bluuebunny/crossref_metadata_2025 huggingface dataset:
Profile of serum immunoreactive insulin-like growth factor I during gestation in Wistar rats
Authors: Sheppard M. S. , Bala R. M.
Published: April 2011

It has been reported that there is a striking homology between the basic insulin-like growth factors (IGF) – somatomedins (SM) found in humans and rats. The radioimmunoassay (RIA) developed for the human hormone IGF-I (basic somatomedin, B-SM) can measure immunoreactive IGF-I in rat serum (IrIGF-I). Using this RIA, the profile of serum IrIGF-I was measured at each day of gestation in groups of inbred and Charles River Wistar rats. In each case IrIGF-I showed a gradual increase in early and mid gestation followed by a sharp decrease that occurred late in gestation to values 20–40% of control. The profile obtained from Charles River Wistars was shifted in time compared with the inbred group. Neither ovariectomy nor progesterone administration to ovariectomized nonpregnant animals altered serum MGF-I levels. Thus, although rat IGF-I and human IGF-I can be measured using the same assay, the changes that occur in gestation are in opposite directions.
Atrioventricular block in low potassium and K dependence of the nodal resting potential
Authors: Ruiz-Ceretti E. , Zumino A. Ponce
Published: April 2011

A progressive conduction block leading to atrioventricular dissociation develops in perfused rabbit hearts within 20–30 min of exposure to Krebs containing 0.5 mM potassium (low K). A decrease in potassium permeability resulting in membrane depolarization (as seen in Purkinje fibers) could be responsible for the loss of excitability in nodal cells. We investigated the K dependence of the resting potential and the long-term effects of low K perfusion on the resting and action potentials of nodal cells in rabbit hearts. The resting potential of atrial, atrionodal, and nodal cells varied by 5 2, 41, and 34 mV per decade of change in Ko within the range of 5–50 mM K. Hyperpolarization of the resting membrane, a progressive decline in action potential amplitude, and a decrease in maximum rate of rise were observed in nodal fibers when exposed to low K. Loss of propagated activity occurred in the middle node within 20–30 min while the cells remained hyperpolarized. There was no evidence of electrogenic Na extrusion and it seems that the low nodal resting potential results from a high resting PNa/PK permeability ratio. The early decrease in rate of rise in low K probably reflects an increase in K-dependent outward currents, whereas the progressive deterioration and final loss of conducted electrical activity may result from an accumulation of internal Na and Ca overload produced by low K inhibition of the Na pump.
Large venous compliance in carboxyhemoglobinemia and hemodilutional anemia
Authors: Biro George P.
Published: April 2011

Anesthetized dogs were prepared for the measurement of compliance of the inferior vena cava by placement of a catheter for pressure measurement and a pair of ultrasonic dimension transducers for the measurement of transverse diameter. Measurements of compliance were made in a control state, after the induction of carboxyhemoglobinemia or hemodilutional anemia, by measuring pressure changes and diameter changes during brief occlusions of the inferior vena cava downstream from the transducers. Carboxyhemoglobinemia cuased an upward shift of the averaged pressure–diameter curve while there was a negligible shift in the hemodiluted group. These results indicate that in carboxyhemoglobinemia a change in the compliance of the vena cava occurs, which favours augmented venous return by improved conductance rather than by a dislocation of blood by constriction of the large venous reservoir. In hemodilutional anemia the change in compliance is insignificant, but venous return is favoured by the reduced viscosity.
Cholera toxin facilitates calcium transport in jejunal brush border vesicles
Authors: Maenz David D. , Forsyth G. W.
Published: April 2011

Cholera toxin is very well characterized in terms of the activation of adenylate cyclase. In some systems, however, this cyclase activation does not seem to account for all of the physiological responses to the toxin. On the premise that cholera toxin may also exert effects through other second messenger compounds we have studied the effect of cholera toxin on the rate of Ca2+ movement across the membrane of intestinal brush border vesicles. Increasing concentrations of cholera toxin progressively accelerated the passive uptake of Ca2+ into, and the efflux of Ca2+ from, an osmotically active space in brush border membrane vesicles. This effect of cholera toxin was saturable by excess Ca2+ and was relatively specific, as the toxin did not affect vesicle permeability to an uncharged polar solute. The toxin had two high affinity Ca2+ binding sites on the A subunit as measured by equilibrium dialysis. Ca2+ transport facilitated by cholera toxin was temperature dependent, required the holotoxin, and could be inhibited by preincubation of the toxin with excess free ganglioside GM1.This increased rate of Ca2+ influx caused by the in vitro addition of cholera toxin to brush border membrane vesicles may have physiological significance as it was comparable to rates observed with the Ca ionophore A23187. Similar effects occurring in vivo could permit cholera toxin to increase cytoplasmic Ca2+ concentrations and to produce accompanying second messenger effects.
The contribution of alkylation to the activity of quinone antitumor agents
Authors: Begleiter Asher
Published: April 2011

