The Cardiovascular Effects of Morphine THE PERIPHERAL CAPACITANCE AND RESISTANCE VESSELS IN HUMAN SUBJECTS

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Abstract

To evaluate the effects of morphine on the peripheral venous and arterial beds, 69 normal subjects were evaluated before and after the intravenous administration of 15 mg morphine. Venous tone was determined by three independent techniques in 22 subjects. The venous pressure measured in a hand vein during temporary circulatory arrest (isolated hand vein technique) fell from 20.2±1.4 to 13.4±0.9 mm Hg (P < 0.01) 10 min after morphine, indicating that a significant venodilation had occurred. With the acute occlusion technique, morphine induced a reduction in forearm venous tone from 12.8±1.1 to 7.9±2.3 mm Hg/ml/100 ml (P < 0.01). Although forearm venous volume at a pressure of 30 mm Hg (VV[30]) was increased from 2.26±0.17 to 2.55±0.26 ml/100 ml, measured by the equilibration technique, the change was not significant (P > 0.1). Of note is that the initial reaction to morphine was a pronounced venoconstriction, demonstrated during the first 1-2 min after the drug. (Isolated hand vein pressure increased to 37.2±5.4 mm Hg, P < 0.01). This rapidly subsided, and by 5 min a venodilation was evident. Morphine did not attenuate the venoconstrictor response to a single deep breath, mental arithmetic, or the application of ice to the forehead when measured by either the isolated hand vein technique or the equilibration technique.

Authors

Robert Zelis, Edward J. Mansour, Robert J. Capone, Dean T. Mason

Use of Inert Gases and Carbon Monoxide to Study the Possible Influence of Countercurrent Exchange on Passive Absorption from the Small Bowel

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The purpose of the present study was to quantitate the influence of countercurrent exchange on passive absorption of highly diffusible substances from the small intestine of the rabbit. The absorption of carbon monoxide, which is tightly bound to hemoglobin and therefore cannot exchange, was compared to the absorption of four unbound gases (H2, He, CH4, and 133Xe), which should exchange freely. The degree to which the observed absorption of the unbound gases falls below that predicted from CO absorption should provide a quantitative measure of countercurrent exchange.

Authors

John H. Bond, David G. Levitt, Michael D. Levitt

Normal Contractile State of Hypertrophied Myocardium after Pulmonary Artery Constriction in the Cat

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The contractile function of right ventricular papillary muscles from normal cats and cats in which the pulmonary artery had been constricted for 6 or 24 wk was examined. Acute pulmonary artery constriction reduced cross-sectional area by an average of 70%, resulting in a 30% mortality from congestive heart failure, all such deaths occurring within the first 3 wk after banding. The increase in right ventricular mass in animals surviving for 6 or 24 wk was similar, averaging 70%. No banded animals had evidence of congestive heart failure at the time of sacrifice, and cardiac output and right atrial pressures were similar to those in control animals.

Authors

John F. Williams Jr., Ralph D. Potter

Specificity of Heteroantisera to Human Acute Leukemia-Associated Antigens

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Antisera have been raised to human leukemic blast cells from individual patients in mice rendered tolerant with cyclophosphamide to remission leukocytes from the same individual. 10 antisera were raised against acute myelogenous leukemia (AML) cells and 5 antisera were raised against acute lymphoblastic leukemia (ALL) cells. Antisera to AML cells were absorbed with ALL cells, and antisera to ALL cells were absorbed with AML cells. Unabsorbed and absorbed antisera as well as antisera raised in nontolerant mice were tested for cytotoxicity against various cells of a panel containing myeloblasts from 35 patients with AML, lymphoblasts from 7 patients with ALL, myeloblasts from 7 patients with chronic myelogenous leukemia (CML) in blast crisis, peripheral blood leukocytes from 12 patients with acute leukemia in remission and 30 nonleukemic patients, and nucleated bone marrow cells from 10 nonleukemic patients. Unabsorbed antisera to AML or ALL cells raised in tolerant mice were highly cytotoxic to leukemic blasts cells but significantly less cytotoxic to remission and control cells. Antisera to AML cells absorbed with ALL cells retained measurable cytotoxicity against AML cells but were not cytotoxic to ALL cells or control cells. Similarly, antisera to ALL cells absorbed with AML cells retained significant cytotoxicity only to ALL cells. Control antisera raised in nontolerant mice were cytotoxic to all cells tested. Although species specific, histocompatibility, differentiation, maturation, and cell cycle-associated antigens may be responsible in part for the cytotoxic activity of the unabsorbed antisera, the absorbed antisera are probably detecting antigens specific for their leukemic cell type.

