bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic studies of taurine in bovine Purkinje fibers.
Authors: Baskin S I , Zaydon P T , Kendrick Z V , Katz T C , Orr P L
Published: June 2012

Taurine (2-aminoethane sulfonic acid) is found in high concentrations in the heart, particularly in Purkinje fibers. We studied the transport of taurine in Purkinje fibers that were excised rapidly from the heart and placed in a vessel containing oxygenated Krebs-Henseleit solution (37 degrees C). After equilibration, 4.4 x 10(-6)M radiolabeled taurine[14C] was added to the bath. A computer compartmental analysis of the uptake and efflux indicated the presence of two pools for uptake--a pool with a rapid kinetics K1 (t1/2 = 0.80 min) and K2 (t1/2 = 176.30 min). These studies suggest that Purkinje fibers have the capacity to transport taurine rapidly. Michaelis-Menten procedures showed the presence of a high affinity and a low affinity transport process. Guanidinotaurine, at a 10:1 ratio, had no appreciable effect on taurine uptake, but 3-aminopropane phosphonic acid decreased taurine uptake by 42.7%. Ouabain and acetylstrophanthidin (10(-5) M) inhibited taurine uptake (K1) by 34% and 73%, respectively. The inhibition of the rapid component of taurine uptake suggests that K1 is an energy-linked process possibly requiring Na+,K+-ATPase. Taurine uptake in a calcium-free medium was decreased by 58%. Verapamil (6 x 10(-6) M) decreased taurine uptake by 42%. Tetrodotoxin (3.4 x 10(-5) M) decreased taurine uptake by 51%. The requirement of calcium and sodium for taurine uptake suggests an important relationship between taurine, calcium, and sodium in the function of fibers in the cardiac conducting system.
Regional edema formation in isolated perfused dog lungs.
Authors: Hales C A , Kanarek D J , Ahluwalia B , Latty A , Erdmann J , Javaheri S , Kazemi H
Published: June 2012

Studies using gravimetric analysis of lungs of frozen animals have suggested that the differences in pulmonary microvascular pressure between non-dependent and dependent lung do not influence the formation of regional pulmonary edema. We wondered if the inability to detect variation in regional extravascular lung water (EVLW) was due to the slow freezing process and, therefore, reassessed the distribution of EVLW in vertically suspended isolated perfused dog lungs with a radioisotopic technique that does not require freezing. Total lung water (TLW), blood or intravascular lung water (IVLW), and EVLW were measured in absolute quantities using a positron camera and the positron-emitting isotopes C15O as a blood label and H2(15)O as a total lung water label. Mean isotopic TLW in 17 lungs that were normal or moderately edematous (wet:dry ratio < 7) was 142 +/- 9 (SE) ml compared to the gravimetric estimate of 148 +/- 7 ml (r = 0.92) and isotopic EVLW was 64 +/- 6 ml compared to the gravimetric estimate of 70 +/- 6 ml (r = 0.8). Analysis of the distribution of regional isotopically measured EVLW in the 17 lungs in various states of spontaneous edema formation revealed a small non-dependent to dependent, gravity-related increase in percent regional EVLW compared to percent regional TLW, which did not vary with the degree of edema in the lung. Serial measurements of absolute regional EVLW in four lungs during spontaneously developing edema also failed to show a disproportionate increase in accumulation of EVLW in any lung zone. Thus, despite the wide variation in microvascular hydrostatic pressure between top and bottom of the vertical isolated lung, edema formation seems to be uniform.
Decreased vascular and increased adrenal and renal sensitivity to angiotensin II in the newborn lamb.
Authors: Siegel S R
Published: June 2012

The effects of two doses of angiotensin II (0.025 micrograms/kg per min and 0.25 micrograms/kg per min) on plasma renin activity (PRA), aldosterone concentration, creatinine clearance, and sodium and potassium excretion were studied in two groups of 2- to 3-week-old lambs. The 0.025 micrograms/kg per min dose of angiotensin II also was studied in six adult ewes. In response to the angiotensin II infusions, PRA decreased in the newborns from baselines of 24.5 +/- 2.3 ng/ml per hr (mean +/- SE) and 22.9 +/- 3.5 to 13.6 +/- 0.8 and 13.0 +/- 2.2 at 30 minutes (P < 0.01), respectively, and returned to baseline at 60 minutes; PRA decreased from 1.7 +/- 0.1 to 0.95 +/- 0.3 ng/ml per hr at 30 minutes (P < 0.01) in the ewe and returned to baseline at 60 minutes. Plasma aldosterone increased in the newborns from baselines of 17.4 +/- 5.0 ng/dl and 14.7 +/0 3.9 to 33.1 +/- 6.9 and 32.5 +/- 6.3, respectively, at 15 minutes (P < 0.01) and returned to baseline at 60 minutes. Plasma aldosterone increased from 4.3 +/- 0.7 to 9.2 +/- 2.0 ng/dl in the ewe, and returned to baseline at 60 minutes. The change in the PRA and aldosterone responses from baseline to peak for the low and high angiotensin dose was similar in the newborn lambs and greater than in the ewe (P < 0.01). There was no change in the creatinine clearance, plasma sodium, or hematocrit. Urine sodium excretion increased from 0.16 +/- 0.04 total mEq/30 min to 0.87 +/- 0.27 (P < 0.05) in the newborns during the 0.25 micrograms/kg per min angiotensin II infusion. We conclude that, under basal conditions, the newborn lamb has high PRA and aldosterone levels with decreased pressor and increased aldosterone and renin release responsiveness to angiotensin II compared to the adult.
Release of vasodilator prostaglandin, PGI2, from isolated rat lung during vasoconstriction.
Authors: Voelkel N F , Gerber J G , McMurtry I F , Nies A S , Reeves J T
Published: June 2012

