bluuebunny/crossref_metadata_2025 huggingface dataset:
Alpha 1b-adrenoceptor-mediated stimulation of Na-K pump current in adult rat ventricular myocytes
Authors: Williamson A. P. , Kennedy R. H. , Seifen E. , Lindemann J. P. , Stimers J. R.
Published: December 2017

The purpose of this study was to determine if myocardial alpha 1a-and/or alpha 1b-adrenoceptors are involved in the increase in Na-K pump current (Ip) elicited by alpha 1-adrenergic agonists. Single rat ventricular myocytes were isolated by enzymatic disaggregation. The whole cell patch-clamp technique was used to examine dose-dependent effects of phenylephrine (PE) on holding current (Ih) and to determine whether observed actions were mediated via alpha 1a-or alpha 1b-adrenergic receptors. To minimize the contribution of transsar-colemmal currents other than Ip to Ih, membrane voltage was held constant -40 mV, and cells were maintained in a Ca-free perfusate containing 1 mM Ba and 0.1 mM Cd. All experiments were conducted in the presence of 3 microM nadolol. PE elicited dose-dependent increases in Ih, with a peak effect of 0.57 +/- 0.03 pA/pF observed at 30 microM. The response to PE was dose dependently inhibited by prazosin and chloroethylclonidine and was totally eliminated by 1 mM ouabain. When used at doses selective for the alpha 1a-subtype, WB4101 failed to significantly antagonize the action of PE. These data suggest that the observed alpha 1-adrenoceptor-mediated increase in Ih in isolated rat ventricular myocytes is the result of an increase in Ip effected via stimulation of alpha 1b-adrenergic receptors.
Coronary blood flow in senescent rats with late-onset hypertension
Authors: Tomanek R. J. , Aydelotte M. R. , Anderson K. E. , Torry R. J.
Published: December 2017

We tested the hypothesis that the imposition of hypertension late in life would markedly limit maximal myocardial perfusion (MP). Young adult (8 mo) and senescent (24 mo) Fischer 344 rats were studied 3 mo after one-kidney, figure-8 renal wrap hypertension (RH) was induced. Sham-operated rats served as controls (Con). Regional MP was determined with radioactive microspheres in conscious rats before and during maximal coronary vasodilation with infusion of dipyridamole. Systolic arterial pressure (SAP) was significantly elevated in both RH age groups during weeks 2-6 following surgery and then fell to normotensive levels. After 3 mo SAP (mmHg) was significantly lower in the senescent RH rats (125 +/- 5) compared with their controls (147 +/- 3). In senescent RH rats left ventricular (LV) end-diastolic pressure increased fivefold. LV mass increased with age but not with treatment. LV minimal coronary vascular resistance (MCVR, mmHg.ml-1.min-100 g) increased significantly both with age and treatment (8 mo: Con = 0.07 +/- 0.01, RH = 0.14 +/- 0.01; 24 mo: Con = 0.11 +/- 0.01, RH 0.17 +/- 0.02). Treatment affected similar changes in the right ventricular MCVR. LV endocardial-to-epicardial perfusion ratio during rest was lower in the senescent groups but was not altered by hypertension. These data indicate that 1) both aging and this model of hypertension compromise maximal coronary perfusion and reserve in Fischer 344 rats, and 2) aging is associated with an increase in coronary vascular resistance in both ventricles at rest and in a relative reduction in maximal endocardial perfusion in the left ventricle.
Influence of hematocrit on tissue O2 extraction capabilities during acute hemorrhage
Authors: Van der Linden P. , Gilbart E. , Paques P. , Simon C. , Vincent J. L.
Published: December 2017

This study was performed to test the hypothesis that tissue O2 extraction capabilities during hemorrhage may be greater when hematocrit (Hct) is initially reduced. Twenty-four anesthetized and splenectomized dogs were randomly assigned in three groups of eight dogs each: group 1 (Hct 40), 40–45% Hct; group 2 (Hct 30), 30–35% Hct; and group 3 (Hct 20), 20–25% Hct. In each animal, the desired Hct was obtained by normovolemic hemodilution using hydroxyethyl starch 450/0.7 and maintained throughout the experiment. O2 delivery (DO2) was progressively reduced by hemorrhage. At each step, DO2 and O2 consumption (VO2) were measured separately. Critical DO2 obtained from a plot of VO2 vs. DO2 was lower in the Hct 30 and Hct 20 groups than in the Hct 40 group [(in ml.min-1.kg-1) Hct 30, 7.9 +/- 2.2; Hct 20, 7.8 +/- 1.0; Hct 40, 10.4 +/- 1.1; P < 0.05]. Critical DO2 obtained from blood lactate levels was also significantly lower in the Hct 30 and Hct20 groups than in the Hct 40 group. Critical O2 extraction ratio was also greater in the Hct 30 and Hct 20 groups than in the Hct 40 group (Hct 30, 73.0 +/- 13.9%; Hct 20, 70.1 +/- 9.6%; Hct 40, 57.1 +/- 11.5%; P < 0.05). In the conditions of our study, moderate hemodilution was associated with an improvement of the O2 extraction capabilities of the body, probably related to the reduction in blood viscosity.
Factors affecting renal microvascular blood flow in rat hyperdynamic bacteremia
Authors: Cryer H. G. , Bloom I. T. , Unger L. S. , Garrison R. N.
Published: December 2017

