bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of angiotensin II on steroid metabolism and hepatic blood flow in man.
Authors: Messerli F H , Nowaczynski W , Honda M , Genest J , Boucher R , Kuchel O , Rojo-Ortega J M
Published: June 2012

Metabolic clearance rates (MCR) of aldosterone, cortisol, 11-deoxycorticosterone (DOC), corticosterone, and progesterone were simultaneously measured by constant infusion in eight control subjects before and during angiotensin II infusion in subpressor (3 ng/min per kg) and pressor (22 ng/min per kg) doses. Plasma levels of aldosterone and cortisol, the heat-labile protein-bound fraction of aldosterone, and hepatic blood flow (HBF) (as estimated by the fractional clearance of indocyanine green) were determined concomitantly. Angiotensin II in a subpressor dose produced a significant decrease of the MCR of aldosterone (by 23%), cortisol (by 16%), DOC (by 26%), corticosterone (by 14%) and progesterone (by 33%). The pressor dose further decreased the respective MCR by 37%, 21%, 40%, 28%, and 42% of the baseline value. Plasma aldosterone levels rose by 317% with subpressor and by 434% with pressor doses. HBF decreased by 18% with subpressor and by 33% with pressor doses of angiotensin II. Furthermore, there were significant negative correlations between the MCR of each steroid and the respective values of the fractional clearance of indocyanine green. We conclude that angiotensin II, by its vasoconstrictive action on the splanchnic vascular bed, decreases the MCR of aldosterone, cortisol, DOC, corticosterone, and progesterone. This decrease has to be taken into account when considering the stimulatory effect of angiotensin II on various plasma steroid concentrations.
Influence of a prostaglandin endoperoxide analogue on the canine pulmonary vascular bed.
Authors: Kadowitz P J , Hyman A L
Published: June 2012

We evaluated the effects of an analogue of the prostaglandin endoperoxide, PGH2, in the canine pulmonary vascular bed. The analogue increased pulmonary arterial pressure whereas cardiac output and left atrial pressure were unchanged. Although pulmonary vascular resistance was increased markedly, only small increases in systemic vascular resistance were observed. In experiments in which blood flow to a lobe was maintained constant, the analogue produced dose-related increases in lobar arterial and small vein pressure but little change in left atrial pressure. These data suggest that the analogue increased resistance to flow by constricting intrapulmonary veins and upstream vessels presumed to be small arteries. The increase in resistance was similar when the lung was perfused with dextran or with blood. In addition, the analogue increased inflation pressure; however, similar increments in vascular resistance were obtained in ventilated and nonventilated lung lobes. Indomethacin, in doses which abolished responses to arachidonic acid, did not attenuate the response to the analogue. These results suggest that interaction with formed elements, increases in airway tone, or stimulation of prostaglandin synthesis contribute little if anything to the pressor response to the analogue. These data show that the analogue is far more potent than the bisenoic prostaglandins in the pulmonary vascular bed and suggest that endoperoxides may represent an active form of the prostaglandins in the lung.
The diastolic viscous properties of cat papillary muscle.
Authors: Noble M I
Published: June 2012

The measurement of ventricular diastolic compliance is complicated by the presence of viscous properties. To approach this problem, cat papillary muscles contracting isometrically at 15/min at 26 degrees C were stretched at different velocities during diastole. At a given length there was no excess of force above that defined by the static force-length curve until velocity of stretch exceeded 1 muscle length/sec. At greater velocities of stretch there was an increase of force with increasing velocity of stretch denoting viscous resistance to stretch. The viscous characteristic was alinear and increased with muscle length. At a given muscle length potentiation of contractile state by paired pulse stimulation caused a change in the diastolic force-length curve but there was no apparent relationship between viscous resistance to stretch and contractile state or the length of the "series viscous element." These results lead one to expect viscous resistance to stretch during rapid filling of the intact left ventricle.
Effects of stroke volume and velocity of ejection on end-systolic pressure of canine left ventricle. End-systolic volume clamping.
Authors: Suga H , Yamakoshi K
Published: June 2012

To study the effects of contraction mode on ventricular end-systolic pressure-volume relationship, we compared the end-systolic pressure of isovolumic contraction with that of ejecting contraction at an identical end-systolic volume. The left ventricle of excised cross-circulated canine hearts was fitted with a water-filled balloon. The balloon was connected to a hydraulic pump that allowed the ventricle to contract to a preset constant end-systolic volume (19-37 ml) from a variable end-diastolic volume. At each of control, enhanced, and depressed levels of contractility, differences of end-systolic pressures of steady state isovolumic and ejecting contractions were evaluated while stroke volume and velocity of ejection were widely varied. The end-systolic pressure in the ejecting contraction tended to decrease by 5-15% from that of the isovolumic beat with increases in either stroke volume to 20-25 ml or peak velocity of ejection to about 800 ml/sec. There was no obvious difference in the results at different levels of contractility. The magnitude of the end-systolic pressure depression due to ejection was, however, relatively small as compared to 4-fold changes in end-systolic pressure due to the changes in contracility. We, therefore, conclude that the ventricular end-systolic pressure-volume relationship is affected slightly by ejection, and that this effect is much smaller than the maximal effect of changing contractility on the end-systolic pressure-volume relationship.
No evidence for product inhibition of the renin-angiotensinogen reaction in the rat.
Authors: Hackenthal E , Hackenthal R , Hofbauer K G
Published: June 2012