Studies have shown that the quinone group can produce tumor cell kill by a mechanism involving active oxygen species. This cytotoxic activity can be correlated with the induction of DNA double strand breaks and is enhanced by the ability of the quinone compound to bind to DNA by alkylation. The cytotoxic activity and the production of DNA damage by model quinone antitumor agents were compared in L5178Y cells, sensitive and resistant to alkylating agents, to assess the contribution of alkylation to the activity of these agents. The resistant L5178Y/HN2 cells were found to be two fold and six fold more resistant to the alkylating quinones, benzoquinone mustard and benzoquinone dimustard, respectively, than parent L5178Y cells. In contrast, the L5178 Y/HN2 cells showed no resistance to the nonalkylating quinones, hydrolyzed benzoquinone mustard and bis(dimethylamino)benzoquinone. The alkylating quinones produced approximately two fold less cross-linking in L5178Y/HN2 cells compared with L5178Y sensitive cells. DNA double strand break formation by hydrolyzed benzoquinone mustard and bis(dimethylamino)benzoquinone was not significantly different in sensitive and resistant cells. However, the induction of double strand breaks by the alkylating quinones benzoquinone mustard and benzoquinone dimustard was reduced by 5-fold and 15-fold, respectively, in L5178Y/HN2 cells. These results show that the alkylating activity of the alkylating quinones cannot directly explain all of the enhanced cytotoxic activity of these agents. Furthermore, they provide strong evidence that the enhanced formation of DNA double strand breaks by alkylating quinone agents is directly related to the ability of these agents to bind to DNA. This increased formation of strand breaks may account for the enhanced cytotoxic activity of the alkylating quinones.
The influence of adrenal medollectomy on the development of ethanol-induced cardiac hypertrophy
Authors: Adams Michael A. , Hirst Maurice
Published: April 2011

Cardiac hypertrophy was assessed in adrenal medullectomized and sham control rats given ethanol in a liquid diet mixture, intragastrically, in severely intoxicating doses at 8-h intervals for 48 and 96 h. The ethanol treatments produced increases of some 20% in wet and dry proportional heart weights in the control animals, but this rapid development of hypertrophy was less apparent in the medullectomized rats. Hearts of the medullectomized animals given ethanol were heavier than those of pair-matched controls given isocaloric maltose–dextrin in the diet mix. These increases were not statistically significant. The ethanol treatments produced, in addition, equivalent increases in the weight of the adrenal glands of both medullectomized and control animals. Medullectomy was evaluated by analysis of adrenal glands and urine samples for catecholamines. The majority of adrenals from the demedullated group had nondetectable amounts of catecholamines and minimal quantities were found in the remainder. Adrenaline was not detected generally in urine samples from this group. The adrenaline contents of adrenals from sham controls given ethanol were markedly reduced by the ethanol treatments, whereas the quantities in urine were many times greater than those from rats given maltose–dextrin. Urinary noradrenaline levels were increased in both control and medullectomized rats given ethanol. The results of this study identify that adrenal medullary catecholamines participate in the rapid development of cardiac hypertrophy that results from severe, continuing ethanol intoxication in the rat.
Mitochondrial and cytoplasmic aspartate aminotransferase enzyme release in the calcium paradox
Authors: Rabkin Simon W.
Published: April 2011

The release of mitochondrial and cytoplasmic aspartate aminotransferase (AST) enzymes from the myocardium was studied in the isolated rabbit heart under conditions of the calcium paradox. Four different periods of calcium-free perfusion for 10, 15, 20, and 25 min were selected to produce different degrees of the calcium paradox and the associated myocardial damage which was indicated by impairment in the left ventricular contractile function. Calcium-free perfusion periods of less than 20 min were associated with partial recovery of ventricular function, while periods of 20 min or greater were associated with little or no recovery of contraction after reperfusion with calcium. Mitochondrial (ASTm) and cytoplasmic (ASTc) aspartate aminotransferase were released from the heart beginning within 1 min of reintroduction of Ca2+. The cumulative amount of ASTm release was about one-tenth the amount of ASTc release. The cumulative amount of ASTm and ASTc released were significantly (p < 0.05) related to the duration of calcium-free perfusion. The time to 90% of maximum AST release was slightly longer for ASTm compared with ASTc (6.8 ± 0.6 vs. 5.7 ± 0.5 min, 0.10 > p > 0.05). ASTc but not ASTm correlated significantly (p < 0.05) with total protein release from the myocardium, while ASTm was not as consistently related to protein loss. The cumulative amount of ASTm and ASTc were inversely related to the extent of recovery of left ventricular contractile function. Disparities did occur as the longest duration of the calcium-free period, which did not produce any further damage to left ventricular function, was nonetheless associated with more enzyme release from the myocardium. Thus, mitochondrial AST release from the myocardium is of lesser magnitude and slightly slower than ASTc release, but both are significantly related to the impairment of or damage to left ventricular function in the calcium paradox.
Effects of taurine on the electrical and mechanical activities of embryonic chick heart
Authors: Sawamura Akihiko , Sperelakis Nick , Azuma Junichi , Kishimoto Susumu
Published: April 2011

The effect of taurine (2-aminoethanesulphonic acid) on myocardial slow action potentials (APs) and accompanying contractions was examined in isolated perfused chick hearts and reaggregated cultured cells. Isoproterenol (ISO), histamine (HIS), or tetraethylammonium (TEA) induced slow APs and contractions in hearts whose fast Na+ channels had been inactivated by elevated K+. Taurine (10 mM) not only failed to induce slow APs, but actually decreased ISO (10−8 M), HIS (10−4 M), or TEA (10 mM) induced slow APs and contractions transiently (about 30s –2 min after the addition of taurine). The properties of the slow APs recovered to control levels by 7–13 min after the addition of the taurine; at this time, there was an increase in developed tension of the contraction accompanying the slow APs. These results suggest that the positive inotropic action of taurine is not mediated through an increase in the slow inward Ca2+ current. However, the transient depression of Ca2+-dependent slow APs by taurine probably explains the transient negative inotropic effect of taurine.
Distribution and metabolism of corticotropin-releasing factor in the rat
Authors: Candas Bernard , Lalonde Josée , Normand Maurice
Published: April 2011

