bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased metabolic heat production following chronic alpha-methyldopa therapy in hypertensives
Authors: Fernandez P. G. , Snedden W. , Snellen J. W. , Galway A. B. , Nath C.
Published: April 2011

The objective of this study was to measure metabolic heat production in mild-moderate hypertensives when given chronic alpha-methyldopa for control of hypertension and to compare this with hydrochlorothiazide. Four men and one woman, age range 29–55 years, euthyroid, and not previously on alpha-methyldopa, had their drugs replaced by placebo for 4 weeks, and then alpha-methyldopa or hydrochlorothiazide was randomized single blindedly to patients. The dose of each drug was increased until the ambulatory diastolic blood pressure was less than 95 mmHg (1 mmHg = 133.322 Pa), and then the dose was maintained for 20–24 weeks. The two active drugs were then crossed over, and each medication was again titrated to attain diastolic normotension (<95 mmHg). Maintenance was for a comparable 20–24 weeks. At week 4 (end of placebo period), weeks 20–24 (for hydrochlorothiazide or alpha-methyldopa monotherapy), and again at weeks 40–48 (end of cross-over period), metabolic heat production (watts), heart rate (beats per minute), and blood pressure (millimetres of Hg) were measured in a resting sitting position for 1 h in a whole body calorimeter (air temperature 28 °C and a dew point temperature <5 °C) for 15 experimental sessions. In four out of five patients, metabolic heat production was significantly (P < 0.05) higher when patients were treated with alpha-methyldopa. We speculate from our data that alpha-methylnorepinephrine, the major metabolite of alpha-methyldopa, may be thermogenic and that this should be considered when the drug is prescribed.
Renal metabolism during four types of lactic acidosis in the dog including anoxia
Authors: Lemieux Guy , Junco Eduardo , Perez Raphael , Allignet Elizabeth , Lemieux Christiane , Aranda Manuel Rengel , Quintana Fernando Valderrabano
Published: April 2011

The present study was undertaken to evaluate the metabolic response of the kidney to lactic acidosis. Four types of lactic acidosis were induced in the dog: infusion of lactic acid, infusion of lactic acid with phenformin, administration of phenformin alone, and hypoxia by breathing 95% nitrogen. In all groups of animals, the same degree of acidosis was observed with plasma bicarbonate ranging from 12.8 to 14.9 mM. Plasma lactate concentration ranged from 3.0 to 8.1 μmol/mL. Renal ammoniagenesis failed to be influenced by lactic acidosis. As a matter of fact, it fell during anoxia. The extraction of glutamine by the kidney rose except during anoxia where it fell. The renal production of alanine rose during the infusion of lactic acid with and without phenformin. This coincided with the extraction of glutamine. The renal extraction of lactate rose in all forms of acidosis as well as the production of pyruvate. In the renal cortical tissue, the concentration of malate, pyruvate, and lactate rose. Alanine also rose except during anoxia. An important fall in cytosolic redox potential (NAD+/NADH lactate dehydrogenase) was observed, as well as a fall in mitochondrial redox (NAD+/NADH beta-hydroxybutyrate dehydrogenase). Lactate also accumulated in the liver and in the muscle. We propose that the kidney is unable to respond to lactic acidosis in terms of ammonia production and that this phenomenon is explained by transamination of pyruvate and glutamate into alanine and also by the observed fall in cytosolic redox potential. It is likely that renal gluconeogenesis is also inhibited and this is reflected by the rise in the concentration of malate in the kidney. Gross anoxia provokes the most severe form of lactic acidosis and the more important biochemical changes including a decrease in the uptake of glutamine and in ammonia production by the kidney.
Biphasic effect of local anesthetics on the adenosine triphosphate-dependent calcium uptake by lysed brain synaptosomes
Authors: Lavoie P.-A. , Mekhail-Ishak K. , Sharkawi M.
Published: April 2011

Previous studies have shown that an adenosine triphosphate-dependent calcium uptake activity in lysed brain synaptosomes is attributable to the neuronal endoplasmic reticulum elements. The present study has examined the effects of tetracaine, lidocaine, and dibucaine on this calcium uptake process. The adenosine triphosphate-dependent uptake of 45Ca2+ was measured (in the absence and in the presence of drug) by Millipore filtration and liquid scintillation spectrometry. The local anesthetics studied exhibited a biphasic effect on 45Ca2+ uptake by lysed synaptosomes from rat brain cortex. High concentrations (5 mM tetracaine, 50 mM lidocaine, 0.6 mM dibucaine) inhibited the uptake of 45Ca2+; the order of potency for this effect was dibucaine > tetracaine > lidocaine. Lower concentrations of these local anesthetics produced either no effect on 45Ca2+ uptake (2 mM tetracaine or 30 mM lidocaine) or a stimulation of 45Ca2+ uptake (1 mM tetracaine, 10 mM lidocaine, and 0.3 mM or 0.1 mM dibucaine); the order of potency for stimulation of 45Ca2+ uptake was dibucaine > tetracaine > lidocaine.
Arteriolar, capillary, and shunt flow gradients along the intestine in relation to the weight distribution of the mucosa, submucosa, and muscularis—a microsphere study
Authors: Dinda P. K. , Beck I. T.
Published: April 2011