The influence of the product of the renin-angiotensinogen reaction, the des-angiotensin I-substrate (des-AI-substrate) on the renin-angiotensinogen reaction has been studied. Des-AI-substrate was prepared from purified rat angiotensinogen by reaction with immobilized renin. The des-AI-substrate had no inhibitory effect on the reaction of partially purified rat renin with rat angiotensinogen at concentrations corresponding to 0.225 or 0.45 micrometer angiotensinogen.
Changes in central catecholaminergic neurons in the spontaneously (genetic) hypertensive rat.
Authors: Saavedra J M , Grobecker H , Axelrod J
Published: June 2012

Catecholamines and catecholamine-synthesizing enzymes have been examined in specific brain areas during the development of spontaneously (genetic) hypertensive (SH) rats. Changes in catecholamine metabolism were localized to regions of the brain implicated in the regulation of blood pressure. Norepinephrine levels and dopamine-beta-hydroxylase (DBH) activities were decreased in specific nuclei of the hypothalamus and in the nucleus interstitialis striae terminalis ventralis, in both young and adult rats. The decrease in the formation of norepinephrine can result in a reduced activation of central alpha-adrenergic receptors which may be related causally to the onset of hypertension. The activity of the epinephrine-forming enzyme, phenylethanolamine-N-methyltransferase (PNMT), was increased in the A1 and A2 areas of the brainstem in young SH rats, but it was normal in adult hypertensive animals. These results implicate adrenergic neurons in the brainstem and noradrenergic neurons in the hypothalamus in the development of spontaneous (genetic) hypertension in rats.
Inhibition of protein degradation in mouse hearts by agents that cause lysosomal dysfunction.
Authors: Wildenthal K , Wakeland J R , Morton P C , Griffin E E
Published: June 2012

Although the heart contains lysosomes, it has been uncertain whether these organelles and their proteolytic enzymes can play an important role in cardiac protein degradation. Recent studies have demonstrated that fetal mouse hearts in organ culture sustain selective derangements in lysosomal structure and function during exposure to chloroquine or nonmetabolizable sugars. Accordingly, we tested the effects of these agents on cardiac proteolysis under controlled conditions in vitro using two techniques (measurement of loss of radioactivity from trichoroacetic acid-precipitable protein after prelabeling with tritiated phenylalanine and measurement of loss of cold phenylalanine after blockade of protein synthesis with cycloheximide). Chloroquine (0.1 mM) reduced the average rate of protein breakdown in hearts of matched littermates from 45%/24 hours to 32%/24 hours (P less than 0.01) and decreased the release of cold phenylalanine by 31 +/- 5% (0.108 vs 0.075 nmol/mg per hour, P less than 0.01). Exposure to 100 mM sucrose for 24-48 hours reduced the rate of breakdown from 44%/24 hours to 33%/24 hours (P less than 0.01) and decreased the release of cold phenylalanine by 35 +/- 9% (0.092 vs. 0.060 nmol/mg per hour, P less than 0.01). The results suggest that interference with lysosomal function in cultured fetal mouse hearts causes a significant reduction in the cardiac capacity to degrade proteins.
Hydrolase activities in the rat aorta. I. Effects of diabetes mellitus and insulin treatment.
Authors: Wolinsky H , Goldfischer S , Capron L , Capron F , Coltoff-Schiller B , Kasak L
Published: June 2012

Vascular disease in diabetics could arise in part from altered vessel wall catebolism. Specific activities of hydrolases in aortic smooth muscle cells from rats with streptozotocin-induced diabetes were measured. Enyzmes included: neutral alpha-glucosidase, alpha-mannosidase, and lysosomal N-acetyl beta-glucosaminidase, beta-galactosidase, cathepsin C, acid alpha-glucosidase, and acid cholesteryl esterase. After 4,8, and 11 weeks of diabetes, activities of all enzymes studied were decreased significantly in diabetic vessels, decreases ranging from 15% for cathepsin C to 62% for alpha-mannosidase. After 3 weeks of diabetes, insulin treatment for 1 week restored enzyme levels to normal. After 7 weeks of diabetes, 1 week of insulin treatment did not restore enzyme levels fully to normal (acid cholesteryl esterase was unchanged); 4 weeks of insulin did. Acid phosphatase and N-acetyl beta-glucosaminidase activities were reduced markedly in histochemical studies of diabetic aortas at all time periods and were restored by insulin treatment. Alloxan-induced diabetes gave results similar to those with streptozotocin. Significant decreases of aortic hydrolase activities, including those of lysosomes, occur in experimental diabetes mellitus and could contribute to accumulation of substrates in vascular smooth muscle cells.
Initial myocardial adjustments to brief periods of ischemia and reperfusion in the conscious dog.
Authors: Pagani M , Vatner S F , Baig H , Braunwald E
Published: June 2012