Authors

Michael A. Baker, K. Ramachandar, Robert N. Taub

Effect of Acute and Chronic Calcium Administration on Plasma Renin

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Abstract

To evaluate the effect of Ca++ on renin release, plasma renin activity (PRA) was measured after acute and chronic Ca++ administration. 1% CaCl2 was infused into one renal artery of 10 anesthetized dogs (0.3 mg/kg/min). The excreted fraction of filtered calcium (EFca++) and EFNa+ from the infused kidney were elevated (P < 0.04) during three successive 15-min infusion periods. Serum calcium concentration was significantly elevated (P < 0.001). Creatinine clearance, systemic arterial pressure, and renal blood flow did not change (P > 0.10). Compared to control (45 ng/ml/h±5.2 SE), renal venous PRA was suppressed (P < 0.0001) after infusion of Ca++ for 15, 30, and 45 min (20 ng/ml/h±4.6, 16 ng/ml/h±4.0, and 13 ng/ml/h±2.7, respectively). 15 and 30-min after infusion, PRA did not differ from control (P > 0.20). Chronic Ca++ loading was achieved in Sprague-Dawley rats by replacing drinking water with 1% CaCl2 for 17 days. At sacrifice, serum Ca++, Na+, and K+ of controls (n = 12) did not differ (P > 0.60) from Ca++-loaded rats (n = 12). Ca++ excretion (467 μeq/24 h±51) was elevated (P < 0.001) compared to controls (85 μeq/24 h±12). PRA (8.6 ng/ml/h±1.4) and renal renin content of Ca++-loaded rats did not differ from controls (P > 0.80). However, after 8 days of sodium deprivation, both PRA and renal renin content of calcium-loaded animals were significantly lower than the respective values in pair-fed controls (P < 0.005). During the period of sodium deprivation, calcium-drinking animals were in greater negative sodium balance than controls (P < 0.005). The data are consistent with the hypothesis that acute and chronic calcium administration inhibit renin secretion.

Authors

Theodore A. Kotchen, Kimball I. Mauli, Robert Luke, Douglas Rees, Walter Flamenbaum

Effects of Volume Expansion, Purified Parathyroid Extract, and Calcium on Renal Bicarbonate Absorption in the Dog

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The role of parathyroid hormone (PTH) and of Ca++ in the regulation of bicarbonate absorption (RHCO3) and its response to extracellular volume expansion (VE) was studied in HCO3--loaded dogs.

Authors

Charles K. Crumb, Manuel Martinez-Maldonado, Garabed Eknoyan, Wadi N. Suki

Differential Susceptibility of Human IgA Immunoglobulins to Streptococcal IgA Protease

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IgA protease, a proteolytic enzyme found in human saliva and colonic fluid, hydrolyzes human serum IgA immunoglobulins to yield Fabα and Fcα fragments. The enzyme is produced by organisms in the normal human microflora and can be purified from culture filtrates of the common human oral organism Streptococcus sanguis (American Type Culture Collection no. 10556). IgA protease is inactive against all other protein substrates examined including the other classes of human immunoglobulins. The role of this enzyme in affecting the function of the secretory IgA immune system is unknown.

Authors

Andrew G. Plaut, Richard Wistar Jr., J. Donald Capra

Bile Acid Kinetics in Relation to Sex, Serum Lipids, Body Weights, and Gallbladder Disease in Patients with Various Types of Hyperlipoproteinemia

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Abstract

Bile acid kinetics were determined in 15 normolipidemic and 61 hyperlipidemic subjects with the aid of [14C]cholic acid and [3H]chenodeoxycholic acid. The diet was standardized and of natural type. The total bile acid formation was within normal limits in patients with hyperlipoproteinemia types IIa and IIb. On the average the production of cholic acid (C) represented less than 50% of the total bile acid synthesis in both groups. The corresponding value recorded for the controls was 64±2% (mean±SEM). The synthesis of C in hyperlipoproteinemia type IIa was significantly below normal. Of the 27 patients with the type IV pattern, 18 had a synthesis of C and C + chenodeoxycholic acid (CD) that exceeded the upper range recorded for the controls. In these subjects the C formation represented 73±3% of the total bile acid synthesis. Similar findings were also encountered in the five patients with the type V lipoprotein pattern studied. The bile acid pool size of the 11 patients with hyperlipoproteinemia type IV, who had been cholecystectomized or suffered from cholelithiasis, was 900 mg smaller on the average than that of the other subjects with the same type of hyperlipoproteinemia. However, the pool size in the former subjects still tended to be higher than that of the control subjects without evidence of gallbladder “disease”. In all groups of subjects the formation of bile acids tended to be higher in the male than in the female subjects. Bile acid synthesis showed no linear correlation to actual body weight, relative body weight, or body surface area. A moderate weight reduction in five patients (one with type IIb and four with type IV pattern) was followed by a 50% reduction of the C and CD synthesis.