The objective of this study was to establish the basal arteriolar (ART), capillary (CAP), and shunt (SH) flow of the three anatomical layers of the gut wall (mucosa, submucosa, and muscularis) along the intestinal tract of the dog employing a microsphere technique. We also examined whether a gradient of blood flow (BF) exists along the intestine, and if so, how this is related to the blood flow and weight distribution of the three anatomical layers along the intestine. We found the following. (i) In all locations of the intestine a higher proportion of the ART inflow passed through the capillaries of the layers with higher metabolic need, i.e., mucosa (68–79%) and the muscularis (50–79%), than through the capillaries of the submucosa (34–46%). Thus, the distribution between CAP and SH flow in the three anatomic layers of the gut wall, as measured by the microsphere technique, appears to correspond to the functional requirements of these tissue layers, (ii) From the duodenum to the ascending colon (but not along the colon), there was a significant decreasing gradient of ART flow (R2 = 50.6%) and a small and barely significant gradient of CAP (R2 = 11.6%) and SH flow (R2 = 9.7%) of the whole gut wall. (iii) All these gradients were present in the mucosa, but their slopes were higher than those in the whole gut wall; the R2 for the mucosal ART, CAP, and the SH flow was 60.5, 52.7, and 21.6%, respectively, (iv) The ART, CAP, or the SH flow of the submucosa and the muscularis showed no such decreasing gradient. Thus, the gradient of blood flow of the whole gut wall appears to be a reflection of a more prominent gradient of ART and CAP flow of the mucosa, (v) Similar to the mucosal blood flow, the weight distribution of the mucosa showed a craniocaudal gradient (R2 = 69.3%). The latter was found to be directly related to the mucosal blood flow of all locations from the duodenum to the ascending colon, except for the duodenum, which had a higher ART and SH flow than those of several, but not all, distal locations. This higher blood flow of the duodenum could be due to a functional difference of this location.
Vascular role of vasopressin in the presence and absence of influence from angiotensin II or α-adrenergic system
Authors: Tabrizchi Reza , King Kathryn A. , Pang Catherine C. Y.
Published: April 2011

The effects of a vasopressin (AVP) pressor antagonist, d(CH2)5Tyr(Me)AVP, on mean arterial pressure (MAP), total peripheral resistance (TPR), cardiac output (CO), and the distribution of CO were investigated by the microsphere technique in three groups of pentobarbital anesthetized rats: intact (I), saralasin pretreated (II), and phentolamine pretreated (III). Saralasin and phentolamine were infused intravenously to inactivate the renin–angiotensin and α-adrenergic systems, respectively. The AVP antagonist decreased MAP and TPR in all groups and it caused a greater depressor effect in groups II and III than in group I. In group I, AVP antagonist increased blood flow (BF) to the stomach and skin. In group II, AVP antagonist increased BF to the muscle and skin. In group III, AVP antagonist markedly increased BF to the muscle. Therefore, the degree of vasoconstrictor influence exerted by AVP in different vascular beds varies depending on endogenous vasomotor tone from the renin–angiotensin and (or) sympathetic nervous systems.
Effect of adrenalectomy on distal tubule water permeability of the Brattleboro rat
Authors: Hirsch David Jay , Hirtle Roy W. M.
Published: April 2011

The mechanism of impaired water excretion in adrenalectomized mammals is unclear. Previous workers have suggested that one cause might be increased water permeability of the distal nephron, allowing back diffusion of water from tubular fluid diluted by the ascending limb. Evidence to support this mechanism in previous studies has been confounded by simultaneous changes in steroid and antidiuretic hormone levels. We compared osmotic and diffusional water permeability of the surface late distal tubule in vivo in intact and adrenalectomized Brattleboro rats, which are free of antidiuretic hormone. The adrtenalectomized rats were demonstrated to have impaired diluting capacity in clearance studies. Adrenalectomized rats had a sixfold increase in osmotic permeability and a 1.5-fold increase in diffusional permeability over intact controls. Adrenal steroids have a specific action on water permeability of the distal nephron, independent of antidiuretic hormone.
The effect of brief physical exercise on free radical scavenging enzyme systems in human red blood cells
Authors: Ohno Hideki , Sato Yuzo , Yamashita Kohki , Doi Rikuo , Arai Katsura , Kondo Takahito , Taniguchi Naoyuki
Published: April 2011

Eleven sedentary male students were studied, using a bicycle ergometer, for 30 min at about 75% of their maximal oxygen uptake, to observe the effects of brief physical exercise on free radical scavenging system enzymes of the erythrocytes. Of the enzymes examined, only total glutathione reductase activity showed a significant elevation immediately after exercise and appeared to remain high at 30 min after exercise. The results suggest that acute physical exercise has some effects on red blood cell glutathione reductase activity, which is related primarily to maintenance of reduced glutathione.
Evidence that substance P may be a modulator rather than a transmitter of noxious mechanical stimulation
Authors: Sweeney Marva Irene , Sawynok J. Ana
Published: April 2011

Substance P (SP), injected intrathecally, produced a dose-related increase in responsiveness (hyperalgesia) in a pressure test for nociceptive thresholds. Pretreatment with two doses of SP produced complete desensitization to this response but did not alter base-line responsiveness. The hyperalgesic response to SP and the lack of change in base line following desensitization to SP suggest a modulator rather than a transmitter role for SP in the transmission of noxious mechanical stimulation.
Reversibility of ultrastructural, contractile function and Ca2+ transport changes in guinea pig hearts after global ischemia
Authors: Singal Pawan K. , Lee Sheu L. , Ganguly Pallab K. , Panagia Vincenzo , Dhalla Naranjan S.
Published: April 2011

