bluuebunny/crossref_metadata_2025 huggingface dataset:
Early in reperfusion, leukocytes alter perfused coronary capillarity and vascular resistance
Authors: Reynolds J. M. , McDonagh P. F.
Published: December 2017

Myocardial no-reflow is a critical consequence of myocardial ischemia-reperfusion (I/R). Recent studies indicate that formed blood elements (e.g., leukocytes and platelets) contribute greatly to the compromise of myocardial blood flow that occurs after I/R. To assess the contributions of leukocytes and platelets to alterations in microvascular perfusion, we measured total coronary vascular resistance and perfused coronary capillary density before and after a 30-min period of no-flow ischemia in isolated rat hearts perfused with either 1) a Krebs-albumin-red cell solution [K(2)RBC]; 2) diluted whole blood (DWB) with Krebs (1:1); or 3) leukocyte-free DWB (LFB). We found that hearts perfused with K(2)RBC before ischemia demonstrated a significant decrease in perfused capillarity (-25%, P less than 0.05) after 25 min of reperfusion. Hearts perfused with LFB before ischemia exhibited a similar decrease in perfused capillarity (-33%, P less than 0.05) during reperfusion. However, in the DWB-perfused hearts, there was a 62% decrease in perfused capillarity (-62%, P less than 0.01) during reperfusion. Moreover, during reperfusion, total coronary vascular resistance was elevated significantly (+76%, P less than 0.01) in the DWB-perfused hearts but not in either the K(2)RBC or LFB groups. These results indicate that 1) platelets do not play a major role in alterations of microvascular perfusion after ischemia; 2) leukocytes are not requisite for the development of microvascular no-reflow early in reperfusion but their presence further exacerbates this deleterious effect; and 3) a relationship exists between perfused capillarity and vascular resistance in the isolated rat heart after global ischemia.
PGE2 and arachidonate inhibit the baroreflex in conscious dogs via cardiac receptors
Authors: Panzenbeck M. J. , Tan W. , Hajdu M. A. , Cornish K. G. , Zucker I. H.
Published: December 2017

Prostaglandin (PG) I2 and PGE2 are known to stimulate left ventricular receptors with nonmyelinated vagal afferents. The present experiments were performed to determine the effects of intracoronary infusion of PGE2 (10-50 ng.kg-1.min-1) and arachidonic acid (50-100 micrograms.kg-1.min-1) on the baroreflex control of heart rate in conscious dogs. Dogs were anesthetized with pentobarbital sodium and were instrumented using sterile surgical techniques. After recovery, baroreflex pressure-heart rate curves were constructed by varying arterial pressure with partial occlusions of the descending aorta or inferior vena cava. Intracoronary infusion of PGE2 significantly inhibited the maximum heart rate achieved during unloading of baroreceptors, attenuated the heart rate range, and decreased the maximum slope of the baroreflex curve; PGE2 had no significant effect on the minimum heart rate during hypertension. Intravenous infusion of PGE2 did not cause significant baroreflex inhibition, and pericoronary nerve block in three dogs prevented the effects of intracoronary PGE2. Intracoronary infusion of arachidonic acid had effects on the baroreflex control of heart rate similar to those of PGE2. The effects of arachidonic acid infusion were prevented by cyclooxygenase blockade. Thus intracoronary PGE2 and arachidonic acid inhibit the baroreflex control of heart rate most likely via stimulation of left ventricular receptors with vagal C-fiber afferents. The effects of arachidonic acid were secondary to synthesis of prostaglandins.
Cell-to-cell interaction: a mechanism to explain wave-front progression of myocardial necrosis
Authors: Garcia-Dorado D. , Theroux P. , Desco M. , Solares J. , Elizaga J. , Fernandez-Aviles F. , Alonso J. , Soriano J.
Published: December 2017

Histological sections performed 24 h after coronary occlusion in eight pigs displayed compact infarcts extending transmurally with well-defined edges; reconstruction and inspection of the area of necrosis showed a geometric distribution of the infarcts with very irregular, interdigitating edges always in continuity with the main mass of necrosis. Reperfusion in 32 pigs after periods of coronary occlusion of 90, 60, 45, and 30 min exponentially reduced infarct size and transmural extension of the infarct but did not modify its geometry. The two-dimensional size, progression, and geometry of the infarcts could be reproduced by a computer model. In the simulated infarcts, each myocardial cell within the area at risk was represented by a pixel. The algorithm included an inner loop, which determined at random at each iteration a status of reversible or irreversible damage to all pixels. The number of iterations could reproduce infarct of various sizes. With the addition of an index of transmural sensitivity to ischemia, progression of the infarct area could also be reproduced. The only possible means of reproducing the geometry of the infarct was to enter into the program a contiguity condition requiring a direct contact between irreversibly damaged pixels. These observations suggest that the physical interaction between cells is an important determinant of progression of necrosis during coronary occlusion.
Brain pH responses to sodium bicarbonate and Carbicarb during systemic acidosis
Authors: Shapiro J. I. , Whalen M. , Kucera R. , Kindig N. , Filley G. , Chan L.
Published: December 2017