To develop a mathematical model of the distribution and metabolism of rat corticotropin-releasing factor (rCRF), the time course of 125I-labelled rCRF in plasma was measured in male Sprague–Dawley rats (i) following a rapid injection of 24 ng rCRF/100 g body weight (BW), or (ii) following a rapid injection of 424 ng rCRF/100 g BW, or (iii) during an infusion at a rate ranging from 0.28 to0.73 ng rCRF∙min−1∙100 g BW−1. The comparison of the one-, two-, and three-compartment models shows that the two-pool structure fits better to the dynamics of CRF in plasma as measured in each rat. Following a rapid injection the decay curve occurs in a biphasic manner; the early phase of disappearance is 25 times faster than the late one. There is no significant difference between the estimates of the metabolic clearance rate following both amplitudes of injection (0.40 ± 0.06 and 0.48 ± 0.05 mL∙min−1∙100 g BW−1). The volume of the first pool, 16.8 ± 1.1 mL/100 g BW, is four times larger than the plasma volume. It would thus appear that CRF is rapidly distributed from plasma into several tissues which are represented in the first pool of the model. The mean residence time of every CRF molecule in the second compartment, from the moment of secretion to its elimination, is from three to four times longer than in the first one. It stays, on average, between 140 min and 3 h in the system before an irreversible exit. At steady state, the disposal rate represents only 3% of the CRF mass of the first compartment every minute. These results could explain the prolonged effects of CRF on pituitary-adrenocortical secretion.
Adrenoceptor function in the bovine pulmonary circulation
Authors: Greenlees Kevin J. , Gamble Robert , Eyre Peter
Published: April 2011

The bovine pulmonary vascular response to α- and β-agonists was studied using an awake intact calf model. Pulmonary arterial pressure, pulmonary arterial wedge pressure, left atrial pressure, systemic arterial pressure, and cardiac output were measured in response to 3 min infusions of isoproterenol (β-agonist; 0.12, 0.24, 0.48, 0.9, and 1.8 μg∙kg−1∙min−1) and phenylephrine (α-agonist, 0.15, 0.30, 0.60, 1.15, and 2.30 μg∙kg−1∙min−1). Phenylephrine caused an increase in vascular resistance in the pulmonary arterial and venous compartments. The slope of the resistance in response to phenylephrine was greater in the pulmonary arterial than pulmonary venous circulation. Isoproterenol resulted in a dose-dependent decrease in vascular resistance in the pulmonary arteries and veins. The vascular resistance was decreased to the same level in the pulmonary arteries and veins although the arteries showed a greater percent change. In addition, isoproterenol infusion resulted in a transient decrease in arterial pH and increase in values for packed cell volume and haemoglobin.
Contribution of Na+ and membrane depolarization to contraction induced by adrenaline in the guinea pig vas deferens
Authors: Usune Sadaharu , Katsuragi Takeshi , Sakamoto Yasuzi , Furukawa Tatsuo
Published: April 2011

The contribution of Na+ and membrane depolarization to biphasic contractions induced by adrenaline were investigated in the smooth muscle of guinea pig vas deferens. Adrenaline (5 × 10−6 M) produced an initial small contraction (first contraction) followed by a large tonic contraction (second contraction) with subsequent rhythmic activity. The entire response to adrenaline was largely inhibited by phentolamine (5 × 10−6 M). By adding an appropriate concentration of Mn2+ (2 × 10−4 M) or nifedipine (3 × 10−7 M), a Ca2+ blocker, the second contraction was strongly reduced, accompanied by abolishment of the rhythmic contraction, whereas the first contraction was virtually unaffected. However, the first contraction was markedly suppressed by a higher concentration of Mn2+. All contractions produced by adrenaline were greatly reduced in Ca2+-free solution containing 0.5 mM EGTA. By lowering external Na+ concentration, the first contraction was markedly increased without greatly affecting the second contraction. By exposure to Na+-free isotonic high K+ solution, which elicited a greater depolarization of the membrane, the first contraction produced by adrenaline was also greatly potentiated, while the second and rhythmic contractions were eliminated. These results suggest that the adrenaline-evoked first contraction may be due to an influx of membrane bound Ca2+ which is independent of membrane depolarization, while the second (rhythmic) contraction is due to an influx of extracellular Ca2+ which is dependent upon depolarization.
The passive role of calcium in hypertension: A position statement as of August 20,1985
Authors: Langford Herbert G.
Published: April 2011

Epidemiologic data suggest that calcium intake is lower in hypertensive individuals than in normotensive individuals. Moreover, hypertensive patients and rats excrete more calcium in their urine than normotensives, and laboratory studies (low ionized calcium, high parathyroid hormone (PTH)) suggest that the hypertensive is somewhat calcium depleted. However, both the low ionized calcium and elevated PTH should tend to lower pressure rather than raise it, leaving only the presumed and poorly documented natriuretic effect of calcium as a hypotensive mechanism. The evidence is better for a high sodium intake producing a conditioned deficiency of calcium by increasing calcium excretion than for a low intake of calcium raising blood pressure.
High potassium diets markedly protect against stroke deaths and kidney disease in hypertensive rats, a possible legacy from prehistoric times
Authors: Tobian Louis
Published: April 2011