To understand the subcellular basis of contractile failure due to ischemia–reperfusion injury, effects of 20, 60, and 90 min of global ischemia followed by 30 min of reperfusion were examined in isolated guinea pig hearts. Cardiac ultrastructure and function as well as Ca2+ transport abilities of both mitochondrial and microsomal fractions were determined in control, ischemic, and reperfused hearts. Hearts were unable to generate any contractile force after 20 min of ischemia and showed a 75% recovery upon reperfusion. However, there were no significant changes in the subcellular Ca2+ transport in the 20-min ischemic or reperfused hearts. When hearts were made ischemic for 60 and 90 min, the recovery of contractile force on reperfusion was 50 and 7%, respectively. There was a progressive decrease in mitochondrial and microsomal Ca2+ binding and uptake activities after 60 and 90 min of ischemia; these changes were evident at various times of incubation period and at different concentrations of Ca2+. Mitochondrial Ca2+ transport changes were only partially reversible upon reperfusion after 60 and 90 min of ischemia, whereas the microsomal Ca2+ binding, uptake and Ca2+ ATPase activities deteriorated further upon reperfusion of the 90-min ischemic hearts. Ultrastructural changes increased with the duration of the ischemic insult and reperfusion injury was extensive in the 90-min ischemic hearts. These data show that the lack of recovery of contractile function upon reperfusion after a prolonged ischemic insult was accompanied by defects in sarcoplasmic reticulum Ca2+ transporting properties and structural damage.
Strophanthidin inotropy in cardiac Purkinje fibers under conditions that vary cellular sodium or calcium
Authors: Li Tung , Bernabei Roberto , Carbonin Pierugo , Vassalle Mario
Published: April 2011

The role of sodium and calcium on strophanthidin inotropy was studied in canine cardiac Purkinje fibers perfused in vitro under conditions that vary cellular sodium and calcium. With high concentrations of strophanthidin (≥ 10−7 M), force increases more in the presence of low [Ca]0 or high [Na]0 and less in the presence of a low sodium–calcium concentration solution than in Tyrode solution. In a solution with a low concentration of sodium–calcium containing strophanthidin, restoring [Na]0 to normal decreases and then re-increases force: when [Na]0 is decreased again, the force transiently overshoots. These effects of strophanthidin are exaggerated by metabolic inhibitors. In a low [Ca] solution, low concentrations of strophanthidin (3 × 10−8 or 5 × 10−8 M) re-increase force a little or not at all. On recovery, the transient force increase is not exaggerated by low strophanthidin and is absent after manganese exposure. The inotropy of low concentrations of strophanthidin is potentiated by norepinephrine, high [Ca]0 (4 mM), or by lowering [Na]0. Thus, the present results suggest that the inotropic action of high strophanthidin concentrations depends primarily on sodium and secondarily on calcium, and that the inotropic action of low concentrations of strophanthidin involves a modification of the cell response to calcium.
A nonocclusive cannula for sampling venous blood from the interscapular brown fat of conscious rats
Authors: Ma Stephanie W. Y. , NaDeau Brita E. , Foster David O.
Published: April 2011

Lack of an adequate method for sampling venous blood from the brown adipose tissue (BAT) of conscious animals has impeded study of the in vivo metabolism of this tissue during physiological activation of its thermogenic function. This paper describes a technique for cannulating the main vein (Sulzer's) of the interscapular BAT (IBAT) of rats in a manner that does not impair blood flow and allows multiple venous sampling over several hours in conscious animals. The technique was tested over the widest possible range of IBAT blood flows by applying it to measurements of IBAT arteriovenous O2 differences in barbital-anesthetized, cold-acclimated rats infused with vehicle or with various doses of noradrenaline. Comparison was made with controls in which samples of IBAT venous blood were obtained by cutting Sulzer's vein. Blood flow was measured by the microsphere method. These tests showed that the presence of the special cannula in Sulzer's vein had no significant effect on the blood flow, arteriovenous O2 difference, or O2 consumption of the IBAT at any level of noradrenaline-induced thermogenesis. The new technique will permit examination of the functioning of BAT in nonshivering thermogenesis and diet-induced thermogenesis under much more physiological conditions than hitherto possible. It should also significantly reduce the number of animals required for such studies.
Further characterization of the receptors involved in the positive inotropic effect of histamine on rabbit papillary muscle
Authors: Elizalde Alejandro , Perez-Chavez Jesús , Sánchez-Chapula José
Published: April 2011

The effects of histamine on the force of contraction and calcium-dependent action potentials were studied in rabbit ventricular papillary muscles. The positive inotropic effect of histamine seems to be dependent on stimulation of H1 and H2 receptors. The H1 antagonist chlorpheniramine produced a competitive blockade of the positive inotropic effects of histamine. Cimetidine produced a competitive blockade, which was apparent only after blockade of H1 receptors. Histamine increased the maximum upstroke velocity of slow action potentials. This effect can be entirely accounted for by stimulation of H2 receptors. The phosphodiesterase inhibitor 3-isobutyl-methyl-xanthine potentiated the H2 receptor mediated effects of histamine on the force of contraction and slow action potentials. We conclude that rabbit ventricular muscle possesses both H1 and H2 receptors that mediate the positive inotropic effect of histamine. The H2-mediated effect seems to be causally related to an increase in the calcium slow inward current and is probably linked to an enhanced cellular cyclic adenosine monophosphate content. The mechanism of the H1-mediated positive inotropic effect remains unknown.
Effects of substance P on the long-term regulation of tyrosine hydroxylase activity and catecholamine levels in cultured adrenal chromaffin cells
Authors: Boksa P.
Published: April 2011