Rats subjected to ammonium chloride-induced metabolic acidosis or respiratory acidosis caused by hypercapnia were given alkalinization therapy with either sodium bicarbonate or Carbicarb. Ammonium chloride induced dose-dependent systemic acidosis but did not affect intracellular brain pH. Hypercapnia caused dose-dependent systemic acidosis as well as decreases in intracellular brain pH. Sodium bicarbonate treatment resulted in systemic alkalinization and increases in arterial PCO2 in both acidosis models, but it caused intracellular brain acidification in rats with ammonium chloride acidosis. Carbicarb therapy resulted in systemic alkalinization without major changes in arterial PCO2 and intracellular brain alkalinization in both acidosis models. These data demonstrate that bicarbonate therapy of systemic acidosis may be associated with "paradoxical" intracellular brain acidosis, whereas Carbicarb causes both systemic and intracellular alkalinization under conditions of fixed ventilation.
Differential effects of sleep stage on coronary hemodynamic function
Authors: Kirby D. A. , Verrier R. L.
Published: December 2017

The sleep-wake cycle results in distinctive patterns of autonomic nervous system activity. The present study examined the effects of rapid eye movement and slow-wave sleep on coronary hemodynamic function in chronically instrumented dogs. Mean arterial blood pressure was measured via a catheter in the aorta, and coronary blood flow was determined with Doppler probes placed around the left circumflex and right coronary artery. Identification of sleep stages was accomplished by means of electrodes implanted via the frontal sinus to record electro-oculogram, electromyogram, and electroencephalogram. Results indicated that during slow-wave sleep there were moderate but significant reductions in heart rate, 9% decreases in left coronary blood flow, and increases in coronary vascular resistance. In rapid-eye-movement sleep, the circumflex coronary blood flow base line returned to awake levels, and there were pronounced, phasic 35% increases in heart rate and 35% increases in coronary blood flow lasting 15-20 s. These surges were eliminated by stellectomy, indicating that they were mediated by the sympathetic nervous system.
Hemodynamic effects of chronic infusion of rANP in renal hypertensive rats
Authors: Fenoy F. J. , Quesada T. , Garcia-Salom M. , Romero J. C. , Salazar F. J.
Published: December 2017

The purpose of this study was to evaluate the hemodynamic effects induced by an infusion of synthetic rat atrial natriuretic peptide (rANP, 0.5 micrograms/h iv) during 5 consecutive days in conscious normotensive and two-kidney, one-clip hypertensive (2K,1C) rats. Changes in plasma ANP (pANP) levels and plasma renin activity (PRA) were also determined. The administration of ANP in 2K,1C rats induced a significant decrease in mean arterial pressure (MAP) from 169 +/- 3 to 138 +/- 3, and 149 +/- 3 mmHg by 2 and 5 days of infusion, respectively. This hypotension was accompanied by a significant fall in cardiac index (CI) from 400 +/- 16 to 348 +/- 14 ml.min-1.kg-1 after 2 days of ANP treatment. However, CI returned to the basal levels at the third day, and a significant decrease in total peripheral resistance (TPR) was observed by 3 and 5 days of ANP infusion. The administration of the same dose of ANP in normotensive rats did not induce changes in MAP, but CI decreased (P less than 0.001) transitorily during the first 2 days and returned to control values thereafter. Basal pANP levels were significantly elevated in the hypertensive animals (176 +/- 40 pg/ml) when compared with the normotensive rats (82 +/- 10 pg/ml). The ANP infusion resulted in lower (P less than 0.05) pANP levels in hypertensive (1,017 +/- 234 pg/ml) than in normotensive rats (3,466 +/- 975 pg/ml). PRA did not change in any group during the administration of ANP.(ABSTRACT TRUNCATED AT 250 WORDS)
Low-threshold current is major calcium current in chick ventricle cells
Authors: Kawano S. , DeHaan R. L.
Published: December 2017

Single myocytes were dissociated from the apical ventricles of 14-day-old chick embryos and were maintained in culture for 24 h. Isolated rounded cells, 13-18 microns in diameter with input capacitance averaging 5.2 pF, were selected for whole cell patch-clamp analysis of calcium current (ICa). Two current components, T-type (IT) and L-type (IL), were identified by differences in their voltage thresholds and pharmacological sensitivity, IL was activated by depolarizing steps from -40 mV and was selectively blocked by 1 microM D 600 (methoxyverapamil). IT was obtained by subtracting IL from total ICa and was blocked by 120 microM Ni2+. Identified by threshold potential, sensitivity to Ni2+, or resistance to D 600, IT had a greater current density than has been reported in any adult cardiac tissue. It was also larger than IL and was therefore the major contributor to ICa in this preparation.
Lipid peroxidation and altered vascular function in vitamin E-deficient rats
Authors: Hubel C. A. , Griggs K. C. , McLaughlin M. K.
Published: December 2017

Female rats deprived of dietary vitamin E for 35 wk postweaning were analyzed for changes in vascular function. A functional state of vitamin E deficiency was indicated by a marked increase in spontaneous hemolysis of washed red cells by 22 wk of feeding. Elevated thiobarbituric acid-reactive material in aorta, liver, and plasma samples from vitamin-E deficient rats indicated increased lipid hydroperoxide formation. Systolic blood pressures and heart rates measured biweekly were unaltered by diet. Before being killed, the rats were catheterized and allowed to recover from anesthesia (methohexital sodium ip). The pressor response to graded doses of angiotensin II was significantly increased in the vitamin E-deficient group relative to its control. Isolated superior mesenteric artery segments from vitamin E-deficient rats demonstrated significantly decreased relaxation responses to acetylcholine. In contrast, artery contractile responses to 50 mM potassium and to graded doses of extracellular calcium did not differ, indicating that contractile capability was maintained. Surface blebbing of the femoral artery endothelium was observed by scanning electron microscopy. These data support a proposed link between lipid peroxidation and development of altered vascular function.
Pulse reflection sites and effective length of the arterial system
Authors: Campbell K. B. , Lee L. C. , Frasch H. F. , Noordergraaf A.
Published: December 2017