Prostaglandins are generated by the lungs and released into the circulation. Since inhibitors of prostaglandin synthesis enhance hypoxic pulmonary vasoconstriction, we wondered whether vasodilator prostacyclin was synthesized by the lungs in response to vasoconstriction. To test this hypothesis, we measured vasoconstriction induced by angiotensin II in isolated rat lungs before and after inhibition of prostaglandin synthetase. We found that sodium meclofenamate enhanced and prostacyclin and its precursor arachidonate abolished pulmonary vasoconstriction. In lungs labeled with 14C-arachidonate, effluent radioactivity increased after angiotensin II-induced vasoconstriction. Hypoxic vasoconstriction, but not hypoxia per se, caused an increase in lung effluent radioactivity. Chromatographic analysis of lung effluent showed that 6-keto-prostaglandin F1 alpha was the major arachidonic acid metabolite released during pulmonary vasoconstriction. We concluded that prostacyclin is produced by the lungs in response to vasoconstriction. Hypoxia per se seems not to be the adequate stimulus for enhanced lung prostacyclin formation. Lung prostacyclin may protect the pulmonary circulation against excessive vasoconstriction.
Pericardial modulation of right and left ventricular diastolic interaction.
Authors: Spadaro J , Bing O H , Gaasch W H , Weintraub R M
Published: June 2012

We studied the effects of the right ventricle (RV) and pericardium on left ventricular (LV) diastolic pressure-volume (P-V) relations in the normothermic isolated blood-perfused dog heart. Studies were performed at a constant heart rate (atrial pacing at 120 beats/min) with a coronary perfusion pressure of 100 mm Hg. LV volume was directly controlled by an intraventricular balloon, whereas RV filling pressure was increased stepwise from zero to 20 mm Hg. During progressive increases in RV filling pressure, with the pericardium intact, the LV diastolic P-V relations were shifted up and to the left; this leftward shift of the LV diastolic P-V relation was associated with an increase in the modulus of LV chamber stiffness. Closing the small pericardial incisions with sutures significantly increased this effect. In the absence of the pericardium, progressive filling of the RV resulted in minor changes in LV diastolic P-V relations. Only when the RV filling pressure was markedly elevated (20 mm Hg) was there a significant effect on LV diastolic pressure. The pericardium has a small but significant effect on LV diastolic P-V relations at physiological RV filling pressures, and this effect becomes considerable at high RV filling pressures. The RV influence on LV diastolic P-V relations is significantly modulated by the presence of tightness of the pericardium.
Inhibitors of oxidative ATP production cause transient vasoconstriction and block subsequent pressor responses in rat lungs.
Authors: Rounds S , McMurtry I F
Published: June 2012

We wondered if depression of oxidative adenosine triphosphate (ATP) production caused pulmonary vasoconstriction. If so, then several chemically different inhibitors of oxidative ATP production all should cause pulmonary pressor responses. The vascular reactivity of isolated, blood-perfused rat lungs was established by eliciting pressor responses to airway hypoxia and to intraarterial angiotensin II. Then, during normoxia, we added to perfusate one of five chemical inhibitors of oxidative ATP production: 10 mM azide, 1 mM cyanide, 1 mM dinitrophenol, 5 or 10 microM antimycin A, or 0.5 microM rotenone. Each of the five chemical inhibitors, but not their solvents, caused a transient pressor response, followed by loss of vascular reactivity to hypoxia, angiotensin II, and chemical inhibitors. The inhibitor pressor responses were not due to an effect on blood cells, since they also were seen in lungs perfused with plasma. The magnitudes of pressor responses to all metabolic inhibitors except azide correlated with the magnitudes of preceding pressor responses to hypoxia, but not to the preceding angiotensin II responses. When verapamil or calcium chloride was added to perfusate, the hypoxic and inhibitor pressor responses were blunted more than was the angiotensin II response. Thus, five chemically different substances, inhibiting different steps of oxidative ATP production, all caused pressor responses that were blocked readily by verapamil and by increased perfusate calcium chloride. These results support the possibility that depression of oxidative ATP production elicits pulmonary vasoconstriction that is dependent on influx of extracellular calcium. Hypoxia might also be sensed in the pulmonary circulation by decreased oxidative ATP production in some as yet unidentified lung cell.
Effects of calcium and its antagonists on the canine mesenteric circulation.
Authors: Walus K M , Fondacaro J D , Jacobson E D
Published: June 2012

We studied circulatory and metabolic responses of the intestinal circulation to intraarterial infusions of solutions containing calcium chloride or calcium antagonists in anesthetized dogs. Measurements included blood flow to the terminal ileum, arteriovenous oxygen content difference, distribution of radiolabeled microspheres to the mucosal-submucosal compartment and intraluminal pressure. Calculated parameters included oxygen consumption and fractional mucosal-submucosal blood flow. Both calcium antagonists, nifedipine and diltiazem, increased intestinal blood flow, mainly to the mucosa-submucosa, depressed intestinal motility, and did not change oxygen consumption. Thus, both agents appear to act mainly on resistance vessels without increasing the nutrient circulation. Calcium chloride (1.0-500.0 microgram/kg per min) had a mild constrictor effect; at a dose of 1000.0 microgram/kg per min, calcium chloride became a dilator agent in the mesenteric circulation. The dilator effect of the highest dose of calcium was reversed by digoxin, suggesting the involvement of Na+,K+-ATPase. Nifedipine completely blocked calcium-induced constriction of the intestinal circulation and partly inhibited norepinephrine-induced constriction. Studies on isolated mesenteric arterial smooth muscle revealed that nifedipine relaxed KCl-contracted strips in the presence of external calcium and relaxed norepinephrine-contracted strips in both the presence and absence of external calcium. These in vitro findings suggest that calcium antagonists interfere with the release of calcium from intracellular sites as well as with the slow inward current of calcium.
Effect of carotid occlusion and of perfusion pressure on renal function in conscious dogs.
Authors: Gross R , Kirchheim H , Ruffmann K
Published: June 2012