Acetylcholine, released from splanchnic nerve terminals innervating adrenal chromaffin cells, is known to increase synthesis of adrenal tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. The neuropeptide substance P is also present in the splanchnic nerve innervating the adrenal medulla, and this study examined whether substance P has any long-term effects on tyrosine hydroxylase activity and catecholamine levels in cultures of adult bovine adrenal chromaffin cells. When cultures were incubated for 3 days with substance P and carbachol, a cholinergic agonist, substance P (10−6 M, and greater) completely inhibited the increase in tyrosine hydroxylase activity normally induced by carbachol. Long-term stimulation with carbachol also depleted endogenous catecholamines from the cells and substance P prevented this carbachol-induced depletion of catecholamine content. Substance P by itself, in the absence of carbachol, had only a slight effect on tyrosine hydroxylase activity. 8-Bromoadenosine 3′:5′-cyclic monophosphate, an analogue of adenosine 3′:5′-cyclic monophosphate, also increases tyrosine hydroxylase activity in chromaffin cells; however, substance P had no effect on the increase in tyrosine hydroxylase activity induced by this analogue. These results indicate that substance P's effects are relatively specific for the carbachol-induced increased in tyrosine hydroxylase activity and that the primary site of action of substance P is not a site common to the mechanism of tyrosine hydroxylase induction by carbachol and 8-bromoadenosine 3′:5′-cyclic monophosphate. During long-term incubation of chromaffin cell cultures, substance P inhibited the carbachol-induced increase in tyrosine hydroxylase activity only if peptidase inhibitors, bacitracin and captopril, were included in the medium, suggesting that chromaffin cell peptidases may be capable of terminating substance P's actions in these cells. The peptidase inhibitors bacitracin and captopril alone increased tyrosine hydroxylase activity and depleted catecholamines from the cells. The results suggest that substance P, released either from the splanchnic nerve or from the chromaffin cells themselves, may play a role in the long-term regulation of tyrosine hydroxylase activity and catecholamine levels in the mature adrenal chromaffin cell.
Effects of endogenous and exogenous prostaglandin in neurotransmission in canine trachea
Authors: Daniel E. E. , Davis C. , Sharma V.
Published: April 2011

The effect of PGE2 on neurotransmission in the canine tracheal strip dissected free of epithelium was studied in the single sucrose gap and organ bath. PGE2 was a potent inhibitor of the initiation of excitatory junction potentials (ejps) by just submaximal nerve stimulation. In a concentration of 10−9 or 10−8 M PGE2 nearly or completely abolished them. Contractile responses to field stimulation in the sucrose gap at 27 °C or in muscle baths at 37 °C were also reduced or abolished by PGE2 in the same dose range; reductions were greater at low frequency. Responses to acetylcholine were also depressed but significantly less than to field stimulation. These are consistent with major presynaptic as well as some postsynaptic inhibitory actions of PGE2. No evidence was obtained that endogenous PGE2 affected excitatory junction potentials and contractions; i.e. they were stable for hours and unaffected by indomethacin 10−6 and 10−5 M under our conditions. Post-stimulus potentiation of ejps amplitude, maximum at 10 s, was observed and became more marked after the first ejp had been markedly reduced or abolished by PGE2. This potentiation was unaffected by indomethacin. It was suggested that a presynaptic process inhibited by PGE2 might participate in this potentiation. The canine trachea is a useful preparation when studied under the experimental condition used here for study of effects of products of arachidonate on neurotransmission.
Vascular responses to agonists in rat mesenteric artery from diabetic rats
Authors: Agrawal Devendra K. , McNeill John H.
Published: April 2011

The effect of diabetes on vascular smooth muscle function was investigated in the muscular arteries from spontaneously and chemically induced diabetic rats. Isolated ring segments of superior mesenteric arteries from BB diabetic and streptozotocin (STZ)-diabetic rats (12 weeks after onset of diabetes) were used for isometric tension studies. Contractile responses to alpha-adrenoceptor agonists (norepinephrine, methoxamine, phenylephrine, B-HT 920, guanabenz, SKF 89748-A), serotonin, and K+ were significantly higher in STZ-diabetic rat arteries as compared with the controls. In spontaneously diabetic rat arteries only the contractile responses to the putatively selective alpha2-adrenoceptor agonists, K+ and prostaglandin E1, were significantly increased. pD2 values of the agonists in both groups of diabetic arteries were not significantly different from the respective controls. Nifedipine inhibited all contractile responses in a dose-dependent fashion. The responses to K+ and alpha2-adrenoceptor agonists were attenuated to a greater extent by nifedipine in both groups of diabetic blood vessels. The calcium channel activator, BAY K 8644, produced a twofold increase in force of contraction in streptozotocin-diabetic and spontaneously diabetic rat arteries as compared with the responses in their respective controls. These results suggest caution in extrapolating all the findings from the streptozotocin-induced diabetic model to the spontaneously diabetic model. However, increased activity of calcium channels in vascular muscle cells in both groups of diabetics may be responsible, at least in part, for the increased vascular contractility in diabetes mellitus.
Metabolic activation of 1,1-dichloroethylene by mouse lung and liver microsomes
Authors: Forkert P. G. , Hofley M. , Racz W. J.
Published: April 2011