The concept of effective length (L) of the arterial system implies that it may be represented by a single viscoelastic tube terminated by an impedance, creating a single reflection site. Although the concept is straightforward, investigators for years have been unable to agree on the value of L. Proposed values range from a few millimeters to a few meters, confounding the identification of arterial reflection sites. This report shows analytically and illustrates with experimental data that the determination of the effective length leaves room for an infinite number of exact solutions for L and the corresponding terminal impedance if the input impedance of the tube is to match the measured input impedance of an arterial system. None of the possible values of L needs to bear any relationship to actual reflection sites.
Control of segment length or force in isolated papillary muscle: an adaptive approach
Authors: Peterson J. N. , Hunter W. C. , Berman M. R.
Published: December 2017

Mechanical studies of isolated cardiac muscle are complicated as a result of damage inflicted on the ends of the muscle during excision and mounting procedures. Inhomogeneities between the healthy central and weakened end portions of the muscle make it difficult to interpret studies where only total muscle length is controlled. Measurement and control of central segment length is clearly desirable but fraught with technical difficulties. We present a novel application of adaptive control methods that minimizes the difficulties encountered with current control techniques. This method, which allows control of either segment length or force, takes advantage of the repetitive, periodic nature of contractions. Here deviations of measured segment length or force signals from a desired response during one twitch are used to modify the muscle length command signal for use on the next twitch. This process continues for successive twitches until either segment length or force is within desired limits. The adaptive method allows greater stability and immunity to noise than classical feedback strategies.
Arteriolar smooth muscle responses are modulated by an intramural diffusion barrier
Authors: Lew M. J. , Rivers R. J. , Duling B. R.
Published: December 2017

Arterioles (40–80 micron diameter) were isolated from the hamster cheek pouch, cannulated at both ends, and perfused with 3-(N-morpholino)propanesulfonic acid (MOPS)-buffered physiological salt solution (PSS). The vessels were observed with an inverted microscope and video system, and arteriolar diameter was measured. Arterioles were found to be 100 times more responsive to the alpha 1-adrenoceptor agonist phenylephrine when applied to the adventitial surface than when applied to the luminal surface. In contrast, SKF 89748-A, also an alpha 1-adrenoceptor selective agonist, but with a much greater lipid solubility than phenylephrine, was equipotent from either surface of the arteriole. We hypothesized that the difference between the two drugs was due to the ability of SKF 89748-A to permeate a diffusion barrier in the arteriolar wall because of its lipid-solubility. To test this hypothesis, a spectrum of antagonists with different sites of action and lipid solubilities was tested. The alpha-adrenoceptor antagonists phentolamine and benextramine and the muscarinic receptor antagonists atropine, scopolamine, and methscopolamine were all found to be more potent at blocking the action of appropriate agonists when applied to the same surface of the arteriole as the agonist than when applied to the opposite surface. Octanol-water partition coefficients were measured for each of the compounds, and these were found to be highly correlated with the ratio of luminal potency to adventitial potency for each of the drugs tested. These data support the hypothesis that the endothelial cell layer in these arterioles forms a barrier to the diffusion of small, water-soluble molecules from the lumen to the smooth muscle cell layer. Such a barrier may have a significant effect on arteriolar reactivity.
Responses of isolated pulmonary arteries to synthetic peptide F-Met-Leu-Phe
Authors: Crowell R. E. , Van Epps D. E. , Reed W. P.
Published: December 2017

The chemoattractant formyl-methionine-leucine-phenylalanine (FMLP) has recently been shown to possess spasmogenic properties in smooth muscle preparations from various organs. In this study we have investigated the actions of this peptide on isolated rabbit pulmonary artery (PA) ring segments. FMLP stimulated concentration-dependent constriction of PA at resting tension. However, in PA that had been preconstricted by norepinephrine, FMLP stimulated concentration-dependent relaxation. FMLP-stimulated PA constriction was inhibited by earlier exposure to indomethacin or to furegrelate, a thromboxane synthetase inhibitor, but not by earlier exposure to the H1 histamine receptor antagonist pyrilamine. FMLP-stimulated relaxation of PA was totally abolished by indomethacin but not by furegrelate or pyrilamine. Disruption of the endothelium in PA preparations decreased both the constriction and relaxation response to the peptide, suggesting that these cells were involved in these responses. These results indicate that the chemotactic factor FMLP can elicit constriction or relaxation of isolated PA, depending on the underlying active PA tension. In addition, both constriction and relaxation are dependent on cyclooxygenase products and intact endothelium.
Morphological and contractile characteristics of rat cardiac myocytes from maturation to senescence
Authors: Fraticelli A. , Josephson R. , Danziger R. , Lakatta E. , Spurgeon H.
Published: December 2017

