhibition with tranexamic acid on pulmonary microvascular permeability during glass bead embolization was investigated in the isolated lung. Lung lobes from nonheparinized dogs were treated in vivo with the equivalent of 0.6 g/kg 100 microns glass bead emboli alone, emboli after tranexamic acid, tranexamic acid alone, or the bead vehicle alone. After 40-50 min, the lobes were isolated for ex vivo perfusion with heparinized autologous blood. There were no changes in any parameter over the 120-min perfusion period. Blood flow at 120 min was decreased after both emboli alone and emboli with tranexamic acid, reflecting an increase in vascular resistance compared with the Tween or tranexamic acid controls. Furthermore, tranexamic acid increased the ratio of pre- to postcapillary resistance in embolized lobes compared with that after emboli alone or in the Tween or tranexamic acid controls. The isogravimetric capillary pressure and the osmotic reflection coefficient were not significantly decreased by tranexamic acid compared with those after emboli alone; however, it did result in an increase in the capillary filtration coefficient compared with that after emboli alone or in the control groups. We conclude that although fibrinolysis inhibition does not clearly exacerbate the lung injury seen after emboli, the tranexamic acid-induced changes in hemodynamics would tend to accelerate edema formation.
Regional vascular resistance during exercise: role of cardiac afferents and exercise training
Authors: DiCarlo S. E. , Bishop V. S.
Published: December 2017

This study was designed to determine whether cardiac vagal afferents exert an inhibitory influence on increases in regional vascular resistance during exercise and to determine whether endurance exercise training enhances the inhibitory influence of cardiac vagal afferents. We measured changes in regional vascular resistance in 12 rabbits at rest and during running at 12.6 m/min, 20% grade, before and after reversible denervation of cardiac afferents (intrapericardial procainamide HCl, 2%). In addition, these procedures were repeated in five of these rabbits following an 8-wk endurance exercise training program. Because intrapericardial injections of procainamide anesthetize both the efferent as well as the afferent innervation to the heart, it was necessary to determine the effects of blocking the efferent innervation on the regulation of regional vascular resistance during exercise. Rabbits were instrumented with Doppler ultrasonic flow probes around the renal (R), mesenteric (M), ascending, and terminal aortic (TA) arteries. Catheters were positioned in the central ear artery and vein and pericardial sac. Mean arterial pressure, heart rate, cardiac output, R, M, TA, and systemic (S) resistances were determined. Exercise changed R (+37 +/- 4%), M (+88 +/- 9%), TA (-62 +/- 6%), and S (-34 +/- 3) resistances. Subsequent cardiac efferent blockade alone had no significant effect on regional vascular resistance during exercise. Combined efferent and afferent blockade resulted in significant increases in R (+62 +/- 6%) and M resistance (+134 +/- 13%) but did not alter TA (-51 +/- 4%) or S (-27 +/- 2%) resistance during exercise. Exercise training significantly enhanced the inhibitory influence of cardiac afferents on R and M regional vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
Altered pressor responses to NE and ANG II during cyclosporin A administration to conscious rats
Authors: Textor S. C. , Smith-Powell L. , Telles T.
Published: December 2017

Vasoconstriction and hypertension have been prominent during cyclosporin A (CSA) administration. To evaluate whether CSA modulates vascular responsiveness to pressor stimuli in the intact organism, CSA was administered via osmotic pump (10 and 20 mg.kg-1.day-1 ip vs. olive oil vehicle) for 2 wk. After 8 days, arterial pressure and dose-response relationships to norepinephrine, angiotensin II, and bradykinin were measured in conscious animals. Despite similar initial pressures, dose-response relationships were markedly attenuated to both norepinephrine and angiotensin II. Maximal responses were not affected, indicating a rightward shift without loss of peak effect. Vasodilation with bradykinin was not diminished. These changes were not evident after an acute CSA infusion at the same dose (10 mg.kg-1.day-1 over 2 h). Treatment with verapamil (0.505 mg/kg over 2 days) lowered basal arterial pressures but did not change the effects of CSA on pressor sensitivity. Despite attenuated pressor responses, renal vascular resistance was elevated and glomerular filtration diminished during CSA administration. These observations indicate that cyclosporin modifies vascular responsiveness to pressor stimuli in the rat and may explain the relative resistance of this species to cyclosporin-induced hypertension.
Modulation of ventricular action potential by alpha 1-adrenoceptors and protein kinase C
Authors: Dirksen R. T. , Sheu S. S.
Published: December 2017

