bluuebunny/crossref_metadata_2025 huggingface dataset:
Removal of the endothelium potentiates canine large coronary artery constrictor responses to 5-hydroxytryptamine in vivo.
Authors: Lamping K G , Marcus M L , Dole W P
Published: June 2012

Recent studies in isolated epicardial coronary artery rings have shown that the endothelium modulates vasomotor responses to certain endogenous neurohumoral agents. It is not known whether the endothelium plays a role in large coronary vasoregulation in the intact coronary circulation. Accordingly, we examined effects of endothelial removal on vasoconstrictor responses of the proximal coronary artery in anesthetized adult mongrel dogs. The left anterior descending artery was perfused at 100 mm Hg with arterial blood from a pressurized reservoir. Coronary diameter was measured continuously with 7-MHz sonomicrometer crystals attached to the adventitia of the artery. Fifteen minutes after mechanical disruption of the endothelium with a balloon-tipped catheter, baseline diameter was unchanged from a control value of 2.60 +/- 0.13 mm (mean +/- SE, n = 17). Endothelial denudation resulted in a dose-dependent potentiation of the constrictor response to intracoronary 5-hydroxytryptamine (1-50 micrograms/min, n = 8). With the endothelium intact, a 5 micrograms/min infusion of 5-hydroxytryptamine reduced diameter by 24 +/- 14 micron, while a 50 micrograms/min dose reduced diameter by 54 +/- 25 micron. After endothelial removal, the decrease in diameter averaged 74 +/- 18 microns at 5 micrograms/min and 132 +/- 29 micron at 50 micrograms/min, indicating a 10-fold increase in the sensitivity to 5-hydroxytryptamine. The constrictor responses to angiotensin II (1 and 5 micrograms/min, n = 7) and phenylephrine (1-5 micrograms/min, n = 7) were not altered by endothelial removal. Thus, endothelial removal selectively potentiates the constrictor responses to 5-hydroxytryptamine in the intact coronary circulation of the dog.
Mechanisms of supersensitivity to sympathomimetic amines in the chronically denervated heart of the conscious dog.
Authors: Vatner D E , Lavallee M , Amano J , Finizola A , Homcy C J , Vatner S F
Published: June 2012

Mechanisms of denervation supersensitivity to sympathomimetic amines were studied in conscious animals. Norepinephrine, 0.1 micrograms/kg, increased left ventricular dP/dt significantly more (4208 +/- 828 mm Hg/sec) in dogs with cardiac denervation than in intact dogs (1029 +/- 280 mm Hg/sec), P less than 0.01, whereas responses to isoproterenol were similar in both groups. Denervation supersensitivity to isoproterenol could be demonstrated only after opposing reflex effects were blocked. After ganglionic blockade, norepinephrine still induced 2- to 3-fold greater increases in left ventricular dP/dt and 3- to 7-fold greater increases in heart rate in cardiac-denervated dogs, whereas isoproterenol and prenalterol, not taken up by presynaptic nerve endings, elicited only 40%-50% greater increases in left ventricular dP/dt and heart rate in dogs with cardiac denervation. The density of beta-adrenergic receptors [( 3H]dihydroalprenolol) was elevated (P less than 0.01) in denervated left ventricles (105 +/- 6.9 fmol/mg protein, n = 8) compared to normal left ventricles (70 +/- 6.3 fmol/mg protein, n = 12). This was accompanied by enhanced isoproterenol-mediated adenylate cyclase activity. However, muscarinic cholinergic receptor density, [( 3H]quinuclidinyl benzilate), decreased from control levels of 251 +/- 11 fmol/mg protein (n = 7) to 193 +/- 14 fmol/mg protein (n = 6). Thus, chronic cardiac denervation results in upregulation of the beta-adrenergic receptor and down-regulation of the muscarinic receptor. The increased beta-adrenergic receptor density and adenylate cyclase stimulation correlated well with the amount of denervation supersensitivity to isoproterenol and prenalterol, but accounted for only a minor fraction of denervation supersensitivity to norepinephrine. The major mechanism of denervation supersensitivity to norepinephrine appears to involve lack of the norepinephrine reuptake.
Diabetes-induced alterations in the translational activity of specific messenger ribonucleic acids isolated from rat hearts.
Authors: Barrieux A , Neeley W E , Dillmann W H
Published: June 2012

During diabetes mellitus, total proteins and ribonucleic acids are significantly decreased in the rat heart, and these parameters can be increased by insulin administration. To determine whether all ribonucleic acids are equally sensitive to insulin, we examined the influence of this hormone on individual translatable ribonucleic acids. Cardiac ribonucleic acid prepared from control, untreated, and insulin-treated diabetic animals was translated in vitro in the presence of [35S]methionine. The radiolabeled peptides were separated by two-dimensional gel electrophoresis and were analyzed by fluorometry. We found that diabetes induces both qualitative and quantitative changes in the predominance of a few specific translatable messenger ribonucleic acid species. The translation of 11 messenger ribonucleic acid species was significantly decreased and that of eight messenger ribonucleic acid species was significantly increased in diabetic preparation. Twelve of the 19 translation products were quantified by digital matrix photometry: three labeled peptides were observed only when cardiac ribonucleic acid from diabetic animals was added to the cell-free translation system, four new peptides appeared when cardiac ribonucleic acid from control animals was added, and although the remaining five peptides were translated in vitro after either control or diabetic ribonucleic acid was added, their relative predominance was altered 2- to 200-fold. When translation products coded for by messenger ribonucleic acids prepared from either diabetic or hypothyroid hearts were compared, we found that most of the alterations induced by diabetes were also induced by hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)
Renin expression by vascular endothelial cells in culture.
Authors: Lilly L S , Pratt R E , Alexander R W , Larson D M , Ellison K E , Gimbrone M A , Dzau V J
Published: June 2012