1,1-Dichloroethylene (1,1-DCE) causes lung and liver necrosis in mice. Covalent binding of [14C] 1,1-DCE to isolated lung and liver microsomes from CD-1 mice required NADPH and was strongly inhibited by carbon monoxide. Lung and liver microsomes isolated from animals treated with phenobarbital demonstrated no changes in covalent binding of [14C]1,1-DCE compared with those from vehicle-treated animals. While 3-methylcholanthrene caused no alterations in binding to lung microsomes, the same pretreatment resulted in significantly increased levels of binding to liver microsomes. Piperonyl butoxide caused significant decreases in covalent binding to lung and liver microsomes; SKF 525-A significantly inhibited binding to liver microsomes but had no effect on lung microsomes. The incubation of liver microsomes with inhibitors required more NADPH than those performed with lung microsomes. The results demonstrate that reactive metabolites of 1,1-DCE can be formed by lung and liver microsomes, and suggest the involvement of cytochrome P-450 isozymes in the lung and liver injury induced by the halocarbon. However, metabolic activation by lung and liver microsomes may additionally involve non P-450 dependent mechanisms as evidenced by relatively high levels of nonspecific binding of 1,1-DCE.
Lysophosphatidylcholine metabolism and cardiac arrhythmias
Authors: Giffin Mitch , Arthur Gilbert , Choy Patrick C. , Man Ricky Y. K.
Published: April 2011

The ability of exogenous lysophosphatidylcholine (LPC) to produce electrophysiological abnormalities in cardiac tissues and cardiac arrhythmias in isolated hearts has been well documented. In this study, the arrhythmogenic nature of LPC in the rat, rabbit, and guinea pig hearts was studied. The rat heart was found to be the most susceptible to LPC-induced arrhythmias, while the guinea pig heart was the least susceptible. Perfusion with labelled LPC revealed that the severity of arrhythmias correlates well with the amount of labelled LPC found in the microsomal membrane. The biochemical basis for the differences in the accumulation of LPC in the microsomal membrane of different animal species was investigated. Our results strongly indicate that the LPC level in the microsomal membrane may be regulated by the activity of microsomal lysophospholipase.
Cardiac inotropic effects of leukotriene C4 and prostaglandin I2 in the unanesthetized American bullfrog, Rana catesbeiana
Authors: Robleto Daniel O. , Reitmeyer Sheila T. , Herman Ceil A.
Published: April 2011

The cardiovascular effects of leukotriene (LT) C4 and prostaglandin (PG) I2 were compared in the unanesthetized American bullfrog, Rana catesbeiana. Bullfrogs were instrumented to measure mean arterial pressure, peak ventricular pressure, its derivative (VP + dP/dt), and heart rate. Two hours after recovery from anesthesia, intravenous injections of LTC4 or PGI2 were tested over a dose range from 0.003 to 3 μg/kg body weight (bw). Both eicosanoids decreased mean arterial pressure, systolic ventricular pressure, and its derivative (VP + dP/dt). The effects of LTC4 and PGI2 on all parameters were similar at doses below 3 μg/kg bw. However, at 3 μg/kg bw, LTC4 had more potent negative inotropic effects than PGI2. Both compounds increased heart rate at 0.3 μg/kg bw, but at 3 μg/kg bw PGI2 caused greater increases than LTC4. The hypotensive and negative inotropic effects of LTC4 were blunted in animals pretreated with indomethacin (4 mg/kg bw) to prevent endogenous prostaglandin and thromboxane synthesis, whereas the cardiovascular effects of PGI2 were unaffected by the blockade. The data show that both eicosanoids have similar qualitative effects on blood pressure and cardiac performance. However, the effects of LTC4 may be partially mediated by release of endogenous cyclooxygenase products, possibly PGI2. These results suggest that the bullfrog, an animal with no coronary arteries, is a useful model for comparative studies of cardiac actions of eicosanoids which are independent of effects mediated by changes in coronary vascular resistance.
Functional impairment induced by lipophilic cationic compounds on mitochondria
Authors: Singh Gurmit , Shaughnessy Stephen G.
Published: April 2011

Lipophilic cations, such as rhodamine 123, have selective anticarcinoma activity both in epithelial-derived tumor cells and in tumor cells injected into mice. The mechanism by which rhodamine 123 and safranin have their effect on mitochondrial function was examined. Rhodamine 123 and safranin inhibit the stimulation of mitochondrial respiration by ADP in a similar concentration range. This inhibition occurs whether the mitochondria are respiring on succinate as a substrate or on ascorbate plus tetramethylphenylenediamine. ATP hydrolysis was stimulated twofold by high lipophilic cation concentration. These results demonstrate that rhodamine 123 and safranin affect oxidative phosphorylation in a similar fashion.
Cardioacceleration produced by close intra-arterial injection of neurotensin into the stellate ganglion of the cat
Authors: Bachoo M. , Polosa C.
Published: April 2011