The changes in left ventricular (LV) dynamics induced by brief periods of ischemia (100 seconds) and subsequent reperfusion were analyzed in conscious dogs. Global LV ischemia, induced by partially occluding the left main coronary artery, reduced LV flow homogeneously and impaired LV function as reflected by decreases in LV stroke "work" (89 +/- 4% M +/- SE), systolic shortening (72 +/- 4%), velocity of shortening (56 +/- 6%), LV systolic pressure (34 +/- 5%), and dP/dt (59 +/- 6%). Regional LV ischemia, induced by occluding either the left circumflex or anterior descending coronary artery completely, reduced flow to the ischemic segment (82 +/- 3%) while decreasing segment work (96 +/- 5%), shortening (82 +/- 3%), and velocity of shortening (70 +/- 5%), with minimal depression of overall LV function. In both groups the extent of shortening was reduced more rapidly and greater (P less than 0.01) than shortening velocity. Moreover, with localized ischemia, segment work was reduced more (P less than 0.01) than shortening. With reperfusion, a transient overshoot in function above preischemic control levels was observed in both groups (global work increased by 60 +/- 12% and regional work by 28 +/- 4% above control). This overshoot was not dependent on adrenergic mechanisms, but was prevented by inhibiting reactive hyperemia. Thus myocardial ischemia induces a dissociation between extent and rate of myocardial shortening. A further dissociation between shortening and work is apparent with regional ischemia. After reperfusion there is a transient overshoot in function which appears to be dependent upon the associated reactive hyperemia.
Electrotonic interaction during canine ventricular repolarization.
Authors: Toyoshima H , Burgess M J
Published: June 2012

Canine ventricular refractory periods were measured during test site drive, during drive of single ectopic sites, during fusion drive from two ectopic sites, and during fusion drive from an ectopic site and the test site. Refractory period duration was dependent on the driving modes employed. Refractory periods were 2.63 +/- 0.73%, 3.42 +/- 0.87%, 3.54 +/- 100%, and 4.68 +/- 1.36% (mean +/- SD) shorter during drive of single ectopic sites 2, 4, 6, and 40-60 mm, respectively, from the test site than during test site drive. During fusion drive from two ectopic sites, refractory periods were an average of 2.44 +/- 1.04 msec (mean +/- SD) less than during drive from a single ectopic site (P less than 0.005). When fusion of activation, induced by ectopic and test site drive, was located within 4 mm or less of the test site, refractory periods during fusion drive were also significantly shorter than during test site drive (P less than 0.05). Refractory periods were as much as 10 msec shorter when fusion occurred within 1 mm of the test site than their durations during test site drive. The differences in refractory periods measured during various driving modes were most likely due to electrotonic interactions during ventricular repolarization and are explicable on the basis of the intracellular distribution of potentials to be expected with each driving mode.
Inhibition of prostaglandin synthesis by indomethacin augments the renal vasodilator response to bradykinin in the anesthetized dog.
Authors: Lonigro A J , Hagemann M H , Stephenson A H , Fry C L
Published: June 2012

It has been proposed that the increase in renal blood flow (RBF) produced by bradykinin (BK) is mediated or amplified by the intrarenal generation of prostaglandins. The present investigation was designed to explore these relationships further. In anesthetized dogs, the renal arterial infusion of BK (100 ng/kg per min), prior to the intravenous administration of indomethacin, produced a 93 +/- 14% increase in RBF and an increase in the renal venous concentration of a prostaglandin E-like substance ("PGE") from 51 +/- 23 to 235 +/- 73 pg/ml as determined by bioassay. Following indomethacin (5 mg/kg), the same dose of BK produced a 151 +/- 18% increase in RBF (P less than 0.001 compared to the preindomethacin increase) and the concentration of "PGE" remained largely below the threshold of sensitivity of the bioassay system. In three experiments, a highly sensitive and specific radioimmunoassay technique was used to obtain better quantitative estimates of concentrations of E2-like ("PGE2") and F2alpha-like ("PGF2alpha") substances so that determinations of renal efflux could be made. Thus, prior to indomethacin, BK administration increased RBF by 142 +/- 39 ml/min and was associated with a 26-fold increase in renal efflux of "PGE2" and a 12-fold increase in "PGF2alpha." After indomethacin, the effluxes of both "PGE2" and "PGF2alpha" decreased to negligible levels and were not influenced by BK infusion, although RBF increased by 225 +/- 75 ml/min. These results are not compatible with the hypothesis that intrarenal prostaglandins mediate or amplify the renal vasodilator response to BK.
Lipoproteins and the inhibitory effect of human endothelial cells on platelet function.
Authors: Nordøy A , Svensson B , Wiebe D , Hoak J C
Published: June 2012

We investigated the effect of plasma low density lipoproteins (LDL), very low density lipoproteins (VLDL), and high density lipoproteins (HDL) on the platelet inhibitory effect of primary cultures of human endothelial cell monolayers (ECM). ECM incubated with lipoprotein-deficient plasma (LDP) for 2 hours at 37 degrees C had an inhibitory effect on ADP- and collagen-induced platelet aggregation and prostaglandin production in platelet-rich plasma similar to that observed when ECM were preincubated with growth medium or plasma. Concentrations of LDL in LDP up to protein concentration of 1600 microgram/ml had an inhibitory effect on the endothelial cells' ability to modulate these platelet reactions. VLDL at the highest concentration (1600 microgram/ml) had a slightly inhibitory effect, whereas HDL showed no such effect. The inhibitory effect of LDL was not observed during the first hour of incubation. When HDL in concentrations similar to or higher than LDL were combined with LDL, the inhibitory effect of LDL was partially reduced. VLDL combined with LDL or HDL did not interfere with the effects of the later fractions. The inhibitory effect of LDL was significantly reduced when LDL were diluted in whole plasma. Prostacyclin which is synthesized and released from the endothelial cells and contributes to the inhibitory effect upon platelets did not change its effect on platelet reactivity by preincubation with the various lipoprotein fractions. The current studies may indicate that LDL have a direct effect on the endothelial cells and that this effect may be partially counteracted by HDL. This effect of LDL on the endothelial cells reduces the endothelium's ability to inhibit platelet aggregation and thus could favor the tendency to thrombus formation.
Effect of changing metabolic rate on local blood flow control in the canine hindlimb.
Authors: Goodman A H , Einstein R , Granger H J
Published: June 2012