The effects of the alpha 1-adrenoceptor agonist methoxamine (MTX) and the direct protein kinase C (PKC) activator phorbol 12,13-dibutyrate (PDBU) on action potentials from guinea pig papillary muscles were studied. Measured with conventional microelectrodes, MTX (1 x 10(-7) to 3 x 10(-4) M) and PDBU (1 x 10(-9) to 1 x 10(-6) M) both caused a dose-dependent and reversible decrease in the action potential duration measured at 90% repolarization (APD90) at 36.5 degrees C. The MTX-mediated response was blocked by both prazosin (3 x 10(-6) M) and phentolamine (1 x 10(-6) M) and mimicked by phenylephrine. Maximal concentrations of the two agents together resulted in only a partial (50%) additive decrease in the APD90. At a lower temperature (27.5 degrees C), PDBU no longer produced a shortening in the APD90 and MTX produced a prolongation in the APD90. These results demonstrate that although alpha 1-adrenoceptor stimulation and PKC activation in guinea pig papillary muscle both lead to a decrease in the APD90, the differences in their effects as related to the magnitude, partial additivity, and temperature dependence suggest that the mechanism of action are not identical. These subtle differences may help to delineate the exact physiological implications of alpha 1-adrenoceptors in cardiac excitation and contraction.
Adenosine-induced changes in atrial action potential: contribution of Ca and K currents
Authors: Visentin S. , Wu S. N. , Belardinelli L.
Published: December 2017

In this study, we examined the relative contribution of the increase in acetylcholine-regulated potassium current (IK ACh) and decrease in calcium current (ICa) to the adenosine (Ado)-induced shortening of action potential duration (APD). In isolated guinea pig atrial myocytes, membrane potentials and currents were measured by the whole cell patch-clamp technique. ICa and IK ACh were individualized by blocking the K currents with Cs+ and ICa with Cd2+. The effects of Ado on membrane potential and currents were concentration dependent. Ado (10 microM) shortened APD at 0 mV and at 90% of repolarization (APD0,90) to 7 +/- 1 and 26 +/- 6 ms from control values of 23 +/- 3 and 89 +/- 6 ms, respectively. Concomitant with the changes in APD, Ado decreased ICa from -9.2 +/- 1.3 to -6.8 +/- 10 microA/microF (26% decrease) but increased IK ACh from +3.5 +/- 0.5 to +7.8 +/- 0.8 microA/microF (123% increase). When rundown of ICa was taken into account, the maximum decrease in ICa caused by Ado was 12%. The effect of Ado on ICa and IK ACh was not altered by treatment of the cells with either Cs+ or Cd2+. The shortening of ADP0,90 strongly correlated with the increase in IK ACh but minimally with the decrease in ICa. A 22% reduction in ICa caused by lowering extracellular Ca2+ concentration ([Ca2+]o) from 3.6 to 1.8 mM was associated with an 11 and 14% shortening of APD0 and APD90, respectively. In the same myocytes an 18% decrease in ICa by 10 microM Ado reduced APD0 and APD90 by 58 and 61%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Activation in frog atrial trabeculae: dependence on temperature and length
Authors: Reiser P. J. , Lindley B. D.
Published: December 2017