Male spontaneously hypertensive stroke-prone (SHRsp) rats were fed 4% NaCl diets containing either 0.75% (normal) K or2.11% (high) K, starting at 6 weeks of age. After 8 months on these diets, 40 out of 58 SHRsp rats on the 0.75% K diet had died(69% mortality) versus 2 dead out of 95 on the 2.11% K diet (2% mortality), a 97% reduction in mortality, p < 0.00001. After 20weeks on the diets, the daytime and night time blood pressures of each rat were measured intraarterially under light ether anesthesia. Using these accurate blood pressures, we selected two groups precisely matched for blood pressure. One matched SHRsp group (BP 182) ate the 0.75% K diet and 30 out of 47 rats died (64% mortality). The other matched SHRsp group (BP 182) ate the 2.11% K diet and 2 out of 35 died (6% mortality), a 91% reduction of mortality, p < 0.0001. Seemingly, this striking reduction in mortality rate with the 2.11% high K diet does not depend on a lowering of blood pressure. High K diets do not change body Na or K. Dry weight of mesenteric arterioles was reduced 29% on the 2.11% K diet versus the 0.75% K diet (5.43 vs. 7.66 mg) (p < 0.0001), indicating a greatly reduced hypertensive hypertrophy. In nine surviving SHRsp rats on the 0.75% K diet, 13 of 36 brain hemisphere slides (4 slides per rat) showed infarcts (36%). In 11 surviving SHRsp rats on the 2.11% K diet, 1 of 44 brain slides showed infarcts (2%), a 94.5% reduction, p < 0.0001. High K diets allow cerebral arteries to carry very high blood pressures without sustaining damage to the artery wall, thereby drastically reducing brain infarcts and lowering the death rate.
Vegetarian approach to hypertension
Authors: Beilin Lawrence J.
Published: April 2011

Cross-sectional epidemiological studies suggest that ovolactovegetarians have lower blood pressures and less of a rise in blood pressure with age than meat eaters. Controlled dietary intervention trials in normotensive and untreated mild hypertensives have provided more direct evidence for a direct dietary effect on blood pressure. Studies designed to identify the nutrients involved suggest that neither polyunsaturated fat, saturated fat, cholesterol, potassium, magnesium, sodium, or total protein intake are independently responsible. The pathophysiological mechanisms involved are also unclear. In view of the complex changes involved in changing to a vegetarian diet, research in this area needs to pay careful attention to experimental design. This is an area of research that has important implications for the control of hypertensive cardiovascular disease in the community by means other than drugs.
Creep of the canine pericardium in vivo
Authors: Kingma Iris , Groves Gerald H. , Smith Eldon R. , Tyberg John V.
Published: April 2011

In eight open chest dogs we assessed the creep of the pericardium by measuring the increase in surface area of the pericardium, occurring after pericardial surface pressure (Ppe) was rapidly increased by inflating an air-containing balloon positioned between the pericardium and the left ventricular (LV) epicardium. We observed an increase in LV end diastolic pressure (EDP) of 3.6 ± 3.4 mmHg (1 mmHg = 133.3 Pa) (p < 0.05) (mean ± SD) and a reduction in LV anteroposterior (AP) diameter of 8.8 ± 6.1 mm (p < 0.01), both of which were stable after 10 s. Mean Ppe increased 11.6 ± 3.3 mmHg (p < 0.001). Pericardial surface lengths at 45 and 135° to the long axis of the LV were measured with two pairs of ultrasonic crystals attached to the outer surface of the pericardium. The beam of ultrasound travelling between each pair was directed parallel to the pericardial surface through a film of conducting medium. Initial increase in surface area (calculated as the product of two pericardial lengths) occurring during the first 15 s after balloon inflation was 5.8 ± 2.5% (p < 0.001). During the next 30 min, while mean pericardial pressure did not change, pericardial surface area increased another 2.8% (p < 0.005). This time-dependent 2.8% increase in pericardial surface area (equivalent to an increase in volume of approximately 5%) is due to creep. Our results are consistent with results of a previous in vitro study and could account for a small, time-dependent, rightward shift of the pericardial pressure–volume relation to be seen when pericardial pressure increases as in volume loading, pericardial effusion, or congestive heart failure.
Postsynaptic α-adrenoceptor characterization and Ca2+ channel antagonist and activator actions in rat tail arteries from normotensive and hypertensive animals
Authors: Su C. M. , Swamy V. C. , Triggle D. J.
Published: April 2011