Cultured bovine aortic endothelial cells were examined for renin activity by biochemical, immunological, and immunohistochemical techniques. When cell sonicates were incubated with renin substrate, linear generation of angiotensin I was observed (1.12 +/- 0.2 ng angiotensin I/10(6) cells per hr). The effect of pH on this activity was similar to that of bovine renal renin, and renin antibodies inhibited a large portion of the enzymatic activity. Furthermore, immunofluorescence microscopy with antirenin antisera confirmed the presence of renin within these cells. Biosynthetic radiolabeling, followed by immunoprecipitation, demonstrated de novo synthesis of a renin precursor in the endothelial cells, which was processed to a more mature protein. Thus, bovine aortic endothelial cells in culture contain and biosynthesize renin, a key component of the renin-angiotensin system. The expression of renin activity by endothelium may contribute to the local regulation of vascular tone.
Mechanical properties of human pericardium. Differences in viscoelastic response when compared with canine pericardium.
Authors: Lee J M , Boughner D R
Published: June 2012

Whereas most experiments on the mechanical function of the pericardium have been performed on dogs, very little is known about the applicability of those data to humans. To examine the tensile viscoelastic properties of fresh human pericardium, we have used the methods from our previous study of canine pericardium. Although the mechanical responses of canine and human pericardium were qualitatively similar, human pericardium displayed a significantly greater viscous character. Human pericardium was 7.3 times thicker than canine pericardium, but was more extensible in stress-strain tests, with lower stiffness at a given strain. The static (elastic) stiffness of human pericardium seems identical to that of canine pericardium; lower stiffness per unit thickness of the human tissue at predicted physiological stresses was almost exactly compensated by the greater wall thickness. This effect was also seen in data on fracture strength and stiffness. However, human pericardium displayed greater viscous responses than the canine tissue. This was seen in doubled cyclic hysteresis losses, and greater stress relaxation and creep. Our results suggest that experiments on the viscoelastic properties of canine pericardium may not be directly applicable to humans, especially where dynamic mechanical properties are most important: i.e., in studies of ventricular function and the time-course of pericardial effusions.
George E. Brown memorial lecture. Oxygen radicals in cerebral vascular injury.
Authors: Kontos H A
Published: June 2012

Acute, severe increases in arterial blood pressure cause sustained cerebral arteriolar dilation, abnormal reactivity to carbon dioxide and to changes in blood pressure, abolition of endothelium-dependent dilation from acetylcholine, discrete morphological lesions of the endothelium and vascular smooth muscle, and breakdown of the blood-brain barrier to plasma proteins. The dilation, abnormal reactivity, and morphological abnormalities are inhibited by pretreatment with cyclooxygenase inhibitors or with free radical scavengers. Superoxide dismutase-inhibitable reduction of nitroblue tetrazolium applied to the brain surface was detectable both during hypertension and one hour after hypertension subsided. Nitroblue tetrazolium reduction is also reduced by inhibitors of the anion channel. The abnormalities seen after hypertension are reproduced by topical application of arachidonate. The results are consistent with the view that acute hypertension induces generation of superoxide anion radical in association with accelerated arachidonate metabolism via cyclooxygenase. This radical enters cerebral extracellular space via the anion channel and gives rise to hydrogen peroxide and hydroxyl radical. All three radicals are capable of causing vasodilation by relaxation of cerebral vascular smooth muscle. The hydroxyl radical is the most likely candidate for vascular wall damage. The significance of this mechanism in chronic experimental hypertension or its relevance to human disease is not known.
The role of oxygen-derived free radicals in ischemia-induced increases in canine skeletal muscle vascular permeability.
Authors: Korthuis R J , Granger D N , Townsley M I , Taylor A E
Published: June 2012

Previous studies indicate that vascular permeability is increased in skeletal muscle subjected to 4 hours of inflow occlusion. However, the mechanism(s) underlying the increase in permeability are unknown. The aim of this study was to assess the role of oxygen-derived free radicals and histamine as putative mediators of the increased permeability in skeletal muscle subjected to 4 hours of inflow occlusion. The osmotic reflection coefficient for total plasma proteins and isogravimetric capillary pressure were estimated in canine gracilis muscle for the following conditions: control, ischemia, and ischemia plus pretreatment with allopurinol (a xanthine oxidase inhibitor), catalase (a peroxidase that reduces hydrogen peroxide to water and molecular oxygen), superoxide dismutase (a superoxide anion scavenger), dimethyl sulfoxide (a hydroxyl radical scavenger), diphenhydramine (a histamine H1-receptor blocker), or cimetidine (a histamine H2-receptor blocker). Ischemia, followed by reperfusion, significantly reduced the reflection coefficient from 0.94 +/- 0.02 to 0.64 +/- 0.02 and isogravimetric capillary pressure from 13.8 +/- 1.0 mm Hg to 6.9 +/- 0.4 mmHg, indicating a dramatic increase in microvascular permeability. Prior treatment with diphenhydramine or cimetidine did not significantly alter the permeability increase induced by ischemia. However, pretreatment with allopurinol, catalase, superoxide dismutase, or dimethylsulfoxide did significantly attenuate the increase in vascular permeability. The results of this study indicate that oxygen radicals are primarily responsible for the increased vascular permeability produced by ischemia-reperfusion, that the hydroxyl radical may represent the primary damaging radical, and that xanthine oxidase may represent the primary source of oxygen-derived free radicals in ischemic skeletal muscle.
Hyperplastic growth response of vascular smooth muscle cells following induction of acute hypertension in rats by aortic coarctation.
Authors: Owens G K , Reidy M A
Published: June 2012

