bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural alterations of blood vessels in hypertensive rats
Authors: Lee Robert M. K. W.
Published: April 2011

Vascular changes in the mesenteric arteries were examined in three animal models for human essential hypertension. These models are: spontaneously hypertensive rats, which develop hypertension with age; Dahl model of genetic, salt-dependent hypertensive rats; and deoxycorticosterone–salt hypertensive rats. Morphometric measurements of the arterial wall components (e.g., endothelium, media) were carried out in the elastic arteries, muscular arteries, and arteriolar vessels from the mesenteric bed. The observed changes were correlated with the stages of hypertension development and the effect of antihypertension therapy, including sympathectomy. Specific emphasis was made to determine whether the changes observed were primary in nature, and related to the causes of hypertension, or they were secondary adaptive changes. A comparison of the three models showed that common changes in the intima, media, and adventitia were present in the three models. Alterations in the endothelium (e.g., enlargement of subendothelial space, necrotic changes), adventitia (collagen increase), and hypertrophy of the smooth muscle cells are secondary adaptive changes, because these changes occur subsequent to the development of hypertension, and antihypertensive therapy also prevent these changes from taking place. In contrast, hyperplasia of the smooth muscle cells is a primary change, because it occurs prior to the onset of hypertension. Functionally, alteration in the media is probably the most important change, because it can cause hyperreactivity of the arteries in response to stimulation. Damage to the endothelial cells may play a role in the maintenance of hypertension during the later phase. Alteration in adventitia is a passive change, which does not appear to have a major role in hypertension. Sympathectomy studies suggest that primary smooth muscle change may be mediated by the sympathetic nervous system.
Renal reflexes in the regulation of blood pressure and sodium excretion
Authors: Stella A. , Golin R. , Genovesi S. , Zanchetti A.
Published: April 2011

The rich innervation of the kidney is distributed to all structures of renal parenchyma thus providing important anatomical support to the functional evidence that the renal nerves can control kidney functions and send signals on the kidney environment to the central nervous system. Efferent renal nerve fibres are known to influence renal haemodynamics by modifying arteriolar vascular tone, renin release by a direct action on juxtaglomerular cells, and the excretion of sodium and water by changing tubular reabsorption of sodium and water at the different tubular levels. Mechano- and chemo-receptors have been shown in the kidney. Afferent fibres connected with renal receptors convey signals to the central nervous system both at spinal and supraspinal levels. The central areas receiving inputs from the kidney are those involved in the control of cardiovascular homeostasis and fluid balance. Activation of renal receptors by the electrical stimulation of renal afferent fibres were found to elicit both excitatory and inhibitory sympathetic responses. Although the existence of excitatory renorenal reflexes has been suggested, electrophysiological and functional data demonstrate that neural renorenal reflexes exert a tonic inhibitory influence on the tubular sodium and water reabsorption and on the secretion of renin from the juxtaglomerular cells.
Role of area postrema pressor mechanisms in the regulation of arterial pressure
Authors: Ferrario Carlos M. , Barnes Karen L. , Diz Debra I. , Block Christine H. , Averill David B.
Published: April 2011

This article discusses the data which established that angiotensin II modulates the tonic and reflex control of cardiovascular function by actions on the nuclear regions of the dorsal medulla oblongata. Although physiological evidence for the modulatory actions of angiotensin II in structures of the lower brainstem has been gathered over the past 16 years, only the recent application of new neurobiological techniques has allowed a more definitive understanding of its role. The identification of high affinity angiotensin II binding sites within the parenchyma of the area postrema with the technique of in vitro receptor autoradiography has provided anatomical validity for a role of angiotensin II in the central nervous system. The added discovery of angiotensin II binding sites in subnuclear components of the nucleus tractus solitarii and the motor nucleus of the tenth cranial nerve provides additional information on the various mechanisms through which angiotensin II may affect the intrinsic activity of the brainstem neuronal circuits involved in the integration of baroreceptor and sensory visceromotor function.
Abnormal regulation of the sympathoadrenal system in deoxycorticosterone acetate – salt hypertensive rats
Authors: Champlain J. de , Bouvier M. , Drolet G.
Published: April 2011

With the use of circulating norepinephrine (NE) and epinephrine (E) levels, the sympathoadrenal activity as well as its local modulation by adrenoceptors were studied in normotensive (NT) and DOCA–salt hypertensive (HT) rats. In anesthetized hypertensive rats, plasma NE levels were higher, whereas in conscious animals both NE and E levels were found to be increased, suggesting an increased basal sympathoadrenal tone in these animals. The finding of a close correlation between blood pressure levels and NE levels suggests that the elevation of blood pressure may be linked to sympathetic system activity in this experimental model of hypertension. The reactivity of the sympathoadrenal system was also found to be increased in DOCA HT rats. Following a bilateral carotid occlusion of 1 min, which specifically activates the adrenal medulla, the elevation of E levels was found to be potentiated in intact or vagotomized HT rats. Moreover, in response to prolonged or acute hypotension in anesthetized and conscious animals, the elevation in plasma NE and E levels was found to be markedly potentiated in DOCA HT rats. The local modulating adrenoceptor-mediated mechanisms of the sympathoadrenal system appeared to be altered in this model of hypertension. Although it was possible to demonstrate that the E response to carotid occlusion can be greatly potentiated by administration of an α2-antagonist (yohimbine) and completely abolished by an α2-agonist (clonidine) in NT rats, the E response was found to be unaffected by the same treatments in HT rats, suggesting a reduced sensitivity in the α2-mediated inhibitory modulation of the adrenal medulla. Moreover, the acute treatment with a β-blocker (sotalol) lowered circulating NE levels and blood pressure only in HT rats, suggesting the possibility of a more sensitive β-receptor-mediated presynaptic facilitatory mechanism on sympathetic fibers of these animals. Finally, it was observed that the functional balance which exists between the activities of sympathetic fibers and the adrenal medulla in normotensive animals appears to be impaired in DOCA HT rats. In conclusion, the present studies suggest that the increased sympathoadrenal tone and reactivity may be due, in part, to a variety of dysfunctions in local adrenoceptor modulatory mechanisms of the sympathoadrenal system in DOCA hypertensive rats.
Central and peripheral mechanisms of arterial pressure lability following baroreceptor denervation
Authors: Alper R. H. , Jacob H. J. , Brody M. J.
Published: April 2011