To determine whether angiotensin II and alpha-adrenergic activity contribute to the mechanism of impaired renal microvascular blood flow during hyperdynamic live Escherichia coli (E. coli) bacteremia, we used in vivo video microscopy in the chronic unilateral hydronephrotic kidney of decerebrate male Sprague-Dawley rats. Intravenous infusion of E. coli caused arteriolar constriction to 83 +/- 4% of baseline (BL) in cortical radial arteries (CRA), 82 +/- 3% of BL in afferent (AFF) arterioles, and decreased flow to 54 +/- 9% of BL. Subsequent local inhibition of renal prostaglandin synthesis with mefenamate increased preglomerular arteriolar constriction to 55 +/- 6% of BL in CRA and 51 +/- 6% of BL in AFF arterioles and decreased renal microvascular blood flow to 26 +/- 8% of BL values in E. coli animals but had no effect on control animals. Subsequent local renal angiotensin II receptor blockade with saralasin acetate increased renal microvascular blood flow in E. coli animals to 64 +/- 9% of BL by dilating CRA to 78 +/- 5% of BL and AFF arterioles to 89 +/- 5% of BL. Phentolamine caused further dilation of CRA to 104 +/- 7% BL and AFF arterioles to 116 +/- 109% and increased flow to 99 +/- 8% of BL. Acetylcholine increased diameters further to 110 +/- 3% of BL in CRA and 136 +/- 12% of BL in AFF arterioles. These data indicate that in our chronic hydronephrotic kidney model during E. coli bacteremia, renal microvascular tone is due to increased angiotensin II and alpha-adrenergic activity and some other, as yet, undefined factor.
Cellular signaling responses mediated by a novel nucleotide receptor in rabbit microvessel endothelium
Authors: Mannix R. J. , Moatter T. , Kelley K. A. , Gerritsen M. E.
Published: December 2017

The adenine nucleotide, ATP, elicits an elevation in intracellular ionized calcium concentration ([Ca2+]i) and phospholipase C-mediated phosphatidylinositol hydrolysis and stimulates the synthesis of the prostaglandins E2 and I2 in cultured endothelial cells derived from rabbit cardiac muscle. Use of various ATP analogues indicated that these events did not fit the classical definition of P1 or P2 purinergic receptors and, furthermore, indicated that the receptor(s) mediating these activities was not specific for purines. The rank order of agonist potency on prostaglandin release, elevations in [Ca2+]i, and inositol phosphate response was UTP > or = ATP > ADP > ADP[beta]S = 2-methylthio ATP > adenosine, suggesting that these three cellular responses are coupled to the same or similar receptors. However, the sensitivity of these three cellular responses to added nucleotides was somewhat different. The half-maximum effective concentration (EC50) for ATP stimulation of prostaglandin release was 100 microM, for inositol phosphate turnover it was 25 microM, and for elevations in [Ca2+]i it was < 1 microM. Similar discrepancies in EC50 UTP values for these three cellular responses were also noted. These observations indicate that purine and pyrimidine nucleotides elicit at least three cellular responses in rabbit cardiac muscle microvessel endothelial cells, all demonstrating similar rank orders of potency. However, the differences in EC50 suggest that if these responses are mediated by a single receptor type, it exhibits divergent coupling to various cellular signaling pathways.
Lack of modulation by dietary unsaturated fats on sympathetic neurotransmission in rat hearts
Authors: Du X. J. , Dart A. M. , Riemersma R. A.
Published: December 2017

We examined the effect of dietary polyunsaturated fatty acids (PUFA) on cardiac sympathetic neurotransmission. Rats were fed semisynthetic diets (18.5% fat wt/wt) high in saturated fatty acids (control diet), high in n-6 PUFA (corn oil), or enriched with n-3 PUFA (Maxepa). A perfused innervated heart model was used to examine different aspects of sympathetic neurotransmission 10 wk after the feeding. Dietary PUFA increased the content of n-6 or n-3 PUFA in myocardial phospholipids compared with animals fed control diets. Myocardial norepinephrine content, sympathetic nerve stimulation-induced norepinephrine release, neural reuptake, presynaptic alpha-adrenergic inhibition of norepinephrine release, and postsynaptic inotropic response (+/- dP/dt) to sympathetic nerve stimulation or to a beta-agonist were essentially not influenced by dietary PUFA. Neural norepinephrine release during prolonged ischemia (60 min) was also similar in hearts from rats fed n-6 PUFA and control diets. Thus a modification of sympathetic neurotransmission was not achieved by feeding PUFA-enriched diets for 10 wk.
Monkey cerebral arterial relaxation caused by hypercapnic acidosis and hypertonic bicarbonate
Authors: Toda N. , Ayajiki K. , Enokibori M. , Okamura T.
Published: December 2017

In helical strips of Japanese monkey cerebral arteries contracted with vasoconstrictors, applications of high CO2 (15% compared with 5% CO2 in control media) and hypertonic NaHCO3 (50 mM) produced relaxations. Similar relaxations were also obtained in human cerebral arterial strips. Hypercapnia increased PCO2 and resulted in acidosis in the bathing media, and the addition of NaHCO3 restored the pH to normal with high PCO2 and increased the osmotic pressure. The relaxant responses were not influenced by endothelium denudation and treatment with indomethacin. The hypercapnia-induced relaxation was suppressed by ouabain but was unaffected by amiloride. On the other hand, hypertonic bicarbonate-induced relaxations were inhibited by ouabain as well as by amiloride. Removal of Na+ from the bathing media abolished the hypercapnia-induced relaxation but did not alter the hyperosmolar relaxation. In contrast to hypertonic NaHCO3, isotonic bicarbonate solutions contracted the arterial strips by neutralizing the pH under hypercapnia. It may be concluded that relaxations elicited by hypercapnic acidosis are associated with a fall of extracellular pH and an activation of the electrogenic Na+ pump, and those caused by hyperosmolarity are due to stimulation of the Na(+)-H+ exchange and the Na+ pump. Endothelium-derived vasoactive substances and cyclooxygenase products do not appear to be involved in these relaxations of monkey cerebral arteries under the experimental conditions used.
Effect of acetylcholine infusion on adrenal vasculature and catecholamine secretion
Authors: Tobin J. R. , Breslow M. J. , Traystman R. J.
Published: December 2017