This study examines the growth response of vascular smooth muscle cells following induction of acute hypertension in rats by partial ligation of the abdominal aorta between the renal arteries. Systolic blood pressures proximal to the ligature increased dramatically within 3 days (from 135 +/- 3 to 195 +/- 7 torr) of surgery while pressures distal to the ligature were reduced from control values. The frequency of smooth muscle cells undergoing DNA replication was increased 25-fold in thoracic aortas of coarctation rats compared to sham-operated controls 9 days post-coarctation, while no differences were observed in cells in abdominal aortic segments 1 cm distal to the ligature. A small but significant increase in the frequency of tetraploid smooth muscle cells was observed in thoracic aortas of coarctation rats, but this increase accounted for less than 2% of the increase in medial DNA content. By far, the major growth response was hyperplasia, as evidenced by a 25% increase in thoracic aortic medial smooth muscle cell number without a change in mean cellular volume (micron3/cell) or mass (ng/cell). Whereas no evidence of endothelial denudation was observed in thoracic aortas of coarctation rats by scanning electron microscopy, endothelial cell turnover rates were increased 23-fold compared to controls, indicating that some form of endothelial "injury" or dysfunction was present. Consistent with this, morphological changes indicative of endothelial injury (e.g., subendothelial edema) were observed by light and transmission electron microscopy. The marked contrast between results of this study and our previous studies showing that aortic medial hypertrophy in spontaneously hypertensive and Goldblatt hypertensive rats was due to cellular hypertrophy and hyperploidy without hyperplasia, clearly demonstrates that the growth response of smooth muscle cells within a given blood vessel can be quite different, depending on the model of hypertension. It is suggested that a non-denuding form of endothelial "injury" may play an important role in the proliferative growth response of smooth muscle cells following induction of coarctation hypertension.
Influence of intravenous and intracerebroventricular vasopressin on baroreflex control of renal nerve traffic.
Authors: Imaizumi T , Thames M D
Published: June 2012

We performed experiments in alpha-chloralose-anesthetized rabbits with vagi sectioned, to determine the influence of intravenous and intracerebroventricular vasopressin on arterial baroreflex control of renal nerve activity. Arterial baroreflex control of renal nerve activity was assessed during phenylephrine-induced increases and nitroglycerin-induced decreases in arterial pressure. Intravenous vasopressin (4 and 40 mU over 1 minute) reduced basal renal nerve activity (from 149 +/- 14 to 101 +/- 13 and 28 +/- 13 impulses/sec) without changing arterial pressure and reduced the sensitivity of the arterial baroreflex control of renal nerve activity. This effect was reversed by vasopressin antagonist (d(CH2)5[Tyr(Me)2]AVP) which blocks vasoconstrictor effects of vasopressin. Intracerebroventricular vasopressin (4, 40, or 400 mU) did not alter basal renal nerve activity or arterial pressure but increased the sensitivity of baroreflex control of renal nerve activity. This effect was not blocked by the vasopressin antagonist. The influence of intravenous vasopressin on basal renal nerve activity was not altered by sinoaortic baroreceptor denervation. In contrast, the inhibitory influence of intravenous vasopressin on lumbar sympathetic nerve activity was abolished by sinoaortic denervation. Finally, intravenous vasopressin inhibited renal nerve activity (by 43 +/- 5%) in six rabbits with spinal cord transection. This effect was abolished by the vasopressin antagonist. We draw the following conclusions from these data: (1) intravenous and intracerebroventricular vasopressin have different effects on basal and baroreflex control of renal nerve activity; (2) these effects are mediated by different vasopressin receptors; (3) the effects of intravenous vasopressin on basal renal nerve activity are not baroreflex dependent, and appear to be mediated by spinal or, possibly, ganglionic mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
Myocardial infarction in rats. Infarct size, myocyte hypertrophy, and capillary growth.
Authors: Anversa P , Beghi C , Kikkawa Y , Olivetti G
Published: June 2012