Deafferentation of sinoaortic baroreceptors produces a marked increase in the lability of arterial pressure that is sustained chronically. Studies reviewed in this paper were designed to determine the mechanisms responsible for generating arterial pressure lability. Pharmacological interruption of the humoral vasopressin and angiotensin systems failed to alter arterial pressure lability. In contrast, blockade of sympathetic nervous system transmission at both ganglionic and alpha-adrenergic receptor levels significantly attenuated lability. A similar effect was observed with the peripheral neurotoxin, 6-hydroxydopamine. After blockade of sympathetic transmission, a further reduction in lability was produced by blocking the renin–angiotensin or vasopressin systems. The dissociation of the level of arterial pressure from lability was achieved with parachloroamphetamine which raised arterial pressure but reduced lability. A substantial peripheral contribution to lability was obtained in experiments in which the alpha-adrenergic agonist, phenylephrine, produced a marked increase in lability in both normal and baroreceptor-denervated animals in which humoral and neural transmission were blocked. These data demonstrate that following baroreceptor deafferentation, arterial pressure lability is produced primarily by the sympathetic nervous system and secondarily by circulating humoral factors that appear to act on vascular smooth muscle to induce fluctuations in the level of arterial pressure.
Is there a role for renal α2-adrenoceptors in the pathogenesis of hypertension?
Authors: Baines A. D.
Published: April 2011

Current information suggests that α2-adrenoceptors do not directly influence vascular resistance or Na reabsorption in the rat kidney. To reexamine the effects of α2-agonists we used isolated rat kidneys perfused at 37.5 °C with precise measurement of renal artery pressure and flow. The recirculating perfusate contained pyruvate as the sole metabolic substrate which enabled us to use gluconeogenesis as an index of proximal tubular α1-responses. Clonidine and guanfacine in 100 nM concentrations decreased phosphate excretion without altering Na, Cl, or K reabsorption or gluconeogenesis; 500 nM concentrations increased vascular resistance and decreased glomerular filtration rate and Na, Cl, and K excretion with no significant effect on gluconeogenesis. Prior thyroparathyroidectomy prevented the antiphosphaturic but not the antinatriuretic or vascular responses. Clonidine, an α2-agonist with some α1-activity, was a more potent vasoconstrictor than methoxamine or guanfacine. In the presence of prazosin (1 μM), norepinephrine (60 nM) stimulated phosphate reabsorption; norepinephrine alone did not stimulate phosphate reabsorption which indicates α1-antagonism of this α2-response to NE. These results and a literature review suggest that increased renal α2-adrenoceptors could raise renal vascular resistance, reduce renin secretion, and antagonize parathyroid hormone effects on Pi Ca, HCO3, and Na reabsorption to produce a low renin type of hypertension with increased proximal Na reabsorption and abnormal Ca and Pi excretion.
Heterogeneity of vascular α-adrenoceptors in man
Authors: Brummelen P. van , Jie K. , Timmermans P. B. M. W. M. , Zwieten P. A. van
Published: April 2011

The knowledge on α-adrenoceptors has expanded enormously in the last decade, mostly as a result of in vitro and in vivo animal experiments. In the face of considerable species differences we have tested several of the newly developed concepts on α-adrenoceptors in the circulation of the human forearm. In this model we were able to show the presence of postsynaptic α1-and α2-adrenoceptors, both contributing to resting vascular tone. Although adrenaline and noradrenaline were shown to have affinity for each α-adrenoceptor subtype, noradrenaline seems to be the natural agonist for both receptors. Evidence is presented for an intrasynaptic location of the α1-adrenoceptor and an extrasynaptic location of the α2-adrenoceptor and also for a functional presynaptic α2-adrenoceptor in the human forearm circulation. Selective hyperresponsiveness to α1- or α2-adrenoceptor stimulation in hypertensive patients could not be established. Calcium entry blockers were shown to attenuate the vasoconstriction induced by selective α2-adrenoceptor stimulation but not by selective α1-adrenoceptor stimulation. These data support the physiological and pharmacological relevance of the new concepts on α-adrenoceptors for the situation in man.
β-Receptor-mediated increase in venous return in humans
Authors: Leenen Frans H. H. , Reeves Richard A.
Published: April 2011