This study examined the effect of changing hindlimb metabolic rate on hindlimb blood flow control in anesthetized dogs. The hyperemias induced by graded levels of arterial hypoxia and the degree of steady state autoregulation evoked by changes in blood pressure were measured. Metabolic rate was increased above the resting value by direct electrical stimulation of hindlimb muscles at rates from 0.5 to 1.5 pulses/second, and in three dogs was reduced by cooling. In response to 6 minutes of arterial hypoxia, hindlimb blood flow steadily increased. At rest, and at each level of muscle stimulation, the steepness of the response increased as arterial oxygen saturation (SAO2) decreased. At all levels of SAO2, the response was steeper at increasing stimulation rates. For SAO2 greater than 50%, the relationship between the percentage increase in blood flow from control and SAO2, however, was unaffected by the degree of muscle activity, suggesting that during mild to moderate hypoxia the dynamics of the response were similar whether the muscles were at rest or exercising. The responses to severe hypoxia (SAO2 less than 50%) during stimulation were significantly enhanced compared with those at rest. Autoregulation of blood flow was measured in the steady state by comparing the relative change in blood flow from control with the relative change in blood pressure that produced it. Steady state autoregulation was weak at rest, but improved markedly with increasing muscle stimulation. Conversely, cooling the hindlimb depressed the resting steady state autoregulation. A close correlation was found between the degree of autoregulation and the hindlimb metabolic rate. The results suggest that tissue metabolic rate determines the precision of local blood flow control.
Interrelations of the renal kallikrein-kinin system and renal prostaglandins in the conscious rat. Influence of mineralocorticoids.
Authors: Nasjletti A , McGiff J C , Colina-Chourio J
Published: June 2012

To investigate possible relationships between mineralocorticoids, the renal kallikreinkinin system, and renal prostaglandins, we studied the effects of aldosterone and deoxycorticosterone acetate (DOCA) and of an inhibitor of kallikrein, aprotinin, on the urinary excretion of kallikrein and prostaglandin E-like substance (PGE) by the conscious rat. Aldosterone (0.25 mg/day, sc), injected into six rats for 14 consecutive days, increased PGE and kallikrein excretion from 52.3 +/- 8.7 (mean +/- SE) ng/day and 29.8 +/- 3.0 U/day to 141.5 +/- 30.7 ng/day (P less than 0.02) and 105.6 +/- 28.1 U/day (P less than 0.05), respectively. Similarly, injections of DOCA (5 mg/day) into 14 rats increased the excretion of PGE and kallikrein, measured before and after 10 days of treatment, from 41.6 +/- 3.9 ng/day and 39.4 +/-4.9 U/day to 194.3 +/- 20.7 ng/day (P less than 0.001) and 90.6 +/- 14.7 U/day (P less than 0.001), respectively. Injections of aprotinin for 4 days (50,000 KIU twice daily, sc) in conjunction with DOCA into eight rats pretreated with the steroid for 10 days decreased the urinary excretion of kallikrein and PGE, measured on the 4th day of aprotinin administration, by 61% (P less than 0.01) and 80% (P less than 0.001), respectively. Urinary potassium excretion decreased throughout the course of aprotinin treatment, whereas sodium excretion and urine volume decreased during the first 2 days but subsequently returned toward control values. This study demonstrates that mineralocorticoids enhance the urinary excretion of PGE, and this effect appears to be a consequence of activation of the renal kallikrein-kinin system by the steroids. Thus, changes in the intrarenal activity of the kallikrein-kinin system may modulate renal prostaglandin release.
Inotropic and toxic effects of a polar cardiac glycoside derivative in the dog.
Authors: Mudge G H , Lloyd B L , Greenblatt D J , Smith T W
Published: June 2012

It has been suggested that central nervous system (CNS) neuroexcitation plays an important role in digitalis-induced cardiac arrhythmias. To elucidate further the role of the CNS in digitalis-induced arrhythmias, the inotropic and toxic effects of a highly polar semisynthetic cardiac glycoside, 3beta-O-(4 amino-4,6 dideoxy-beta-D-galactopyranosyl)-digitoxigenin (ASI-222) were compared to those of digoxin and correlated with plasma and cerebrospinal fluid (CSF) concentrations of each drug. Thirteen dogs anesthetized with sodium pentobarbital were given repeated intravenous doses of digoxin or ASI-222. Ventricular tachycardia was elicited at a mean dose of digoxin of 0.12 mg/kg, compared with 0.09 mg/kg for ASI-222 (not significant). Terminal ventricular fibrillation occurred after 0.18 mg/kg of digoxin, a value significantly larger than the ASI-222 dose (0.14 mg/kg, P less than 0.05) required to produce lethal arrhythmias. Digoxin produced a 21% increase in LV dP/dt at a plasma digoxin concentration of 20.0 +/- 2 ng/ml (mean +/- SEM) 30 minutes after 0.05 mg/kg; the CSF digoxin concentration at this time averaged 0.7 +/- 0.1 ng/ml. At death, the plasma digoxin concentration was 88 +/- 16 ng/ml and CSF digoxin concentration was 5.7 +/- 1.6 ng/ml. ASI-222 produced a similar 25% increase in LV dP/dt 30 minutes after administration of 0.05 mg/kg, with a plasma concentration of 18 +/- 2 ng/ml as determined by a newly developed radioimmunoassay. The plasma ASI-222 concentration at death, 95 +/- 18 ng/ml, was similar to that of digoxin. However, CSF samples at 30 minutes and at death showed no detectable levels of ASI-222. Thus, despite similar inotropic and toxic responses and similar plasma drug concentrations compared to digoxin, ASI-222 was demonstrated to have limited if any access to the CNS as judged by CSF concentrations. These findings suggest that direct CNS stimulation does not play a primary part in the genesis of digitalis-induced cardiac arrhythmias in this experimental model, or that CNS effects are mediated by an area or areas lacking an effective blood-brain barrier.
The [18F]fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man.
Authors: Reivich M , Kuhl D , Wolf A , Greenberg J , Phelps M , Ido T , Casella V , Fowler J , Hoffman E , Alavi A , Som P , Sokoloff L
Published: June 2012