To determine the compensatory reserve capacity of the ventricular myocardium following infarction, the left coronary artery in rats was ligated, and the animals were killed 40 days later. Infarcts affecting an average 23% of the left ventricle were characterized by a 27% hypertrophic growth of the remaining myocardium that produced a complete replacement of the necrotic tissue. In contrast, infarcts with an average 50% loss of mass resulted in 83% expansion of the spared myocardium that was inadequate for a complete restoration of ventricular tissue. Myocyte hypertrophy was 26% and 78% in small and large infarcts, respectively. Cellular hypertrophy in both cases involved significant increases in myocyte transverse area and myocyte length. After large infarcts, there was an 18% reduction in capillary surface and a 16% increase in the diffusion distance. Corresponding values for small infarcts were -10% and 9%. These alterations combined with the deficient reconstitution of myocardial mass following large infarcts resulted in 25%, 29%, and 30% deficits in the absolute amounts of capillary lumen, surface, and length per ventricle respectively. Even with small infarcts, a deficit was seen in capillary luminal surface (-16%), and length (-19%). In conclusion, we have demonstrated that cardiac hypertrophy following myocardial infarction is consistent with cellular shape changes characteristic of a combination of concentric and eccentric hypertrophic growth. However, cardiac muscle cells appear to be unable to compensate for the loss of mass induced by a 50% infarct. The inadequate adaptation of the capillary vasculature in the infarcted hearts suggests that the injured ventricle is more vulnerable to additional ischemic episodes.
Analysis of systolic bulging. Mechanical characteristics of acutely ischemic myocardium in the conscious dog.
Authors: Akaishi M , Weintraub W S , Schneider R M , Klein L W , Agarwal J B , Helfant R H
Published: June 2012

To determine the mechanical factors affecting regional segmental motion after acute coronary occlusion, we studied seven conscious dogs, instrumented with sonomicrometers. Loading conditions were changed by the withdrawal of 500 ml of blood and the transfusion of 800 ml of blood. To express segmental motion, percent systolic shortening, percent systolic elongation, and early diastolic shortening were calculated. Blood withdrawal decreased left ventricular preload, increased percent systolic elongation (from 6.9 +/- 3.1% to 9.9 +/- 3.5%) and early diastolic shortening (12.9 +/- 5.3% to 16.6 +/- 5.3%), and decreased percent systolic shortening. Blood transfusion increased left ventricular preload, decreased percent systolic elongation (to 5.2 +/- 1.8%) and early diastolic shortening (8.8 +/- 2.9%), and increased percent systolic shortening. Manipulation of loading did not change regional myocardial blood flow. In acutely ischemic myocardium, the tension-length loop showed an exponential upstroke during isovolumic systole and a nearly superimposed exponential downstroke during the isovolumic relaxation phase after systole, compatible with essentially passive movement as seen with an elastic material. The changes in loading conditions affected the tension-length curve to a very minor extent. The uniformity of the curve and its exponential shape explain the load-dependency of systolic bulging and segmental motion. It is concluded that systolic bulging depends on the change in the preload tension due to the compliant portion of tension-length curve, and that shortening of ischemic myocardium during the isovolumic relaxation phase is a completely passive phenomenon.
Electrophysiological mechanisms underlying rate-dependent changes of refractoriness in normal and segmentally depressed canine Purkinje fibers. The characteristics of post-repolarization refractoriness.
Authors: Davidenko J M , Antzelevitch C
Published: June 2012

Tissues from diseased hearts are known to exhibit post-repolarization refractoriness and rate-dependent changes of the refractory period that are often inconsistent with changes in action potential duration. To examine the electrophysiological mechanisms responsible for such rate-dependent changes of the refractory period, a narrow inexcitable zone was created by superfusing the central segments of Purkinje fibers with an "ion-free" isotonic sucrose solution. The degree of conduction impairment could be finely regulated by varying the resistance of the extracellular shunt pathway. At intermediate or low levels of block, the refractory period remained unchanged or decreased, respectively, as the rate was increased. At relatively high levels of block, however, we observed marked increases of the refractory period in response to increases in the stimulation rate. The disparity of refractoriness between normally conducting fibers and fibers exhibiting discontinuous conduction characteristics and post-repolarization refractoriness increased dramatically as a function of increasing stimulation rate. With the aid of current clamp techniques, we demonstrate that the differential behavior is due to the interplay between rate-dependent changes in the restitution of excitability at the site beyond the depressed zone secondary to changes in passive and active membrane properties and in the intensity of local circuit current provided to that site by activity generated in the segment proximal to the zone of block. Our data suggest that rate-dependent changes of refractoriness in Purkinje tissue are principally governed by attendant changes in membrane resistance.
Effects of plasmapheresis and of hypoproteinemia on lung liquid conductance in awake sheep.
Authors: Dodek P M , Rice T W , Bonsignore M R , Yamada S , Staub N C
Published: June 2012

The Starling equation, which describes net transvascular liquid flow, does not include the possibility that a reduction in plasma protein concentration may have a direct effect on lung liquid conductance or microvascular protein permeability. Nevertheless, both effects have been reported. Since these results were not predictable, we wondered whether the changes were due to the decrease in plasma protein concentration or to the process by which protein depletion was accomplished (batch plasmapheresis which involves considerable handling of blood). To separate these factors, we did control (sham) and protein removal plasmapheresis in awake sheep by two plasmapheresis methods (batch and continuous-flow). We monitored pulmonary hemodynamics, measured lung lymph flow, and determined protein concentrations in lymph and plasma. We calculated or measured the protein osmotic pressures of plasma and lymph. After control plasmapheresis, lymph flow increased and lymph:plasma protein concentration decreased but had returned to baseline levels by 4 hours. After protein removal plasmapheresis, the changes persisted for 24 hours. However, lung microvascular conductance (filtration coefficient) was not increased, except during the first 4-hour period. The changes in lymph flow and protein concentration ratio are explained using a simple two-pore model. We conclude that, over the range studied, hypoproteinemia does not increase lung microvascular liquid conductance or protein permeability.
Vagus nerve stimulation alters regional acetylcholine turnover in rat heart.
Authors: Lund D D , Oda R P , Pardini B J , Schmid P G
Published: June 2012