To assess the involvement of β1 and β2-receptors in the regulation of venous return in humans, changes in left ventricular end-diastolic (LVED) dimension were determined during β-receptor stimulation either by exogenous catecholamines or by increased endogenous sympathetic activity after hydralazine, after placebo and during nonselective versus β1 -selective blockade. Taking changes in heart rate and LV emptying into account, the three β-agonists (isoproterenol, terbutaline, and epinephrine) as well as hydralazine increased venous return as inferred from LVED dimension. After hydralazine, nonselective and β1-selective blockade were equally effective in blunting the increases in venous return, in heart rate, and in positive inotropic response. β1-Selective blockade did not affect the increase in heart rate caused by epinephrine and partially inhibited the positive inotropic effect and the increase in venous return. Nonselective blockade not only blocked the increase in venous return owing to epinephrine but actually led to a decrease, as evidenced by a decrease in LVED dimension despite the marked bradycardia and high afterload with this combination. The present findings in healthy humans indicate that stimulation of both β1- and β2-receptors increases venous return, heart rate, and myocardial contractility. β1-Receptors appeal to predominate in the response to neuronal sympathetic activity.
β-Adrenergic receptor alterations in hypertension—physiological and molecular correlates
Authors: Feldman Ross D.
Published: April 2011

In hypertensive animals, there is physiological and biochemical evidence that β-adrenergic responsiveness is diminished. In contrast, in man the physiological evidence of reduced β-adrenergic responsiveness is not completely convincing and few biochemical studies have been reported. The lymphocyte has been widely used as a model for the human β-adrenergic receptor complex. In studies comparing young normotensive and mild hypertensive subjects we demonstrated a reduction in β-adrenergic mediated adenylate cyclase activity in lymphocytes from hypertensive subjects. A parallel reduction in β-adrenergic receptor affinity for agonists was also seen. These changes are consistent with a functional uncoupling of the receptor from the adenylate cyclase complex. To determine the role of dietary sodium intake on β-adrenergic receptor properties in hypertension we studied lymphocytes from hypertensive and normotensive subjects fed either a low (10 mequiv.) or high (400 mequiv.) NaCl diet. We demonstrated that a low NaCl diet corrected the defect in lymphocyte β-adrenergic responsiveness in hypertension. These studies emphasize the utility of biochemical approaches to the study of alterations in β-adrenergic responsiveness in human hypertension and suggest an important role of dietary sodium in the reduction in β-adrenergic responsiveness in the hypertensive state.
Renal responses to saline and atrial natriuretic factor infusions in Dahl rats
Authors: Sonnenberg H. , Honrath U. , Chong C. K. , Milojevic S. , Veress A. T.
Published: April 2011

Weanling Dahl rats of the salt-sensitive and salt-resistant strains were kept either on a low salt diet for 10–15 weeks, or the diet was supplemented with 7% NaCl for the last 30 days. Animals were anesthetized and the renal responses to acute saline infusion and infusion of synthetic atrial natriuretic factor (ANF) were studied on both dietary regimens. Arterial blood pressures of sensitive and resistant groups were not different on the low salt intake. As expected, addition of dietary salt increased pressure markedly in the sensitive animals. Resistant rats also had smaller, but statistically significant, increases in pressure. On the low salt diet, salt-sensitive rats showed a larger renal response to saline infusion, whereas on the high salt diet there were no significant differences between strains. The responses to ANF infusion were not different between groups on either diet, although NaCl feeding potentiated the natriuresis and diuresis. Under the conditions of the present experiments there was, therefore, no indication that Dahl salt-sensitive rats had a relative inability to respond either to an acute saline load or to exogenous ANF administration.
Role of the autonomic nervous system, renin–angiotensin system, and arginine vasopressin during the onset and maintenance of ACTH hypertension in sheep
Authors: Spence Campbell D. , Coghlan John P. , Denton Derek A. , Mills Eric H. , Nelson Mark A. , Whitworth Judith A. , Scoggins Bruce A.
Published: April 2011

The roles of the autonomic nervous system, renin–angiotensin system, and arginine vasopressin (AVP) during the onset of ACTH-induced hypertension were investigated in conscious sheep. Autonomic ganglion blockade or combined adrenergic and cholinergic receptor blockade demonstrated that an intact sympathetic nervous system was not essential for the development or maintenance of the hypertension. Autonomic blockade augmented the pressor response to ACTH, indicating that baroreceptor-mediated reflexes normally operate to suppress the degree of hypertension produced by ACTH. Evidence was obtained suggesting that the renin–angiotensin system and AVP may partially contribute to the maintenance of ACTH hypertension in the presence of autonomic blockade. However, the precise mechanism by which ACTH raises arterial pressure remains to be elucidated.
Evaluation of the dermal carcinogenic potential of liquids produced from the Cold Lake heavy oil deposits of Northeast Alberta
Authors: McKee R. H. , Lewis S. C.
Published: April 2011