To evaluate effects of cholinergic receptor stimulation on regional adrenal blood flow (Q, radiolabeled microspheres) and catecholamine secretion, acetylcholine (ACh) was infused into pentobarbital-anesthetized, ventilated dogs. Unilateral adrenal denervation and placement of lumboadrenal catheters preceded intra-aortic infusion of 1) ACh alone (n = 6), 2) ACh plus hexamethonium (Hex) 20 mg/kg (n = 6), or 3) ACh plus atropine (Atr) (0.5 mg/kg) and Hex. ACh alone and in combination with Hex elicited similar dose-related (2, 20, and 100 mumol/min) increases in catecholamine secretion (181 +/- 61 to 1,055 +/- 229, 31,644 +/- 9,411, and 179,181 +/- 69,659 ng.min-1 x g medulla-1), whereas Hex and Atr together inhibited ACh-induced secretion by 95%. ACh caused marked medullary vasodilation (0.71 +/- 0.05 to 0.14 +/- 0.03 mmHg.ml-1 x min.100 g) in all three groups. To determine whether medullary vasodilation was due to incomplete muscarinic blockade, Hex-pretreated animals (n = 4) received ACh (100 mumol/min) and three increasing doses of Atr (0.5, 5, and 25 mg/kg). Catecholamine secretion was inhibited by all doses of Atr; however, vasodilation was blocked only by the two higher doses of Atr. These data suggest possible different mechanisms of muscarinic receptor-mediated catecholamine secretion and vasodilation.
Antagonism of LTD4-evoked relaxation in canine renal artery and vein
Authors: Pawloski J. R. , Chapnick B. M.
Published: December 2017

The goal of this study was to characterize further the manner in which the peptide leukotriene (LT) D4 evokes endothelium-dependent relaxation of the canine renal vein (RV) and artery (RA). The effects of four chemically and structurally dissimilar LT receptor antagonists and pertussis toxin (PTX), on LTD4-evoked relaxation of RV and RA rings, were determined and compared. In the presence of ICI 198,615 (10(-5) M), relaxation of both the RA and RV evoked by LTD4 was markedly attenuated. MK-571 (10(-5) M) altered neither RA nor RV relaxation evoked by LTD4. Relaxation of the RV but not the RA, evoked by LTD4, was attenuated in the presence of LY171,883 (10(-5) M). L649,923 (10(-5) M) solely inhibited LTD4-evoked relaxation of the RA. Pretreatment of vascular rings with PTX (250 ng/ml) for 2 h attenuated the vasomotor relaxation evoked by LTD4 in the RA but not in the RV. These observations suggest that LTD4-evoked relaxation of the RA and RV is dependent on different mechanisms. The endothelium-dependent response produced in the RA apparently involves a PTX-sensitive G protein. It is proposed that multiple signal transduction pathways and perhaps different LTD4 receptors may account for the diverse activity of LTD4.
Angiopeptin enhances acetylcholine-induced relaxation and inhibits intimal hyperplasia after vascular injury
Authors: Light J. T. , Bellan J. A. , Chen I. L. , Longenecker L. L. , Murphy W. A. , Coy D. H. , Kadowitz P. J. , McNamara D. B.
Published: December 2017

The effects of the somatostatin analogue, angiopeptin (BIM-23014), on neoendothelial function, as evidenced by formation of prostaglandin (PG) I2 and by acetylcholine-induced relaxation (formation of endothelial-derived relaxing factor), were investigated in the rabbit aorta. A balloon catheter injury of the thoracic and abdominal aorta was induced in New Zealand White rabbits. Animals treated with angiopeptin for 2 or 4 wk were compared with untreated rabbits at 2 or 4 wk after the induction of injury, as well as to sham-operated controls. When the rabbits were killed, vascular rings were assessed for arachidonic acid-stimulated PGI2 formation, acetylcholine-induced relaxation, and the degree of intimal hyperplasia. Vascular rings from animals treated with angiopeptin exhibited enhanced acetylcholine-induced relaxation; however, angiopeptin treatment had no effect on arachidonic acid-stimulated PGI2 formation. Intimal hyperplasia in treated animals was reduced by 36%. Treatment with another somatostatin analogue, BIM-23030, did not enhance relaxation or inhibit intimal hyperplasia. These data suggest that treatment with angiopeptin may inhibit intimal hyperplasia in part by its beneficial effect on neoendothelial function.
Hemodynamic responses to paraventricular nucleus disinhibition with bicuculline in conscious rats
Authors: Martin D. S. , Haywood J. R.
Published: December 2017

The present study was undertaken to determine the hemodynamic responses associated with stimulation of the hypothalamic paraventricular nucleus (PVN). Male Sprague-Dawley rats (n = 21) were instrumented with guide cannulas directed bilaterally at the PVN, with an electromagnetic flow probe placed on the ascending aorta and with femoral venous and arterial catheters. Bicuculline methiodide (BMI, 2 mM) was infused bilaterally (100 nl/20 min) into the PVN region before and after treatment with the beta 1-adrenergic antagonist, metoprolol bitartrate (2 mg/kg iv) or the alpha 1-adrenergic receptor antagonist, prazosin hydrochloride (2 mg/kg iv). Infusion of BMI into the PVN increased mean arterial pressure by 17 +/- 2 mmHg, and heart rate rose by 91 +/- 8 beats/min. Cardiac index increased 17 +/- 3%, whereas total peripheral resistance index was not altered significantly. After metoprolol treatment, the mean arterial pressure response to BMI was similar to control (16 +/- 2 mmHg), but the tachycardia was reduced significantly (10 +/- 4 beats/min). In addition, the blood flow response was changed qualitatively. Total peripheral resistance increased 13 +/- 3%, whereas the cardiac index response was abolished (1 +/- 2%). After prazosin treatment, BMI administration into the PVN failed to increase arterial pressure (-1 +/- 4 mmHg). Nevertheless, the BMI infusion was associated with significant hemodynamic effects. Total peripheral resistance index decreased (-24 +/- 6%), whereas cardiac index and stroke volume index increased 34 +/- 8 and 17 +/- 5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Alpha-adrenergic-mediated reflex responses to induced muscular contraction are changed with age in dogs
Authors: Haidet G. C.
Published: December 2017