We studied the effect of bilateral common carotid occlusion (implanted pneumatic cuffs) on renal blood flow (electromagnetic flowmeter) and renal function (implanted ureteral catheter) in nine chronically instrumented, conscious dogs on a high sodium diet (14 mmol/kg body weight per day). By means of suprarenal aortic constriction (pneumatic cuff) the influence of renal perfusion pressure was investigated. There was no change in renal blood flow or glomerular filtration rate (inulin clearance) with either reflexly increasing (+49.6%) or constant renal perfusion pressure. Carotid occlusion caused an increase of urine output by 80.5% and of sodium excretion by 85.3% due to a fall in fractional sodium reabsorption (-0.9%) when renal perfusion pressure was allowed to rise. Neither an increase of diuresis or sodium excretion nor an antinatriuresis was observed when renal perfusion pressure was kept constant during carotid occlusion. We conclude that, in conscious dogs at rest, the moderate sympathetic activation associated with carotid occlusion is too small to induce renal sympathetic vasoconstriction or antinatriuresis. The "carotid sinus polyuria" is a pressure-diuresis.
Role of the prostaglandin in norepinephrine release during augmented renal sympathetic nerve activity in the dog.
Authors: Oliver J A , Sciacca R R , Pinto J , Cannon P J
Published: June 2012

To determine the role of the prostaglandins on renal norepinephrine release, the effect of inhibition of prostaglandin synthesis was examined in anesthetized dogs during reflex activation of the renal adrenergic nerves. Hypotension increased the renal vein plasma concentrations of norepinephrine from 380 +/- 59 to 608 +/- 106 pg/ml (mean +/- SEM; P less than 0.01) and of PGE2 from 55 +/- 7 to 81 +/- 41 pg/ml (P less than 0.05). Subsequent administration of indomethacin or meclofenamate lowered the renal venous concentration of PGE2 to 26 +/- 3 pg/ml (P less than 0.01), had no significant effect on the norepinephrine concentration (620 +/- 89 pg/ml). Administration of indomethacin or meclofenamate to dogs with sodium depletion lowered renal venin plasma concentration of PGE2 from 108 +/- 40 to 20 +/- 3 pg/ml (0.05 less than P less than 0.1) but had no effect on the renal venous norepinephrine concentration (475 +/- 50 vs. 397 +/- 46 pg/ml). In dogs fed a normal salt diet, inflation of a balloon placed in the thoracic inferior vena cava lowered cardiac output and increased the renal venous concentrations of norepinephrine from 212 +/- 60 to 496 +/- 112 pg/ml (P less than 0.01) and of PGE2 from 28 +/- 5 to 96 +/- 18 pg/ml (P less than 0.01). Subsequent administration of indomethacin lowered the renal venous concentration of PGE2 to 16 +/- 5 pg/ml (P less than 0.01), but had no significant effect on the concentration of norepinephrine (548 +/- 91 pg/ml). During the three experimental conditions examined, renal blood flow was lowered by inhibition of prostaglandin synthesis. These results in the dog suggest that the attenuating effect that prostaglandins exert on the renal vascular action of the adrenergic nerves is not due to inhibition of norepinephrine release.
Non-uniform electrophysiological properties and electrotonic interaction in hypertrophied rat myocardium.
Authors: Keung E C , Aronson R S
Published: June 2012

We studied the distribution and nature of the electrical changes associated with myocardial hypertrophy induced by renal hypertension in rats. Standard microelectrode techniques were used to study transmembrane action potentials recorded from endocardial, papillary muscle, and epicardial stimulation from hypertrophied (HBP) and normal (SHAM) hearts. We also determined the effects of stimulation frequency on the action potentials recorded from these preparations. To assess whether altered intercellular electrical connections contribute to the electrophysiological changes associated with hypertrophy, we analyzed the spatial steady state voltage decrement produced by passing intracellular constant current pulses and determined the effective input resistance (Rin) of endocardial HBP and SHAM preparations. Our results show that the action potential prolongation that accompanies hypertrophy is not uniform. Thus, the entire course of repolarization is prolonged in epicardial and papillary muscle fibers, but only the latter half of repolarization is prolonged in epicardial fibers. Endocardial action potentials is general, and HBP action potentials in particular, have a distinctive steep relation between duration and stimulation frequency which may be due to a difference in the rate dependence of a membrane conductance(s), although relatively greater accumulation of extracellular potassium or altered activity of the Na+-K+ pump cannot be excluded as contributing factors. In addition, the similarity in the profile of spatial voltage decrement and the values for Rin in HBP and SHAM preparations indicates that alterations in electrotonic coupling between cells are unlikely to account for the prolonged action potentials of hypertrophied myocardium.
Dobutamine infusion in conscious dogs with and without acute myocardial infarction. Effects on systemic hemodynamics, myocardial blood flow, and infarct size.
Authors: Liang C S , Yi J M , Sherman L G , Black J , Gavras H , Hood W B
Published: June 2012