Isolated frog atrial trabeculae were activated using the method of Na+ withdrawal to induce contractures of relatively steady tension. External Na+ concentration [( Na+]o) during contractures was varied between 0.25 and 45 mM. Isometric contracture tension was measured at cold (4 degrees C) and warm (20 degrees C) temperatures. In addition, rapid temperature jumps (complete in approximately 400 ms) were imposed during cold contractures, resulting in tension transients that consisted of an initial increase in tension followed by a decrease, the latter phase being greater at small and moderate reductions in [Na+]o. Peak contracture tension varied with relative muscle length. The trabeculae became more sensitive with stretch to Na+ withdrawal at 20 degrees C and generated relatively greater tensions at a given [Na+]o. The initial tension increase after a temperature jump was directly proportional to the peak contracture tension immediately preceding the increase in temperature and was therefore interpreted as reflecting an effect of the higher temperature on the attached force-generating cross bridges. The effects of cold and warm steady temperatures and temperature jumps during isometric twitches were also studied. Peak twitch tension varied inversely with temperature (stimulus frequency = 0.2 Hz). In contrast, temperature jumps imposed during the rising phase of twitches at a steady cold temperature (approximately 4 degrees C) resulted in a large initial increase in tension followed by relaxation at a rate that was characteristic of the elevated temperature. The results suggest that, at the warmer temperature (approximately 20 degrees C), activation (i.e., number of attached cross bridges) of the myocardium is significantly less than maximal during the twitch response. The dependence of the tension vs. [Na+]o curves and the tension transients resulting from the temperature jumps on relative muscle length provide evidence for a length dependency of contractile activation in intact atrial trabeculae under conditions of steady-state tension development.
Influence of cardiac innervation on intrinsic heart rate in dogs
Authors: Evans J. M. , Randall D. C. , Funk J. N. , Knapp C. F.
Published: December 2017

Intrinsic heart rate is defined as the rate at which the heart beats when all cardiac neural and hormonal inputs are removed. We determined the effect of prevailing autonomic innervation of the heart on the intrinsic heart rate in chronically maintained, sedated, normally innervated dogs (n = 14), and in 14 other dogs that had previously (greater than 12 day) undergone complete surgical cardiac denervation. Intrinsic rate was determined in both groups using the following two procedures: 1) pharmacological effector blockade; and 2) pharmacological ganglionic blockade. The intrinsic rate determined by effector blockade was 142.9 +/- 7.2 (SE) beats/min in the dogs with intact cardiac innervation. When the same treatment was given after total surgical cardiac denervation, intrinsic rate was 97.9 +/- 4.8 beats/min. Intrinsic heart rate was significantly (P less than 0.05) lower in surgically denervated dogs. Ganglionic blockade in surgically denervated animals yielded an intrinsic rate of 90.0 +/- 8.5 beats/min, which was again significantly lower than the corresponding value of 128.4 +/- 5.5 beats/min in normal dogs. There was no difference in the intrinsic heart rate as determined by effector vs. ganglionic blockade in either group of dogs. An additional six dogs were subjected to selective surgical sinoatrial nodal parasympathectomy; their intrinsic rate (effector blockade) in the conscious state was 115.8 +/- 4.3 beats/min; this was significantly lower than the corresponding value for normal dogs and significantly greater than in dogs subject to total surgical cardiac denervation. The lower rate observed in the totally denervated and selectively denervated dogs after effector and/or ganglionic blockades implies that intrinsic heart rate depends on the level or nature of prevailing autonomic activity.
Cerebral blood flow and end-tidal PCO2 during prolonged acetazolamide treatment in humans
Authors: Friberg L. , Kastrup J. , Rizzi D. , Jensen J. B. , Lassen N. A.
Published: December 2017

One oral dose of 1,000 mg of acetazolamide caused an acute 38% increase in cerebral blood flow (CBF) in eight healthy volunteers. During the following 10 days the subjects took 1,000 mg acetazolamide daily. CBF normalized within the first 2 days. The drug induced mild hyperventilation, gradually decreasing alveolar PCO2 to 70% of the control value at the end of the treatment period. In healthy humans the hyperventilation will not increase brain oxygenation significantly at sea level. But at high altitudes the enhanced ventilatory drive will improve oxygenation of the brain, and this may account for the beneficial effects of the drug on the symptoms of acute mountain sickness. During the treatment there was a significant 10% decrease of the hematocrit but an unaltered hemoglobin concentration. In combination with data in the literature our studies suggest that the initial CBF increase is a consequence of a transient extracellular acidosis dilating brain arterioles, whereas increased ventilatory drive results from a gradually increasing mild intracellular acidosis in the brain.
Nerve-induced nonadrenergic vasoconstriction and vasodilatation in skeletal muscle
Authors: Ohlen A. , Persson M. G. , Lindbom L. , Gustafsson L. E. , Hedqvist P.
Published: December 2017