Authors

Kurt Einarsson, Kjell Hellström, Mora Kallner

The Secondary Structure of Human Hageman Factor (Factor XII) and its Alteration by Activating Agents

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Hageman factor (factor XII) is activated by exposure to surfaces such as glass or by solutions of certain compounds, notably ellagic acid. Changes in the structure of Hageman factor accompanying activation have been examined in this study by circular dichroism spectroscopy. The spectrum of unactivated Hageman factor in aqueous solutions suggests that its conformation is mainly aperiodic. Various perturbants altered the conformation of Hageman factor in differing ways, demonstrating the sensitivity of Hageman factor to its environment.

Authors

Carl R. McMillin, Hidehiko Saito, Oscar D. Ratnoff, Alan G. Walton

Decreased Insulin Binding to Lymphocytes from Diabetic Subjects

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We have studied insulin binding to circulating lymphocytes isolated from 20 untreated adult, nonobese, nonketotic, diabetic subjects with fasting hyperglycemia, 20 normal subjects, and four patients with fasting hyperglycemia secondary to chronic pancreatitis. The results of these studies show that lymphocytes from diabetic patients have decreased ability to specificity bind insulin when compared to lymphocytes from normal subjects. For example, when lymphocytes from diabetic patients and a trace amount of [125I]insulin (3.3 × 10-11 M) were incubated, binding was less than 50% of the value obtained with lymphocytes from normal subjects (2±0.2% vs. 4.2±0.4%). Furthermore, the data show that lymphocytes from diabetic patients have only 1,200 insulin receptor sites per cell compared to 2,200 sites per cell for lymphocytes from normal subjects. Competitive inhibition studies using unlabeled insulin indicate that the affinity for insulin of lymphocytes from both groups is comparable. Consequently the decreased insulin binding of diabetics' lymphocytes is primarily due to a decreased number of available receptors rather than decreased binding affinity. This decreased insulin binding is not due to chronic hyperglycemia since insulin binding to lymphocytes, obtained from four patients with fasting hyperglycemia secondary to chronic pancreatitis, was completely normal. The possibility that some factor present in the plasma of diabetic patients could cause decreased insulin binding also seems unlikely since we could demonstrate no in vitro effects of diabetics' plasma on insulin binding. Lastly, the proportion of lymphocytes which were thymus derived and bone marrow derived were the same in each of the study groups indicating that differences in lymphocyte subpopulations do not account for our results.

Authors

Jerrold M. Olefsky, Gerald M. Reaven

Effect of Adrenalectomy on the Renal Response to Chloride Depletion in the Rat

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Abstract

These experiments were aimed at investigating renal behavior towards chloride, as distinct from sodium, during dietary deprivation of these ions in adrenalectomized rats. Adrenalectomized and shamoperated control rats were maintained on saline for 3 wk, then chloride conservation during a very low chloride intake was assessed both with an abundant sodium intake (as buffered sodium phosphate in the drinking water) and after subsequent withdrawal of sodium. When sodium intake was high, there was no difference in chloride conservation between adrenalectomized and control animals, and sodium balance and weight were maintained similarly in both groups. At the same time, both experimental and control rats developed significant hypokalemia and elevation of the plasma bicarbonate levels as compared to other control rats ingesting a normal diet. In another group of adrenalectomized rats sodium phosphate was withdrawn, after normal chloride conservation was observed, and the low-salt diet continued. Negative sodium balance developed and was associated with a negative chloride balance, whereas sham-operated rats continued to conserve sodium and chloride. In further studies during polyuria, both adrenalectomized and control rats developed urinary chloride concentrations of less than 1 meq/liter.

Authors

R. G. Luke

Effects of Corticosteroids on Human Monocyte Function

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This report examined the effect of corticosteroids in vitro on human peripheral blood monocytes, essential cells in both immune and nonimmune cellular defense mechanisms. Monocyte chemotaxis in response to sera, Escherichia coli filtrate, and lymphokine chemotactic factor was markedly reduced (P < 0.01) by hydrocortisone succinate (HCS) at 16 μg/ml. Methylprednisolone succinate and unesterified hydrocortisone produced similar impairment of monocyte chemotaxis while two drugs which unmodified do not enter cells, hydrocortisone phosphate (HCP) and cortisone acetate, had no effect on chemotaxis. HCS also significantly impaired monocyte random migration at 16 μg/ml. Monocyte bactericidal activity was reduced by HCS at 16 μg/ml (P < 0.01)) but was not affected by HCP even at 120 μg/ml. In comparison, HCS did not alter granulocyte chemotaxis even at 500 μg/ml, and bactericidal activity was reduced at 16 μg/ml (P < 0.01). Monocyte phagocytosis of cryptococci was reduced only 20% (P < 0.05) at 120 μg/ml. HCS at 120 μg/ml did not alter monocyte base-line or postphagocytic hexosemonophosphate shunt activity, viability by trypan blue exclusion, adherence to tissue culture flasks, or surface binding of IgG globulin. These corticosteroid-induced defects in monocyte function may contribute to reduced cellular defense during corticosteroid therapy.