We infused dobutamine (20 microgram/kg per min) intravenously, once before and once after coronary artery occlusion, in 10 chronically instrumented dogs. Both infusions increased cardiac output and left ventricular dP/dt and dP/dt/P, but divergent effects on heart rate and aortic blood pressure were observed. Dobutamine decreased heart rate and increased mean aortic blood pressure before coronary artery occlusion, whereas after occlusion it increased heart rate while mean aortic blood pressure remained unchanged. A greater decrease in total peripheral vascular resistance occurred during dobutamine infusion after coronary artery occlusion than before. These differences may relate to withdrawal of enhanced sympathetic tone after coronary occlusion. Similar infusions of normal saline (n = 9) produced no systemic hemodynamic changes either before or after coronary artery occlusion. Myocardial blood flow increased to both non-ischemic and ischemic regions of the heart during dobutamine infusion, but the endocardial:epicardial blood flow ratio did not change significantly. In addition, infarct size, measured by nitroblue tetrazolium stain, was smaller in the dobutamine group (10 +/- 1 g) than in the normal saline group (15 +/- 2 g). Neither left ventricular weight nor risk zone differed between the two groups. These results indicate that dobutamine may be a useful inotropic agent during acute myocardial infarction.
Preservation of platelets during extracorporeal circulation in sheep. A comparison between aspirin and sulfinpyrazone.
Authors: Townsend E R , Duffin J , Ali M , McDonald J W , Thiesson J J , Masterson J , Klement P , Cooper J D
Published: June 2012

We studied the effect of aspirin and sulfinpyrazone on changes in platelet count, thromboxane B2 production, and pulmonary vascular resistance following the onset of veno-venous membrane oxygenator perfusion in sheep. Perfusion under identical circumstances was performed in three groups of animals, with one group serving as controls, one group receiving pretreatment with 1.5 grams of sulfinpyrazone iv, and one group receiving pretreatment with aspirin 50 mg/kg, iv. Both aspirin and sulfinpyrazone eliminated the rise in thromboxane B2 and the increase in pulmonary vascular resistance seen in control animals. Platelet preservation was improved significantly with sulfinpyrazone pretreatment, but not affected by aspirin. We conclude that sulfinpyrazone and aspirin have different mechanisms of action as far as platelet preservation during extracorporeal perfusion is concerned. The major difference may be sulfinpyrazone's ability to reduce platelet adhesion to the membrane surface. Since both aspirin and sulfinpyrazone eliminated the pulmonary vascular-response, but only sulfinpyrazone preserved platelets, it is apparent that the pulmonary vascular response is more closely related to thromboxane synthesis than to platelet disappearance.
Mechanism of action of nitroglycerin during exercise in a rat model of heart failure. Improvement of blood flow to the renal, splanchnic, and cutaneous beds.
Authors: Flaim S F , Weitzel R L , Zelis R
Published: June 2012

The radioactive microsphere technique was used to trace regional blood flow and total cardiac output distribution in rats in heart failure secondary to biventricular volume overload during acute intravenous infusion of nitroglycerin. Data from rats with heart failure (chronic arteriovenous shunt) were compared to data obtained from rats subjected to sham surgical procedures. In both glycerin and normal saline (control). In heart failure, nitroglycerin slightly increased cardiac output at rest and during exercise, increased stroke volume, and reduced systemic vascular resistance at rest but not during exercise. In the heart failure group, exercise reduced flow to the renal, gastrointestinal, and cutaneous circulations but had little or no effect in the sham group. Nitroglycerin dramatically increased renal, gastrointestinal, and cutaneous blood flow during exercise in the heart failure group but had minimal effects on active hyperemia in the skeletal muscle bed. In the sham group, nitroglycerin decreased blood flow in the renal, gastrointestinal, and cutaneous beds and had no effect on skeletal muscle blood flow. Thus, in the renal, gastrointestinal, and cutaneous circulations during exercise, nitroglycerin increased flow in the heart failure group and decreased flow in the sham group to the extent that the respective values in the two groups were equal.
Relative location of alpha- and beta-adrenoceptors to sites of release of sympathetic transmitter in the rabbit facial vein.
Authors: Winquist R J , Bevan J A
Published: June 2012

We studied alpha- and beta-adrenoceptor-mediated responses of rabbit facial vein rings to adrenergic stimulation to determine the location of the two types of receptors in relation to the sympathetic nerve terminals. Transmural electrical nerve stimulation (TNS) at low frequency elicited large beta-receptor-mediated relaxation responses in rings pretreated with phentolamine (6 x 10(-7)M). These responses were significantly greater than the corresponding alpha-receptor-mediated contractions in rings pretreated with propranolol (10(-6)M). Blockade of neuronal uptake with desmethylimipramine (DMI, 10(-7)M) increased significantly the neurogenic relaxation but had little effect on neurogenic contractility. DMI pretreatment caused a shift to the left (x 5.6) in the relaxant dose-response curve to exogenous l-norepinephrine (NE). The NE contractile dose-response curve was also shifted to the left after DMI pretreatment but by a significantly smaller amount (x 3.1). Neurogenic activation of beta-receptors evoked almost maximal relaxations in facial vein rings (85% at 2 Hz), whereas the maximum neurogenic contraction was approximately half the maximum contraction with exogenous NE (40% at 6 Hz). These results imply that the beta-adrenoceptors in the rabbit facial vein are located in close proximity to sites of adrenergic transmitter release and neuronal reuptake, whereas the alpha-receptors are more distant.
Does the calcium current modulate the contraction of the accompanying beat? A study of E-C coupling in mammalian ventricular muscle using cobalt ions.
Authors: McDonald T F , Pelzer D , Trautwein W
Published: June 2012