This study assessed the dermal carcinogenic potential of raw bitumen derived from the Cold Lake Oil Sands deposit (located in Northeast Alberta, Canada) and two liquids which were under evaluation as part of a process to refine the crude bitumen at the Cold Lake site. The crude bitumen was dermally carcinogenic, inducing tumors in 26% of the treated animals with a median latency of 106 weeks. This response was significantly greater than the tumor yield previously reported for a raw bitumen derived from Athabasca tar sands by the Syncrude process, but was not substantially different from the carcinogenic potential of two crude petroleum oils. The GO-FINING product, a high boiling (259–519 °C), catalytically cracked gas oil was a relatively potent dermal carcinogen, inducing tumors in 86% of the treated animals with a median latency of 46 weeks. This result is consistent with the fact that the GO-FINING product contained appreciable levels of high boiling aromatic compounds. The HYCRACKING product, a high boiling (102–498 °C), severely hydroprocessed liquid was noncarcinogenic. This result was also consistent with the compositional data; the high boiling components were predominantly saturated species. Thus the carcinogenic properties of the liquid products prepared by these two processes were as predicted from the compositional information.
T4-induced cardiac hypertrophy and the perfused and total microvasculature of the heart
Authors: Weiss Harvey R. , Grover Gary J.
Published: April 2011

The purpose of the present investigation was to determine the effects of thyroxine (T4), which induces myocardial hypertrophy, on the number per square millimetre and volume per cubic millimetre of both the total and perfused portions of the arteriolar and capillary beds of the heart. Studies were conducted in the subendocardial and subepicardial regions of the left ventricle of anesthetized open-chest rabbits. Fluorescein isothiocyanate–dextran (i.v.) or radioactive microspheres (intra-atrial) were injected to label the perfused microvessels or to determine coronary flow in three groups of rabbits: controls, and rabbits given 0.5 mg/kg T4 for 3 days and for 16 days. Fluorescent photography was used to identify the perfused microvessels. An alkaline phosphatase stain was employed to locate the total microvascular bed. There were 2369 ± 638 (SD) capillaries/mm2 and 4 ± 3 arterioles/mm2 in control hearts. These decreased significantly to 1380 ± 199/mm2 and 1 ± 1/mm2, respectively, after 16 days of T4. In controls, 60 ± 5% of the capillaries and 59 ± 21% of the arterioles were perfused. This increased significantly to 90 ± 5 and 86 ± 18%, respectively, by 16 days of T4 treatment. Similar changes, although smaller, were observed after 3 days of T4. Coronary blood flow increased to 1.7 times control after 3 days and 2.9 times after 16 days of T4. No significant subepicardial versus subendocardial differences were observed in any condition or measurement. Thus, the physiological response to the increased work and increase in anatomic minimum diffusion distance is to increase flow and the proportion of the capillary bed perfused to at least maintain physiological diffusion distances.
Effects on animal growth and lipid composition of heart, liver, and adipose tissue in male rats fed different levels and types of fats
Authors: Farnworth E. R. , Kramer J. K. G.
Published: April 2011

Weanling male rats were fed diets containing 5, 10, or 20% (by weight) fat. Diets were made isocaloric by decreasing the amount of starch as the diet fat level increased. At each fat level, three oil mixtures were fed which contained 13, 32, or 79% saturated fatty acids. The polyunsaturate level was 11% of total fatty acids in all mixtures. After 12 weeks, animals eating the high fat diets had gained significantly less weight and had eaten less feed. These animals also had significantly lighter livers and more liver lipids. The level and type of fat in the diet affected the amount (mg/g) of several phospholipids in the liver and heart. The fatty acid patterns (total saturates, n − 3, n − 6 fatty acids) of the major phospholipids were generally constant, the monounsaturated fatty acids being the major exception.
Effects of LY83583, nordihydroguaiaretic acid, and quinacrine on cyclic GMP elevation and inhibition of tension by muscarinic agonists in rabbit aorta and left atrium
Authors: Diamond Jack
Published: April 2011

Elevation of cyclic GMP by muscarinic agonists has been suggested to be responsible for the negative inotropic effects of these agents in cardiac muscle, and for the endothelium-dependent relaxation caused by these agents in vascular smooth muscle. These relationships were studied by monitoring the effects of muscarinic agonists on tension and cyclic GMP levels in rabbit left atrial strips and aortic rings, in the presence and absence of the cyclic GMP lowering agent, LY83583. LY83583 completely blocked both the cyclic GMP increase and the relaxation caused by acetylcholine in rabbit aortic rings with intact endothelial cells. Acetylcholine-induced cyclic GMP elevation and relaxation in these preparations were also blocked by quinacrine and nordihydroguaiaretic acid (NDGA), but neither response was blocked by the 5-lipoxygenase inhibitor U-60257. In the experiments with rabbit left atrium, LY83583 blocked the acetylcholine-induced cyclic GMP elevation but did not block the negative inotropic effects of the drug. Quinacrine, NDGA, and a guanylate cyclase inhibitor, methylene blue, failed to block either the cyclic GMP increase or the decrease in contractile force caused by carbachol in atrial strips. These results support the suggestion that an increase in cyclic GMP may be responsible for the endothelium-dependent relaxation of rabbit aorta by muscarinic agonists, but not for the direct negative inotropic effects of these drugs in rabbit atrium. Muscarinic agents appear to increase cyclic GMP levels in rabbit atrium and aorta by different mechanisms. Although both are blocked by LY83583, they differ not only in their requirements for endothelial cells, but also in their susceptibility to other blocking agents.
Refractory heart failure and age-related differences in adriamycin-induced myocardial changes in rats
Authors: Weinberg Leah E. , Singal Pawan K.
Published: April 2011