Aging significantly affects reflex cardiovascular (CV) responses to induced muscular contraction in anesthetized dogs. To further investigate whether age-related changes in alpha-adrenergic-mediated responses to muscular contraction contribute to these previously reported age-related changes in CV responses associated with advanced age, hemodynamic and regional blood flow (BF) responses at baseline and during hindlimb contraction (HLC) were evaluated both before and after alpha-blockade (alpha-AB) in older (8-14 yr old) and in younger (2-3 yr old) beagles during alpha-chloralose anesthesia. alpha-AB with phentolamine resulted in significant (P < 0.05) reductions in mean arterial pressure before and during HLC, regardless of age. However, age-related differences in the systemic vascular resistance, cardiac output, and stroke volume responses to HLC, observed before alpha-AB, were eliminated after phentolamine as the result of an age-related difference in each of these responses to alpha-AB. Baseline BF (microspheres) was unchanged after alpha-AB in seven of eight abdominal organs, regardless of age. However, reductions in BF during HLC were attenuated in seven of eight abdominal organs in the younger dogs after alpha-AB, but in none of these organs in the older dogs, indicative of diminished alpha-mediated vasoconstriction in these organs in the older dogs during HLC. Furthermore, the age-related difference in the combined BF reduction to all eight abdominal organs before alpha-AB was eliminated after alpha-AB. Finally, BF increases to two of four contracting muscles, as well as the combined increase in blood flow to all four contracting muscles, were attenuated after alpha-AB, regardless of age. These results demonstrate that alpha-blockade eliminates many of the age-related differences in CV responses to HLC observed before alpha-AB and suggest that alpha-adrenergic-mediated responses to HLC change with age in beagles.
Endothelin-1 and -3 cause endothelium-dependent hyperpolarization in the rat mesenteric artery
Authors: Nakashima M. , Vanhoutte P. M.
Published: December 2017

The present study was designed to determine whether endothelin (ET) induces endothelium-dependent hyperpolarization in the isolated rat mesenteric artery and, if so, to identify the receptor subtype involved. Main superior mesenteric arteries of Wistar-Kyoto and spontaneously hypertensive rats were used for the measurement of electrical responses of smooth muscle cells, using glass microelectrode. In tissues with endothelium of both strains, ET-1 (10(-8) M) caused an initial transient hyperpolarization followed by a sustained depolarization. In tissues without endothelium, only depolarization was observed. ET-3 (10(-8) M) produced transient hyperpolarizations only in preparations with endothelium. There was no significant difference in maximal amplitude of hyperpolarization between the two strains. BQ-123 (selective ETA-receptor antagonist) blocked the depolarization to ET-1 but did not inhibit hyperpolarizing responses to either isopeptide. IRL-1620 (specific ETB-receptor agonist) produced transient membrane hyperpolarizations in tissues with endothelium. The hyperpolarizations induced by ET were not affected by NG-nitro-L-arginine. These data suggest that both ET-1 and ET-3 can cause endothelium-dependent hyperpolarization in the rat mesenteric artery and that the endothelial receptor involved may belong to ETB subtype.
Nicotine increases microvascular blood flow and flow velocity in three groups of brain areas
Authors: Hans F. J. , Wei L. , Bereczki D. , Acuff V. , Demaro J. , Chen J. L. , Otsuka T. , Patlak C. , Fenstermacher J.
Published: December 2017

To examine the mechanism of local cerebral blood flow (LCBF) elevation, nicotine (1.75 mg/kg sc) was administered to rats, and LCBF plus the distribution spaces of radiolabeled albumin (RISA) and red blood cells (RBC) in parenchymal microvessels were measured throughout the brain. Microvascular blood spaces and transit times were calculated from the data. From 1.5 to 3 min after nicotine administration, LCBF was raised by 40–150% in 16 of the brain areas and unaltered in the remaining 28 areas. The affected structures included parts of the visual-auditory, sensorimotor-cortical, and interpeduncular systems. RBC spaces were not changed by nicotine treatment. RISA and blood spaces were increased slightly but not significantly in some of the LCBF-affected areas but nowhere else. Nicotine seemingly elevates LCBF in the affected areas mainly by increasing linear velocity of flow through the microvascular beds. In agreement with this, mean transit time, which is inversely related to velocity, was decreased from 0.3-0.5 to approximately 0.2 s in the microvascular systems of the nicotine-affected areas.
Circulatory and metabolic effects of anemia in hyperinsulinemic ovine fetuses
Authors: Papparella A. , Berard D. , Stonestreet B. S.
Published: December 2017

Pages H250–H257: A. Papparella, D. Berard, and B. S. Stonestreet. “Circulatory and metabolic effects of anemia in hyperinsulinemic ovine fetuses.” Page H252: the unit of measure for oxygen content in Table 1 should be ml/dl. Therefore the corrected Table 1 should appear as follows.