Authors

John J. Rinehart, Stanley P. Balcerzak, Arthur L. Sagone, Albert F. LoBuglio

Intestinal Absorption of Hemoglobin Iron-Heme Cleavage by Mucosal Heme Oxygenase

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Hemoglobin and myoglobin are a major source of dietary iron in man. Heme, separated from these hemoproteins by intraluminal proteolysis, is absorbed intact by the intestinal mucosa. The absorbed heme is cleaved in the mucosal cell releasing inorganic iron. Although this mucosal heme-splitting activity initially was ascribed to xanthine oxidase, we investigated the possibility that it is catalyzed by microsomal heme oxygenase, an enzyme which converts heme to bilirubin, CO, and inorganic iron.

Authors

Steven B. Raffin, Choong H. Woo, Kenneth T. Roost, David C. Price, Rudi Schmid

Competitive Binding of Bilirubin and Drugs to Human Serum Albumin Studied by Enzymatic Oxidation

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The mechanism of drug-induced displacement of bilirubin from the blood into tissues was studied. A model of simple, competitive binding of bilirubin and drug to one site on serum albumin was established. Variations of the free bilirubin concentration after addition of drugs were studied in vitro by measuring velocities of oxidation with hydrogen peroxide and horseradish peroxidase. In all cases, the results were in agreement with the model. The competitive effects of 20 drugs were measured and expressed quantitatively as binding constants to the bilirubin site on human serum albumin. Several drugs caused changes of the bilirubin-albumin light absorption spectrum, indicating simultaneous binding of both ligands, without an effect on the free bilirubin concentration. Noncompetitive site-to-site effects on bilirubin binding could not be demonstrated.

Authors

R. Brodersen

The Central Nervous System as a Site of Action for the Coronary Vasoconstrictor Effect of Digoxin

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Abstract

Digitalis is known to have a vasoconstrictor effect in the coronary circulation. Recent studies have demonstrated that the coronary vasoconstrictor effects of acetylstrophanthidin and digoxin are neurally mediated via alpha adrenergic fibers. In the present study, experiments were done in 20 dogs anesthetized with chloralose and urethane to study the central nervous system as a possible site of action for this vasoconstrictor effect of digoxin. After the intravenous administration of 1.0 mg digoxin, cerebrospinal fluid concentrations of digoxin rose to a peak of 2.3±0.4 (SEM) ng/ml at 15 min, temporally corresponding to the peak in coronary vascular resistance change of +20.0±2.5% of control in the paced canine heart. Submicrogram digoxin injections into the lateral cerebral ventricle produced a significant increase in coronary vascular resistance, the latter injection producing a peak increase in coronary vascular resistance of 12.4±1.2% of control. Cross-perfusion experiments, where the isolated head of the operative dog was perfused from a donor dog receiving digoxin, thus keeping digoxin levels in the remainder of the operative dog very low, showed a similar degree of coronary vasoconstriction. Thus, the central nervous system appears to be an important site of action for the early coronary vasoconstrictor effect of digoxin.

Authors

Hasan Garan, Thomas W. Smith, Wm. John Powell Jr.

Superficial and Deep Juxtaglomerular Apparatus Renin Activity of the Rat Kidney EFFECT OF SURGICAL PREPARATION AND NaCl INTAKE

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The intrarenal gradient of renin activity was determined in rats by using superficial (S) and deep (D) cortical juxtaglomerular apparatuses (JGA's), identified and microdissected after silicone-rubber compound injection. Angiotensin generated from single JGA's using partially purified sheep renin substrate was quantified by rat bioassay. When, in rats on a normal NaCl diet, silicone-rubber was injected into a carotid artery, alone or with abdominal aorta catheterization, S:D renin activity ratios were 1.18±0.08 (SEM) and 1.21±0.12, respectively. The S:D renin activity ratios obtained when silicone-rubber was injected into the abdominal aorta (2.52±0.09) or a chronic carotid artery catheter (3.44±0.40) were significantly higher (P < 0.001). The lower S:D renin activity ratios after carotid artery manipulation were due to significantly higher D-JGA renin activities. This increased D-JGA renin activity and the lack of a renin gradient appear to be related to acute carotid artery manipulation.