A method has been developed to measure local glucose consumption in the various structures of the brain in man with three-dimensional resolution. [18F]-2-deoxy-2-fluoro-D-glucose is used as a tracer for the exchange of glucose between plasma and brain and its phosphorylation by hexokinase in the tissue. A mathematical model and derived operational equation are used which enable local cerebral glucose consumption to be calculated in terms of the following measurable variables. An intravenous bolus of [18F]-2-deoxy-2-fluoro-D-glucose is given and the arterial specific activity monitored for a predetermined period of from 30 to 120 minutes. Starting at 30 minutes, the activity in a series of sections through the brain is determined with three-dimensional resolution by an emission tomographic scanner. The method was used to measure local cerebral glucose consumption in two normal volunteers. The values in gray matter structures range from 5.79 mg/100 g per minute in the cerebellar cortex to 10.27 in the visual cortex, whereas, in white matter structures, the values range from 3.64 mg/100 g per minute in the corpus callosum to 4.22 in the occipital lobe. Average values for gray matter, white matter, and whole brain metabolic rates, calculated as a weighted average based on the approximate volume of each structure, are 8.05, 3.80, and 5.90 mg/100 g per minute, respectively. The value of 5.9 mg/100 g per minute compares favorably with values previously reported.
Choline uptake into renal phospholipids following renal ischemia in rats.
Authors: Siegel M B , Lowenstein L M , Levinsky N G
Published: June 2012

Renal phospholipid metabolism was studied after ischemia was induced by occlusion of the left renal artery in the rat. There was no change in the rate of cellular [14C]choline uptake after 25 or 60 minutes of ischemia. However, [14C]choline incorporation into phospholipid was two to three times greater in slices from the ischemic kidney than in slices from the contralateral control kidney. The increase occurred after 25 minutes of ischemia plus 15 minutes of reflow, and after 60 minutes of ischemia with or without reflow. When [14C]choline was injected into rats after a 60-minute period of renal ischemia, the rate of incorporation into phospholipid in the ischemic kidney was almost twice that of the control kidney. These results were similar to those of the in vitro experiments. Since virtually all of the cellular phospholipids of the kidney are present in cellular membranes, renal ischemia affects membrane metabolism. The mean distribution ratio of alpha-aminoisobutyric acid in slices of kidneys ischemic for 60 minutes was similar to that of control slices: 4.11 +/- 0.2 (SEM) vs. 4.30 +/- 0.30. The normal uptake of alpha-aminoisobutyric acid indicates that the increased incorporation of choline is associated with functional integrity of the membrane.
Supraventricular pacemaker underdrive in the absence of sinus nodal influences in the conscious dog.
Authors: Loeb J M , Murdock D K , Randall W C , Euler D E
Published: June 2012

The ability to reduce and maintain heart rate by electrical stimulation (underdrive) was tested in three groups of chronically instrumented dogs: sinoatrial node intact, ectopic atrial pacemaker produced by injection of rapidly hardening latex into the sinoatrial nodal artery, and idioventricular pacemaker produced by injection of formalin into the atrioventricular node. In the conscious unsedated state, underdrive of sinoatrial or idioventricular pacemakers resulted in competition between driven and intrinsic foci. However, the cycle length of ectopic atrial pacemakers could be increased by 148.4 +/- 30.7 msec (P less than 0.001) and maintained at that value. Cessation of underdrive resulted in a period of pacemaker suppression similar to that produced following overdrive. Single premature stimuli produced marked cycle length prolongations in dogs with ectopic atrial foci. Total autonomic blockade had no significant effect on the production of underdrive. Thus, the results of the present experiments provide evidence for maintained capture of cardiac pacemakers at rates significantly below intrinsic control and indicate that underdrive varies as a function of pacemaker site. Underdrive may explain the failure of junctional escape in the presence of slower atrial rhythms.
Prostaglandins and renin release: the effect of PGI2, PGE2, and 13,14-dihydro PGE2 on the baroreceptor mechanism of renin release in the dog.
Authors: Gerber J G , Keller R T , Nies A S
Published: June 2012