The effect on heart rate of close i.a. injection of neurotensin (NT), substance P (SP), and vasoactive intestinal peptide (VIP) into the decentralized right stellate ganglion was tested in anaesthetized spinal cats. These peptides are present in the stellate ganglion and may mediate the stellate ganglion cell excitation underlying a previously described slow cardioacceleration evoked by preganglionic stimulation during block of cholinergic transmission. NT (Tyr11-NT) at doses of 25–200 μg produced increases in heart rate of 10–125 beats/min (bpm) and of slow time course. At the dose of 100 μg, NT produced a cardioacceleration of 56 ± 8.4 bpm(mean ± SEM, n = 13) with an onset latency of 23 ± 4 s, a slow rise to peak (rise time 62 ± 4.5 s), and a half decay of 167 ± 14 s. A cardioacceleration of comparable magnitude (78 ± 3.8 bpm) caused by close i.a. administration of acetylcholine (100 μg, n = 13) had an onset latency of 2 ± 1 s, a fast rise to a sharp peak (rise time 3 ± 1 s), and a half decay of 23 ± 4 s. The analogues, Phe11-NT and Trp11-NT, as well as the stereoisomer, D-Tyr11-NT, had no effect on heart rate when injected at doses up to 400 μg. The NT-evoked cardioacceleration was blocked by propranolol or by section of the inferior cardiac nerve and may therefore be attributed to prolonged excitation of stellate ganglion cells. Administration of hexamethonium and atropine was without effect on the NT response. Intravenous injection of NT at the same doses used by intra-arterial injection (25–200 μg) was without appreciable effect on heart rate. At doses of up to 400 μg by close i.a. injection, VIP and SP had no effect on heart rate. Two observations suggest that NT is a likely candidate as mediator of noncholinergic excitation of stellate ganglion cells. One is the finding, reported here, of a similarly slow time course for the NT-evoked cardioacceleration and for the slow cardioacceleration evoked by preganglionic stimulation during block of cholinergic transmission. The other is the previously reported finding that NT-like immunoreactivity in the stellate ganglion is depleted by prolonged stimulation causing loss of the neurally evoked slow cardioacceleration.
Coronary sinus norepinephrine concentrations during ventricular tachycardia induced by left stellate ganglion stimulation in dogs
Authors: Nadeau Réginald , Lamontagne Daniel , Cardinal René , Champlain Jacques de , Armour J. Andrew
Published: April 2011

Coronary sinus catecholamine overflow was measured in open-chest dogs, anesthetized with sodium thiopental and α-chloralose, during left sympathetic stimulation. Uniform ventricular tachycardias were induced in 9 out of 16 dogs during either left stellate ganglion or left ventrolateral cardiac nerve stimulations. Significant increases in norepinephrine (8.1 ng/mL, plasma) and epinephrine (0.19 ng/mL, plasma) overflows were obtained after 30 and 90 s of stimulation, respectively. Maximum norepinephrine overflow was significantly higher in dogs with ventricular tachycardia than in those without it (16.0 vs. 7.4 ng/mL, p < 0.05). This suggests that the induction of ventricular tachycardia in the normal myocardium is related to the amount of local secretion of norepinephrine during nerve stimulation.
Release of platelet-activating factor (PAF) and accelerated healing induced by a PAF antagonist in an animal model of chronic colitis
Authors: Wallace John L.
Published: April 2011

The role of platelet-activating factor as a mediator of inflammation was examined using a rat model of colitis. Release of platelet-activating factor by samples of colonic tissue, as measured by bioassay, was determined at various times after induction of inflammation by intracolonic administration of trinitrobenzene sulfonic acid. At the same times, colonic damage was scored and the extent of neutrophil infiltration was assessed by measuring tissue levels of myeloperoxidase activity. Platelet-activating factor release from normal colon averaged 46 ± 17 pg/g, while not being detectable in samples taken 24 h after induction of inflammation, a time when neutrophil infiltration was maximal. However, substantial release of platelet-activating factor (12–16 times control levels; p < 0.05) was observed in samples from rats sacrificed 1–3 weeks after induction of inflammation. In a second series of experiments, the effects of treatment with BN52021, a specific platelet-activating factor receptor antagonist, were assessed using this model. Treatment with BN52021 during either the 1st or 2nd weeks after induction of colitis resulted in significant (p < 0.05) reductions of colonic damage scores and the wet weight of the distal colon. These results demonstrate that platelet-activating factor release is significantly elevated during the chronic phase of colitis in this animal model, and that inhibition of the action of platelet-activating factor, through receptor antagonism, leads to a significant reduction of colonic inflammation and ulceration. These observations are therefore consistent with a role for platelet-activating factor as an inflammatory mediator in chronic inflammation of the rat colon.
Vascular escape from vasoconstriction and post-stimulatory hyperemia in the superior mesenteric artery of the cat
Authors: Lautt W. Wayne , Legare Dallas J. , Lockhart Leslie K.
Published: April 2011