Clinical use of adriamycin, an effective chemofherapeutic agent, has been restricted because of a demonstrated dose-limiting cardiotoxicity. To study age-related differences in adriamycin-induced cardiotoxicity, clinical status, developed force, ultra-structure, and lipid peroxide changes in the myocardium were investigated in two age groups of rats termed younger (Cy) and older (Co). Experimental animals (Cy + A; Co + A) received a cumulative dose of 15 mg/kg of adriamycin over 2 weeks. Animals in the Co + A group showed hydroperitoneum, higher mortality, and a greater decline in weight and feed consumption. Decline in base-line developed force in papillary muscles from Cy + A and Co + A group was not significant, but responsiveness to different interventions was attenuated. Papillary muscles from the Co + A group showed a significantly lesser increase over its control (Co) group in peak developed force in response to higher Ca2+. The decline in the peak developed force due to low Ca2+ and frequency increase was also significantly less in the Co + A group. Qualitatively similar but quantitatively less or even statistically insignificant changes were seen in the younger treated (Cy + A) group compared with its controls. A greater cell damage indicated by the loss of myofibrils, swelling of the mitochondria as well as the tubular system and accumulation of lipofuscin granules was seen in the Co + A group. While there was no significant change in the malondialdehyde content in the Cy + A group compared with the age-matched controls, a 100% increase in myocardial malondialdehyde content was seen in the Co + A group. These data show that chronic adriamycin administration causes greater myocardial cell damage and heart failure in the older group indicating that age is one of the risk factors in adriamycin cardiotoxicity. Irrespective of the age, adriamycin treatment reduced responsiveness of the papillary muscles to inotropic interventions and these observations may explain the refractoriness of adriamycin-affected hearts to cardiotonic drugs.
Calcium channels in isolated cells and strips of longitudinal muscle of rat myometrium
Authors: Kyozuka M. , Crankshaw J. , Daniel E. E.
Published: April 2011

The properties of Ca2+ channels in strips and single muscle cells of longitudinal muscle of estrogen-dominated rat myometrium were studied under the effects of elevation of K+ concentration, the partial channel agonist Bay K 8644, and nitrendipine. In isolated strips in 0.5 mM Ca2+, Bay K 8644 (pD2 = 7.8–8.0) lowered the threshold for and enhanced the contractions in response to an elevation of K+ concentration, including the maximum response to K+ elevation alone. Bay K 8644 alone in concentrations up through 10−6 M did not initiate contractions in 0.5 mM Ca2+ solutions. At higher concentrations (10−5 M), Bay K 8644 behaved as an antagonist to contractions induced by elevation of K+. In isolated cells 10−7 M Bay K 8644 enhanced the shortenings to elevated K+ and lowered the threshold K+ concentration required. Also no significant contraction occurred with 10−7 M Bay K 8644 at normal K+ concentration. In contrast with its effect in isolated strips, no significant increase in maximum shortening (to 60 mM K+) was observed, possibly because cells without a mechanical load were maximally shortened by K+ alone. From these studies, we conclude that Ca2+ channels of isolated strips and cells of rat myometrium behave similarly and have similar properties to those of other smooth muscles in their interactions with elevation of K+, nitrendipine, and Bay K 8644.
Separan AP-273 and renal function: a novel natriuretic substance
Authors: Smyth Donald D. , Blandford Dorothea E. , Jones Donald R. , Polimeni Philip I.
Published: April 2011

Recent studies have demonstrated that an anionic polyacrylamide (Separan, Union Carbide Corp.) decreased the formation of atherosclerotic lesions in the rabbit (Separan AP-30) and increased cardiac output (Separan AP-273) in the rat. Since the effect of these compounds on renal function was unknown, we investigated the dose–response relationship between Separan AP-273 and the renal excretion of electrolytes and water. In the anesthetized rat, intravenous injections of Separan at 0.01, 0.03, 0,10, and 0.30 mg/kg produced a dose-related increase in urine volume, sodium excretion, and osmolar clearance. Potassium excretion was increased less than twofold only at the maximal dose tested. At this high dose, the effect on sodium and water excretion was greater (five- and seven-fold, respectively). Creatinine clearance was not altered by these interventions. As well, the maximal dose studied was previously shown to have no effect on blood flow. These results indicate that Separan AP-273 is a potent diuretic and natriuretic substance. Taken together with similar studies using the poly(ethylene oxide) Polyox WSR N-60K, these results suggest that drag-reducing polymers may represent a novel group of compounds with diuretic and natriuretic effects.
The elucidation of the structure of atrial natriuretic factor, a new peptide hormone
Authors: Flynn T. Geoffrey
Published: April 2011

The benchmark experiments of Adolfo de Bold and Harald Sonnenberg revealed that heart atria contained a substance or substances (atrial natriuretic factor) which when injected into rats caused a profound diuresis, natriuresis, and fall in blood pressure. Acid extraction and purification of atrial natriuretic factor resulted initially in the purification of a low molecular weight peptide containing a disulfide bond. This peptide was named cardionatrin I. Amino acid sequencing of less than 1 nmol of cardionatrin I revealed it to be a 28-residue peptide with the following structure: [Formula: see text]The position of the disulfide bond was verified by a radioactive method. From the sequence of complementary DNA for atrial natriuretic factor, the 28-residue peptide was shown to be the C-terminal portion of a larger protein called pro-atrial natriuretic factor. The discovery and characterization of atrial natriuretic factor substantiated the idea that the heart atria serve in an endocrine capacity.
The physiology of atrial natriuretic factor
Authors: Sonnenberg H.
Published: April 2011