Authors

Walter Flamenbaum, Robert J. Hamburger

Human Parathyroid Hormone IMMUNOLOGICAL CHARACTERIZATION OF ANTIBODIES AGAINST A GLANDULAR EXTRACT AND THE SYNTHETIC AMINO-TERMINAL FRAGMENTS 1-12 AND 1-34 AND THEIR USE IN THE DETERMINATION OF IMMUNOREACTIVE HORMONE IN HUMAN SERA

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Antibodies to a urea-trichloroacetic acid extract [hPTH-(TCA)] of human parathyroid tumors and to the synthetic NH2-terminal fragments of human parathyroid hormone hPTH-(1-12) and -(1-34) were developed in goats to characterize immunochemically various PTH preparations and to estimate immunoreactive PTH (iPTH) in human sera. They were quantitated on the basis of their capacity to bind [131I]-hPTH-(1-12), [131I]hPTH-(1-34) or [131I]bovine PTH (bPTH-(1-84)). The quality of the antibodies was assessed by reference to inhibition of their interaction with labeled peptides by synthetic hPTH comprising 34 NH2-terminal amino acid residues or fragments thereof [hPTH-(1-12), -(13-34), -(18-34), -(25-34), -(18-24)] or by the Sephadex G-100-purified full-length peptide hPTH-(1-84) [hPTH-(1-84)G-100]. The synthetic peptides used in this work correspond in their structure to the NH2-terminal amino acid sequence 1-34, as elucidated by Brewer and collaborators (1972. Proc. Natl. Acad. Sci. U. S. A.69: 3583-3588). Inhibition studies were also carried out with bPTH-(1-34) and bPTH-(1-84). Anti-hPTH-(TCA) exhibited specificities directed to determinants in the COOH-terminal and NH2-terminal part of hPTH-(1-84) and exhibited cross-reactivity with bPTH-(1-84). Anti-hPTH-(1-34), on the other hand, showed immunological specificities mainly directed to antigenic determinants located in the COOH-terminal half of hPTH-(1-34). In addition, some reactivity with the NH2-terminal hPTH-(1-12) and with the extractive full-length peptides of human and bovine origin was observed. Antibodies to hPTH-(1-12) cross-reacted with hPTH-(1-34) and -(1-84)G-100.

Authors

Jan A. Fischer, Ulrich Binswanger, Felix M. Dietrich

Somatostatin-Induced Changes in Insulin and Glucagon Secretion in Normal and Diabetic Dogs

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In conscious dogs intravenously infused somatostatin (3.3 μg per min for 1 h) caused prompt and sustained declines in mean plasma insulin and glucagon, even during alanine infusion and intraduodenal casein hydrolysate feeding; plasma glucose declined, but not significantly. 6.7 μg per min of somatostatin significantly lowered pancreatoduodenal vein glucagon and insulin within 2.5 min and profoundly suppressed their secretion throughout the infusion. Consistent bihormonal suppression occurred at rates as low as 24 ng per kg per min, but was variable at 12 and 2.4 ng per kg per min. When somatostatin-induced (3.3 μg per min) hypoglucagonemia was corrected by exogenous glucagon, hyperglycemia occurred. In dogs with long-standing insulin-requiring alloxan diabetes 3.3 μg per min of somatostatin suppressed glucagon to 55 pg per ml throughout the 30-min infusion and lowered glucose by 36.4±6.1 mg per dl, about 1 mg per dl per min. Glucagon suppression was maintained despite alanine infusion, and glucose, which rose 29 mg per dl during alanine infusion without somatostatin, declined 58 mg per dl in the somatostatin-treated diabetic dogs despite alanine. Continuous infusion of somatostatin for 24 h in five insulin-requiring alloxan-diabetic dogs suppressed glucagon and lowered glucose significantly, usually to below normal.

Authors

Hideo Sakurai, Richard Dobbs, Roger H. Unger

Glucagon Secretion from the Perfused Rat Pancreas STUDIES WITH GLUCOSE AND CATECHOLAMINES

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The isolated in situ perfused rat pancreas was used to study glucose and catecholamine control of glucagon secretion, and to investigate the possible role of endogenous cyclic AMP as a mediator of this secretory process. When perfusate glucose was acutely dropped from 100 to 25 mg/100 ml, glucagon was released in a biphasic pattern with an early spike and a later plateau-like response. 300 mg/100 ml glucose suppressed glucagon secretion to near the detection limit of the radioimmunoassay (15 pg/ml). When perfusate glucose was dropped from 300 to 25 mg/100 ml, a delayed, relatively small peak occurred suggesting persisting alpha cell suppression by prior high glucose exposure. 2-Deoxy d-glucose stimulated glucagon secretion and inhibited insulin secretion.

Authors

Gordon C. Weir, Stephen D. Knowlton, Donald B. Martin

Comparison of the Effects on Renin Release of Beta Adrenergic Antagonists with Differing Properties

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Continuous 6-h infusions of the beta adrenergic blockers d,l-propranolol or oxprenolol significantly reduced plasma renin activity (PRA) and mean blood pressure in the resting rabbit and prevented the stimulatory effects of isoproterenol on renin release and heart rate. These actions were due to blockade of beta receptors, for the inactive isomer, d-propranolol, had no effect. Despite sustained high plasma concentrations of d,l-propranolol (0.2 μg/ml) in the unstimulated animal, PRA did not fall below 36% of control values, suggesting that basal renin secretion is maintained partly by factors other than beta adrenergic mechanisms.