(See PDF)
Inhibition of metabolism abolishes transient outward current in rabbit atrial myocytes
Authors: Ogbaghebriel A. , Shrier A.
Published: December 2017

Outward currents were measured in single rabbit atrial myocytes using the whole cell configuration of the patch-clamp technique in the presence of tetrodotoxin (5–10 microM) and MnCl2 (2 mM) to block inward currents. Depolarizing voltage-clamp steps from a holding potential of -80 mV elicited a predominant 4-aminopyridine (4-AP)-sensitive transient outward current (Ito). Inhibitors of oxidative metabolism, 2,4-dinitrophenol (DNP; 100 microM) and cyanide (3 mM) abolished Ito and caused a large increase in the steady-state outward current. This steady-state outward current was inhibited by glibenclamide (5 microM), a blocker of the ATP-regulated potassium current (IKATP). In the presence of DNP, glibenclamide (5 microM) not only inhibited IKATP but also partially restored Ito. Absence of ATP from the pipette produced effects on outward currents similar to those induced by DNP or cyanide. We conclude that metabolic inhibition abolishes Ito in rabbit atrial myocytes and suggest that ATP may be required for the activation of the channel.
Role of endogenous ANG II on resetting arterial baroreflex during development
Authors: Segar J. L. , Merrill D. C. , Robillard J. E.
Published: December 2017

Angiotensin II (ANG II) has been shown in adults to modulate baroreflex responses in heart rate (HR) and sympathetic outflow. To test the hypothesis that high circulating levels of ANG II in the newborn period contribute to the resetting of the arterial baroreflex observed postnatally, we studied baroreflex-mediated changes in HR and renal sympathetic nerve activity (RSNA) before and after angiotensin-converting enzyme (ACE) inhibition in fetal and newborn sheep. In the newborn, administration of the ACE inhibitor enalaprilat produced significant (P < 0.05) decreases in baseline RSNA (69 +/- 5 vs. 47 +/- 7% maximum) and HR (81 +/- 3 vs. 59 +/- 4% max), as well as in the baroreflex curve midpoints for RSNA (93 +/- 4 vs. 87 +/- 3 mmHg) and HR (95 +/- 4 vs. 81 +/- 5 mmHg); no change in the sensitivities (gains) of the baroreflex responses were seen. In contrast, no significant changes in baseline RSNA, HR, baroreflex curve midpoint, or sensitivity were demonstrated in the fetus. Infusion of ANG II in newborn lambs reversed the effects of ACE inhibition on the baroreflex responses. Additional experiments evaluating the effects of ACE inhibition in vagotomized newborns again showed resetting of the baroreflex, demonstrating that vagally mediated mechanisms are not involved in regulating the changes in sympathetic outflow during the neonatal period. These results suggest that endogenous ANG II contributes to the resetting of the baroreflex observed postnatally.
Circulating neutrophil kinetics during tolerance in hemorrhagic shock using bacterial lipopolysaccharide
Authors: Barroso-Aranda J. , Chavez-Chavez R. H. , Mathison J. C. , Suematsu M. , Schmid-Schonbein G. W.
Published: December 2017

The objective of this study was to investigate mechanisms by which circulating polymorphonuclear neutrophils (PMNs) may contribute to the tolerance to hemorrhagic shock induced by pretreatment with lipopolysaccharides (LPS). Tolerance was developed by daily injections of sublethal doses of LPS for four subsequent days while controls received saline injections. During shock, both groups of rats were maintained for 3 h at 40 mmHg mean arterial pressure and were then observed for survival during a 24-h period. This protocol resulted in 40% survival in the untreated controls and 89% survival in the tolerant group (P < 0.0068). Hypotension caused an initial neutropenia in both groups. The circulating PMN counts remained lower in the tolerant than in the controls rats for most of the low flow period. The number of circulating activated PMNs in whole blood, as assessed by spontaneous nitroblue tetrazolium reduction, was lower in tolerant animals before and during most of the hypotensive period, except immediately after bleeding when both groups have low circulating leukocyte counts. No detectable tumor necrosis factor activity was observed in the plasma of either group. Adhesion of circulating PMNs to nylon fibers in vitro and the number of PMNs adhering to the endothelium in the mesentery in vivo was significantly lower in the tolerant rats. We conclude that LPS pretreatment produces a reduction in the activated circulating PMNs and in the degree of PMN adhesion to endothelium with subsequent improvement of survival after hemorrhagic shock.
Autoregulation of cochlear blood flow in guinea pigs
Authors: Brown J. N. , Nuttall A. L.
Published: December 2017

Autoregulation of blood flow in the inner ear following uncontrolled changes in systemic blood pressure (BP), which was induced by the application of pharmacological agents that cause local and/or systemic vascular effects, has been reported in previous studies. In the current study, carotid BP was systematically manipulated without drugs, while the resulting cochlear blood flow (CBF) changes were measured using a laser Doppler flowmeter (LDF). Anesthesized guinea pigs were used, and the probe of a LDF was held against the ventral-posterior portion of the surgically exposed cochlea. A mechanical occluder was placed around the descending aorta or the inferior vena cava. BP could be elevated or lowered over a wide range and was held stable during 2-min occlusions. The mean level (+/- SD) of regulation (% delta CBF/% delta BP) for BP changes less than +/- 35% of preocclusion baseline was 0.24 +/- 0.2 (or 0.18 +/- 0.2 if BP is corrected by subtracting central venous pressure). Significant regulation occurred for BP between 20 and 70 mmHg. A demonstration of the cochlear origin of the regulatory response was obtained by “pharmacological blockade” following topical application of the vasodilator, sodium nitroprusside, to the cochlea. In this condition, CBF changed in nearly direct proportion to BP.
Beneficial actions of CP-0127, a novel bradykinin receptor antagonist, in murine traumatic shock
Authors: Christopher T. A. , Ma X. L. , Gauthier T. W. , Lefer A. M.
Published: December 2017