The turnover of neurotransmitter is a direct measure of neuronal function, varying with the impulse activity of the nerve. It is not known if vagal stimulation increases acetylcholine release uniformly throughout the heart, or if modification of neural signals occurs between the vagal nerve trunks and postganglionic synaptic terminals. The rate constant of acetylcholine turnover was measured in conduction and contractile regions of heart by quantifying the incorporation of [3H]choline into acetylcholine after labeling of the blood choline pool in urethane-anesthetized rats during two levels of vagal activity. Choline and acetylcholine were assayed by high pressure liquid chromatography with electrochemical detection of post-column enzymic reaction product, peroxide. The specific activities of choline and acetylcholine in the tissues at sacrifice were used to calculate the fractional turnover rates in cardiac regions. Supramaximal bilateral vagal stimulation for 20 minutes decreased heart rate (P less than 0.05), while mean arterial blood pressure remained constant. The rate constants for acetylcholine turnover in right atrial regions containing the sinoatrial node, left atrial tissues, and interatrial septum doubled from control values during vagal stimulation. In contrast, the fractional rate constants of acetylcholine turnover did not change in the right and left ventricles during vagal stimulation. We interpret these results to indicate general activation of postganglionic parasympathetic fibers to the atria and selective modulation of postganglionic parasympathetic neural function to the ventricles.
Cyclic guanosine monophosphate inhibition of contraction may be mediated through inhibition of phosphatidylinositol hydrolysis in rat aorta.
Authors: Rapoport R M
Published: June 2012

The purpose of this study was to determine whether cyclic guanosine monophosphate inhibits contraction through inhibition of phosphatidylinositol hydrolysis. Sodium nitroprusside and atriopeptin II, agents which activate soluble and particulate guanylate cyclase, respectively, inhibited norepinephrine-induced contraction and accumulation of inositol monophosphate, a measure of phosphatidylinositol hydrolysis. Acetylcholine, an agent which elevates smooth muscle cyclic guanosine monophosphate levels through release of an endothelial-derived relaxing factor, induced similar inhibitory effects on contraction and inositol monophosphate accumulation in the presence but not absence of the endothelium. The cyclic nucleotide analogue 8-bromo cyclic guanosine monophosphate also inhibited contraction and inositol monophosphate accumulation. These results suggest that cyclic guanosine monophosphate may inhibit contraction through inhibition of phosphatidylinositol hydrolysis. Furthermore, the inhibition of phosphatidylinositol hydrolysis was independent of the mechanism by which cyclic guanosine monophosphate elevation occurred.
Cardiovascular effects associated with antidiuretic activity of vasopressin after blockade of its vasoconstrictor action in dehydrated dogs.
Authors: Liard J F
Published: June 2012

In view of our previous findings that a specific antidiuretic (V2) agonist, 4-valine-8-D-arginine vasopressin, acutely increased cardiac output and heart rate in dogs, we examined the hypothesis that interaction with V2-like receptors might contribute to the hemodynamic response seen after blockade of the vasoconstrictor (V1) effect of arginine-vasopressin in dehydrated dogs. After 48 hours of water restriction which increased plasma vasopressin to 10.6 +/- 2.0 pg/ml, the V1 antagonist 1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid) 2-(O-methyl)tyrosine arginine-vasopressin, 10 micrograms/kg, was injected intravenously into six conscious dogs, and the combined V1 + V2 antagonist 1-(beta-mercapto-beta,beta,cyclopentamethylene propionic acid) 2-(O-ethyl)-D-tyrosine, 4-valine arginine-vasopressin, 10 micrograms/kg, was administered to another six dogs. Mean arterial pressure, cardiac output (electromagnetic flowmeter), and regional blood flows (radioactive microspheres) were measured before and 20-30 minutes after antagonist administration. Mean arterial pressure did not change significantly in either instance. Cardiac output increased by 31.0 +/- 7.1% after V1 blockade, but by only 10.8 +/- 2.1% following V1 + V2 blockade. Blood flow increased significantly and to a similar extent in the skin, the skeletal muscles, and the fat following both antagonists. Conversely, kidney, arterial liver, and bone blood flow increased only after V1 blockade. In six additional, normally hydrated conscious dogs, it was shown that the V1 + V2 antagonist had no significant hemodynamic effects, a finding previously established for the V1 antagonist. The V1 + V2 antagonist completely prevented the hemodynamic effects associated with administration of the V2 agonist 4-valine-8-D-arginine vasopressin, 200 ng/kg, whereas the V1 antagonist did not. Both antagonists had similar effects on the hemodynamic changes induced by nitroprusside infusion, namely a potentiation of the blood pressure lowering action. These results suggest that part of the hemodynamic response to blockade of the vasoconstrictor action of vasopressin in dehydration is caused by unmasking cardiovascular effects linked to the antidiuretic activity of the arginine-vasopressin molecule.
Load regulation of the properties of adult feline cardiocytes. The role of substrate adhesion.
Authors: Cooper G , Mercer W E , Hoober J K , Gordon P R , Kent R L , Lauva I K , Marino T A
Published: June 2012