Following the discovery of the natriuretic effect of atrial extract, our laboratory attempted to dissect the possible physiological role of atrial natriuretic factor. Initial micropuncture experiments demonstrated that the reduction of tubular sodium reabsorption was localized in the medullary collecting duct, a nephron site in which sodium transport was known to be inhibited after acute hypervolemia. Partial removal of the endogenous source of atrial natriuretic factor was associated with a reduced renal response to hypervolemia, confirming that the factor is causally involved in acute sodium balance. In vitro incubation of atrial tissue was used to investigate mechanisms of release of atrial natriuretic factor. It was found that agonists known to activate the intracellular polyphosphoinositide system in other tissues were effective in releasing natriuretic activity from the atria into the incubation medium. To determine whether atrial natriuretic factor might play a role in hypertension, atrial natriuretic content was measured in spontaneously hypertensive rats and their normotensive controls. Hypertension was associated with increased content. Since the renal response to exogenous factor was not impaired in these animals, we suggested that the increased content might play a compensatory role. Our early studies thus indicated that atrial natriuretic factor was a previously unrecognized hormone involved in cardiovascular regulation.
Functions of polyamine acetylation
Authors: Seiler Nikolaus
Published: April 2011

Acetylation is a means to decrease the net positive charge of the plyamines and thus liberate polyamines from anionic binding sites. The acetyl derivatives can be removed from the cells by transport and catabolism. Intracellular polyamine metabolism can be formulated as a cyclic process, which explains the transformation of one polyamine into another. As a net result, this pathway metabolizes (in an energy-requiring manner) methionine to 5′-deoxy-5′-methylthioadenosine and β-alanine, and thus appears to be futile. It is suggested that the cyclic process is necessary for the precise control of cellular polyamine concentrations, as it allows relatively rapid spermine and spermidine concentration changes, in spite of a slow basal turnover rate. For the regulation of cellular polyamine metabolism, two decarboxylases, L-ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase; the cytosolic acetyl-CoA:spermidine/spermine N1-acetyltransferase; and a polyamine transport system are required. The activity of the nucelar acetyltransferase is assumed to be the rate-limiting enzyme of nuclear polyamine turnover. The complexity and high level of sophistication of polyamine regulation is strong evidence for the important functional significance of the natural polyamines.
Current status of the rat prolactin releasing factor
Authors: Shin S. H. , Papas S. , Obonsawin M. C.
Published: April 2011

The release of prolactin is governed by both inhibiting and releasing factors. Basal plasma concentration of prolactin is controlled mainly through inhibition by a prolactin release-inhibiting factor (PIF), while acute stimulation of prolactin release is believed to be caused by a prolactin-releasing factor (PRF). It is the general consensus that PIF is dopamine. The PRF plays an important role in stimulation of prolactin release, and there are promising putative PRFs.
Increased axonal excitability during exposure to hyperbaric oxygen
Authors: Bitterman N. , Grossman Y.
Published: April 2011

The effect of high oxygen pressure on neural function was studied in the isolated nervous system of the cockroach. Intracellular and extracellular action potentials were recorded from single giant axons during exposure to 7 ATA (atmosphere absolute) (1 ATA = 0.1 MPa) of oxygen. Axonal excitability was measured as changes in stimulus strength–duration relationship. Initially, a transient increase in the rheobase current was observed followed by a significant decline to 75% of air control values. This decrease was accompanied by a parallel increase in the membrane time constant. The results demonstrate that hyperbaric oxygen increases axonal excitability. Such changes are consistent with the epileptogenic properties of high oxygen pressure.
Heart-rate variability in children. Spectral analysis of developmental changes between 5 and 24 years
Authors: Finley John P. , Nugent Sherwin T. , Hellenbrand Wiebke
Published: April 2011

The variation in instantaneous heart rate is most prominent in infants and younger subjects. In a preliminary study of the effects of maturation on heart rate, we compared the heart rate variations of 29 children and young adults in three groups between 5 and 24 years of age. We used spectral analysis to determine the intensity of the variations in each of the two main frequency bands in which variations occur: HF, 0.15–0.45 Hz, and LF, 0.03–0.15 Hz. Three-minute segments of continuous instantaneous heart rate were recorded for each subject in standing and supine positions. The group mean LF and HF amplitudes and the L/H ratio decreased between 5 and 10 years of age in both positions, significantly for LF and L/H in the supine position (p < 0.05). Half of the youngest group of children had adult LF amplitude values by 5 years of age; the others had much higher levels, indicating increased low frequency variation at this age. Thus the high variation in heart rate in very young subjects is most prominent in the LF range. These preliminary results, considered with previous pharmacological studies, suggest that many children have a significant decrease in sympathetic activity between 5 and 10 years of age and possibly a slight decrease in parasympathetic activity. Spectral analysis of heart rate appears a promising technique for investigating the development of neural control of the heart.
Adrenergic–cholinergic interactions in left atria. II. Comparison of the antagonism of inotropic responses to α- and β-adrenoceptor stimulation and BAY K 8644 by carbachol, D-600, and nifedipine
Authors: MacLeod K. M.
Published: April 2011

