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Biomedical subjects

E Q Colquhoun

Publications and source records attributed to E Q Colquhoun.

At least 37 records · Page 2Linked to original sources
PubMed1995

Constant-pressure perfusion of rat hindlimb shows alpha- and beta-adrenergic stimulation of oxygen consumption.

Isolated rat hindlimbs were perfused at 37 degrees C and constant physiological pressure (80 +/- 0.5 mmHg) while the flow rate that was allowed to freely self-adjust was monitored. Under these conditions, evidence was obtained for both alpha- and beta-adrenergic stimulation of oxygen consumption (VO2) in contrast to constant-flow perfusion, which has only convincingly shown alpha-adrenergic stimulation of VO2 in response to adrenergic agents. Addition of norepinephrine (NE; 1-33 nM) led to an increase in VO2 with a maximum of 29% above the basal value at 3.3 nM, even though the flow rate decreased. Phenylephrine (3.3-33 nM) and vasopressin (10-100 pM) also showed similar, but lesser in magnitude, vasoconstriction-associated stimulatory effects on VO2. Prazosin (an alpha 1-antagonist) completely reversed the NE-mediated decrease in flow rate and significantly blocked the increased VO2. In contrast, isoproterenol (10-1,000 nM) increased both flow rate (30%) and VO2 (32%). The isoproterenol-stimulated VO2 was not blocked by the beta 1-, beta 2-antagonist propranolol (10 microM), although the increased flow was reversed. In the presence of propranolol (1 or 10 microM), BRL-35135A (a beta 3-agonist) also stimulated VO2 (18%) without significant change in flow rate. These results lend further support to the role of the alpha 1-adrenoceptor in muscle VO2. In addition there is evidence for the presence of a functional beta 3-adrenoceptor as an additional subtype responsible for NE-mediated thermogenesis in the rat hindlimb.

Adrenergic Agents↗
PubMed1995

Vasoconstrictors alter oxygen, lactate, and glycerol metabolism in the perfused hindlimb of a rat kangaroo.

The Tasmanian bettong (Bettongia gaimardi) is a small marsupial rat kangaroo without detectable brown adipose tissue (BAT). The hindlimb was perfused with constant flow at 25 degrees C after cannulation under anesthesia of the femoral artery and vein to one hindlimb. Norepinephrine (NE, 25 nM-2.5 microM) and vasopressin (VP, 10 nM-0.1 microM) each increased perfusion pressure, oxygen consumption (VO2), and lactate and glycerol efflux of the perfused hindlimb. NE-mediated increases in VO2 and the efflux of lactate and glycerol were unaffected by propranolol (10 microM) but were completely blocked by the further addition of phentolamine (10 microM). In contrast, serotonin (5-HT; 0.1-2.5 microM) inhibited VO2 and inhibited lactate efflux. The changes induced by NE, VP, and 5-HT were all rapidly reversed by nitroprusside. These results suggest that resting thermogenesis in bettong hindlimb can be differentially controlled by the vasculature, which may also contribute to the induced VO2. This vascular control of skeletal muscle VO2 appears widespread in homeotherm evolution.

Adrenergic Antagonists↗
PubMed1994

Resiniferatoxin and piperine: capsaicin-like stimulators of oxygen uptake in the perfused rat hindlimb.

The naturally occurring capsaicin-like molecules, resiniferatoxin (RTX, Euphorbia spp.) and piperine (Piper nigrum), each stimulated oxygen uptake (VO2) in association with increased vascular resistance in a concentration-dependent manner when infused into the perfused rat hindlimb. 5 microM glyceryl trinitrate (GTN, a nitrovasodilator) significantly blocked the oxygen and pressure responses to both RTX and piperine, indicating a close relationship between changes in VO2 and the vasoconstriction. Concentrations greater than those required for maximal VO2 resulted in an inhibition of VO2, although perfusion pressure continued to increase. Time course studies showed that both RTX and piperine at high doses resulted in a tri-phasic response. An initial phase of transient VO2 stimulation was followed by a second phase of inhibition. A third phase involving an often larger but transient stimulation of VO2 followed removal of the agents and continued after the pressure returned to basal. The actions of RTX and piperine were similar to those of other active capsaicin-like molecules tested previously in this system, including capsaicinoids (Capsicum spp.), gingerols (Zingiber officinale), and shogoals (Zingiber officinale). RTX was the most potent, and piperine the least potent of this series. Although receptor involvement has yet to be unequivocally established, the data are consistent with the presence of a functional capsaicin-like (vanilloid) receptor in the vasculature of the rat hindlimb that mediates vasoconstriction and oxygen uptake. These findings may have implications for the future development of thermogenic agents.