Vascular escape is seen as a partial recovery from initial vasoconstriction despite continued constrictor stimuli. Escape in the feline intestine (superior mesenteric artery) occurred for i.a. norepinephrine (NE) infusions (56% escape for low dose, 40% for high dose NE) and for sympathetic nerve stimulation (SNS) (65% for 1 Hz, 49% for 3 Hz, 44% for 9 Hz). Adenosine infusion or blockade of adenosine receptors (8-phenyltheophylline) did not alter the escape, showing that endogenous adenosine levels are unlikely to play any role in the mechanism of escape. Other aspects of escape were studied: equiconstrictor doses of NE given i.a. or i.v. lead to similar degrees of escape; propranolol and ouabain did not alter escape; the degree of escape was significantly greater for the low dose NE and the 1-Hz SNS than for higher intensities of stimulation, however, escape did not inversely correlate significantly with the initial degree of vasoconstriction when all data were pooled. Post-stimulatory hyperemia occurs upon cessation of vasoconstrictor stimuli, reaches a peak conductance within 1 min, and returns to baseline within about 3 min. Hyperemia was quantitated from the peak vasodilation and from the area under the flow–hyperemia curve. The hyperemias were not related to NE dose or SNS frequency nor did they correlate with initial vasoconstriction or extent of vascular escape. Contrary to the hypothesis that adenosine may mediate hyperemia, adenosine infusions reduced the response and adenosine receptor antagonism tended to elevate the response. Propranolol and ouabain did not produce significant effects on post-stimulatory hyperemia. A discussion of the merits of using vascular resistance or conductance to assess vascular tone and vascular escape concludes that in the in vivo systems in which changes in vascular tone result mainly in changes in blood flow, the use of resistance is unacceptable and may lead to serious error in data interpretation.
Mechanism of action of platelet-activating factor on guinea-pig lung parenchyma strips
Authors: Jancar Sonia , Thériault Patrick , Provençal Brigitte , Cloutier Solange , Sirois Pierre
Published: April 2011

The contribution of thromboxane A2 to platelet-activating factor (PAF)induced contraction of guinea-pig lung parenchyma strips (GPLPS) was investigated using an experimental design that allowed us to record the contractions of the tissues in parallel with the determination of thromboxane B2 (TXB2) levels in the organ baths by enzyme immunoassay. It was found that the first injection of PAF induced the contraction of GPLPS and the release of TXB2. Following subsequent additions of PAF to the same tissue, the contractile response was abolished but TXB2 levels were not significantly reduced. Pretreatment of the tissue with the thromboxane synthetase inhibitor OKY-046 (3.5, 170, and 350 μM) strongly inhibited the release of TXB2 but had no effect on the contraction of the tissues induced by PAF. The mechanism of PAF-induced contraction of GPLPS was further investigated using several drugs that interfere with arachidonic acid metabolism. It was found that pretreatment of the tissues with the cyclooxygenase and thromboxane synthetase inhibitors indomethacin (2.8, 28, and 56 μM) and OKY-046 (170 μM) or with the thromboxane antagonist SKF-88046 (1.25 and 12.5 μM) had no significant effect on the contractile response to PAF. The compound L-655,240 (2.5, 25, and 50 μM), which acts simultaneously as an antagonist of thromboxane and inhibitor of lipoxygenase, significantly reduced GPLPS contractions induced by PAF. Another lipoxygenase inhibitor, nordihydroguaiaretic acid (33 μM), and the inhibitor of both pathways of arachidonic acid metabolism, BW775c (110 μM), both reduced PAF-induced contractions of GPLPS. We conclude that although PAF induces release of thromboxane from GPLPS, this mediator does not contribute significantly to the myotropic activity of PAF, which seems to be mediated by products of the lipoxygenase pathway.
The 1987 Borden Award Lecture.: Protein metabolism in premature human infants
Authors: Pencharz Paul B.
Published: April 2011

Our studies have focused on the regulation of whole body and skeletal muscle protein metabolism in premature infants. Net deposition of protein is the result of a positive balance between protein synthesis and breakdown. To measure protein metabolism we have employed end-product studies with [15N]glycine and 13[C]leucine. Myofibrillar protein degradation was estimated by measuring the excretion of N-t-methylhistidine in urine. Energy expenditure and substrate utilization were also measured. Premature infants have high rates of protein synthesis (12 g∙kg−1∙d−1), twice those measured in children and four times those found in adults. Intrauterine malnourished babies have increased rates of protein turnover. Very low birth weight infants (< 1500 g) have higher myofibrillar protein turnover than larger babies. Intravenous feeding decreases whole body protein turnover, and we estimate visceral protein synthesis to be approximately 4 g∙kg−1∙d−1. Suboptimal energy intake worsens nitrogen utilization by reducing the reutilization of endogenous amino acids for protein synthesis. We have also examined the effects of varying the source of nonprotein energy (i.e., glucose only versus glucose plus lipid) at requirement levels and have shown there is no effect on protein metabolism. Recent improvements in technology have opened the way to detailed study of individual amino acid metabolism in neonates in the future.
Calcium transport through the placenta
Authors: Brunette Michèle G.
Published: April 2011

The calcium content of the foetus increases exponentially during gestation. The transfer of calcium from the mother to the foetus is believed to occur via an active mechanism, based on observations that the calcium concentration is higher in foetal than in maternal blood, and that perfusion in situ of the umbilical artery of the placenta results in a net increase in the calcium concentration of the perfusate even when the calcium content of the perfusate is threefold higher than in the maternal blood. The calcium concentration in the foetal blood is mainly regulated by foetal parathyroid hormone and the plasma concentration of 1,25-(OH)2 vitamin D3. Several experiments suggest that this vitamin D metabolite plays a key role in calcium transport through the syncytial cell. A vitamin D dependent calcium binding protein has been detected in the placenta, which might intervene in the hormonal control of this transport. The cellular mechanisms of calcium transport through the placenta are not clearly defined. An ATP-dependent calcium uptake by microsomal membrane vesicles from human plancenta has been described by several investigators. This calcium transport is saturable, magnesium dependent, and displays Michaelis–Menten kinetics with a Km of approximately 70 nM ionized calcium. Two Ca2+ ATPases with low and high affinities for calcium are described. Since there are discrepancies concerning the exact localization of these enzymes in the syncytial cell, it has not been established whether they intervene in calcium transport through the placenta. Finally, the presence of adenylate cyclase in the basal plasma membrane, and a cAMP-dependent protein kinase in cytosol, microsomes, and brush border membranes, suggests, by analogy with the kidney, that this system might be involved in calcium transport. Further experiments are warranted to confirm this hypothesis.
Hypertensive factor: calcium stimulatory activity obtained from different tissues and animal species
Authors: Wright G. L. , Huang B. S. , Johnson P. J. , McCumbee W. D.
Published: April 2011