Authors

Michael A. Weber, Gordon S. Stokes, Judith M. Gain

Coronary Reperfusion in Primates SERIAL ELECTROCARDIOGRAPHIC AND HISTOLOGIC ASSESSMENT

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After acute coronary occlusion in primates, the time period during which reperfusion results in significant salvage of reversibly injured myocardium was investigated. In 23 monkeys, the left anterior descending coronary artery was occluded from 1 to 6 h; and in 5 others, occlusion was maintained for the 1-wk study. Unipolar epicardial electrocardiograms were monitored from mapping points on the anterior and lateral left venticle. S-T segment elevation (S-T↑) and R + S wave amplitude (RS) were measured before occlusion and at regular intervals during occlusion and reperfusion. Summated S-T↑ (ΣS-T↑) and summated RS (ΣRS), computed for mapping points demonstrating greater than 2 mV S-T↑, were used as serial measures of electrical injury. ΣS-T↑ peaked within 2-h postocclusion and then gradually declined throughout the period of occlusion suggesting the progress of infarction within the area of injury. After reperfusion ΣS-T↑ rapidly declined to near cnotrol values indicating the extent of reversible injury. During the period of occlusion, the magnitude of voltage loss in ΣS-T↑ as a percent of maximum ΣS-T↑ was proportional to the duration of occlusion, though the rate of loss decreased with increasing time of occlusion. Reperfusion after 6 h of occlusion resulted in reversal of only a small remaining component of the maximum current of injury. The voltage decrease in ΣRS (from control values) was proportional to the duration of occlusion, though the decrease was accelerated during the first 2-h postocclusion. Whereas reperfusion interrupted the decline in ΣRS, a consistent increase in ΣRS postreperfusion was observed only after occlusion of 1 h. With respect to reperfusion groups, significance in ΣS-T↑ voltage loss as a percent of maximum ΣS-T↑ was demonstrated between 2-h and 4-h, 4- and 6-h, and 6-h and chronically ligated animals. Significance in ΣRS voltage loss as a percent of control ΣRS was demonstrated between 2- and 4-h, and 4- and 6-h reperfusion groups. Hearts were excised at 7 days for histological assessment of infarct size. Planimetric determination of left ventricular areas and areas of necrosis using slides made from 10 serial cross sections were used in estimating the percent of left ventricle infarcted. A significant reduction in infarct size was demonstrated between reperfused animals at 2 h and the 4- and 6-h reperfusion groups. A trend was noted suggesting increasing infarct size up to 6 h after experimental occlusion.

Authors

Gregory T. Smith, John R. Soeter, Harold H. Haston, J. Judson McNamara

Dependence of Saline-Induced Natriuresis upon Exposure of the Kidney to the Physical Effects of Extracellular Fluid Volume Expansion

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In many previous studies, the natriuresis induced by saline loading has been demonstrated to persist even though glomerular filtration rate (GFR) has been decreased to below pre-expansion levels by a reduction in renal artery pressure. In such studies, however, the kidney has been exposed to the effects of volume expansion for varying periods of time before renal artery pressure was controlled. The present experiments were designed to evaluate whether this period of exposure induces critical changes in intrarenal factors that are responsible for the natriuresis.

Authors

John P. Fitzgibbons, F. John Gennari, Howard B. Garfinkel, Stanley Cortell

The Stimulatory Effect of Platelets and Platelet Membranes on the Procoagulant Activity of Leukocytes

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Abstract

Leukocytes can generate procoagulant (tissue factor) activity when incubated with endotoxin. These studies were undertaken to determine whether platelets could influence the procoagulant activity generated by leukocytes. Intact or disrupted platelets (rabbit or human) enhanced the clot-promoting properties of rabbit leukocytes.

Authors

Julian Niemetz, Aaron J. Marcus

Immunochemical Studies of Plasma Kallikrein

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A monospecific antibody against human plasma kallikrein has been prepared in rabbits with kallikrein further purified to remove gamma globulins. The antisera produced contained antikallikrein and also anti-IgG, in spite of only 8% contamination of kallikrein preparation with IgG. The latter antibody was removed by adsorption of antisera with either Fletcher factor-deficient plasma or with purified IgG. Both kallikrein and prekallikrein (in plasma) cross-react with the antibody with no apparent difference between the precipitation arcs developed during immunoelectrophoresis and no significant difference in reactivity when quantified by radial immunodiffusion.