This study was prompted by a conclusion that emerged from experiments by others on mammalian ventricular muscle i.e., that the magnitude of the calcium current (Isi) does not influence contraction on the accompanying beat. In the key experiments, muscles were potentiated with paired pulses, rested for 2 minutes, and then re-stimulated. When Co2+ was present during the rest, the first post-rest action potential (and presumably Isi) was depressed but contraction was unchanged. In the present study, we have measured the effect of Co2+ on the action potential, Isi, and tension of bovine, cat, and rabbit ventricular muscle. All three parameters were depressed by 1-2 mM Co2+ when muscle was stimulated at 20/min. The key experiments of the earlier study were repeated. Co2+ (1-2 mM depressed both the action potential plateau and contraction on the first post-rest response. We conclude that the use of Co2+ in this type of experiment does not provide evidence against a role for Lsi in the modulation of contraction.
Left ventricular diastolic pressure-volume relations in rats with healed myocardial infarction. Effects on systolic function.
Authors: Fletcher P J , Pfeffer J M , Pfeffer M A , Braunwald E
Published: June 2012

To determine the effects of healed myocardial infarction on the diastolic compliance of the left ventricle, we studied 36 rats 26 days after left coronary artery ligation. Peak cardiac output and stroke volume were measured under ether anesthesia during volume loading, and peak left ventricular developed pressure was determined during occlusion of the ascending aorta. During a slow infusion of saline into the potassium-arrested left ventricle, diastolic pressure and volume were measured continuously over the pressure range -5 to 30 mm Hg. Infarct size was determined by planimetry of serial sections taken from each heart at 1-mm intervals from apex to base. In rats with healed infarcts, left ventricular volume was increased in proportion to infarct size and the diastolic pressure-volume relationship was shifted so that at pressures below 2.5 mm Hg volume was increased, resulting in an increased ventricular compliance in this low pressure range. Above this pressure, the slopes of the pressure-volume curves were similar in rats with and without infarctions. Peak cardiac output and pressure-generating capacity were impaired in proportion to infarct size. This impairment of cardiac performance correlated with the infarct size-related increase in diastolic volume, which served to offset the reduction in flow generating capacity caused by systolic dysfunction, while contributing directly to the impairment of pressure generating capacity.
Alterations in aldosterone biosynthesis in essential hypertensives.
Authors: Dawson-Hughes B F , Moore T J , Dluhy R G , Podolsky S , Williams G H
Published: June 2012

We studied hypertensives with decreased adrenal responsiveness to infused angiotensin II (AII) to assess their responsiveness to other aldosterone secretagogues, ACTH and potassium, which are thought to stimulate aldosterone synthesis in sites different from one another and from AII. All subjects, following sodium restriction, received an infusion of AII in increasing doses (0.1-3 ng/kg per min). The increment in aldosterone between control and the highest infusion dose divided by the increment in plasma AII was used as the index of adrenal responsiveness. All normotensive controls (NC) had a ratio greater than 0.5. Hypertensives with a normal ratio were designated normal responders (NR) and those with a lower ratio were abnormal responders (AbR). The slope of the regression line between aldosterone and AII was significantly less for the AbR (0.02 +/- 0.04) than for the NR (1.20 +/- 0.02, P less than 0.001) and the NC (1.00 +/- 0.03, P less than 0.001) groups. During infusion of cosyntropin in increasing doses (0.05-1.5 mIU/kg per 30 min), the aldosterone response of the AbR was significantly less than that of the NR (P less than 0.016) or the NC (P less than 0.05) groups. Similarly, after infusion of potassium (0.33 mEq/min), the increment in aldosterone in the AbR group (7.6 +/- 2.2 ng/dl) was significantly less than that in the NR (14.2 +/- 2.5 ng/dl, P less than 0.05) and the NC (18 +/- 5 ng/dl, P less than 0.05) groups. Thus hypertensives with decreased aldosterone responsiveness to infused AII also had decreased responsiveness to infused ACTH and potassium, suggesting that their defect lies in the intracellular aldosterone biosynthetic pathway.
Effects of chronic digitalization on cardiac and renal Na+ + K+-dependent adenosine triphosphate activity and circulating catecholamines in the dog.
Authors: Nechay B R , Jackson R E , Ziegler M G , Neldon S L , Thompson J D
Published: June 2012