Postsynaptic α-adrenoceptors in the rat tail artery have been examined by determining the pA2 values for antagonists against several α-adrenoceptor agonists. In this tissue the α-adrenoceptor agonists all produce concentration-dependent mechanical responses with the following rank order of potency: clonidine > norepinephrine > phenylephrine > UK 14304 > B-HT 920. Antagonism by prazosin and yohimbine of phenylephrine, norepinephrine, and clonidine responses does not reveal the anticipated discrimination between α1- and α2-adrenoceptors. Thus, pA2 values for prazosin (9.1–9.5), yohimbine (7.2–7.4), and corynanthine (7.0–7.1) and idazoxan (7.6) do not show large differences between these receptor agonists and suggests the predominance of α1-adrenoceptor mediated contractile responses in this preparation. Significant differences between antagonist activities (pA2 values) in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) artery preparations have not been observed. The sensitivity sequence of α-adrenoceptor agonist-induced responses to nifedipine and D 600 is B-HT 920 > clonidine > phenylephrine > norepinephrine. Dependence of agonist response upon extracellular Ca2+ parallels the sensitivity to Ca2+ channel antagonists. Sensitivity to D 600 of phenylephrine responses increased with decreasing concentration of phenylephrine or with receptor blockade by phenoxybenzamine: sensitivity of responses to B-HT 920 was not affected by these procedures. Tail artery strips from WKY and SHR do not exhibit major differences in sensitivity to D 600 or to Ca2+ depletion. Bay k 8644, a Ca2+ channel activator, produces concentration-dependent mechanical responses in the tail artery in the presence of modestly elevated K+ concentrations (10–15 mM): these actions of elevated K+ can be mimicked by both α1- and α2-adrenoceptor agonists including methoxamine, St 587, UK 14304, and clonidine. These studies do not provide clear evidence for the existence of discrete postsynaptic α1- and α2-adrenoceptor populations in rat tail artery as indicated by pA2 values or Ca2+ dependence of response.
Amiloride acts as an α-adrenergic antagonist in the isolated rat tail artery
Authors: Palatý Vladimír
Published: April 2011

In the final concentration of 100 μM, amiloride increased substantially the overflow of endogenous noradrenaline and decreased that of 3,4-dihydroxyphenylethylene glycol from the rat tail artery into Krebs solution supplemented with 10 μM veratridine. The overflow of the amine into a 120 mM-K version of Krebs solution was unaffected by amiloride, while that of the glycol was reduced. Abolition of the contractile response to 10 μM veratridine by 2 μM phentolamine indicated that the response was due to release of endogenous noradrenaline. Addition of amiloride in the final concentrations of 10 and 100 μM caused relaxation of strips contracted by the alkaloid. The dose–response relations for exogenous noradrenaline measured in the absence or presence of 50 μM amiloride indicated that the drug acted as a reversible competitive α-adrenergic antagonist. The phentolamine-resistant component of the contractile response to the 120 mM-K solution was unaffected by 100 μM amiloride. Although the exact site of action of amiloride remains to be determined, it can be concluded that amiloride inhibits adrenergic transmission at a postsynaptic site at a step preceding elevation of myoplasmic Ca2+.
Effects of plasma norepinephrine elevation on the heart's adaptation to chronic aortic constriction in rats
Authors: Siri Francis M. , Smith Richard M.
Published: April 2011

Chronically elevated plasma norepinephrine has the potential for supporting function of diseased hearts, yet may also initiate harmful biochemical and (or) structural changes in the myocardium. The present study investigated the dosage-related effects of chronic norepinephrine infusion on markers of myocardial damage and then tested the influence of a relatively low norepinephrine infusion rate (0.05 μg∙kg−1∙min−1) on the heart's adaptation to pressure overload in aortic constricted rats. Norepinephrine infusion at 0.50 μg∙kg−1∙min−1 led to significantly increased myocardial hydroxyproline concentration and significant mortality. A rate of 0.25 μg∙kg−1∙min−1 increased myocardial hydroxyproline concentration and mortality in aortic constricted rats but had no such effects on sham-operated rats. The lowest rate tested (0.05 μg∙kg−1∙min−1) significantly increased mean arterial pressure and lung weight of aortic constricted rats, without affecting the degree of left ventricular hypertrophy. This infusion rate and aortic constriction each increased plasma norepinephrine and impaired cardiac performance during rapid preloading, although their combination did not cause further impairment. Thus, it appears that even modest plasma norepinephrine elevation has a negative effect on the heart's adaptation to sustained pressure overload.
Effects of para-substitution on tissue levels and α-adrenoceptor antagonist properties of tolazoline
Authors: Danielson Terry J.
Published: April 2011

Tolazoline and a series of para-substituted analogues were examined in mice to determine the effects of para substitution on α-adrenoceptor antagonist potency and tissue disposition. α-Adrenoceptor antagonism was measured as abilities to attenuate the hypothermic or sedative actions of clonidine. In general, para substitution by electron-withdrawing metabolically stable groups (Cl, F) resulted in increased or unchanged brain levels of drug relative to tolazoline. The para substitution by electron-donating metabolically labile groups (CH3, OCH3) leads to reduced brain levels. Effects on α-adrenoceptor antagonist properties did not follow a similar pattern. Thus, increased or decreased antagonism of clonidine effects by para-chloro- or para-methyl-tolazoline, respectively, could be attributed solely to increased or decreased brain levels of drug. para-Fluorotolazoline did not antagonize clonidine but was present in brain at levels equivalent to those of tolazoline. para-Methoxytolazoline on the other hand could not be detected in any tissue but antagonised hypothermia more readily than sedation. These data indicate that the factors governing the disposition or α-adrenoceptor antagonist properties of tolazoline analogues are different and independent of each other.
Endothelium-dependent relaxation of rabbit aorta by acetylcholine requires ethylenediaminetetraacetic acid
Authors: Nakatsu K. , Vandenberghe M. , Kobus S. , Kawamoto J. , Brien J. F. , Marks G. S.
Published: April 2011