We studied the effects of CP-0127, a novel bradykinin receptor antagonist, in a rat model of traumatic shock. Pentobarbital-anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, significant increases in plasma-free amino-nitrogen (8.6 +/- 0.97 vs. 2.3 +/- 0.15 U/ml in control rats) and intestinal myeloperoxidase (MPO) activity (2.7 +/- 0.33 vs. 0.08 +/- 0.03 U/100 mg control rats, intestinal tissue), and a survival time of only 110 +/- 9 min. Moreover, superior mesenteric artery (SMA) rings isolated from rats subjected to traumatic shock relaxed to the endothelium-dependent vasodilator acetylcholine (ACh) significantly less than rings isolated from control rats (21 +/- 4 vs. 92 +/- 4%, P < 0.001). Administration of CP-0127 at a dose of 10 mg/kg subcutaneously completely blocked the hypotensive response to 2.5 micrograms/kg bradykinin injected intravenously in sham traumatic shock rats. CP-0127 given immediately posttrauma prolonged survival time to 219 +/- 27 min (P < 0.01) and attenuated the increases in plasma-free amino-nitrogen (3.7 +/- 0.41 U/ml, P < 0.01) and tissue MPO activities (1.2 +/- 0.71 U/100 mg intestinal tissue, P < 0.05). Furthermore, SMA endothelial function was significantly preserved (relaxation to ACh: 57 +/- 6%, P < 0.01) in CP-0127-treated traumatic shock rats. These results indicate that bradykinin plays an important role in tissue injury associated with traumatic shock and that CP-0127 affords significant protection, which may be achieved through inhibition of neutrophil-endothelial interaction and protection of vascular endothelial function.
Differential modulation by adenylate cyclase of Ca2+ and delayed K+ current in ventricular myocytes
Authors: Harada K. , Iijima T.
Published: December 2017

This study was designed to investigate the differential modulation of the L-type Ca2+ (ICa) and the delayed rectifier K+ (IK) currents by direct activation of adenylate cyclase in guinea pig ventricular preparations. Action potentials were measured with conventional microelectrodes in excised papillary muscles. Isoproterenol significantly shortened the action potential duration at 90% repolarization (APD90) at 0.1 nM but significantly prolonged it at a higher concentration (10 nM). A water-soluble forskolin derivative, 6-(3-dimethylaminopropionyl) forskolin (NKH-477), slightly but significantly shortened APD at 12 nM but not at a higher concentration (120 nM). Effects of isoproterenol and NKH-477 on ICa and IK were also investigated by use of the whole cell voltage-clamp technique in single ventricular cells. Isoproterenol increased not only IK but also ICa at the same threshold concentration (0.3 nM). In contrast, the threshold concentration of NKH-477 for increasing IK (approximately 1 nM) was clearly lower than that for increasing ICa (10 nM). These results indicate that ICa and IK channels could be differentially regulated during beta-adrenoceptor stimulation.
Pressure sensitivity of flow oscillations in postocclusive reactive skin hyperemia
Authors: Strucl M. , Peterec D. , Finderle Z. , Maver J.
Published: December 2017

Skin blood flow was monitored using a laser-Doppler (LD) flowmeter in 21 healthy volunteers after an occlusion of the digital arteries. The peripheral vascular bed was exposed to occlusion ischemia of varying duration (1, 4, or 8 min) and to a change in digital arterial pressure produced by different positions of the arm above heart level to characterize the pattern of LD flow oscillations in postocclusive reactive hyperemia (PRH) and to elucidate the relevance of metabolic and myogenic mechanisms in governing its fundamental frequency. The descending part of the hyperemic flow was characterized by the appearance of conspicuous periodic oscillations with a mean fundamental frequency of 7.2 +/- 1.5 cycles/min (SD, n = 9), as assessed by a Fourier transform frequency analysis of 50-s sections of flow. The mean respiratory frequency during the periods of flow frequency analysis was 17.0 +/- 2.2 (SD, n = 9), and the PRH oscillations remained during apnea in all tested subjects. The area under the maximum flow curve increased significantly with prolongation of the occlusion (paired t test, P < 0.001; n = 9), but showed no dependence on the estimated blood pressure in the digital arteries, which suggests the predominant role of a metabolic component in this part of the PRH response. In contrast, the fundamental frequency of PRH oscillations exhibited a significant decrease with a reduction in the estimated digital arterial pressure (linear regression, b = 0.08, P < 0.001; n = 12), but did not change with the prolongation of arterial occlusion despite a significant increase in mean LD flow (paired t test, P < 0.001; n = 9).(ABSTRACT TRUNCATED AT 250 WORDS)
Involvement of nitric oxide and nitrosothiols in relaxation of pulmonary arteries to peroxynitrite
Authors: Wu M. , Pritchard K. A. , Kaminski P. M. , Fayngersh R. P. , Hintze T. H. , Wolin M. S.
Published: December 2017

Peroxynitrite (ONOO-) is an inflammatory cell-derived oxidant, formed by the reaction of superoxide anion (O2-) with nitric oxide (NO), which was recently reported to relax vascular tissues. In the present study, the potential role of NO in the mechanism of relaxation in isolated bovine endothelium-denuded pulmonary arterial smooth muscle rings to ONOO- was evaluated. Potassium-preconstricted pulmonary arterial rings rapidly relaxed for a prolonged period of time on exposure to ONOO- (0.01-0.1 mM). The relaxation after 1 min of exposure to ONOO- (0.1 mM) was reduced 49 and 87%, respectively, by inhibitors of the stimulation of soluble guanylate cyclase, methylene blue, and LY-83583. In contrast, a scavenger of hydroxyl radicals, dimethyl sulfoxide, did not alter this response. Decomposed 0.1 mM ONOO- (which is primarily nitrite) and 0.1 mM nitrite caused a relaxation of pulmonary artery, which slowly developed over 15 min. Small quantities of NO were detected by chemiluminescence quantification methods when ONOO- was added to buffer. Exposure of pulmonary arterial tissue or buffer containing glutathione (GSH) to ONOO- caused a time-dependent increase in the observed generation of NO, whereas decomposed ONOO- produced 10% of the NO generated by ONOO- on incubation with pulmonary arterial tissue. Treatment with diethyl maleate, an agent that depletes tissue GSH, reduced both the relaxation and the formation of NO detected from pulmonary artery on exposure to ONOO-. GSH solutions treated with ONOO- appear to have generated a nitrosothiol-like vascular relaxant compound. Thus ONOO- appears to relax vascular tissue, in part, by nitrosylating tissue GSH (or other thiols), which subsequently releases NO over prolonged time periods.
Cytosolic [Ca2+] measurements in endothelium of rabbit cardiac valves using imaging fluorescence microscopy
Authors: Laskey R. E. , Adams D. J. , van Breemen C.
Published: December 2017