Morphological and contractile characteristics of individual myocytes isolated from rats of 2, 6–9, and 24–25 mo of age were measured. The average myocyte length measured under high power light microscopy in unattached cells increased from 133 microns at 2 mo to 146 microns at 6–9 mo to 162 microns at 24–25 mo of age. The average slack sarcomere length was 1.85, 1.83, and 1.82 microns at 2, 6–9, and 24–25 mo, respectively. The average cell volume measured via Coulter counter techniques approximately doubled between 2 and 24 mo. During the electrically stimulated twitch in individual unloaded myocytes contracting from slack length the absolute amplitude of cell shortening increased with age, but when expressed relative to cell length or as sarcomere shortening the age effect was obliterated. Neither the maximal velocity of myocyte shortening (cell length/s) nor the calculated maximal sarcomere shortening velocity varied with age. The time course of the twitch increased with aging, due largely to an increase in the time to peak shortening. Thus aging is associated with an increase in cell size due to the addition of sarcomeres. Except for a prolonged time course, the twitch contraction characteristics normalized for cell length and sarcomere number in unloaded ventricular myocytes contracting over a range of sarcomere lengths below the slack length do not change appreciably with age.
Canine arteries release two different endothelium-derived relaxing factors
Authors: Hoeffner U. , Feletou M. , Flavahan N. A. , Vanhoutte P. M.
Published: December 2017

Experiments were designed to analyze the effects of ouabain on the response of vascular smooth muscle to endothelium-derived relaxing factors released under basal conditions and on stimulation with acetylcholine or bradykinin. Bioassay rings of canine coronary artery (without endothelium) were superfused with perfusate from canine left circumflex coronary arteries with endothelium (donor arteries). During contractions of the bioassay ring evoked by prostaglandin F2 alpha, the relaxations caused by endothelium-derived relaxing factor(s), released under basal conditions or on exposure of the endothelial cells of the donor artery to maximally effective concentrations of acetylcholine, were reduced by incubation of the bioassay ring with ouabain. However, the relaxations evoked by infusion of bradykinin were not altered by incubation of the bioassay rings with ouabain. These experiments demonstrate the release of two endothelium-derived relaxing factors that can be distinguished using ouabain.
Interstitial fluid pressure of ileum measured from chronically implanted polyethylene capsules
Authors: Mortillaro N. A. , Taylor A. E.
Published: December 2017

Steady-state fluid pressure measurements were obtained from polyethylene capsules chronically implanted in the walls of cat ileum. Measurements were performed while ileal venous outflow pressure was maintained at 0, 10, 20, or 30 mmHg. The resulting mean steady-state capsule pressure ranged from -0.56 to 7.3 mmHg over the range of imposed venous outflow pressures. The data provide evidence that at an ileal venous outflow pressure in the range of 10 mmHg, comparable to a normal portal pressure, interstitial fluid pressure is positive, increasing as tissue hydration increases, and is a significant contributing force opposing increases in the transcapillary filtration force. Additionally, the qualitative response of implanted capsules to close intra-arterial infusion of normal saline (transcapillary filtration), Dextran 40 (transcapillary absorption), and histamine (transcapillary filtration-permeability changes), and during and after an arterial occlusion of 60-s duration (transcapillary absorption-filtration) were obtained. The results demonstrate that the implanted capsules appropriately track changes in interstitial fluid pressure when the state of tissue hydration is altered by an induced net transcapillary fluid filtration or absorption. Finally, total protein concentration of capsule fluid was not significantly different from lymph fluid derived from a lymphatic vessel draining the ileal segment.
Transcapillary adenosine transport and interstitial adenosine concentration in guinea pig hearts
Authors: Wangler R. D. , Gorman M. W. , Wang C. Y. , DeWitt D. F. , Chan I. S. , Bassingthwaighte J. B. , Sparks H. V.
Published: December 2017

We used the multiple-indicator-dilution technique to observe the capillary transport of adenosine in isolated Krebs-Henseleit-perfused guinea pig hearts. Tracer concentrations of radiolabeled albumin, sucrose, and adenosine were injected into the coronary inflow; outflow samples were collected for 10–25 s and analyzed by high-performance liquid chromatography (HPLC) and by gamma- and beta-counting. The albumin data define the intravascular transport characteristics; the sucrose data define permeation through interendothelial clefts and dilution in interstitial fluid (ISF). Parameters calculated from adenosine data include permeability-surface area products for endothelial cell uptake at the luminal and abluminal membranes and intraendothelial metabolism. We found that in situ endothelial cells avidly take up and metabolize adenosine. Tracer adenosine in the capillary lumen is twice as likely to enter an endothelial cell as it is to permeate the clefts. There was no adenosine in the arterial perfusate. Under control conditions, the steady-state venous adenosine concentration was 3.6 +/- 0.8 nM, which from the flow and the parameters estimated from the tracer data gave a calculated ISF concentration of 6.8 +/- 1.5 nM. During dipyridamole infusion (10 microM) at constant pressure, the cell permeabilities went essentially to zero, whereas the venous adenosine concentration increased to 44.0 +/- 12.6 nM, giving an estimated ISF concentration of 191 +/- 53 nM. With constant flow perfusion, venous concentration during dipyridamole infusion was 30.9 +/- 6.3 nM, and estimated ISF concentration was 88 +/- 20 mM. We conclude that in this preparation, at rest, the ISF adenosine concentration is about twice the venous concentration and the ISF adenosine concentration increases with dipyridamole administration.
Intramyocardial pressure: interaction of myocardial fluid pressure and fiber stress
Authors: Rabbany S. Y. , Kresh J. Y. , Noordergraaf A.
Published: December 2017