The muscarinic agonist carbachol has previously been shown to reverse positive inotropic responses of rabbit left atrial strips to equiactive doses of the β-adrenoceptor agonist isoproterenol and to the α-adrenoceptor agonist phenylephrine. Responses to phenylephrine were measured in the presence of the β-blocker timolol. However, carbachol was not able to reverse the increase in tension produced by elevating the extracellular Ca2+ concentration. To gain more information about the nature of the functional interaction of carbachol with α- and β-receptor stimulants in left atria, the interaction of carbachol with these agonists, as well as with elevated Ca2+ and the Ca2+ activator compound BAY K 8644, was compared with that of the Ca2+ antagonists D-600 and nifedipine. The results demonstrate that the Ca2+ antagonists exhibit a selectivity similar to that of carbachol, in that responses to both isoproterenol and phenylephrine plus timolol were blocked by low concentrations of D-600 and nifedipine, which had no effect on positive inotropic responses to elevated Ca2+. Higher concentrations of these antagonists shifted the Ca2+ dose–response curve to the right. In addition, although phenylephrine and BAY K 8644 increased tension to a similar extent, responses to phenylephrine were more sensitive than responses to BAY K 8644 to inhibition by both carbachol and D-600. These similarities between the effects of low concentrations of D-600 and nifedipine and those of carbachol are consistent with the hypothesis that carbachol antagonizes responses to α- and β-receptor stimulation in left atria primarily by blocking increases in Ca2+ influx produced by these agonists. In addition, the observation that responses of left atria to α- and β-adrenoceptor agonists are blocked more readily than responses to elevated Ca2+ and those to BAY K 8644 by both carbachol and the Ca2+ antagonists may be indicative of differences in the way agonists on one hand, and elevated Ca2+ and BAY K 8644 on the other, increase Ca2+ influx into myocardial cells.
Diffusion and electrogenic components of the resting potential in explanted neonatal rat ventricle cells
Authors: LeFloch Martine , Schanne Otto F. , Ruiz-Ceretti Elena
Published: April 2011

Spontaneously beating explanted neonatal rat ventricle cells stop beating and show a steady potential (the mean resting potential, −46.2 mV at 6.0 mM Ko) when exposed to 10 mM Cao or 4 mM Mn. When Ko was increased, resting potential changed only slightly between 3 and 15 mM, but the resting potential versus Ko characteristically approached the slope of a K electrode at high Ko Elimination of Cl from the medium did not alter the K dependence of the resting potential. However, a hyperpolarization of 9 mV per 10-fold change was observed when Nao was decreased from 50 to 4 mM. Ouabain (10−4 M) depolarized the membrane within 2 min to a stable level of about −30 mV in spontaneously beating cells and in those treated with Ca channel blockers. This potential was considered as the diffusion component of the membrane potential, Vdiff. Consequently the difference between resting potential and Vdiff represents the ouabain-sensitive or the electrogenic component of the resting potential. Using linearized versions of the Mullins and Noda as well as the Goldman – Hodgkin – Katz equations, we calculated that a PNa/PK between 0.25 and 0.35, a Na/K exchange ratio of 2.0, and a Ki of 160 mM adequately described the K dependence of the resting potential. We demonstrated the contribution of electrogenic Na extrusion to the resting potential of mammalian cardiac cells in culture. Therefore the existence of a composite resting potential precludes the direct comparison of potential measurements obtained under conditions liable to independently modify either the diffusion or the electrogenic component.
A derivative of befunolol, BFE-55, interacts with only the high affinity sites in β-adrenoceptors
Authors: Koike Katsuo , Nakagoshi Akihiro , Takayanagi Issei
Published: April 2011

The effect of BFE-55, a derivative of befunolol (a β-adrenergic partial agonist) on specific [3H]befunolol binding to a microsomal fraction from the guinea pig taenia caecum was tested. A Scatchard plot of specific [3H]befunolol binding in the absence of BFE-55 was concave, suggesting an existence of high and low affinity sites in β-adrenoceptors. In contrast, the Scatchard plot of data in the presence of BFE-55 (3 × 10−7 M) was straight. In the presence of BFE-55, the high affinity sites disappeared and the low affinity site was unaffected. In the absence and presence of BFE-55 there was no difference between the pKD values or Bmax values at the low affinity site. These findings indicate that BFE-55 interacts with only the high affinity sites in β-adrenoceptors.
Effects of hemorrhage and hepatic nerve stimulation on venous compliance and unstressed volume in cat liver
Authors: Greenway C. V.
Published: April 2011

Intrahepatic blood volume–pressure relationships were studied using plethysmography to measure hepatic blood volume and a hepatic venous long-circuit to control intrahepatic pressure. In cats anesthetized with pentobarbital or with ketamine–chloralose, hemorrhage (to reduce hepatic blood flow to 60% of control) caused marked reductions in hepatic blood volume and intrahepatic pressure but did not significantly change hepatic blood volume–pressure relationships. We were unable to demonstrate an active reflex venous response to hemorrhage in these preparations, although a large passive response occurred. The volume–pressure relationships in innervated livers were different from those in denervated livers: apparent venous compliance was much greater and apparent unstressed volume was zero or negative. Hepatic nerve stimulation in denervated livers caused a marked decrease in hepatic blood volume at low intrahepatic pressures but failed to alter hepatic blood volumes at high intrahepatic pressures (15 mmHg) (1 mmHg = 133.3 Pa). This resulted in large apparent compliances and apparently negative unstressed volumes, as seen in the innervated livers. Thus blood volume–pressure relationships in innervated livers may not give valid measurements of compliance and unstressed volume. A remarkable feature in all these experiments was the linearity of the relationship between hepatic blood volume and intrahepatic pressure. Exudation of fluid begins at higher intrahepatic pressures in innervated compared with denervated livers.
Alterations in cardiac lysosomal hydrolases following induction of the calcium paradox
Authors: Kutryk Michael J. B. , Dhalla Naranjan S.
Published: April 2011