Intravital microscopy was used to study the effect of motor nerve stimulation on microvessel diameters in the rabbit tenuissimus muscle. Stimulation of the motor nerve (0.5-5 ms, 2-20 Hz, 5-15 V) evoked pulse duration- and frequency-dependent constriction of transverse and terminal arterioles. The vasoconstriction induced by low-frequency stimulation (2 Hz) was abolished by the alpha-adrenoceptor antagonist phentolamine, whereas high-frequency stimulation (10-20 Hz) resulted in a response that was only partially inhibited by phentolamine. However, desensitization of the tissue to the vasoconstrictor effects of neuropeptide Y (NPY) changed the response remaining after phentolamine into vasodilatation. Independent of stimulation parameters, pretreatment of the tissue with the adrenergic neuron blocker guanethidine reversed the constriction into dilatation that was resistant to propranolol, atropine, and indomethacin. The results document the functional presence of both vasoconstrictor and vasodilator fibers in the rabbit tenuissimus muscle motor nerve, and they suggest that part of the nerve-induced vasoconstriction at higher stimulation frequencies is caused by neuronally released NPY.
Baroreflex regulation of regional blood flow in congestive heart failure
Authors: Creager M. A. , Hirsch A. T. , Dzau V. J. , Nabel E. G. , Cutler S. S. , Colucci W. S.
Published: December 2017

In patients with congestive heart failure (CHF), the distribution of the cardiac output is altered. Cardiopulmonary and arterial baroreceptors normally can regulate regional blood flow, but their contribution in heart failure is not known. To examine the role of baroreceptors in the regulation of regional blood flow in CHF, the effect of lower body negative pressure (LBNP) on forearm, renal, and splanchnic blood flow was evaluated in 12 patients with heart failure. Incremental LBNP at -10 and -40 mmHg decreased central venous pressure but had not effect on systolic blood pressure or pulse pressure. Renal blood flow decreased from 505 +/- 63 to 468 +/- 66 ml/min during LBNP -10 mmHg (P less than 0.05) and to 376 +/- 74 ml/min during LBNP -40 mmHg (P less than 0.01). Splanchnic blood flow decreased from 564 +/- 76 to 480 +/- 62 ml/min during LBNP -10 mmHg (P less than 0.01) and to 303 +/- 45 ml/min during LBNP -40 mmHg (P less than 0.01). Forearm blood flow did not decrease during LBNP -10 mmHg or -40 mmHg. To determine whether the absence of limb vasoconstriction during LBNP was confined to abnormalities in the baroreflex arc or was secondary to impaired end-organ responsiveness, six patients with heart failure and six normal subjects received an intrabrachial artery infusion of phenylephrine. Phenylephrine increased forearm vascular resistance comparably in each group. These data demonstrate that baroreceptors can regulate splanchnic and renal but not limb vascular resistance in patients with congestive heart failure and may contribute to the redistribution of blood flow that occurs in this disorder.
Chronic transvascular fluid flux and lymph flow during volume-loading hypertension
Authors: Valenzuela-Rendon J. , Manning R. D.
Published: December 2017

The chronic roles of the transcapillary fluid flux and lymph flow in the distribution of extracellular fluid volume during volume-loading hypertension were investigated in five conscious dogs. Similarly, the distribution of plasma proteins across the microvasculature was evaluated. During the early phases of volume-loading hypertension the fluid balance was positive, which caused the extracellular fluid volume and the plasma volume to increase 25 and 15%, respectively. The thoracic duct lymph flow more than doubled, but the increase in transcapillary fluid flux was even greater. Therefore the interstitial fluid volume increased 30%. This fluid shift from the vasculature into the interstitium probably prevented an even greater rise in arterial pressure. In addition, the transcapillary protein flux more than doubled, but the accompanying increase in lymph protein transport prevented any change in plasma protein mass. During the latter part of the saline-infusion period, the lymph flow declined toward its control, which caused a net transfer of fluid into the interstitium. In conclusion, the transcapillary fluid flux and lymph flow play significant roles in extracellular fluid volume distribution.
Differential cardiac sympathetic activity during acute myocardial ischemia
Authors: Neely B. H. , Hageman G. R.
Published: December 2017