To extend our understanding of the mechanism of action of digitalis drugs, we studied electrocardiograms (ECGs), renal function, plasma concentrations of catecholamines, and myocardial and renal Na+ + K+-dependent adenosine triphosphate (Na+ + K+ ATPase) activity in chronically digitalized dogs. Five healthy, male, mongrel dogs received a therapeutic regimen of digoxin (0.1 mg/kg on day 1 in three divided doses followed by 0.025 mg/kg per day) orally for 2-4 months. This resulted in plasma digoxin concentrations of 1.1 to 4.7 ng/ml as determined by radioimmunoassay. Six control dogs received daily gelatin capsules by mouth. ECGs monitored throughout the study showed no changes. Digitalized dogs had elevated plasma norepinephrine concentrations (347 vs. 137 pg/ml in controls) and no change in plasma epinephrine concentrations. Digitalized dogs had elevated glomerular filtration rates (0.74 vs. 0.94 ml/min per g of kidney) without significant changes in renal handling of electrolytes and water. All of the above studies were done without the aid of restraining drugs or infusions. The animals were killed with an overdose of pentobarbital for in vitro studies. In digitalized dogs, microsomal Na+ + K+ ATPase-specific activity was 26 to 33% lower in the renal cortex, medulla, and papilla, and 46% lower in the cardiac left ventricle than in control dogs. Digitalization did not alter the osmolalities of renal tissues. We conclude that chronic reduction Na+ + K+ ATPase activity by one-third dose does not cause abnormalities in renal handling of electrolytes and water, and inhibition of Na+ + K+ ATPase in the left ventricular muscle by one-half is associated with no obvious ECG changes in the dog. Further, elevated plasma norepinephrine concentrations may contribute to both the therapeutic and the toxic effects of digitalis.
EPR and fluorescence depolarization studies on bovine cardiac myosin.
Authors: Stone D B , Mendelson R A , Botts J , Cheung P H
Published: June 2012

To test for possible differences in local conformation and S1 flexibility, bovine cardiac and rabbit skeletal myosins were labeled with a fluorophore (1,5-IAEDANS) and a spin label having iodoacetamide reactivity. The marked activation of the Ca2+-ATPase (6- to 8-fold) and inhibition of the K+ (EDTA)-ATPase (80-90%) by both labels indicated specific labeling of the fast-reacting thiols (SH1) of both myosins. Fluorescence depolarization studies of 1,5-IAEDANS-labeled cardiac myosin indicated that, like skeletal myosin, the SI moieties of cardiac myosin exhibit considerable segmental flexibility with respect to the rod portion of the molecule. This indicates that segmental flexibility may be a property of all myosins. Cardiac and skeletal myosins immobilized spin labels to approximately the same extent, indicating a similarity in steric restraints around the SH1 thiol of the two myosins. The magnitude of the changes in spin label mobility accompanying binding of MgADP and hydrolysis of MgATP was reduced in cardiac myosin relative to skeletal myosin. This suggests that the lower catalytic center activity of cardiac myosin is associated with more restricted conformational changes accompanying formation of M.ADP and M.ADP.Pi. From measurements of spin label mobility, the affinity of cardiac and skeletal myosin for ADP were similar: Kd (ADP) = 7 microM, n = 1.6. The EPR spectrum of spin labels attached to cardiac and skeletal myosin showed similar saturation effects upon actin binding indicating immobilization of myosin heads occurs with both proteins.
Ultrastructural distribution of vasodilator and constrictor nerves in cat cerebral arteries.
Authors: Lee T J
Published: June 2012

This study examined the ultrastructural distribution of agranular vesicle-containing nerve (AVN) and granular vesicle-containing nerve (GVN) in cat cerebral blood vessels fixed in KMnO4. The percentages of the AVN and GVN throughout the adventitial layer in the basilar, middle cerebral, and anterior cerebral arteries were 63.4 and 36.7, 53.9 and 46.1, and 60.2 and 39.8, respectively. The AVN in the cat basilar artery is approximately 37 times denser than that in the rabbit basilar artery. This morphological result, in correlation with the previous pharmacological findings, provides indirect evidence that the AVN are the dilator nerves. The lack of neurogenic vasoconstriction in the cat basilar, middle cerebral, and anterior cerebral arteries may be attributable in part to a combination of denser dilator than constrictor nerves, a possible closer synaptic cleft distance for dilator than for constrictor nerves, and the reported insensitivity of the postsynaptic alpha-receptors. The small pial vessels (branches of the middle cerebral arteries), on the other hand, contain predominantly GVN (88%), suggesting that dilator nerves relative to constrictor nerves decrease as the size of the cerebral blood vessels becomes smaller. Furthermore, the synaptic cleft distance is found not parallel to the outer diameter of the artery. Thus, the results of this study indicate that the neurogenic control of brain circulation varies with brain region, lending further support to the theory that the dual cerebral innervation varies among species.
Electrotonically mediated delayed conduction and reentry in relation to "slow responses" in mammalian ventricular conducting tissue.
Authors: Antzelevitch C , Moe G K
Published: June 2012

A narrow zone of block in isolated false tendon preparations was created by perfusion of the central compartment (gap) of a three-compartment tissue bath with either an isotonic sucrose solution or a solution designed to mimic the extracellular milieu in ischemic tissue. Driven responses on the proximal side of the gap were transmitted to the distal side after long delays. The characteristics of the "ischemic" gap model were found to be qualitatively similar to those of the sucrose gap model in which impulse transmission is electrotonically mediated. In both models, the effects of driven action potentials were mimicked by electrotonic displacement of membrane potential by current pulses passed across the gap. Foot-potentials representative of electrotonic potentials bringing the distal membrane to threshold were present in all cases and were found to be largely unaffected by the slow channel-blocking agent, verapamil. Transmembrane activity recorded from the central portion of the gap segment was shown to be electrotonic in nature. Ectopic activity in the form of reflected reentry was readily demonstrable in the ischemic gap model in the presence or absence of verapamil as well as in the sucrose gap model. When propagation across the gap was mediated by "slow" responses, transmission was relatively prompt and reentry did not occur. Our observations suggest that very slow conduction through ischemic areas may result from step delays imposed by electrotonic transmission of impulses across inexcitable segments of cable rather than from uniform slow conduction of propagated action potentials with slow upstrokes.
Sites of prostaglandin synthesis in the bovine heart and isolated bovine coronary microvessels.
Authors: Gerritsen M E , Printz M P
Published: June 2012