Cytosolic Ca2+ plays a critical role in the secretion of endothelium-derived factors. A new preparation that allows fluorescence imaging of intracellular free Ca2+ concentration ([Ca2+]i) in endothelial cells of rabbit cardiac valves is described. Electron micrographs of the valves revealed no underlying smooth muscle cells that might influence endothelial cell responses or contribute to [Ca2+]i signaling. The valve leaflets, which were < 100 microns in diameter, were visualized using a specially designed chamber and a long working distance fluorescence objective. The semilunar valves (pulmonary and aortic) responded to endothelium-dependent vasodilators, including acetylcholine, with an increase in [Ca2+]i. Synchronized [Ca2+]i transients were observed in the endothelial monolayer in response to agonist stimulation in K(+)-free solutions. The ability to monitor changes in [Ca2+]i in a native endothelial monolayer provides a more realistic assessment of stimulus-response coupling within individual cells and communication between cells of native endothelium. In addition, this preparation affords an opportunity for comparative studies of endothelium-related pathophysiologies, which can be induced experimentally in animal models.
Microcirculatory structure-function relationships in skeletal muscle of diabetic rats
Authors: Sexton W. L. , Poole D. C. , Mathieu-Costello O.
Published: December 2017

Pages H1502–H1511: W. L. Sexton, D. C. Poole, and O. Mathieu-Costello. “Microcirculatory structure-function relationships in skeletal muscle of diabetic rats.” Page H1508: Figure 6 was inadvertently printed upside down and should appear as follows.

(See PDF)
Rubidium entry into brain and cerebrospinal fluid during acute and chronic alterations in plasma potassium
Authors: Stummer W. , Keep R. F. , Betz A. L.
Published: December 2017

To elucidate whether K+ uptake across the blood-brain barrier (BBB) or blood-cerebrospinal fluid (CSF) barrier is subject to acute or chronic regulation, rats were rendered acutely or chronically hyper- or hypokalemic (range: 2.8–7.2 mM). Measurements were made of the permeability-surface (PS) products of 86Rb+, a marker for K+, and alpha-[3H]aminoisobutyric acid (AIB), a passive permeability marker, and of CSF K+ concentration ([K+]CSF). [K+]CSF decreased by 8% in chronic hypokalemia P < 0.01), but otherwise remained unchanged. The AIB PS products were unaltered in any group, excluding a change in passive permeability. The Rb PS product, however, increased by 31% for brain tissue (P < 0.01) and by 46% for CSF (P < 0.05) during acute hypokalemia, but was unchanged during acute hyperkalemia. During chronic hypokalemia the Rb PS product increased by 40% for brain (P < 0.01) and 55% for CSF (P < 0.01) and decreased during chronic hyperkalemia by 37% for brain (P < 0.01) and 49% (P < 0.01) for CSF. Unidirectional K+ fluxes were calculated, revealing greater regulation of K+ influx into both brain tissue and CSF during chronic compared with acute changes of plasma K+ concentration ([K+]pl). Our results suggest that K+ transport is saturable at both the BBB and the blood-CSF barriers under normal conditions and that both barriers adapt to chronic changes in [K+]pl by modifying specific, transcellular routes of K+ entry.
Blood volume redistribution from a passive elastic permeable microcirculation due to hypovolemia
Authors: LaForte A. J. , Lee L. P. , Rich G. F. , Skalak T. C. , Lee J. S.
Published: December 2017

We measured the variations in blood and plasma density for a cyclic hemorrhage protocol in conscious rabbits to calculate delta Vf [the volume of fluid restituted into the circulation from the time the blood volume was at its control to that after the hemorrhage of a blood volume (delta V)] and delta Vs (the volume shift from micro- to macrocirculation over the same time interval). We found that delta Vf is 7% of delta V and delta Vs 60% of delta V. They combine to reduce the effect of hemorrhage on macrovascular volume by 67% of delta V. Based on a two-resistor circulation model, the change in microcirculatory pressure (delta Pmic) from control to hemorrhage was estimated from the measured cardiac outputs and arterial and venous pressures. The computations indicate that delta Vs (or delta Vf) is linearly related to delta Pmic. With one relation fitting all data of rabbits that were conscious, infused with hexamethonium, and anesthetized with pentobarbital sodium, we concluded that the two short-term volume redistributions are not direct neural control or local regulation, but the response of a passive, permeable microcirculation to delta Pmic. From the linear relations, we obtained 0.88 ml.mmHg-1.kg-1 as the compliance of the rabbit microcirculation and 0.21 ml.min-1.mmHg-1.kg-1 as its filtration coefficient.
Effects of chronically elevated pulmonary arterial pressure and flow on right ventricular afterload
Authors: Ha B. , Lucas C. L. , Henry G. W. , Frantz E. G. , Ferreiro J. I. , Wilcox B. R.
Published: December 2017