Efferent sympathetic activities were simultaneously recorded from two thoracic cardiac nerves in 33 chloralose-anesthetized dogs. Efferent innervation patterns were determined by electrical stimulation prior to recording in each animal. One of the nerves selected for recording was shown to innervate the proposed ischemic region, whereas the other nerve was selected because it was shown to innervate nonischemic regions. Left ventricular ischemia was produced by occlusion of a branch of either the left anterior descending (LAD) or left circumflex (LCX) coronary arteries. Heart rate was paced. Cardiac postganglionic sympathetic efferent activities were recorded during a 30-min coronary occlusion in 22 animals. Thirty minutes after LAD occlusion (n = 10), postganglionic sympathetic activity to ischemic myocardium was decreased (84 +/- 5% of control; P less than 0.05) while activity to nonischemic myocardium was unchanged. Thirty minutes after LCX occlusion (n = 12), postganglionic sympathetic activity to ischemic myocardium was also decreased (87 +/- 3% of control; P less than 0.01); however, sympathetic activity to nonischemic myocardium was increased (159 +/- 10% of control; P less than 0.001). Thus, in the anesthetized canine, regional left ventricular ischemia elicits differential sympathetic neural responses that are dependent on the location of the ischemic myocardium as well as the efferent destinations of the nerves. Changes in cardiac postganglionic sympathetic efferent activities are characterized by decreased activity to ischemic regions, with either no change or increased activity to nonischemic regions.
Rapid ventricular pacing in pigs: an experimental model of congestive heart failure
Authors: Chow E. , Woodard J. C. , Farrar D. J.
Published: December 2017

To develop an improved animal model of congestive heart failure, 11 female farm pigs (wt, 42-46 kg) underwent rapid ventricular pacing at 230 beats/min for 7 days with a modified Medtronic unipolar pacemaker connected to an apical pacing lead. After 7 days the pacemaker was turned off, anesthesia induced, the chest opened, and cardiac hemodynamic and dimensional studies were performed. Results were subsequently compared with data from 12 control pigs that received no pacing. Two pigs died before measurements could be determined. Cardiac output in the paced animals (0.061 +/- 0.018 l.min-1.kg-1) was significantly less (P less than 0.05) than in control pigs (0.085 +/- 0.016 l.min-1.kg-1), when compared at the same resting heart rate. Left ventricular (LV) end-diastolic pressure (23.2 +/- 7.7 vs. 8.6 +/- 3.6 mmHg, P less than 0.01) and right ventricular (RV) end-diastolic pressure (9.0 +/- 3.1 vs. 4.4 +/- 1.7 mmHg, P less than 0.01) were significantly greater in the paced pigs. Significant increases in both septal-lateral LV end-diastolic dimension (60.3 +/- 3.9 vs. 52.1 +/- 7.2 mm, P less than 0.01) and RV end-diastolic dimension (47.2 +/- 5.7 vs. 40.8 +/- 4.7 mm, P less than 0.05) indicated biventricular dilation in the paced pigs. They also exhibited a significantly greater heart weight-to-total body weight ratio and clinical evidence of congestive heart failure, with hepatomegaly and ascites. These results demonstrate that 1 wk of rapid ventricular pacing at 230 beats/min produces a realistic model of congestive heart failure in the pig.
Pulmonary arterial compliance at rest and exercise in normal humans
Authors: Slife D. M. , Latham R. D. , Sipkema P. , Westerhof N.
Published: December 2017

We evaluated the feasibility of determining pulmonary arterial compliance (Cp) by a parameter estimation procedure based on the three-element windkessel model. Eight normal patients studied with multisensor micromanometry technology had simultaneous rest and exercise pulmonary artery pressures (PAP) and flows recorded. These were submitted to the model and independent methods to determine Cp, pulmonary characteristic impedance (Zc), and pulmonary vascular resistance (PVR). Significant changes in heart rate, PAP, and stroke volume (P less than 0.05) occurred with exercise. In comparing rest and exercise Zc and PVR values determined by the model and independent methods, and in comparing each method for these values, there was no significant difference. Model-derived and independently derived estimates of Cp were significantly different at rest (P less than 0.04) and exercise (P less than 0.001). There was no significant difference between rest and exercise values of Cp by either method. The model estimates of PVR at rest (64 +/- 11 dyn.s.cm-5) and exercise (41 +/- 7 dyn.s.cm-5) (P = 0.06) and the model Zc value at rest (22 +/- 3 dyn.s.cm5) were appropriate. The model Cp values at rest (0.22 +/- 0.05 ml.mmHg-1.kg-1) correlated with previously reported normalized values in other species. This study reports the successful use of a parameter estimation procedure based on the three-element windkessel model to describe pulmonary artery compliance in normal humans.