We compared the ability of the vasodilator prostaglandins PGI2, PGE2, and 13,14-dihydro PGE2 to release renin when infused into the denervated, nonfiltering canine kidney in vivo. Papaverine was used as a nonprostaglandin vasodilator. All the prostaglandins tested were capable of stimulating renin secretion, with the scale of potency being 13,14-dihydro PGE2 greater than PGI2 greater than PGE2; papaverine had no effect on renin secretion. These results indicate that both PGE2 and PGI2 can stimulate renin secretion but that vasodilation per se is not a stimulus. 13,14-Dihydro PGE2 was included because it is a poorer substrate than PGE2, both for transport into cells and catabolism to inactive products, but has comparable potency to PGE2 when tested in systems with limited ability to catabolize PGE2. The fact that 13,14-dihydro PGE2 was the most potent prostaglandin tested suggests that the effects of PGE2 in our system are reduced by the kidneys' recognized ability to extract and catabolize PGE2. Since PGI2 is less avidly metabolized than PGE2 by the kidney, the differences in observed potency between PGE2 and PGI2 could be largely the result of differences in renal catabolism of the two prostaglandins rather than differences in intrinsic potency. Therefore, both PGE2 and PGI2 are candidates for the endogenous prostaglandin responsible for stimulating renin secretion.
Effects of some components of ischemia on electrical activity and reentry in the canine ventricular conducting system.
Authors: Senges J , Brachmann J , Pelzer D , Mizutani T , Kübler W
Published: June 2012

We used intracellular microelectrodes to study the electrophysiological effects of combinations of components of ischemia and their relation to the occurrence of ventricular arrhythmias in the specialized conducting system of isolated canine right ventricles. The middle area of the free wall was exposed to various test solutions in the center compartment of a three-chambered bath; the base and apex of the preparation were superfused with normal Tyrode's solution in the outer control compartments. Hypoxia (Po2 40 mm Hg), lactic acidosis (pH 6.5), and orciprenaline (10(-6) M), either alone or combined, failed to affect the action potential amplitude or the conduction velocity of the subendocardial fibers, and no arrhythmias occurred. The action potential duration and the effective refractory period were markedly prolonged by lactic acidosis. Exposure of the test regions to 15 mM K+ plus orciprenaline resulted in marked decreases in action potential amplitude and conduction velocity. Abnormalities of impulse transmission through the depressed area included high degrees of rate-dependent block, one-way block, warming-up phenomenon, and the Wenckebach phenomenon. Such conditions regularly provoked the appearance of single, sustained, or concealed reentrant depolarizations. The combined effects of hypoxia, 15 mM K+, and orciprenaline resulted in further depression of the already depressed action potential in the depolarized fibers. Our results indicate that regional increases of extracellular K+ may be the predominant factor of the components of ischemia we studied which facilitates the initiation of reentrant arrhythmias.
The effects of cocaine and metanephrine on the cardiac responses to sympathetic nerve stimulation in dogs.
Authors: Matsuda Y , Masuda Y , Levy M N
Published: June 2012

The effects of infusions of cocaine (COC) and metanephrine (MET) on the inotropic and chronotropic responses to cardiac sympathetic nerve stimulation were studied in open-chest, anesthetized dogs. COC blocks the neuronal uptake of norepinephrine (NE), whereas MET blocks the extraneuronal uptake. Both blocking agents slightly enhanced the inotropic but not the chronotropic responses. COC prolonged the cardiac responses significantly, particularly the chronotropic responses, whereas MET had no appreciable effect on the durations of these responses. Hence, it appears that the neuronal uptake mechanism plays a major role in the dissipation of neurally released NE in the heart, but that the extra-neuronal uptake mechanism plays only a minor role in its dissipation. In contrast to the results in certain other tissues, the combined effects of COC and MET on the cardiac responses were no greater or more prolonged than the sum of the effects produced by each agent acting alone.
Extracellular potentials related to intracellular action potentials during impulse conduction in anisotropic canine cardiac muscle.
Authors: Spach M S , Miller W T , Miller-Jones E , Warren R B , Barr R C
Published: June 2012

This paper considers a quantitative description of intracellular and transmembrane currents in anisotropic muscle, with emphasis on the factors that determine the extracellular potentials. Although Vmax of the intracellular action potential had no relation to changes in conduction velocity in anisotropic tissue with constant membrane properties, the extracellular waveforms were quite sensitive to velocity changes. Large amplitude biphasic deflection occurred in the fast areas, and in the slow areas the waveforms were of lower amplitude and triphasic in shape; i.e., negative potentials preceded the biphasic positive-negative deflection. The extracellular potentials were simulated on the bases of a model of intracellular currents, and the theoretical and measured results showed good agreement. In tissue with anisotropic conductivity, the relationship between the spatial intracellualr potential gradient and the magnitude of the extracellular potential of the excitation wave was opposite to the classical relationship in isotropic tissue. Due to the influence of the effective intracellular conductivity on the spread of intracellular currents and on conduction velocity, in anisotropic tissue the extracellular potential decreased as the intracellular potential gradient increased. The peak values of the positive and negative potentials and the spatial distribution of the potential gradients varied considerably along the activation front. These findings were accounted for by differences in the distribution and spatial extent of the transmembrane currents, which were determined by the intracellular currents. The theoretical analysis showed that intracellular and transmembrane currents were proportional to the local conduction velocities of the wavefront. Thereby, it was not possible to have a "uniform layer" of current when there were differences in conduction velocity along the length of the excitation wave. The implications of the analysis are considerable, since the gratifying agreement between the theoretical and measured results indicates that the details of the extracellular waveforms can be explained on the basis of the distribution of intracellular currents; i.e., extracellular potentials provide a sensitive index of intracellular current flow.
Changes in mitochondrial DNA in cardiac hypertrophy in the rat.
Authors: Rajamanickam C , Merten S , Kwiatkowska-Patzer B , Chuang C H , Zak R , Rabinowitz M
Published: June 2012