Previous measurements of intramyocardial pressure (IMP) have yielded systolic pressures that range from values lower than to far exceeding systolic left ventricular pressure (LVP). This study identifies a possible mechanism underlying these divergent observations by building on established morphology of the ventricular wall. It is hypothesized here that the generation of fiber stress as a manifestation of myocardial contraction increases fluid pressure in the myocytes and the interstitial spaces. This increase in fluid pressure in turn generates the pressure in the ventricular cavity. Thus there are two quantities of interest: intramyocardial fluid pressure (IFP) and intramyocardial fiber stress (IFS). To test the hypothesis, we conducted experiments on conditioned dogs, utilizing a side-mounted catheter-tip strain gauge transducer to sense IMP as the sum of IFP and some component of IFS. In addition, a recessed end-tip fiber-optic transducer with its sensing element shielded from local myocardial fibers was employed to sense IFP. Both IFP and IMP were measured at various depths in the left ventricular free wall. The effects of inotropic interventions by administration of epinephrine and propranolol, mechanical interventions via clamping of the aorta and ligation of the left anterior descending coronary artery, and neural interventions by stimulation of the ansa subclavian of the stellate ganglion and right vagus were recorded. A transmural gradient in the wall for both IMP and IFP was observed. Systolic values of IFP recorded in the endocardium match those of LVP, with peak IMP exceeding both. The results support the hypothesis and offer an interpretation of the long-standing controversy regarding the magnitude of IMP with respect to LVP.
Nonuniform transmural recovery of contractile function in stunned myocardium
Authors: Bolli R. , Patel B. S. , Hartley C. J. , Thornby J. I. , Jeroudi M. O. , Roberts R.
Published: December 2017

With the use of an epicardial Doppler probe, systolic wall thickening was selectively measured in the inner, mid, and outer layers of the left ventricular (LV) wall in 16 conscious dogs undergoing a 15-min left anterior descending artery (LAD) occlusion followed by 7 days of reperfusion (REP). Under control conditions, percent thickening fraction (ThF) was significantly greater (P less than 0.01) in the inner layer [36.0 +/- 2.3% (mean +/- SE)] than in the mid (28.6 +/- 2.1%) or outer (21.3 +/- 2.2%) layers. During LAD occlusion, 11 dogs exhibited transmural dyskinesis (group 1), whereas 5 had transmural hypokinesis (group 2). In group 1, all layers exhibited comparable degrees of paradoxical systolic thinning during LAD occlusion. After REP, however, recovery was delayed in the inner compared with the mid and outer layers. At 2 h, ThF averaged 34.2 +/- 11.9% of base line in the endocardium vs. 61.7 +/- 16.2% in the midmyocardium and 51.0 +/- 12.3% in the epicardium (F = 4.29, P less than 0.002); similar differences were noted at 3 and 4 h. In the mid and outer layers, ThF returned to base-line values by 24 h, whereas in the inner layer it was still significantly depressed (P less than 0.05) at 24 h (77.3 +/- 5.1% of base line) and recovered by 48 h. The inner-to-outer ThF ratio was decreased (P less than 0.01) for 24 h after REP, indicating maldistribution of thickening in the "stunned" myocardium. In group 2, all layers exhibited hypokinesis during LAD occlusion. Again, recovery of function after REP was delayed in the endocardium compared with the other layers. This study demonstrates that after both severe ischemia resulting in dyskinesis and mild ischemia resulting in hypokinesis, REP is associated with slower recovery of function in the inner than in the outer layers. Thus myocardial "stunning" is a nonuniform phenomenon with maximal severity in the subendocardium.
Effect of linoleic acid infusion on blood pressure in normotensive and hypertensive rats
Authors: Reddy S. R. , Talwalkar R. , Downs J. , Kotchen T. A.
Published: December 2017

High dietary intake of linoleic acid lowers arterial pressure, and, in vitro, linoleic acid inhibits the enzymatic activity of renin. The purpose of the present study was 1) to evaluate the effect of intravenous infusion of linoleic acid on blood pressure in normotensive and hypertensive Sprague-Dawley rats and 2) to determine whether the hypotensive response to linoleic acid infusion is caused by inhibition of circulating renin. Blood pressure was decreased (P less than 0.01) by linoleic acid infusion in normotensive sodium chloride-deprived animals and in animals with two-kidney, one-clip hypertension. In contrast, linoleic acid infusion did not affect blood pressure in normotensive rats on a "normal" or high sodium chloride intake, in rats with deoxycorticosterone acetate (DOCA)-salt hypertension, and in anephric rats. In sodium chloride-deprived rats, the reduction of blood pressure by linoleic acid infusion was associated with increased plasma renin activity (P less than 0.05); serum angiotensin-converting enzyme activity was unchanged. The in vitro enzymatic activity of exogenous renin in plasma of anephric rats was not affected by linoleic acid infusion. In two-kidney, one-clip hypertensive animals, pretreatment with indomethacin did not alter the hypotensive response to linoleic acid. Thus, although linoleic acid infusion lowered blood pressure in high renin but not in low renin states, the reduction of blood pressure was not related to inhibition of circulating renin or to alterations of endogenous prostaglandin biosynthesis.
Mechanism of pressor response to posterior hypothalamic injection of neuropeptide Y
Authors: Martin J. R. , Knuepfer M. M. , Beinfeld M. C. , Westfall T. C.
Published: December 2017