Authors

Andranik Bagdasarian, Biswajit Lahiri, Richard C. Talamo, Pat Wong, Robert W. Colman

Mechanisms Mediating Bradycardia during Coronary Arteriography

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Cardiac slowing occurring during diagnostic coronary arteriography was studied in 78 patients. Comparable degrees of slowing occurred with injections into the right and into the left coronary arteries into the contralateral artery, and with injections into the coronary artery giving rise to the sinus node artery and into the contralateral artery. Rapid intracoronary injections of isosmotic dextrose solution produced significantly less slowing than comparable injections of contrast medium. Slow injections of contrast medium produced cardiac slowing comparable to that caused by rapid injections of contrast medium. However, the cardiac slowing was significantly greater than that produced by rapid injections of dextrose solution. Inhalation of 100% oxygen did not alter the heart rate response to injections of contrast medium. Atropine produced dose-related attenuation of cardiac slowing. Bradycardia persisting after cholinergic blockade was significantly greater after injections into the coronary artery supplying the sinus node than it was after injections into the contralateral artery. Coronary arteriography produced transient, occasionally profound, arterial hypotension in 38 of 41 patients in whom arterial pressures were recorded. Arterial pressure did not change in three patients.

Authors

Dwain L. Eckberg, Carl W. White, Michael Kioschos, Francois M. Abboud

Myocardial Blood Flow Distribution during Ischemia-Induced Coronary Vasodilation in the Unanesthetized Dog

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This study was designed to determine whether coronary vasodilation distal to a flow-limiting coronary artery stenosis could result in redistribution of myocardial blood flow to produce subendocardial underperfusion. Studies were performed in 10 awake dogs chronically prepared with electromagnetic flow-meters and hydraulic occluders on the left circumflex coronary artery. Regional myocardial blood flow was measured using radionuclide-labeled microspheres, 7-10 μm in diameter, injected into the left atrium. A 5-s coronary artery occlusion was followed by reactive hyperemia with excess inflow of arterial blood effecting 375±20% repayment of the blood flow debt incurred during occlusion. When, after a 5-s occlusion, the occluder was only partially released to hold arterial inflow to the preocclusion level for 20 s before complete release, the delayed reactive hyperemia was augmented (mean blood flow repayment = 610±45%, P < 0.01). This augmentation of the reactive hyperemia suggested that ischemia was continuing during the interval of coronary vasodilation when coronary inflow was at the preocclusion level. Measurements of regional myocardial blood flow demonstrated that endocardial flow slightly exceeded epicardial flow during control conditions. When arterial inflow was limited to the preocclusion rate during vasodilation after a 5-s total coronary artery occlusion, however, flow to the subepicardial myocardium was increased at the expense of underperfusion of the subendocardial myocardium. Thus, in the presence of a flow-limiting proximal coronary artery stenosis, ischemia-induced coronary vasodilation resulted in redistribution of myocardial blood flow with production of subendocardial ischemia in the presence of a net volume of arterial inflow which, if properly distributed, would have been adequate to prevent myocardial ischemia.

Authors

Robert J. Bache, Frederick R. Cobb, Joseph C. Greenfield Jr.

Mechanism of Effect of Thoracic Inferior Vena Cava Constriction on Renal Water Excretion

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Abstract

Persistent secretion of vasopressin and/ or diminished distal fluid delivery have been proposed to explain the impaired water excretion associated with low-output cardiac failure. In the present investigation cardiac output (CO) was diminished in anesthetized dogs undergoing a water diuresis by constriction of the thoracic inferior vena cava (TIVC). In intact animals (group I) acute TIVC constriction decreased CO from 3.5 to 2.2 liters/min (P < 0.005) as urinary osmolality (Uosm) increased from 103 to 543 mosmols/ kg (P < 0.001) and free water clearance (CH2o) decreased from 2.1 to -0.6 ml/min (P < 0.001). This antidiuretic effect was disassociated from changes in renal arterial and venous pressures, glomerular filtration rate, solute excretion, and renal innervation. To examine the role of vasopressin in this antidiuresis, studies (group II) were performed in acutely hypophysectomized, steroid-replaced animals. In these animals TIVC constriction decreased CO to a similar degree from 3.4 to 2.1 liters/min (P < 0.001). However, the effects on Uosm (87-104 mosmols/kg) and CH2o (2.1-1.6 ml/min) were significantly less than in intact dogs. In another group of hypophysectomized animals, (group III) renal arterial and venous pressures were not controlled, and the effect of TIVC constriction on Uosm was not significant (65-79 mosmols/kg) although CH2o decreased from 3.3 to 1.9 ml/min (P < 0.001). In both the group II and III studies, there were linear correlations between the changes in CH2o and the urine flow. Studies were also performed in baroreceptor-denervated animals with intact hypothalamo-neurohypophyseal tracts, and acute TIVC constriction altered neither Uosm nor CH2o when renal arterial pressure was controlled. These results therefore indicate that the effect of TIVC constriction on Uosm is primarily vasopressin mediated while the effect on CH2o is mediated both by vasopressin release and diminished distal fluid delivery. A decrease in renal arterial pressure, or some consequence thereof, seems to be an important determinant of the latter effect.