We have recently described rapid and reversible changes in cardiac structure, function, and composition in response to surgical load alteration in vivo. In the present study, we used a simple, well-defined in vitro experimental model system, consisting of terminally differentiated quiescent adult cat ventricular cardiocytes maintained in serum-free culture medium, to assess more definitively the role of loading conditions in regulating these same biological properties of heart muscle. Cardiocytes considered to be externally loaded were adherent throughout their length to a protein substrate, such that the tendency for the ends of the cells to retract was prevented. Cardiocytes considered to be unloaded were not adherent to a substrate and, thus, were free to assume a spherical shape. Cardiocyte structure and surface area were assessed, in initially identified cells, both by serial light microscopy and by terminal electron microscopy. Cardiocyte function was assessed in terms of the ability to exclude trypan blue, to remain quiescent with relaxed sarcomeres containing I-bands, and to shorten in response to electrical stimulation. Cardiocyte composition was first assessed by quantitative gel electrophoresis of proteins and then by microfluorimetric measurement of ribonucleic acid, protein, and deoxyribonucleic acid. In addition, cardiocyte incorporation of [3H]thymidine into deoxyribonucleic acid and [3H]uridine into ribonucleic acid were measured. Loading via substrate adhesion was found to be very effective in terms of each of these measurements in retaining the differentiated features of adult cardiocytes for up to 2 weeks in culture; unattached and thus unloaded cardiocytes quickly dedifferentiated. Conditions thought to stimulate cardiac growth, including catecholamine stimulation, were found to be ineffective. These experiments demonstrate that external load has a primary role in the maintenance of the basic differentiated properties of adult mammalian cardiocytes.
Comparison between the sarcomere length-force relations of intact and skinned trabeculae from rat right ventricle. Influence of calcium concentrations on these relations.
Authors: Kentish J C , ter Keurs H E , Ricciardi L , Bucx J J , Noble M I
Published: June 2012

To investigate the extent to which the properties of the cardiac myofibrils contribute to the length-force relation of cardiac muscle, we determined the sarcomere length-force relations for rat ventricular trabeculae both before and after the muscles were skinned with the detergent Triton X-100. Sarcomere length was measured continuously by laser diffraction. In the unskinned trabeculae stimulated at 0.2 Hz, the relation between active force and sarcomere length at an extracellular calcium concentration of 1.5 mM was curved away from the sarcomere length axis, with zero force at sarcomere length of 1.5-1.6 micron. At 0.3 mM calcium, the sarcomere length-force relation was curved toward the sarcomere length axis. Chemical skinning of the muscle with 1% Triton X-100 in a "relaxing solution" caused an increase in intensity and decrease in dispersion of the first order diffraction beam, indicating an increased uniformity of sarcomere length in the relaxed muscle. During calcium-regulated contractures in the skinned muscles, the central sarcomeres shortened by up to 20%. As the calcium concentration was increased over the range 1-50 microM, the relation between steady calcium-regulated force and sarcomere length shifted to higher force values and changed in shape in a manner similar to that observed for changes in extracellular calcium concentration before skinning. The sarcomere length-force relations for the intact muscles at an extracellular calcium concentration of 1.5 mM were similar to the curves at calcium concentration of 8.9 microM in the skinned preparations, whereas the curves at an extracellular calcium concentration of 0.3 mM in intact muscles fell between the relations at calcium concentrations of 2.7 and 4.3 microM in the skinned preparations. A factor contributing to the shape of the curves in the skinned muscle at submaximal calcium concentrations was that the calcium sensitivity of force production increased with increasing sarcomere length. The calcium concentration required for 50% activation decreased from 7.71 +/- 0.52 microM to 3.77 +/- 0.33 microM for an increase of sarcomere length from 1.75 to 2.15 micron. The slope of the force-calcium concentration relation increased from 2.82 to 4.54 with sarcomere length between 1.75 and 2.15 micron. This change in calcium sensitivity was seen over the entire range of sarcomere lengths corresponding to the ascending limb of the cardiac length-force relation. It is concluded that the properties of the cardiac contractile machinery (including the length-dependence of calcium sensitivity) can account for much of the shape of the ascending limb in intact cardiac muscle.
Kinetics of cellular proliferation after arterial injury. IV. Heparin inhibits rat smooth muscle mitogenesis and migration.
Authors: Clowes A W , Clowes M M
Published: June 2012

Heparin inhibits the development of intimal thickening after carotid injury in the rat; however, the specific cellular events responsible for this effect have not been defined. In this study, smooth muscle cell growth fraction and migration into the intima were quantitatively measured in heparin-treated animals. All rats were subjected to left carotid balloon injury and received continuous intraperitoneal infusion of tritiated thymidine; they were given either heparin or lactated Ringer's solution intravenously for periods of time up to 7 days. Both smooth muscle cell growth fraction and migration of nondividing smooth muscle cells were markedly reduced in heparin-treated rats. If heparin was administered for only the first 3 days after carotid injury, both smooth muscle growth fraction and migration were reduced at 7 days; on the other hand, heparin had no effect on growth fraction and migration if given from day 4 to day 7. Finally, heparin given for a period of 1 week produced marked reduction in smooth muscle cell accumulation in injured arteries at 2 and 4 weeks. These results suggest that the effect of heparin on injury-induced intimal thickening might be due to inhibition of both smooth muscle cell entry into the growth fraction and migration of medial smooth muscle cells into the intima. These effects are long lasting, and are not reversed even if heparin is stopped after a short course of administration.
Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog.
Authors: Pagani M , Lombardi F , Guzzetti S , Rimoldi O , Furlan R , Pizzinelli P , Sandrone G , Malfatto G , Dell'Orto S , Piccaluga E
Published: June 2012