We studied DNA (mtDNA) replication in adult female rat hearts undergoing hypertrophy secondary to constriction of the ascending aorta. MtDNA was measured in isolated mitochondria by a fluorometric method adapted for that purpose. The conditions for removal of contaminating nuclear DNA were developed, and the purity of the mtDNA was assessed from its molecular conformation (open and closed circles) and by renaturation-kinetic analysis. The mtDNA concentration in mitochondria, expressed as micrograms of DNA per milligram of mitochondrial protein, increased 2, 4, and 7 days postoperatively by 21, 73, and 98%, respectively. Similar results were obtained when mtDNA was expressed per nonomole of cytochrome a. The population of replicative intermediates of mtDNA was analyzed by electron microscopy. In normal hearts, we observed molecular forms characteristic of animal mtDNA, such as circular monomers and dimers, catenated molecules, D-loops, expanded D-loops, and gapped molecules. D-loop frequency, which was near 50% in the mtDNA of control hearts, was markedly reduced to 5-7% in hypertrophying hearts. This result indicates that the increase in replicative flux of mtDNA is associated with the removal of a block in the conversion of D-loops to other intermediates.
Transient responses of rabbit cerebral blood vessels to norepinephrine: correlation with intrinsic myogenic tone.
Authors: Bevan J A
Published: June 2012

Transient contractile responses to norepinephrine (NE) of vascular segments from the rabbit vertebral, internal carotid, and basilar arteries rise to a peak within several seconds, and in the presence of the agonist, reverse rapidly, relaxing with a half-time of 15 +/- 3.2 seconds. In the basilar artery, peak contraction is approximately 25% of the maximum response mediated via the "alpha-like" adrenoreceptors and is elicited by NE 10(-7) M. Steady state contractions are seen with higher concentrations. Transient contractile responses are absent in segments from the brachiocephalic and external carotid arteries, and their incidence increases the more rostral along the length of the vertebral and internal carotid artery the origin of the segment studied. They were seen in all preparations of the intracranial vertebral and basilar arteries. There is a good correlation between the occurrence in any particular vascular segment of the transient contractile response and intrinsic tone as assessed by relaxation to papaverine (10(-6) M). The response was blocked by alpha-adrenergic receptor blocking agents and was not elicited by d-NE nor tetrahydrazoline or oxymetazoline. This response may be analogous to the first phase of the biphasic contraction found in many other blood vessels. Since in cerebral vessels the agonist concentration to elicit the first phase is several orders of magnitude lower than the second, it can appear in the absence of the latter.
In vivo assessment in sheep of thromboresistant materials by determination of platelet survival.
Authors: Lindon J N , Collins R E , Coe N P , Jagoda A , Brier-Russell D , Merrill E W , Salzman E W
Published: June 2012

The thromboresistance of 13 potentially blood-compatible polymers was assessed in sheep by determining survival of 51Cr-labeled platelets. Polymer tubing (120-150 cm x 2.0-2.3 mm i.d.) coiled around the neck was incorporated into the circulation through silicone rubber connectors as a carotid artery-external jugular vein shunt. The mean platelet half-life in control animals ("shunt control") was 78.2 +/- 2.8 (SEM) hours. Eleven of the 13 polymers tested significantly shortened platelet half-life. Polyvinyl chloride (T1/2 = 45.4 +/- 3.0 hours), polyperfluoro ethylene (T1/2 = 47.0 +/-1.6 hours), and a polymethylacrylate (PMA)/acrilonitrile copolymer (T1/2 = 50.7 +/- 7.0 hours) produced the greatest shortening. Only silica-free polydimethyl siloxane (T1/2 = 74.7 +/- 4.9 hours) and PMA (T1/2 = 81.5 +/- 3.4 hours) were indistinguishable from shunt controls. Pretreatment of PMA tubing with autologous plasma in a paired trial significantly increased platelet half-life (P less than 0.05 vs. untreated PMA). This system offers an economical, reproducible, sensitive, and biologically relevant method for assessment of the reactivity of artificial surfaces with platelets.
Effect of afterload reduction on myocardial energetics.
Authors: Ford L E
Published: June 2012

Consideration of muscle energetics suggests that the ventricle has a very definite optimum range of operating wall tensions, and that clinical advantage can be gained by maintaining the tension within this range.
Role of peripheral vasodilation in the hypotensive response to left ventriculography in anesthetized dogs.
Authors: Shaw D D , Wolf G L , Baltaxe H A
Published: June 2012