Alkaloids↗
PubMed1994

Vasoconstrictor-mediated release of purines and pyrimidines from perfused rat hindlimb, perfused mesenteric arcade and incubated de-endothelialized aorta.

1. Reperfusion of hindlimbs that had previously been exposed to either 10 or 60 min global ischaemia resulted in transient washouts of uracil and uric acid in approximate proportion to the interval of ischaemia. However, changing the interval of sequential angiotensin II infusions from 10 to 60 min did not affect the magnitude of sustained uracil and uric acid release. 2. Perfused rat mesenteric artery arcade released uracil and uric acid and each was further increased approximately 2-fold by exposure to the vasoconstrictor, serotonin (6.7 microM). 3. Incubated de-endothelialized rat aorta also released purines and pyrimidines and this was increased further when subjected to increased work loads. 4. The increased rates of release of purines and pyrimidines from hindlimb, and the simpler vascular preparations of mesenteric arcade and aorta, were in proportion to the relative rates of increase in oxygen consumption under maximum vascular load. 5. It is concluded that the release of purine and pyrimidine nucleosides and their catabolites from perfused rat hindlimb occurring as a consequence of vasoconstriction is not the result of release from previously ischaemic tissue. In addition, release of purines and pyrimidines appears to be a general feature of vascular smooth muscle subjected to high workloads.

Analysis of Variance↗
PubMed1994

Characterization of perfused periaortic brown adipose tissue from the rat.

A technique was developed for the perfusion of periaortic brown adipose tissue (BAT) with a view to assessing vascular system involvement in BAT thermogenesis. The procedure involved cannulation of the thoracic aorta and ligation of the intercostal branches and the distal thoracic aorta. Perfusion was conducted in a buffer-filled chamber using constant flow at 37 degrees C. Lactate dehydrogenase leakage was less than 2%/h, and after 30 min of perfusion the energy charge was 0.72 +/- 0.05 (n = 4) and differed little from freshly sampled interscapular BAT (0.71 +/- 0.03 (n = 7)). Periaortic BAT was indistinguishable from interscapular BAT in enzyme content, mitochondrial size, mitochondrial cristae, lipid content, and cell size. Basal oxygen consumption (VO2) was 64.3 +/- 7.4 mumol.h-1.g-1 wet weight, and basal perfusion pressure was 65 +/- 3 mmHg (1 mmHg = 133.3 Pa). Norepinephrine and isoproterenol each increased VO2 of perfused periaortic BAT in a time-dependent and reversible manner. Half-maximal stimulation of VO2 occurred at 12 nM norepinephrine and 8 nM isoproterenol; maximally stimulated tissue had a VO2 of approximately 150 mumol.h-1.g-1 wet weight. Norepinephrine (50 nM) had no consistent effect on perfusion pressure, but the increase in VO2 by this agonist was completely blocked by 10 microM DL-propranolol and unaffected by phentolamine (1-20 microM) or nitroprusside (0.01-1 mM). Increasing the perfusion flow rate increased pressure and had no effect on basal VO2 but increased the VO2 response due to norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗
PubMed1994

Potential defect in the vascular control of nonshivering thermogenesis in the obese Zucker rat hind limb.

Vascular control of nonshivering thermogenesis in the perfused hind limb of obese and lean Zucker rats were compared using two vasoconstrictors, norepinephrine and serotonin. For hind limbs of both phenotypes, norepinephrine infusions resulted in a dose-dependent uninterrupted increase in perfusion pressure and a biphasic change in oxygen uptake (VO2), characterized by a stimulation at low concentrations, and an increasing inhibition at higher concentrations that gradually overcame the stimulation in a dose-dependent manner. At concentrations of norepinephrine greater than 1 microM, the inhibitory effect predominated and gave rise to values for VO2 less than basal. The obese hind limb had a lower basal VO2 and a lower maximal VO2 mediated by norepinephrine than the lean rat, but these differences appeared to relate largely to the lower muscle mass and higher content of fat of the obese hind limb. Serotonin infusions resulted in dose-dependent increase in perfusion pressure and an accompanying decrease in VO2. Pressure changes were identical for the obese and lean hind limbs, but the decrease in VO2 due to serotonin was greater in the hind limbs from the lean rats, and this difference remained when the data were expressed in terms of muscle mass perfused. It is concluded that the relatively lower content of muscle of the obese hind limb accounts for its lower basal and lower maximal norepinephrine-mediated thermogenesis. In addition, an intrinsic defect in obese hind limb muscle response to serotonin is present, which may be indicative of a decrease in the potential for vasoconstrictor-regulated thermogenesis that could have implications for whole-body energy balance by the obese phenotype.

Animals↗
PubMed1994

Aerobic muscle contraction impaired by serotonin-mediated vasoconstriction.