Unilateral microinjection of neuropeptide Y (NPY) into the posterior hypothalamic nucleus was previously found to evoke an increase in mean arterial pressure (MAP) in urethan-anesthetized rats. In this study, the mechanism by which this increase occurs was examined. Pretreatment of rats with 2.0 mg/kg (iv) of phenoxybenzamine, or 7.5 mg/kg (iv) of pentolinium, resulted in a significant reduction in the peak MAP evoked by microinjection of NPY (2.35 nmol) into the posterior hypothalamic nucleus. Administration of the vasopressin V1-receptor antagonist [d(CH2)5Tyr(Me)]AVP (10 micrograms/kg iv) before microinjection of NPY failed to attenuate the increase in MAP. Similar results were obtained with respect to the effect of these three antagonists on the increase in MAP evoked by injection of the cholinergic muscarinic agonist carbachol (5.48 nmol) into the posterior hypothalamic nucleus. Furthermore, microinjection of NPY or carbachol elicited a significant elevation of renal sympathetic nerve activity and an increase in resistance of the hindquarter vascular bed. However, NPY elicited a decrease and carbachol an increase in the resistance of the mesenteric bed, whereas NPY elicited an increase and carbachol a decrease in the resistance of the renal bed. These results suggest that NPY elicits an increase in MAP via centrally mediated sympathetic excitation. Furthermore, NPY and carbachol differentially affect sympathetic outflow to peripheral vascular beds after microinjection into the posterior hypothalamic nucleus.
Mechanism for depression of heart sarcolemmal Ca2+ pump by oxygen free radicals
Authors: Kaneko M. , Elimban V. , Dhalla N. S.
Published: December 2017

To understand the involvement of changes in sulfhydryl groups in causing depression of the sarcolemmal Ca2+-pump activities, this study was undertaken to examine the effects of oxygen free radicals on rat heart sarcolemmal sulfhydryl groups, Ca2+-stimulated adenosinetriphosphatase (ATPase), and ATP-dependent Ca2+ accumulation. In addition, the effects of sulfhydryl reagents such as dithiothreitol, cysteine, and N-ethylmaleimide on Ca2+-pump activities were investigated. The inhibition of sarcolemmal Ca2+-pump activities by O2-. (xanthine + xanthine oxidase) and H2O2 was decreased by the addition of dithiothreitol or cysteine in a dose-dependent manner. N-ethylmaleimide also showed inhibitory effects on Ca2+-pump activities both in a dose- and time-dependent manner; dithiothreitol and cysteine prevented changes in Ca2+-pump activities because of N-ethylmaleimide. Heart sarcolemmal sulfhydryl groups were depressed by O2-., H2O2, and .OH (H2O2 + Fe2+) both in a dose- and time-dependent manner. Superoxide dismutase, catalase, and D-mannitol showed protective effects on the sulfhydryl group depression by O2-., H2O2, and .OH, respectively. A significant correlation between changes in sarcolemmal Ca2+-stimulated ATPase activity and sarcolemmal sulfhydryl groups was seen. These results indicate that oxygen free radicals may depress the heart sarcolemmal Ca2+-pump activities by modifying the sulfhydryl groups in the sarcolemmal membrane.
Hemodilution causes size-dependent constriction of pial arterioles in the cat
Authors: Hudak M. L. , Jones M. D. , Popel A. S. , Koehler R. C. , Traystman R. J. , Zeger S. L.
Published: December 2017

Cerebral blood flow (CBF) rises as hematocrit (Hct) falls. We previously attributed this rise in CBF to two independent factors of equal importance, decreased arterial O2 content and decreased blood viscosity. We hypothesized that decreased arterial O2 content would dilate cerebral arterioles and that the magnitude of the vasodilation would depend on the magnitude of the passive fall in vascular resistance attributable to decreased viscosity. The present study was designed to test the hypothesis that anemia is accompanied by cerebral vasodilation. Using a closed cranial window, we measured the diameters of 42 pial arterioles (35-305 microns) in 7 cats as serial isovolemic hemodilution lowered Hct by 44% from 31 +/- 4 to 17 +/- 3%. Hemodilution increased CBF (microsphere technique) but did not change mean arterial blood pressure or arterial blood gases. Anticipated vasodilation did not occur; instead, pial arterioles constricted as Hct fell. Maximum vasoconstriction was observed when Hct reached 65-70% of the initial value. Vasoconstriction lessened as Hct was lowered further, but arteriolar diameters at the lowest Hcts remained less than base-line levels. Constriction was greater in small (less than 100 microns) than in large (greater than or equal to 100 microns) arterioles. The initial constriction of pial arterioles may represent myogenic vasoconstriction in response to flow-induced vasodilation of more proximal portions of the cerebrovascular bed and/or to washout of an endogenous vasodilator. Arteriolar relaxation with more profound hemodilution may reflect superimposed metabolic vasodilation.
Endothelium-dependent and -independent responses to vasoactive substances of isolated human coronary arteries
Authors: Toda N. , Okamura T.
Published: December 2017

In epicardial conduit coronary artery strips obtained during autopsy within 2.5 h after death, relaxations induced by low concentrations of histamine were reversed to contractions by removal of endothelium, whereas those caused by bradykinin, substance P, and Ca2+ ionophore A23187 were almost abolished. In the artery strips with intact endothelium, which responded to histamine, bradykinin, and substance P with moderate or marked relaxations, acetylcholine elicited contractions. Endothelium denudation failed to potentiate the contractile response to acetylcholine and serotonin. Relaxant responses to histamine, bradykinin, and substance P did not significantly differ in coronary arteries from adults (35–48 yr old) and seniors (63–82 yr old). Two strips from a 2-mo-old male responded to acetylcholine only with contractions, and their responses to the vasodilators were not greater than those seen in the adult and senior arteries. Histamine increased guanosine 3',5'-cyclic monophosphate (cGMP); the increments did not differ in the arteries from adults and seniors. It may be concluded that endothelium is a major site for relaxant actions of histamine, bradykinin, and substance P, whereas muscarinic receptors, if any, in endothelium do not play an important role in the generation of relaxing factor from human coronary arteries. The endothelium-dependent relaxations do not appear to be altered with increasing age or in the arteries with slight atherosclerotic changes.
Control of organ blood flow in fetal sheep during normoxia and hypoxia
Authors: Jansen A. H. , Belik J. , Ioffe S. , Chernick V.
Published: December 2017