Metabolically active coronary microvessels (generally less than 100 micrometers in diameter) were isolated from bovine hearts. These preparations were virtually free of contaminating myocytes and consisted of a mixture of arterioles, venules, capillaries, and collagen fibers. The prostaglandin biosynthetic capacity of isolated coronary microvessels was assessed by quantitating conversion of 14C-arachidonic acid and 14C-prostaglandin endoperoxide (PGH2) to prostaglandins. Coronary microvessels were found to exhibit low cyclooxygenase activity, i.e., minimal conversion (less than 1%) of arachidonic acid (AA) to prostaglandins when compared with either the coronary artery (3.6% conversion of AA) or coronary vein (3.3%). Isolated myofibril fractions demonstrated virtually no cyclooxygenase activity (less than 0.1%). Two enzymatic endoperoxide metabolizing activities were evident in the microvessels, prostacyclin synthetase and PGE isomerase. When compared on a microsomal protein basis, the coronary artery exhibited higher prostacyclin synthetase activity than the microvessels but was devoid of PGE isomerase activity. In contrast, whereas PGE isomerase activity was detectable in the coronary vein, the activity was lower than that of the microvessels; further, it could not be demonstrated in the other myocardial fractions. A glutathione-enhanced PGD-forming activity was present in high speed supernatants derived from the coronary artery and vein preparations, but was not present in the coronary microvessel or isolated myofibril fractions. From these studies we conclude that (1) the major source of prostaglandins released into the coronary circulation is the coronary vasculature, and (2) the resistance elements of the coronary circulation differ from the larger elements (i.e., arteries and veins) in the enzymes of the prostaglandin biosynthetic pathway present and thus in the nature and perhaps quantity of prostaglandins biosynthesized.
Beta-adrenergic vasodilator mechanism in the finger.
Authors: Cohen R A , Coffman J D
Published: June 2012

The digital vasospastic phenomena, which are induced by beta-adrenergic-blocking agents, suggest a beta-adrenergic finger vasodilator mechanism. We measured fingertip total blood flow with venous occlusion plethysmography and studied nutritional blood flow with Na131I clearance. During fingertip vasoconstriction caused by branchial artery infusion of norepinephrine or angiotensin, intra-arterial isoproterenol caused a sustained increase in fingertip total blood flow. Furthermore, propranolol significantly potentiated the vasoconstriction caused by intra-arterial norepinephrine and attenuated the vasodilator action of isoproterenol. No change in branchial artery blood pressure occurred to explain the changes in fingertip blood flow. Isoproterenol did not change nutritional flow, implying beta-adrenergic vasodilation solely of the fingertip arteriovenous shunts. When fingertip vasoconstriction was induced by reflex sympathetic nerve action during environmental cooling and mental stress, or by norepinephrine release from sympathetic nerves caused by intra-arterial tyramine infusion, isoproterenol and propranolol had no effect on fingertip total blood flow. This effect is probably specific for the beta-receptor agonist, since intra-arterial histamine caused a large increase in finger blood flow during environmental cooling. We conclude that there is a beta-adrenergic vasodilator mechanism in human digital arteriovenous shunts that may be humorally activated, but which has no apparent functional role in modulating sympathetic vasoconstriction. Our results suggest a spatial dissociation of the effector sites for vasoactive humoral agents and sympathetic vasoconstrictor nerves.
Reversibility of diabetic cardiomyopathy with insulin in rats.
Authors: Fein F S , Strobeck J E , Malhotra A , Scheuer J , Sonnenblick E H
Published: June 2012

Diabetes appears to cause a cardiomyopathy independent of atherosclerotic coronary artery disease and hypertension. Left ventricular papillary muscle function studies in rats made severely diabetic with streptozotocin have shown a slowing of relaxation and a depression of shortening velocity. However, the effects of insulin therapy on the myocardial mechanics of diabetic rats have not been studied. Therefore, rats diabetic for 6-10 weeks were treated with PZI insulin for 2, 6, 10, or 28 days and the mechanical performance of their left ventricular papillary muscles was compared to that of untreated diabetics and age-matched controls; cardiac contractile protein enzymatic activity was also measured. Neither 2 nor 6 days of therapy had any effects on the depressed cardiac muscle performance of diabetic animals, although plasma glucose concentration was restored to normal. By 10 days of therapy, recovery of mechanical performance was nearly complete, and by 28 days of therapy, complete reversal of the altered myocardial mechanics was observed. Crystalline insulin added to the bath (9 mU/ml) had no effect on myocardial mechanics in either diabetics or controls. A gradual recovery of actomyosin and myosin ATPase activity in the hearts of insulin-treated diabetic animals was also found, complementing the mechanical studies. In addition to demonstrating a gradual but complete reversibility of the abnormalities in papillary muscle function in diabetic rats (although control of hyperglycemia was less than ideal), this study confirms that this model of a cardiomyopathy is not a result of streptozotocin-induced cardiac toxicity. Additional data are provided indicating that depressed thyroid hormone levels in diabetic rats are not responsible for the mechanical changes observed.
Studies on phosphorylation of canine cardiac sarcoplasmic reticulum by calmodulin-dependent protein kinase.
Authors: Bilezikjian L M , Kranias E G , Potter J D , Schwartz A
Published: June 2012