Hypotension after left ventriculography (LVG) is believed to result from direct myocardial toxicity, peripheral vasodilation, or a combination of both. The contribution of each has not been established. Thus, LVG was performed in anesthetized dogs under conditions in which peripheral vascular reactivity (PVR) was altered pathophysiologically (aortic coarctation) or pharmacologically (acetylcholine infusion). Ventricular pressure (LVP), its first derivative (dP/dt), aortic pressure (AoP), and carotid and femoral flows were monitored. When PVR was normal, LVG was associated with significant hemodynamic changes which reached a maximum 25-35 seconds after injection. Left ventricular and aortic diastolic pressures were decreased by 22 and 48%, whereas carotid and femoral systolic flows were increased by 41 and 59%. During acetylcholine infusion, LVG did not cause systolic hypotension and peripheral flows were maintained strikingly constant. Similarly, LVG also was associated with insignificant changes in systolic pressures and carotid flow in the presence of aortic coarctation. These results demonstrate that the hypotension attendant with LVG is directly related to the augmentation in peripheral flow, suggesting that the response is mediated almost exclusively by peripheral vasodilation.
Electrophoretic profiles of nonhistone nuclear proteins of human hearts with muscular subaortic stenosis.
Authors: Liew C C , Sole M J , Silver M D , Wigle E D
Published: June 2012

Muscular subaortic stenosis (MSS) is a genetically determined cardiomyopathy, whereas right ventricular infundibular hypertrophy (IH) apparently is an acquired condition. Since genetic expression in eukaryotic cells may be regulated primarily by DNA-associated proteins, we isolated and characterized the proteins of heart nuclei from nine patients with MSS, eight with IH, and two with normal (N) hearts. More than 150 proteins could be identified by two-dimensional polyacrylamide gel electrophoresis. Proteins in the entire region from pH 7.0 to 9.0 with molecular weights (Mr) ranging from 35,000 to 41,000 and a protein focusing from pH 5.2 to 5.3 with Mr of 55,000 were strikingly reduced in MSS. Again the electrophoretic patterns of N and IH were similar. The electrophoretic patterns of nonhistone nuclear protein (NHNP) in MSS relative to N showed a striking resemblance to those demonstrated previously for the early stage (myolytic phase) of hamster cardiomyopathy relative to the matched control. Since NHNP interacting with DNA appears to play a major role in genetic expression, it is possible that some of the manifestations of MSS could be due to different components of NHNP in the affected hearts.
Anti-alprenolol antibodies in the rabbit. A new probe for the study of beta-adrenergic receptor interaction.
Authors: Rockson S G , Homcy C J , Haber E
Published: June 2012

We immunized rabbits with an antigen prepared by covalent linkage of alprenolol, a beta-adrenergic receptor antagonist, to bovine serum albumin. Competitive inhibition of [3H]dihydroalprenolol binding to antisera with a variety of unlabeled ligands revealed broad antibody specificity for beta-adrenergic antagonists and agonists. The antiserum was subjected to affintiy fractionation on hydroxybenzylpindolol-Sepharose 4B. Successive elution with 100 mM Tris HCl, 1M NaCl, 4 M LiBr, and 5 M guanidine yielded fractions with increasing affintiy for hydroxybenzylpindolol. The ligand-binding properties of these affinity-fractionated antibodies suggest that certain of these fractions recognize structural aspects of individual beta-adrenergic ligands which are irrelevant to their biological activity, whereas others can be used to distinguish shared functional properties, such as the ethanolamine side chain, within the structural heterogeneity of beta-adrenergic drugs. In particular, elution of hydroxybenzylpindolol-adsorbed antibody with (-)-propranolol allowed identification of an antibody fraction specific for the (-)-stereoisomer. Thus, affinity fractionation of antibodies raised against beta-adrenergic ligands can provide useful analogues for the further study of the recognition properties of the beta-adrenergic receptor.
Inlet and intrachamber concentration distributions in tracer studies of the canine central circulation and their relation to the isotope dilution residue function.
Authors: Castellana F S , Snapinn S M , Tam S Y , Case R B
Published: June 2012

We analyzed the isotope dilution residue function from a single cardiac chamber for an arbitrary inlet distribution of tracer and arbitrary mixing within the chamber, and established a general relationship between cardiac output and the chamber residue function. In our experiments, we made simultaneous temperature measurements in three left ventricular chamber subregions of the dog subjected to left and right atrial injections of chilled saline. Flow-proportional tracer labeling always occurred at the left ventricular inlet when injection was into the right atrium. This state almost never obtained, however, with direct left atrial injection, although it was approximated most closely when multiple side hole cathers were used. We also demonstrated that imperfect tracer mixing in the normal ventricle can lead to significant regional temperature inequalities during tracer passage. These inequalities are more pronounced in the ventricle with compromised function, but in both normal and compromised ventricles they are minimal several beats after tracer concentration peaks if injection is into the right atrium.
Structure of the freeze-fractured sarcolemma in the normal and anoxic rabbit myocardium.
Authors: Frank J S , Beydler S , Kreman M , Rau E E
Published: June 2012

The purpose of this study was to examine the ultrastructure of the sarcolemma in the normal and severely anoxic rabbit heart with the technique of freeze-fracture. Severe anoxia and subsequent reoxygenation cause a significant decrease (31%) in intramembranous particles (IMP) in the P face of the membrane and a 25% decrease in the E face. P face IMP's are severely aggregated. The decrease in density and the redistribution of IMP's indicate a severely altered lipoprotein structure of the sarcolemma. In addition, the necks of caveolae open and the caveolae become flattened in the plane of the membrane. With reoxygenation, many rupture. Spherical projections of cytoplasmic vesicles appear in the membrane (possibly of sarcoplasmic reticulum or lysosomal origin) and also can be seen to rupture after reoxygenation. When glucose is present in the perfusate, it affords some protection against these structural defects. We propose that the fragmentation or holes in the sarcolemma reported in severe anoxia are directly related to the structural changes reported in this study.