Experiments were conducted to determine if ethylenediaminetetraacetic acid (EDTA) was essential for the acetylcholine (ACh)-induced relaxation of blood vessels. Isolated rabbit aortic rings were prepared for recording isometric tension. They were maintained in Krebs bicarbonate solution with various concentrations of EDTA. With EDTA concentrations of 0 or 0.003 mM, no ACh-induced relaxation was observed; only the contractile effect of ACh was seen. With 0.03 and 0.30 mM EDTA, Ach induced relaxation with EC50 values of 0.11 and 0.098 μM, respectively. Under the experimental conditions used, EDTA was essential for demonstration of ACh-induced relaxation.
Pharmacokinetics of ethanol and its metabolite, acetaldehyde, and fetolethality in the third-trimester pregnant guinea pig for oral administration of acute, multiple-dose ethanol
Authors: Clarke David W. , Steenaart Nancy A. E. , Slack Christopher J. , Brien James F.
Published: April 2011

The pharmacokinetics of ethanol and its metabolite, acetaldehyde, were determined in the third-trimester pregnant guinea pig (56–59 days gestation) for oral intubation of four doses of 1 g ethanol/kg maternal body weight, administered at 1-h intervals. Animals (n = 4–7) were sacrificed at each of selected times during the 26-h study. Ethanol and acetaldehyde concentrations were determined by headspace gas-liquid chromatography. The maternal and fetal blood ethanol concentration–time curves were virtually superimposable, which indicated unimpeded bidirectional placental transfer of ethanol in the matemal–fetal unit. The blood and brain ethanol concentrations were similar in each of the maternal and fetal compartments during the study, which indicated rapid equilibrium distribution of ethanol. There was accumulation of ethanol in the amniotic fluid resulting in higher ethanol concentration compared with maternal and fetal blood during the elimination phase, which indicated that the amniotic fluid may serve as a reservoir for ethanol in utero. Acetaldehyde was measurable in all the biological fluids and tissues at concentrations that were at least 1000-fold less than the respective ethanol concentrations and were variable. There was ethanol-induced fetolethality that was delayed and variable among animals, and was 55% at 23 h. At this time interval, the ethanol concentrations in maternal blood and brain, fetal brain, and amniotic fluid were 35- to 53-fold greater and the acetaldehyde concentrations in maternal blood and fetal brain were four- to five-fold higher in the animals with dead fetuses compared with the guinea pigs with live litters. These data indicated that decreased ethanol elimination from the maternal–fetal unit was related temporally to the fetolethality.
Role of β2-adrenoceptors in the biological effect of autoimmune orchitis spleen cells
Authors: Borda Enri , Leiros Claudia Perez , Sterin-Borda Leonor
Published: April 2011

Autoimmune orchitis induced an increment in β2-adrenoceptor populations in intact mouse spleen lymphocytes. Normal and autoimmune lymphocytes incubated with soterenol increased the mechanical response of isolated atria. Autoimmune cells were more effective than normal cells in inducing this response. Soterenol or spleen cells alone did not modify the contractility at the concentration used. Inhibitors of β2-adrenoceptors of spleen cells completely blunted the reaction between soterenol and lymphocytes, while when atria were exposed to butoxamine, mechanical activity induced by soterenol plus lymphocytes was not affected. Cell-free supernatants of lymphocytes exposed to soterenol elicited the reaction in the same way as soterenol-treated lymphocytes. Direct contact of cells with the assay organ was not necessary. Inhibitors of cyclooxygenase on lymphocytes blocked the reaction of soterenol-treated lymphocytes on atria, while inhibitors of lipoxygenase(s) completely blocked the reaction of atria exposed to soterenol-stimulated lymphocytes or supernatants. These results suggest that soterenol reacts with β2-adrenoceptors of normal and autoimmune cells. From this reaction, soluble factors are released that in turn trigger stimulation of the atrial contractility as a consequence of the release of oxidative products of the lipoxygenase(s) pathway of arachidonic acid from atria. The high activity of atria in the presence of autoimmune spleen cells is probably related to the increment in number of β2-adrenoceptors of these cells.
Nutritional status and endocrine response to hemorrhage
Authors: Ljungqvist Olle , Efendic Suad , Eneroth Peter , Hamberger Bertil , Nylander Gunnar , Ware James
Published: April 2011

Hyperglycemia-inducing hyperosmolality has recently been proven beneficial in the maintenance of blood volume and extracellular fluid volume during early hemorrhagic hypotension. Fed animals benefitted from better plasma refill compared with starved ones when subjected to equal blood loss. Using lightly sedated fed and 24–30 h starved rats, hormones with relevance to glucose homeostasis were studied during 90 min of hemorrhagic hypotension of 70 mmHg (1 mmHg = 133.32 Pa). Marked differences in the overall hormonal developments were found between the two groups. In fed rats, insulin and glucagon responses were initially attenuated, while somatostatin increased to an early peak level at 30 min, returning to basal at 90 min. In starved rats, somatostatin increased gradually during the 90 min. Adrenaline release was massive in both groups. Corticosterone showed no increase from basal levels in the fed group during hemorrhage, while starved rats increased their basal level fourfold already at 30 min. These data are presented as evidence that changing nutritional status alters hormonal response to hypovolemic stress.
Cerebellar cortical activity during stretch of antagonist muscles
Authors: Bourbonnais Daniel , Krieger Charles , Smith Allan M.
Published: April 2011