Authors

Robert J. Anderson, Pravit Cadnapaphornchai, Judith A. Harbottle, Keith M. McDonald, Robert W. Schrier

The Role of Collagen Quaternary Structure in the Platelet:Collagen Interaction

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Abstract

We have investigated whether collagen queternary structure is required for the platelet: collagen interaction. Quaternary structure refers to the assembly of collagen monomers (tropocollagen) into polymers (native-type fibrils). Purified monomeric collagen was prepared from acetic acid extracts of fetal calfskin. Polymeric collagen was prepared by dispersion of bovine Achilles tendon collagen and by incubation of monomeric collagen at 37°C and pH 7.4. The state of polymerization was confirmed by electron microscopy. Release of platelet serotonin in the absence of platelet aggregation was used to determine the effectiveness of the platelet: collagen interaction. All forms of collagen produced serotonin release only after a lag period, but polymeric collagen gave a shorter lag period than did monomeric collagen. Monomeric collagen was also quanidinated selectively to convert collagen lysine groups to homoarginine, while leaving the arrangement of polar groups intact. Guanidination of monomeric collagen increased the rate of polymerization and reduced the lag time in serotonin release. Glucosamine (17 mM) retarded polymerization and inhibited the release of platelet serotonin by monomeric collagen but had little effect on release produced by thrombin or polymeric collagen. At the same concentration, glucosamine did not reduce the sensitivity of platelets to stimulation by collagen or block the platelet: collagen interaction. The only effect of glucosamine was on the collagen: collagen interaction. Galactosamine had a similar effect, but glucose, galactose, and N-acetylglycosamine had no effect. We conclude from this data that collagen monomers cannot effectively interact with platelets and that, therefore, collagen quaternary structure has a role in the recognition of collagen by platelets.

Authors

Lawrence F. Brass, Howard B. Bensusan

Characteristics of the Relationship between the Flow Rate of Tubular Fluid and Potassium Transport in the Distal Tubule of the Rat

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Abstract

The flow rate of tubular fluid has been suggested as one of several factors which may influence potassium transport in the distal convoluted tubule of the kidney. In the present micropuncture studies, the relationship between the flow rate of distal tubular fluid and potassium transport was examined in four groups of rats. Three groups of rats (I, II, and IV) were fed normal rat chow before study whereas one group (III) was fed chow containing 10% KCl. Group II received 10-20 μg/kg per h of d-aldosterone throughout the study. Distal tubular potassium transport in groups I, II, and III was examined before and after an increase in the flow rate of distal tubular fluid as induced by the infusion of an isotonic saline-bicarbonate solution equivalent to 10% of body weight. In group IV, distal tubular potassium transport was examined before and after enhancement of the flow rate by the infusion of hypertonic (15%) mannitol.

Authors

Robert T. Kunau Jr., Harold L. Webb, Susan C. Borman

The “No-Reflow” Phenomenon after Temporary Coronary Occlusion in the Dog

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Abstract

The role of microvascular damage in the genesis of the “no-reflow” phenomenon was investigated in the left ventricular myocardium of dogs subjected to temporary occlusions of a major coronary artery for 40 and 90 min. Intravenous carbon black or thioflavin S (a fluorescent vital stain for endothelium) were used to demonstrate the distribution of coronary arterial flow in control and damaged myocardium. These tracers were injected simultaneously with release of the coronary occlusion or after 5 or 20 min of reflow of coronary arterial blood. After 40 min of ischemia plus arterial reperfusion, usually the tracers were evenly distributed throughout the damaged tissue at each time of reperfusion. On the other hand, when reflow was allowed after 90 min of ischemia, portions of the inner half of damaged myocardium were not penetrated by the tracers. Electron microscopic study of this poorly perfused tissue revealed severe capillary damage; endothelial cells with large intraluminal protrusions and decreased pinocytic vesicles were common. Also, occasional intraluminal fibrin thrombi were noted, as well as extravascular fibrin deposits and erythrocytes. Myocardial cells were swollen in both poorly perfused and well-perfused irreversibly injured tissue. Contraction bands and mitochondrial Ca2+ accumulation were prominent features of irreversible injury with reflow at 40 min but were not noted after 90 min of ischemia in areas with poor perfusion. These results suggest that 40 min of ischemia were tolerated by the capillary bed of the dog heart without serious capillary damage or perfusion defects, but that 90 min of ischemic injury was associated with the “no-reflow” phenomenon, i.e., failure to achieve uniform reperfusion. This failure of reflow was associated with extensive capillary damage and myocardial cell swelling. Death of severely ischemic myocardial cells in this model occurs before the onset of capillary damage and the no-reflow phenomenon.

Authors

Robert A. Kloner, Charles E. Ganote, Robert B. Jennings