It was recently shown that a peptide (hypertensive factor, HF) isolated from erythrocyte hemolysates from spontaneously hypertensive rats induced a prolonged elevation of blood pressure in normotensive rats. In addition, the peptide produced a marked stimulation of the in vitro uptake of lanthanum-resistant calcium by the aortae and enhanced the contractile response of aortic rings to constrictor agents. The present report describes findings of calcium stimulatory activity, enhancement of contractile function, or pressor activity in extracts of homogenates from several tissues of the rat and from erythrocyte hemolysates of several mammalian species. Significant stimulation of calcium uptake in aortic rings was obtained with preparations from rat brain, liver, and kidney. The activity per weight of tissue was similar for brain and kidney (approximately 2 units/g), while liver exhibited somewhat higher concentrations (4 units/g). The diffusate of cardiac tissue did not significantly alter in vitro calcium uptake by aortae. The injection of the cardiac and liver diffusates into normotensive Wistar–Kyoto rats produced slight (10 Torr) (1 Torr = 133.3 Pa) and moderate (25 Torr) elevations of blood pressure, respectively. Finally, a peptide purified from homogenates of rat brain by the protocol developed for the purification of HF from erythrocytes was shown to significantly enhance the contractile response of aortic rings to K+ and norepinephrine. Diffusates of erythrocytes from the rat, rabbit, dog, and guinea pig each caused a significant stimulation of calcium uptake and contained approximately the same level of activity (500 units/L of whole blood). Diffusates prepared from outdated human erythrocytes had no significant effect on calcium uptake, whereas those of freshly drawn samples exhibited high levels of activity. Purification of the causal compound from several rat tissues and from erythrocytes of freshly drawn human blood indicated a peptide whose amino acid composition was qualitatively similar to that of the peptide isolated from erythrocytes of rats. The results suggest that a peptide or family of similar compounds may be present in a variety of tissues of the rat and occurs in the erythrocytes of several mammalian species. These peptides influence blood pressure, but we suggest that their principal role is in the regulation of cellular calcium metabolism.
Improved myocardial performance induced by dofibrate during reperfusion after acute myocardial infarction
Authors: Prasad M. Renuka , Clement Ronald , Otani Hajime , Jones Randall , Das Dipak K. , Engelman Richard M. , Breyer Robert H. , Rousou John A.
Published: April 2011

The increase of cellular fatty acids appears to be one of the causes of the myocardial injury during ischemia and reperfusion. This study was designed to examine whether a hypolipidemic drug such as clofibrate can reduce the myocardial injury during ischemia and reperfusion. Clofibrate was fed to experimental pigs for 9 days. Isolated in situ hearts from both experimental and control pigs were subjected to 60 min of regional ischemia induced by occluding the left anterior descending coronary artery, followed by 60 min of global ischemia by hypothermic cardioplegic arrest and 60 min of reperfusion. The clofibrate feeding resulted in the better cardiac performance as judged by increased coronary blood flow, improved left ventricular function, and reduced myocardial injury as judged by creatine kinase release. Although the clofibrate-fed animals contained higher levels of thiobarbituric reactive materials, the free fatty acid levels of plasma and myocardium were much lower compared with control animals. The clofibrate feeding was also associated with increased peroxisomal catalase and (β-oxidation of fatty acids. These results suggest that decreased levels of free fatty acids in the plasma and the myocardium and increased catalase activity induced by antilipolytic therapy appear to provide beneficial effects to the myocardium during ischemia and reperfusion.
β-Adrenergic receptor function and oxygen radical production in bovine pulmonary alveolar macrophages
Authors: Conlon P. D. , Ogunbiyi P. O. , Black W. D. , Eyre P.
Published: April 2011

Reactive oxygen species production by bovine pulmonary alveolar macrophages was evaluated by a chemiluminescence assay utilizing luminol and opsonized zymosan. Incubation with dobutamine (5 × 10−8 and 5 × 10−7 M) or isoproterenol (5 × 10−8 and 5 × 10−7 M) prior to zymosan challenge significantly (p < 0.05) increased the time for chemiluminescence to begin, and significantly decreased the level of maximum chemiluminescence. The agonists' inhibitory effects on maximum chemiluminescence were significantly reduced by pre-incubation with the appropriate antagonist (atenolol at 1 × 10−6 M for dobutamine; and propranolol at 1 × 10−6 M for isoproterenol). Salbutamol at 1 × 10−6 M significantly reduced the level of maximum chemiluminescence only, but did not increase the time for chemiluminescence to begin. This effect was significantly reduced by the presence of the β2-antagonist ICI 118,551 at 1 × 10−6 M. The results reveal the presence of (β1- and (β2-adrenoceptors on bovine pulmonary alveolar macrophages, and suggest that these receptors are important in the regulation of reactive oxygen species production by these cells.