In 57 normal subjects (age 20-60 years), we analyzed the spontaneous beat-to-beat oscillation in R-R interval during control recumbent position, 90 degrees upright tilt, controlled respiration (n = 16) and acute (n = 10) and chronic (n = 12) beta-adrenergic receptor blockade. Automatic computer analysis provided the autoregressive power spectral density, as well as the number and relative power of the individual components. The power spectral density of R-R interval variability contained two major components in power, a high frequency at approximately 0.25 Hz and a low frequency at approximately 0.1 Hz, with a normalized low frequency:high frequency ratio of 3.6 +/- 0.7. With tilt, the low-frequency component became largely predominant (90 +/- 1%) with a low frequency:high frequency ratio of 21 +/- 4. Acute beta-adrenergic receptor blockade (0.2 mg/kg IV propranolol) increased variance at rest and markedly blunted the increase in low frequency and low frequency:high frequency ratio induced by tilt. Chronic beta-adrenergic receptor blockade (0.6 mg/kg p.o. propranolol, t.i.d.), in addition, reduced low frequency and increased high frequency at rest, while limiting the low frequency:high frequency ratio increase produced by tilt. Controlled respiration produced at rest a marked increase in the high-frequency component, with a reduction of the low-frequency component and of the low frequency:high frequency ratio (0.7 +/- 0.1); during tilt, the increase in the low frequency:high frequency ratio (8.3 +/- 1.6) was significantly smaller. In seven additional subjects in whom direct high-fidelity arterial pressure was recorded, simultaneous R-R interval and arterial pressure variabilities were examined at rest and during tilt. Also, the power spectral density of arterial pressure variability contained two major components, with a relative low frequency:high frequency ratio at rest of 2.8 +/- 0.7, which became 17 +/- 5 with tilt. These power spectral density components were numerically similar to those observed in R-R variability. Thus, invasive and noninvasive studies provided similar results. More direct information on the role of cardiac sympathetic nerves on R-R and arterial pressure variabilities was derived from a group of experiments in conscious dogs before and after bilateral stellectomy. Under control conditions, high frequency was predominant and low frequency was very small or absent, owing to a predominant vagal tone. During a 9% decrease in arterial pressure obtained with IV nitroglycerin, there was a marked increase in low frequency, as a result of reflex sympathetic activation.(ABSTRACT TRUNCATED AT 400 WORDS)
Effects of thyroid hormone on alpha-actin and myosin heavy chain gene expression in cardiac and skeletal muscles of the rat: measurement of mRNA content using synthetic oligonucleotide probes.
Authors: Gustafson T A , Markham B E , Morkin E
Published: June 2012

Effects of thyroid hormone on alpha-actin and myosin heavy chain gene expression were compared in ventricle, soleus, and extensor digitorum longus muscles of hypothyroid rats. Changes in mRNA content were analyzed using synthetic oligonucleotide probes complementary to the unique 3' untranslated regions of four striated myosin heavy chain mRNAs and cardiac and skeletal muscle alpha-actin mRNAs. The results indicate that daily treatment with 3,5,3'-triiodo-L-thyronine (2 micrograms/100 g body weight) increased alpha-myosin heavy chain mRNA content in heart muscle by 500% and decreased beta-myosin heavy chain mRNA by 65% within 48 hours. beta-mRNA in extensor digitorum longus was decreased by 60% at 48 hours while in soleus, beta-mRNA levels were not affected by 9 weeks of treatment. Fast IIa mRNA was present in small amounts in hypothyroid soleus and increased by 150% and 200% after 7 and 9 weeks of thyroid hormone administration, respectively. Fast IIb mRNA also was found in hypothyroid soleus and a small increase (60%) was observed after 1 day of treatment. In extensor digitorum longus, Fast IIb mRNA increased by 200% and Fast IIa mRNA decreased by 50% after 1 week of treatment. When larger daily doses of thyroid hormone (15 micrograms/100 g body weight) were administered, similar changes in mRNA levels were observed, except that beta-mRNA content of soleus muscle was decreased slightly (25%). Expression of the cardiac form of alpha-actin was induced transiently in ventricle, but the skeletal form of alpha-actin mRNA in soleus and extensor digitorum longus did not change significantly after thyroid hormone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Myocardial oxygen tension determines the degree and pressure range of coronary autoregulation.
Authors: Dole W P , Nuno D W
Published: June 2012