Single unit activity was recorded from the anterior lobe of the cerebellum during ramp and hold stretches of limb muscles in chloralose anesthetized cats. The activity of 95 "phasic" units showed a transient response during dynamic stretch of at least one muscle usually lasting for less than 350 ms following the stimulus onset. The activity of 59 phasic–tonic units was modified not only during dynamic stretch but also during the 1 s of maintained muscle length. All Purkinje cells, identified by their complex spikes, that responded to muscle stretch demonstrated exclusively phasic changes in discharge. Fourteen of 25 Purkinje cells (56%) responded to stretch of both antagonist muscles and these responses were always similar rather than reciprocal. From the 129 units without complex spikes, 70 demonstrated phasic discharge patterns whereas 59 had tonic responses. Seventy-five (59%) of these unidentified units revealed convergent responses to stretch of both antagonists, compared with 54 which responded to stretch of one muscle only. Of the unidentified units receiving convergent afferents from antagonist muscles, 62 (83%) had similar responses and only 13 (17%) had reciprocal reactions. There appeared to be no evidence that muscle afferents alone can induce reciprocal discharge patterns in Purkinje neurons of the cerebellar cortex. The firing frequency of some phasic–tonic units was correlated with both the velocity and amplitude of muscle stretch. No Purkinje cells were found with activity related to either velocity or amplitude of muscle stretch. One phasic and seven phasic–tonic unidentified units were activated at fixed latencies following trains of electrical stimulation applied to the thoracic spinal cord at frequencies exceeding 200 Hz, implying they were terminal portions of mossy fibers originating from direct spinocerebellar tracts. A few recordings of compound potentials were presumed to arise from the cerebellar glomeruli. The changing form of one of these potentials suggested that the glomerulus might be a site at which somatosensory peripheral information is modified by the cerebellar cortex.
Protein production by sheep embryos during the period of maternal recognition of pregnancy
Authors: Manns J. G. , Lewing P. J.
Published: April 2011

An embryo must be present in the uterus 12–13 days after estrus to prevent regression of the ovine corpus luteum. The present experiments were designed to determine if embryo-specific secretory proteins could be detected in the maternal blood at the time of maternal recognition of pregnancy. In two experiments, 92 embryos were flushed from 47 ewes at 14–15 days after estrus. Embryos were incubated in vitro for 24 h and the proteins in the media were harvested. Antisera to proteins in both flushing and incubation medium were produced in rabbits. In experiment 1, crude fractions were used for antibody production and radioimmunoassays were established for protein peaks separated on a 1.1 × 75 cm G-100 Sephadex column. Two low molecular weight fractions (EPiv and EPv) appeared to be embryo specific but were not detectable in jugular vein sera of 14- to 15-day pregnant animals. In experiment 2, proteins derived from uterine flushes and from embryo incubations were chromatographed on a 2.5 × 85 cm column of G-100 Sephadex. The protein peaks were measured, pooled, lyophilized, and used for immunization of rabbits. As in experiment 1, antisera were generated, some of which seemed to be directed against embryo-specific proteins. However, we could not detect these fractions in the uterine vein blood of pregnant animals. Thus, embryo-specific proteins are either confined to the uterus or they appear in the blood in quantities that are undetectable with our assay system.
Myocardial and vascular lesions in the LA/N-corpulent rat
Authors: Russell J. C. , Amy R. M.
Published: April 2011

The LA/N-corpulent (LA/N-cp) rat is a normotensive strain derived from Koltesky's original mutant strain of the spontaneously hypertensive rat (SHR). When homozygous for the cp gene (cp/cp), the rats are hyperphagous, hyperlipidemic, hyperinsulinemic, and obese. The rats have been shown, by scanning electron microscope observation of the arterial system, to develop arterial lesions and occasional occlusive thrombi. These are significantly more frequent in the corpulent rats. Histological examination of the heart has shown the presence of four distinguishable types of lesions: type A, muscle scar or cell dropout with pigment deposition and inflammatory cell accumulation; type B, necrosis of a small number of myocytes with reactive inflammatory cells; type C, nodule of chronic inflammatory cells; type D, muscle scar without chronic inflammatory cells. Complete transverse sections of three regions of the heart were examined from rats 3, 6, and 9 months of age. Rats that were homozygous normal (+/+) showed an absence of all types of cardiac lesions. Male corpulent rats showed frequent lesions of all types with the frequency rising consistently with age. Female corpulent rats showed a similar incidence of types C and D lesions to males, but no type B lesions were found. Type A lesions, the most common in corpulent males, were found at a greatly reduced relative frequency. In some instances, we have found occlusive thrombi in a coronary artery of corpulent rats. The disease process in these animals occurs with a normal low fat, virtually cholesterol-free diet and no experimental manipulation.
Intracellular chloride activity in rabbit papillary muscle: effect of serum
Authors: Caillé Jean-Pierre
Published: April 2011