Two endogenous protein kinase activities, cAMP-dependent and calmodulin-Ca2+-dependent, are associated with isolated cardiac sarcoplasmic reticulum (SR) vesicles. Both kinases phosphorylate an endogenous substrate of approximately 22,000 daltons (phospholamban). The phosphorylation of phospholamban by either the intrinsic or by exogenous cAMP-dependent protein kinase is found to be Ca2+-independent between 0.05 and 100 microM free Ca2+. Calmodulin-dependent phosphorylation, on the other hand, does not require cAMP and is absolutely dependent on the presence of free Ca2+ over a concentration range that corresponds to physiological levels (10(-7) to 10(-5) M). Phosphorylation of SR vesicles by both kinases is additive and the extent of saturation of the cAMP-specific sites has no effect on the degree of stimulation by calmodulin or its Ca2+-dependence. Trifluoperazine, an inhibitor of calmodulin, inhibits calmodulin-dependent phosphorylation without affecting cAMP-dependent phosphorylation, indicating the presence of two types of kinases. This is made further evident by the selectivity of each kinase for exogenous substrates. Whereas cAMP-dependent protein kinase appears to phosphorylate histone ILA (a basic protein) preferentially, calmodulin-dependent protein kinase prefers phosvitin (an acidic protein).
Biochemical Studies on Cholesterol in in vivo Cultivated Connective Tissue
Authors: BOUCEK ROBERT J. , NOBLE NANCY L.
Published: June 2012

In vivo cultivated connective tissue is rich in lipids. That obtained from man and chicken has larger concentrations of neutral fat and cholesterol than connective tissue of other species. Connective tissue synthesizes cholesterol and possesses a striking avidity for retention of either endogenous or exogenous cholesterol. The fibrous portion of sponge-connective tissue of the rabbit incorporates cholesterol at a characteristic rate, indicating some inherent inter-relationship between the lipid and the scleroprotein. Marked reduction of a previously elevated serum cholesterol in the rabbit does not lower connective tissue cholesterol concentration. Connective tissue of the rabbit intima requires prolonged exposure to an elevated serum cholesterol before increased cholesterol incorporation occurs.
Ventricular Excitation in Experimental Bundle-Branch Block
Authors: ERICKSON ROBERT V. , SCHER ALLEN M. , BECKER ROLFE A.
Published: June 2012

Multipolar recording apparatus has been used to study the pattern of ventricular excitation in experimental bundle-branch block. After block, the wave of activation spreads uniformly from the contralateral ventricle across the septum to the free wall of the homolateral ventricle. Septal activation consumes more time than in the normal. Changes occur in the site and extent of early endocardial activity in the blocked ventricle. Alterations in both septal and mural depolarization contribute to QRS changes. Endocardial depolarization is described during recovery from transient bundle-branch block.
Evidence for a Red Cell Shunting Mechanism in the Kidney
Authors: LILIENFIELD LAWRENCE S. , ROSE JOHN C. , PORFIDO FRANK A.
Published: June 2012

Simultaneous tagged red cell and tagged plasma albumin concentration-time curves were obtained from the renal vein without recirculation, following rapid injection of the indicators into a renal artery. The mean transit time of the red cells was consistently faster than that of the plasma albumin, but the washout downslopes of the indicators was found to be identical. This is interpreted as indicating that some red cells are shunted through those pathways of shortest length. The dynamic circulating hematocrit of the kidneys averaged 89 per cent of the large vessel hemato-crit. Intrarenal circulating blood volume averaged 24 ml./100 Gm. of dog kidney
An Experimental Study on Intercoronary Reflexes
Authors: WANG HSUEH-HWA , FRANK CHARLES W. , KANTER DONALD M. , WÉGRIA RENÉ
Published: June 2012

There is no evidence in the anesthetized dog that occlusion of one of the three coronary arteries leads to vasoconstriction in the vascular areas irrigated by the other two arteries. On the contrary, occlusion of one coronary artery appears to lead to a decrease in the resistance of the two adjacent vascular beds in most experiments. The mechanisms and the implications of this effect are discussed.
Effect of Experimental Renal Hypertension on Experimental Thiouracil-Cholesterol Atherosclerosis in Dogs
Authors: WAKERLIN G. E. , MOSS W. G. , KIELY J. P. , Fein Mrs. Gloria , Kejikawa Mr. Frank
Published: June 2012

Experimental renal hypertension accelerated the onset and accentuated the severity of thiouracil-cholesterol atherosclerosis in dogs. Increased blood pressure and other hemodynamic changes appear to be responsible for these effects. Hypertension and sex were without significant effect on serum cholesterol, cholesterol: phospholipid ratio and low density lipoproteins. Sex had no significant effect on the incidence or severity of this experimental atherosclerosis, including coronary involvement.
Hemodynamic Effects of Quantitatively Varied Experimental Aortic Regurgitation
Authors: WELCH GEORGE H. , BRAUNWALD EUGENE , SARNOFF STANLEY J.
Published: June 2012

A canine preparation was devised in which aortic regurgitant flow could be acutely produced, metered and controllably varied. Aortic regurgitant flows in excess of the dog's resting cardiac output resulted in a marked decrease of effective cardiac output, a substantial rise of peripheral resistance and left ventricular end-diastolic pressure, and a marked depression of the left ventricular function curve, with little change in the mean left atrial pressure. When mitral regurgitation was added to aortic regurgitation, effective cardiac output, stroke work and left ventricular end-diastolic pressure fell, while left atrial pressure rose.
Spontaneous Pressure Elevations in Small Veins and Effects of Norepinephrine and Cold
Authors: WALLACE JOHN M. , STEAD EUGENE A.
Published: June 2012

This paper reports the occurrence of spontaneous pressure changes in human small veins recorded by retrograde venous catheterization and experiments on the effects of norepinephrine and cold.