Experiments were designed to separate effects of myocardial oxygen tension and oxygen consumption on coronary autoregulation. The approach was to measure coronary hemodynamic and metabolic responses to decreases in perfusion pressure during interventions that altered the balance between myocardial oxygen supply and demand. Studies were conducted in anesthetized heart-blocked dogs with the left coronary artery perfused from a pressure-controlled blood reservoir. Decreasing oxygen consumption by lowering heart rate from 120 to 40 bpm increased coronary venous oxygen tension and reduced the degree of flow autoregulation between 120 and 80 mm Hg by threefold. In contrast to effects of bradycardia, coronary constriction with vasopressin or indomethacin (heart rate 120 bpm), which produced comparable increases in baseline vascular resistance, decreased coronary venous oxygen tension, and augmented flow autoregulation by nearly twofold. Initial coronary venous oxygen tension but not oxygen consumption was strongly correlated with a quantitative index of autoregulation (-0.052 PO2 + 2.01, R2 = 0.86) over the pressure range of 120 to 80 mm Hg. When heart rate was lowered to 40 bpm and coronary venous oxygen tension subsequently reduced with vasopressin to control values (120 bpm), autoregulation was completely restored. Parallel studies examined the effects of metabolic and pharmacologic interventions on coronary pressure-flow relations over a wide range of pressures. For each 20 mm Hg decrement in pressure between 160 and 80 mm Hg, lowering heart rate attenuated autoregulation whereas pharmacologic coronary constriction augmented autoregulation. The observed variations in the autoregulation index were largely explained by differences in the prevailing venous oxygen tension. Furthermore, the upper pressure limit for autoregulation was dependent on venous oxygen tension with a threshold oxygen tension for autoregulation of 32 mm Hg. These results indicate that coronary autoregulation is closely coupled to the prevailing venous oxygen tension but not oxygen consumption and is facilitated at low venous oxygen tension.
Calcium channels in muscle cells isolated from rat mesenteric arteries: modulation by dihydropyridine drugs.
Authors: Bean B P , Sturek M , Puga A , Hermsmeyer K
Published: June 2012

The patch clamp technique was used to make whole-cell recordings of calcium channel currents from single muscle cells freshly isolated from rat mesenteric arteries. The cells were found to contain two types of calcium channels; one type is activated by small depolarizations and inactivates quickly, whereas the other requires stronger depolarizations for activation and inactivates more slowly. Nitrendipine blocked the second type of channels with a potency that depended on membrane potential. Interpreted by a modulated receptor hypothesis, these results suggest that nitrendipine binds to the inactivated state of the channel with a KD of about 0.5 nM, similar to concentrations effective in relaxing blood vessels. The magnitude of the calcium channel current was small compared with other excitable cells, but the "calcium agonist" drug BAY K8644 produced a 10-fold augmentation of calcium channel current, suggesting the existence of a large "reserve" of calcium channel current.
Intra- and extracellular actions of proton on the calcium current of isolated guinea pig ventricular cells.
Authors: Irisawa H , Sato R
Published: June 2012

External or internal application of proton on the calcium current was investigated using the whole-cell patch clamp technique in single ventricular cells of the guinea pig. The effect of acid pHo on the calcium current depended on the strength of the buffer in the internal solution. In the presence of 5 mM HEPES in the pipette, external acidification depressed calcium current with the half maximum inhibition of pHo 5.5. When the intracellular pH was buffered strongly to pH 7.2 by 50 mM HEPES within the pipette solution, half maximum inhibition of the calcium current was shifted to the acidic side markedly. When acid was applied in the patch electrode, calcium current was hardly affected by the pH values down to 6.0 in the pipette solution but was depressed by approximately half on further acidification to pH 4.5. When the Na+-H+ exchange system was blocked by superfusing the cell with either amiloride or Na+-deficient solutions (Tris substituted), calcium current was decreased by half at a pipette pH of around 6.5 and was completely and irreversibly blocked at pHpip 6.0. From the above results, we concluded that the calcium current of the ventricular cell is much more sensitive to intracellular protons than extracellular ones.
Induction of delayed afterdepolarizations and triggered activity in canine Purkinje fibers by lysophosphoglycerides.
Authors: Pogwizd S M , Onufer J R , Kramer J B , Sobel B E , Corr P B
Published: June 2012

Lysophosphoglycerides accumulate in ischemic myocardium and induce electrophysiologic alterations in normoxic tissue in vitro closely resembling those seen with ischemia in vivo. Delayed afterdepolarizations and triggered activity may be particularly important in the pathogenesis of arrhythmias in the ischemic heart. The present study was performed to determine whether lysophosphatidylcholine (LPC), at concentrations comparable to those present in ischemic myocardium, can induce delayed afterdepolarizations and/or triggered activity in normoxic canine Purkinje fibers. In the present study, as little as 75 microM LPC was found to induce delayed afterdepolarizations and as little as 100 microM LPC was found to induce delayed afterdepolarizations and triggered activity even at low cycle lengths. The amplitude of the induced delayed afterdepolarizations was enhanced by augmentation of the extracellular concentration of calcium (7 mM) or by exogenous epinephrine (10(-9) to 10(-6) M). The amplitude was decreased by verapamil (1 mg/l) or Mn++ (2.5 mM). Epinephrine at a concentration of 10(-6) M also initiated triggered activity in Purkinje fibers exposed to LPC (75 microM), a response blocked by l-propranolol (2 X 10(-7) M and 10(-6) M) but not by the alpha 1-adrenergic blocking agent BE-2254 (10(-6) M). Delayed afterdepolarizations induced by LPC (75 microM) and epinephrine (10(-6) M) persisted even in the presence of acidosis (pH 6.7) and hyperkalemia ([K+]o = 7 mM). Thus, delayed afterdepolarizations and triggered activity induced by LPC may contribute to the induction and/or maintenance of arrhythmias early after the onset of myocardial ischemia. However, because of the reversal of these effects after superfusion with media devoid of LPC, they may occur with ischemia in vivo but not be seen in tissue isolated from ischemic regions and evaluated in vitro.