The role of peripheral chemoreceptors in the circulatory adaptation to hypoxia and the effects of rapid-eye-movement (REM) and non-REM (NREM) sleep and breathing activity on organ blood flow were assessed in fetal sheep. Blood flow was measured with isotope-labeled microspheres on intact, vagotomized (VX), and sinoaortic-denervated (SAD) fetuses. Denervation did not change the biventricular cardiac output (Biv. CO) or organ blood flows during normoxia. In intact fetuses the blood flow was increased during hypoxemia in brain, adrenals, and heart but not in kidneys, skeletal muscles, or placenta. The increase in organ blood flow during hypoxemia was reduced in the VX group and even more in SAD fetuses, but in the latter group, blood flow was still increased in mid-brain, medulla, pons, skeletal muscles, and heart. Sleep states per se did not significantly affect the blood flow to any organs tested. However, the Biv. CO and blood flow to all organs except kidneys and adrenals was increased during fetal breathing in REM sleep. We conclude that 1) during moderate hypoxemia both aortic and carotid bodies plus an additional mechanism are involved in redistributing fetal blood flow, and 2) changes in organ perfusion during REM sleep are due to concomitant fetal breathing.
Alpha-adrenergic effects on relative refractory period in Purkinje system of intact canine left ventricles
Authors: Martins J. B. , Wendt D. J.
Published: December 2017

To investigate the electrophysiological effects of alpha-agonists, we studied 23 chloralose-anesthetized sinoaortic and vagotomized dogs, measuring epicardial and endocardial effective refractory period and relative refractory period of the Purkinje system during graded infusions of norepinephrine and phenylephrine. In group 1, epicardial and endocardial effective refractory periods shortened equivalently with norepinephrine. These effects were blocked with metoprolol. In group 2, epicardial and endocardial refractory periods did not prolong with phenylephrine despite addition of metoprolol. In group 3, phenylephrine, after the addition of metoprolol, prolonged the relative refractory period of Purkinje only at the highest phenylephrine dose of 50 micrograms.kg-1.min-1. In group 4, these latter effects were not produced by raising pressure with descending aortic occlusion. However, the effects of phenylephrine were blocked with prazosin (1.0 mg/kg). Taken together, these data demonstrate that alpha-adrenergic influences prolong Purkinje but not muscle refractory period in the intact canine ventricle. The high dose of phenylephrine and resulting hypertension suggest that this may be a pharmacological and not a physiological response.
Dilator effects of amino acid neurotransmitters on piglet pial arterioles
Authors: Busija D. W. , Leffler C. W.
Published: December 2017

We examined the effects of topically applied amino acids (glutamate, aspartate, glycine, and taurine) and a synthetic glutamate analogue [N-methyl-D-aspartate (NMDA)] on pial arteriolar tone and cortical surface cerebrospinal fluid (CSF) dilator prostanoid concentrations in anesthetized newborn pigs. We also determined whether prolonged contact of pial arterioles with glutamate (10(-3) M) and aspartate (10(-3) M) would alter arteriolar responses to exogenous isoproterenol or norepinephrine. Vascular responses were determined using the closed cranial window technique and intravital microscopy. Concentrations of prostaglandin E2 and 6-ketoprostaglandin F1 alpha in CSF under the cranial window were determined using radioimmunoassay. At the highest dose tested (10(-3) M), NMDA dilated arterioles by 30 +/- 4% (n = 8), glutamate by 21 +/- 5% (n = 6), aspartate by 28 +/- 10% (n = 5), and taurine by 21 +/- 2% (n = 7). Glycine application did not change pial arteriolar diameter significantly (n = 8). The amino acids tested (NMDA and glutamate) did not increase CSF levels of dilator prostagnoids, and intravenous indomethacin trihydrate did not change vascular responsiveness to NMDA. Furthermore, dilator responsiveness to isoproterenol and constrictor responsiveness to norepinephrine were not affected significantly after 30 min of topical application of glutamate and aspartate to the pial surface (n = 4). We conclude that these amino acids are potent dilators of the neonatal cerebral circulation. The mechanism of dilation in the cases of NMDA and glutamate does not appear to involve dilator prostanoids. Furthermore, prolonged contact with excitatory amino acids under these conditions does not alter subsequent cerebrovascular responsiveness.
Electrophysiological effects of left ventricular free wall traction in intact hearts
Authors: Gornick C. C. , Tobler H. G. , Tuna I. C. , Benditt D. G.
Published: December 2017