The intracellular chloride activity (aiCl), measured with Cl-selective microelectrodes on stimulated rabbit papillary muscles (1 Hz) incubated in serum, was 7.2 ± 2.2 mM (48 measurements). Under the same condition, on the quiescent muscle, aiCl was 7.5 ± 2.8 mM (45 measurements). The membrane potential of quiescent papillary muscles and diastolic potential of stimulated papillary muscles were −79.0 ± 0.7 (50 measurements) and −83.5 ± 0.5 mV (50 measurements), respectively. The experimental conditions were chosen to reproduce the in vivo conditions where the Cl equilibrium potential is close to the membrane potential or to the diastolic potential. After correcting for cytoplasmic interference (4 mM) on the aiCl measurements, the Cl equilibrium potential (ECl) was −84 mV. In conclusion, the Cl distribution in cardiac cells bathed in serum is passive as for in vivo cardiac cells.
Renal tissue metabolism in the rat during chronic metabolic alkalosis: importance of glycolysis
Authors: Lemieux Guy , Berkofsky James , Lemieux Christiane
Published: April 2011

Chronic metabolic alkalosis was induced in rats drinking 0.3 M NaHCO3 and receiving 1 mg furosemide/100 g body weight per day intraperitoneally. Another group of animals received a potassium supplement in the form of 0.3 M KHCO3. In this group, hypokalemia did not develop and muscle potassium fell by only 18% versus 50% in those not receiving potassium. In vitro renal production of ammonia and uptake of glutamine fell by 40% with a decrease in the activity of glutaminase I and glutamate dehydrogenase. Activity of phosphofructokinase, a major enzyme of glycolysis, rose only in the kidney of animals receiving a potassium supplement. Fructose-1,6-diphosphatase fell as well as phosphoenolpyruvate carboxykinase. Malate dehydrogenase also fell. The activity of phosphofructokinase also rose in the liver, heart, and leg muscle. The major biochemical changes in the renal cortex were the following: glutamate, α-ketoglutarate, malate, lactate, pyruvate, alanine, aspartate, and citrate rose as well as calculated oxaloacetate. The concentration of intermediates like 2-phosphoglycerate, 3-phosphoglycerate, and glucose-6-phosphate fell. The cytosolic redox potential (NAD+/NADH) decreased. In addition to the fall in ammoniagenesis, it could be demonstrated in vitro that the renal tubules incubated with glutamine showed decreased glucose production and increased production of lactate and pyruvate. The concentration of lactate was elevated in all tissues examined including liver, heart, and leg muscle. This study confirms in the rat that decreased renal ammoniagenesis takes place following decreased uptake of glutamine in metabolic alkalosis. All other changes are accounted for by the process of increased glycolysis, which appears to take place in all tissues in metabolic alkalosis. All reported changes were more significant in animals receiving supplement of potassium, indicating that associated potassium deficiency plays a role in counteracting the observed changes now expected in metabolic alkalosis.
The inhibitory effects of some adenosine analogues on transmitter release at the mammalian neuromuscular junction
Authors: Singh Yadhu N. , Dryden William F. , Chen Hsinyo
Published: April 2011

An electrophysiological study was made of the effects of four adenosine analogues, 2-chloroadenosine (2-CIA), 5′-N-ethylcarboxamidoadenosine (NECA), L-N6-phenylisopropyladenosine (L-PIA), and 2-(p-methoxyphenyl)-adenosine (CV-1674) on neurotransmitter release in the mouse phrenic nerve–hemidiaphragm preparation. All four drugs decreased miniature end-plate potential frequency in a dose-dependent manner. Evoked transmitter release in the cut diaphragm preparation was depressed by 2-CIA and CV-1674 to a similar extent. The ability of theophylline to antagonize the inhibitory effect of CV-1674 on spontaneous transmitter release was also established. On the basis of these results, the rank order of potencies was: L-PIA>NECA>2-CIA>CV-1674. A clear classification of receptor type could not be made, since the ratio of potencies of L-PIA and NEC A was narrow. Different slopes of the concentration–effect curves for 2-CIA and CV-1674 compared with L-PIA and NEC A suggest an additional component to simple agonist action in their overall effects.
Effects of hydralazine on blood pressure, pressor mechanisms, and cardiac hypertrophy in two-kidney, one-clip hypertensive rats
Authors: Tsoporis James , Leenen Frans H. H.
Published: April 2011

In 2-kidney, 1-clip hypertensive rats, the time course of changes in blood pressure (BP), heart rate, activity of the sympathetic nervous system and the renin–angiotensin system, plasma and blood volumes, left ventricular (LV) and right ventricular (RV) weight, and LV dimensions were evaluated during treatment with hydralazine 80 and 120 mg/L drinking water for 2 days or 1, 2, 3, 5, and 8 weeks. Hydralazine induced initially a clear antihypertensive effect (mean BP from 170–180 down to 135–145 mmHg (1 mmHg = 133.32 Pa)), subsequently tolerance developed. Heart rate, plasma catecholamines, and the blood pressure response to hexamethonium were not affected by treatment. Significant increases in plasma renin activity occurred during the initial 1–3 weeks of treatment. Plasma and blood volumes showed only small increases with prolonged treatment. RV weight and LV internal diameter showed significant increases at 3, 5, and 8 weeks of treatment, LV weight at 5 and 8 weeks. LV wall thickness did not change significantly. Thus, treatment with the arterial vasodilator hydralazine causes both RV hypertrophy and eccentric LV hypertrophy. Intravascular volume expansion, associated possibly with redistribution of blood volume to the central compartment, may play a major role in these cardiac effects. Increased renin release but not a generalized increase in sympathetic tone may play a role in the development of tolerance to the antihypertensive effect.