Although perfusion of the heart with calcium-free medium for a brief period followed by reperfusion with calcium-containing medium results in marked structural derangements (calcium paradox), the mechanisms for this cell damage are far from clear. Since activation of lysosomal enzymes has been associated with pathological damage, it was the purpose of this study to examine alterations in the activities of several lysosomal enzymes in rat hearts subjected to calcium paradox. No significant changes in the activities of (β-acetylglucosaminidase, β-galactosidase, α-mannosidase, or acid phosphatase were seen in the homogenates of hearts exposed to the calcium paradox. However, there were dramatic alterations in the lysosomal enzyme activities in the sedimentable and nonsedimentable fractions during calcium paradox. The lysosomal enzyme activities were also detected in the perfusate collected during reperfusion with calcium-containing medium. These changes occurred during the reperfusion period since no alterations were apparent after calcium-free perfusion and were dependent upon the time of reperfusion with medium containing Ca2+ as well as the time of perfusion with Ca2+ -free medium before inducing Ca2+ paradox. These data indicate that alterations in lysosomal enzymes owing to reinstitution of calcium in Ca2+-deprived hearts may occur as a part of cardiac damage and general cellular disintegration.
Alterations in tissue antioxidant systems in the spontaneously diabetic (BB Wistar) rat
Authors: Wohaieb Saleh A. , Godin David V.
Published: April 2011

Tissue antioxidant status in insulin-dependent spontaneously diabetic BB Wistar rats (ISDBB), diabetes-prone nondiabetic littermates (NDLM), and weight-matched non-BB control Wistar rats was investigated in pancreas, heart, and liver, as well as kidney. Pancreatic activities of CuZn – superoxide dismutase and glutathione reductase (GSSG-RD) were higher in ISDBB rats, while catalase (CAT) activities were elevated in both ISDBB and their NDLM compared with control animals. On the other hand, pancreatic reduced glutathione (GSH) levels were decreased in both ISDBB and NDLM rats. Cardiac tissues of ISDBB rats had higher activities of CAT and GSSG-RD and elevated levels of GSH compared with weight-matched control rats. Hepatic GSH levels in both ISDBB and their NDLM were lower than those of control rats. ISDBB rats showed higher renal activities of glutathione peroxidase compared with control rats. Our results demonstrate the presence of alterations in tissue antioxidant status in BB Wistar rats (both diabetic BB rats and their diabetes-prone nondiabetic littermates). The fact that most of the enzyme changes present in BB rats with overt diabetes paralleled those we have previously reported in rats with uncontrolled streptozotocin-induced diabetes and the fact that the latter alterations were corrected with insulin therapy suggest that the alterations in diabetic BB rats were probably related to suboptimal insulin therapy. The significance of the alterations in antioxidant status seen in the nondiabetic BB animals is as yet unknown.
Prostaglandin formation in feline cerebral microvessels: effect of endotoxin and interleukin-1
Authors: Bishai Isis , Dinarello Charles A. , Coceani Flavio
Published: April 2011

The pathogenesis of fever involves the appearance of interleukin-1 in the circulation in response to appropriate noxae (e.g., endotoxin) and subsequent generation of prostaglandin E2 in the CNS. The present study was undertaken to determine whether the cerebral microvasculature may function as a source of the fever-producing prostaglandin E2. Microvessels, consisting predominantly of capillaries, were isolated from the cat forebrain by selective sieving and glass bead elutriation. Preparations contained enzymes for the synthesis of 6-keto-prostaglandin F1α (hence prostaglandin I2), prostaglandin E2, and possibly prostaglandin F2α. No prostaglandin D2 was detected, nor was evidence obtained for the formation of 6-keto-prostaglandin E1. Intact microvessels released prostaglandin E2 and 6-keto-prostaglandin F1α under basal conditions, the latter compound exceeding the former by about sevenfold. Endotoxin stimulated prostaglandin E2 release without significantly altering 6-keto-prostaglandin F1α release. In contrast, monocyte-derived interleukin-1 reduced the release of both compounds, while recombinant interleukin-1 was ineffective. Endotoxin stimulation is likely directed on the cleavage of substrate arachidonic acid from precursor lipids, while inhibition from monocyte-derived interleukin-1 is ascribed to the presence of an interfering substance. This substance, like endotoxin, is thought to act prior to the cyclooxygenase cascade and its identity remains to be ascertained. We conclude that the cerebral microvasculature does not lend itself to an active role in the genesis of fever by being the site at which blood-borne interleukin-1 promotes prostaglandin E2 synthesis. However, the demonstration of a selective increase in prostaglandin E2 release from endotoxin-treated microvessels, if indicative of a normal event, raises the possibility of a direct effect of blood-borne endotoxin on the CNS.