The effects of pulsatile hemodynamics on right ventricle-pulmonary circulation interactions were studied in control lambs and in two lamb models of altered pulmonary hemodynamics induced at infancy: elevated pulmonary arterial pressure (PAP) was created by the infusion of monocrotaline pyrrole (MCTP), and elevated pulmonary arterial blood flow was obtained by the creation of an arteriovenous fistula (Shunt). High-fidelity PAP, midvessel Doppler blood velocity (PAV), and cardiac output (CO) were measured in open-chest, anesthetized lambs. PAV waveforms were normalized to match the measured CO. Measured pressure and flow signals were separated in the time domain into forward and backward components. Pulmonary input impedance and indexes quantifying the timing of the reflected wave pulse (beginning of reflected pulse, duration of reflected pulse in systole, and duration of reflected wave in diastole) were calculated for each group. Results indicate that in control animals the reflected wave returned late in systole and extended through much of diastole, thereby increasing diastolic pressure like a counterpulsation balloon. No significant differences in the timing indexes were found between Shunt and control animals. In the MCTP group, the reflected wave returned significantly earlier than normal with the peak reflected pulse occurring before valve closure. The resulting augmentation of systolic pressure and, therefore, large pulse pressure is consistent with pressure waveforms observed in clinical pulmonary hypertension. We conclude that early wave reflection exerts a detrimental effect in pulmonary hypertension by unfavorably loading the still-ejecting right ventricle.
Clopidogrel is more effective than aspirin as adjuvant treatment to prevent reocclusion after thrombolysis
Authors: Yao S. K. , Ober J. C. , Ferguson J. J. , Maffrand J. P. , Anderson H. V. , Buja L. M. , Willerson J. T.
Published: December 2017

Clopidogrel is a thienopyridine derivative and a potent inhibitor of ADP-induced platelet aggregation. We compared clopidogrel with aspirin as an adjunctive treatment to tissue-type plasminogen activator (t-PA) for thrombolysis and reocclusion. Thrombosis was induced in coronary arteries of 32 dogs by injuring the endothelium with an electric charge. Coronary blood flow velocity was monitored by a pulsed Doppler flow probe placed around the artery. After the artery had been occluded by a thrombus for 3 continuous hours, each animal was given one of the following intravenous treatments: 1) t-PA (80 micrograms/kg + 8 micrograms.kg-1.h-1) and heparin (200 U/kg) (group 1, n = 7); 2) t-PA, heparin, and aspirin (5 mg/kg) (group 2, n = 8); 3) t-PA, heparin, and clopidogrel (5 mg/kg) (group 3, n = 9); and 4) t-PA, heparin, and clopidogrel (10 mg/kg + 2.5 mg.kg-1.h-1) (group 4, n = 8). After treatment, thrombolysis developed in 45 +/- 12 min in group 1, 39 +/- 10 min in group 2, 39 +/- 10 min in group 3, and 27 +/- 10 min in group 4 (compared with group 1, P > 0.05). After thrombolysis, reocclusion occurred in 5 of 5 dogs in group 1 and 7 of 7 in group 2, but only 2 of 7 in group 3 and none of 7 in group 4 (compared with groups 1 and 2, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Brain edema resolution by CSF pathways and brain vasculature in cats
Authors: Marmarou A. , Hochwald G. , Nakamura T. , Tanaka K. , Weaver J. , Dunbar J.
Published: December 2017

Brain edema is a major contributor to the brain swelling process and raised intracranial pressure, yet the specific pathways involved in clearance of brain edema (fluid and proteins) and their relative contribution to the resolution process remain unknown. The objective of this study was to document the temporal course of edema resolution from brain to cerebrospinal fluid (CSF) and by the brain vasculature. Radioiodinated (125I) cat serum albumin (RICSA) was infused continuously into the white matter of anesthetized adult cats for 8 h, and ventriculocisternal perfusion was used to monitor the RICSA activity in CSF at 15-min intervals and to compare with the blood taken at 15-min intervals. The RICSA that cleared from the brain in 8 h measured 29.8% of the amount infused. Of the amount of RICSA leaving the brain, we found that the CSF compartment accounted for 87.14% of the cleared RICSA volume, while only 10.96% of RICSA was found in the blood during the 8-h experiment. The amount of RICSA remaining in the brain when the animal was killed equaled 71.2 +/- 15.9% (mean +/- SD) of the RICSA infused. We conclude that vascular clearance during the acute stage of resolution is minimal and that clearance of RICSA occurs predominantly via the CSF pathways.
Chronic administration of nifedipine induces upregulation of dihydropyridine receptors in rabbit heart
Authors: Chiappe De Cingolani G. E. , Mosca S. M. , Vila Petroff M. , Cingolani H. E.
Published: December 2017

In rabbits chronically pretreated with nifedipine (20 mg/day for 25 days), we demonstrate upregulation of Ca2+ channels in mammalian heart (maximal binding capacity = 222 +/- 14 and 421 +/- 55 fmol/mg protein for control and treated, respectively; P < 0.05) without significant changes in dissociation constant. No changes in calcium sensitivity or maximal force were detected by pretreatment with nifedipine in chemically skinned fibers. Cardiac contractility at different extracellular Ca2+ concentrations was similar in control and pretreated animals. This upregulation of Ca2+ channels in mammalian heart offers an explanation for the lack of significant negative inotropic effect after chronic administration of nifedipine.
Effect of platelet depletion and inhibition of platelet cyclooxygenase on C5a-mediated myocardial ischemia
Authors: Ito B. R. , Del Balzo U.
Published: December 2017

Activation of the complement cascade is involved in the myocardial injury resulting from transient ischemia and reperfusion. We previously showed that the complement anaphylatoxin C5a causes myocardial ischemia in vivo, mediated in part via thromboxane (Tx) A2. In the present study, we assess the role of platelets in the C5a-induced myocardial ischemia and Tx release. The left anterior descending coronary artery of anesthetized pigs was perfused with arterial blood at constant pressure and measured flow (coronary blood flow). Segment function (percent segment shortening) was measured with sonomicrometry, and regional coronary venous blood was sampled and assayed for TxB2 (by radioimmunoassay). We found that the C5a-induced decrease in coronary blood flow and percent segment shortening and the release of Tx were indistinguishable whether the left anterior descending coronary artery bed was perfused with normal arterial blood, with arterial blood obtained from animals depleted of platelets (cyclophosphamide, n = 6), or with arterial blood from aspirin-treated animals (n = 9) in which the platelets were unable to produce Tx. These data demonstrate that platelet-derived Tx does not contribute to the C5a-induced myocardial ischemia and Tx release in this model and that these cells do not play an integral role in this phenomenon.