Vasoconstriction mediated by serotonin (5-HT) inhibits muscle metabolism in resting constant-flow-perfused rat hindlimb and may do so by vascular shunting. In the present study, the effects of 5-HT on tension development and contraction-induced oxygen uptake by the sciatic nerve-stimulated gastrocnemius-plantaris-soleus muscle group of the perfused rat hindlimb and tension development by electrically stimulated isolated incubated soleus and extensor digitorum longus muscles were examined. In both erythrocyte and erythrocyte-free perfusions, 0.25 microM 5-HT increased perfusion pressure and markedly decreased contraction-induced tension, oxygen uptake, and lactate release. The release of metabolic vasodilators from exercising skeletal muscle did not appear to affect 5-HT-mediated vasoconstriction; rather, vascular resistance increased during the period of muscle contraction. In contrast, vasoconstriction during muscle contraction mediated by alpha-adrenoceptor stimulation did not impair tension and was partially overcome by metabolic vasodilators. In addition, contraction of isolated incubated soleus and extensor digitorum longus muscles was not affected by 5-HT addition to the incubation medium. We conclude that 5-HT impairs contractility of working muscle during the aerobic phase by limiting oxygen delivery through redistributing perfusate flow. The results are consistent with a vasoconstrictor action of 5-HT on larger vessels, perhaps at feed arteries external to the working muscle. When constricted by 5-HT, these vessels are apparently insensitive to metabolic vasodilatation.

Aerobiosis↗
PubMed1993

[32P]phosphate autoradiography as an indicator of regional myocardial oxygen consumption?

The present study was undertaken to assess whether [32P]uptake and autoradiography could be used as an indicator of regional myocardial oxygen consumption. Rat hearts were perfused in the Langendorff mode with medium containing [32P]orthophosphate (32Pi) and the incorporation of label into ATP, perchloric acid-insoluble and soluble material and total tissue was determined. Oxygen uptake and perfusion pressure were continuously monitored. For control hearts the rate of incorporation of radioactivity into all four fractions was linear. Isoproterenol and pressure loading each increased total 32Pi uptake rate and the incorporation rate of 32Pi into ATP. Significant positive correlations were noted between the rates of total 32Pi uptake and oxygen uptake (r = 0.895; P < 0.001) and between the rates of 32P incorporation into ATP and oxygen uptake (r = 0.890; P < 0.001). Autoradiography of diffusible radioactive material (representing total 32Pi uptake) indicated that label correlated with oxygen uptake (r = 0.850; P < 0.001) and was distributed uniformly across the ventricle wall. Hearts subjected to 30 min of regional ischemia followed by reperfusion were indistinguishable from the control group in terms of either total 32Pi uptake or total oxygen uptake, but showed a marked necrotic area that was unlabeled surrounded by an area that was intensely labeled. It is concluded that autoradiography of diffusible radioactive material representing total 32Pi uptake may be applicable for assessing regional myocardial oxygen uptake. The technique has identified a region of tissue in reperfused ischemic hearts that surrounds necrotic tissue and which may have a compensatory increase in a oxidative metabolism.

Animals↗
PubMed1993

Serotonin-mediated acute insulin resistance in the perfused rat hindlimb but not in incubated muscle: a role for the vascular system.

We have recently shown that the vasoconstrictor serotonin (5-HT) inhibits oxygen uptake in perfused hindlimb possibly due to vascular shunting. Thus in the present study the effect of 5-HT on insulin-mediated glucose uptake was assessed. Rat hindlimbs were perfused at constant flow with medium containing 8.3 mM glucose and a tracer amount of 2-deoxy-D-[1-3]glucose (2DG) with and without 10 microM 5-HT, 15 nM insulin and a combination of the two. 5-HT inhibited insulin-mediated stimulation of glucose uptake by 30.4% when added after insulin and 34.4% when added before insulin. In addition, 5-HT inhibited insulin-mediated 2DG uptake by perfused muscles with inhibition ranging from 32% (soleus) to 80% (extensor digitorum longus). The effects of 5-HT on insulin-mediated glucose uptake were partially reversed by vasodilation with carbachol. In contrast to the results for the hindlimb, 10 microM 5-HT had no significant effect on either basal glucose uptake or the stimulation of glucose uptake mediated by 15 nM insulin by isolated incubated soleus or extensor digitorum longus muscles. It is concluded that 5-HT impairs insulin-mediated glucose uptake in the perfused rat hindlimb that may derive from vascular shunting not apparent when muscles are incubated with 5-HT in vitro. These findings may have implications for the link between hypertension and diabetes.

Animals↗
PubMed1993

Role of extracellular UTP in the release of uracil from vasoconstricted hindlimb.