Transmural multipolar electrodes, sonomicrometers implanted within the left ventricular wall, and cardiac electrical stimulation techniques were used to examine the effect of transient mechanically applied traction to the left ventricular free wall on local electrophysiological properties. Twenty-five open-chest dogs were atrially paced (cycle length 400 ms) followed by insertion of timed premature extrastimuli at left ventricular epicardial pacing sites either in the vicinity of (traction zone) or remote from (nontraction-control zone) the site of left ventricular free wall traction. Electrophysiological recordings were made before and during intermittent left ventricular free wall traction applied in late diastole (rate 25 cm/s; duration 170 ms). In 22 of 25 dogs, application of traction resulted in early local ventricular activation (mean activation advancement 64 +/- 15 ms), altered QRS morphology of the last conducted atrial drive train beat, and a relative prolongation of ventricular refractoriness in the traction zone. Conversely, in the nontraction-control zone, early activation did not occur and refractoriness was unchanged. Alterations in regional myocardial blood flow (assessed by microsphere technique) did not appear responsible for the observed changes. Furthermore, phenol interruption of local sympathetic or combined sympathetic and parasympathetic innervation or verapamil pretreatment had no impact on the mechanically induced electrophysiological changes. Thus, in normal myocardium in situ, regional abnormalities in wall motion may be associated with alterations of local ventricular activation and refractoriness, factors that in the diseased heart could lead to increased susceptibility to arrhythmias.
Mathematical model of edema in the isolated rabbit lung perfused with oleic acid
Authors: Hempling H. G. , Katz S. A.
Published: December 2017

The development of edema by the isolated, perfused rabbit lung in response to oleic acid was analyzed with the equations of Kedem and Katchalsky (Biochim. Biophys. Acta 27: 229–246, 1958). A perfused cylinder and annulus surround was chosen as a model. Isolated lungs, perfused with an isosmotic solution containing dextran as an oncotic agent, received a bolus injection of oleic acid into the pulmonary artery, resulting in marked edema without a rise in mean pulmonary arterial pressure. Hydrostatic pressure was kept constant and in the model was converted to its equivalent concentration of osmotically active impermeant solute, with a reflection coefficient (sigma) of 1. Fluid changes could be analyzed with three principal components as follows: the capillary permeability to solute (Pk), the hydraulic coefficient (Lp), and sigma. The equations were solved using Euler's method for integration, and the values for the three coefficients were adjusted to fit the data. The analysis indicated that the edema measured experimentally could be simulated by a progressive increase in Lp at constant or increasing values of Pk and decreasing values for sigma but not after selective increases in Pk and/or decreases in sigma alone. The analysis suggests that an expanding hydraulic conductivity may be the rate-limiting factor in oleic acid-induced pulmonary edema in the isolated, perfused rabbit lung.
Tedisamil inactivates transient outward K+ current in rat ventricular myocytes
Authors: Dukes I. D. , Morad M.
Published: December 2017

The action of tedisamil, a new bradycardiac agent with antiarrhythmic properties, was investigated in single rat ventricular myocytes using the whole cell voltage-clamp technique. Under current clamp conditions, 1-20 microM tedisamil caused marked prolongations of the action potential. Over the same concentration range, in voltage-clamped myocytes, tedisamil suppressed the transient outward current (ito) and enhanced its inactivation in a dose-dependent manner. The half-maximal dose for the effect of tedisamil on ito was approximately 6 microM. Tedisamil had no significant effects on the inwardly rectifying potassium current and calcium current but did suppress the sodium current at concentrations greater than 20 microM. Our findings suggest that tedisamil represents a new type of antiarrhythmic agent that primarily suppresses the transient outward K+ current.
Evidence for adenosine receptor-mediated hyperpolarization in coronary smooth muscle
Authors: Sabouni M. H. , Hargittai P. T. , Lieberman E. M. , Mustafa S. J.
Published: December 2017

The effects of adenosine and its analogues, 5'-N-ethyl-carboxamidoadenosine (NECA) and 2-chloroadenosine (CAD), were studied on resting membrane potential of bovine coronary artery. The resting membrane potential averaged -51 +/- 1 mV. KCl (50 mM) caused a significant decrease of the resting membrane potential (-30 +/- 1 mV). In separate series of experiments suffusion of the arterial strips with adenosine, NECA, or CAD, at concentrations of 10(-5)M, produced significant increases in resting membrane potential (-68 +/- 1, -80 +/- 2, and -88 +/- 4 mV, respectively). The hyperpolarizing responses to adenosine, NECA, and CAD appeared to have been mediated by an adenosine receptor, since they were blocked by the adenosine receptor antagonist, 8-phenyltheophylline (10(-5) M). The data suggest that activation of an adenosine receptor can result in hyperpolarization of coronary smooth muscle cells.
Contributions of a transient outward current to repolarization in human atrium
Authors: Shibata E. F. , Drury T. , Refsum H. , Aldrete V. , Giles W.
Published: December 2017

Conventional microelectrode recordings combined with enzymatic cell dispersion methods and a single microelectrode voltage-clamp technique were used to record transmembrane action potentials and ionic currents in isolated single myocytes and in excised segments of human right atrium. Recordings of the outward current(s), which is responsible for the resting potential and early repolarization of the action potential in human right atrium, consistently showed that this tissue has 1) a relatively small inwardly rectifying background potassium current (IK1) which generates the resting potential in mammalian ventricular tissue and Purkinje fibers, and 2) a large time- and voltage-dependent, but Ca2(+)-independent, transient outward current. A somewhat similar K+ current was originally described in neurons and recently has also been identified in a variety of mammalian cardiac tissues. As expected from previous work, this transient outward current in human atrium is blocked by 4-aminopyridine (4-AP; 0.5 mM) and exhibits time- and voltage-dependent inactivation and reactivation. Measurements of action potential shape changes and phasic tension as a function of stimulus frequency, or after 4-AP application, show that in human atrium this current can produce pronounced changes in both the early repolarization of the action potential and force generation.