The source and function of elevated uracil release during vasoconstriction in the perfused rat hindlimb was investigated. The possibility that uracil release derived from the breakdown of released vasoactive uridine 5'-triphosphate (UTP) was examined. Exogenous UTP was found to be a potent vasodilator in the perfused rat hindlimb, opposing norepinephrine and angiotensin-induced increases in vasoconstriction and oxygen consumption. UTP was rapidly catabolized by the hindlimb to uridine 5'-monophosphate (UMP), uridine, and uracil, which were all devoid of vasoactivity. UTP was similarly catabolized by incubated rat aorta. Degradation of exogenous UTP by perfused hindlimb or aorta was inhibited by alpha, beta-methylene-adenosine 5'-diphosphate (AMP-CP), an inhibitor of ectonucleotidases. However, AMP-CP did not decrease uracil and uridine output by the hindlimb during angiotensin-mediated vasoconstriction and increased oxygen consumption. In particular, simultaneous infusion of AMP-CP with angiotensin did not increase efflux of UMP. Although exogenous UTP is a potent vasodilator in the perfused rat hindlimb, it appears not to be released intact during vasoconstriction. Hence, extracellular UTP is unlikely to be the precursor of the uracil release.

Adenosine Diphosphate↗
PubMed1992

Spicy meal disturbs sleep: an effect of thermoregulation?

Tabasco sauce and mustard taken with the evening meal markedly disturbed sleep of six, young, healthy male subjects; reducing slow wave and stage 2 sleep, increasing total time awake and tending to increase sleep onset latency. Whilst post meal effects on temperature and oxygen consumption were not significantly different from control meals the spicy food condition elevated body temperature during the first sleep cycle. The possibility that the spice principle capsaicin affects sleep via changes in body temperature is discussed.

Adult↗
PubMed1992

A close association between vasoconstrictor-mediated uracil and lactate release by the perfused rat hindlimb.

1. Angiotensin II (5 nM) increased perfusion pressure, O2 uptake and the release of lactate, uracil and uric acid from the perfused rat hindlimb. The release of all three substances was greatest 5 min after commencement of angiotensin II infusion and then decreased over the next 20 min to reach a plateau value that was approx. 2.5-fold basal values. Following removal of angiotensin, pressure, O2 uptake as well as lactate, uracil and uric acid release each returned to pre-infusion (basal) values. 2. Cyanide (1 mM) when added during angiotensin II (5 nM) infusion blocked the pressor effect and completely inhibited all O2 uptake. Cyanide (1 mM) also inhibited the angiotensin-induced increase in uric acid, uracil and lactate release, but the effects differed. Whereas uric acid release remained inhibited throughout the cyanide infusion, uracil and lactate release were only temporarily interrupted and a secondary release of both ensued. 3. Nitroprusside (0.5 mM) when added during angiotensin II (5 nM) infusion blocked pressure and O2 uptake. Lactate and uracil release were partly blocked and returned to pre-infusion (basal) values. However uric acid release was totally blocked and no release occurred when nitroprusside was present with angiotensin II. 4. Combined data showed a significant correlation (r = 0.831; P less than 0.001) between effluent lactate and effluent uracil. 5. It is concluded that lactate and uracil release which increase markedly during vasoconstriction of the hindlimb reflect an association between glycolysis and uracil nucleotide turnover within the same tissue, possibly vascular smooth muscle.

Angiotensin II↗
PubMed1992

Serotonin and norepinephrine vasoconstriction in rat hindlimb have different oxygen requirements.

Serotonin (5-HT) and norepinephrine (NE) are potent vasoconstrictors in the non-erythrocyte constant-flow perfused hindlimb at 25 degrees C. Because 5-HT inhibits and NE stimulates oxygen uptake, these agonists may exert control at different sites in the vasculature that have different metabolic requirements. In this study, it was found that hypoxia, cyanide, or azide had no significant effect on 5-HT-mediated vasoconstriction; however, in the presence of cyanide and absence of glucose, vasoconstriction was transient. NE-mediated vasoconstriction displayed two prazosin-sensitive components. At low concentrations (less than 50 nM), NE-mediated vasoconstriction was totally blocked by hypoxia, cyanide, or azide. At concentrations of NE significantly greater than 50 nM, oxygen-independent vasoconstriction was observed. In conclusion, NE and 5-HT sites are biochemically distinguishable, with 5-HT sites probably located on larger vessels and supportable by anaerobic metabolism and oxygen-dependent NE sites probably located on smaller arteries or arterioles. Supraphysiological concentrations of NE may interact with a subgroup of vascular alpha 1-adrenoceptors on larger vessels giving results similar to 5-HT, thus highlighting problems with high levels of NE in the perfused rat hindlimb.

Animals↗
PubMed1992

Vasoconstrictor-mediated release of lactate from the perfused rat hindlimb.

The effects of different vasomodulators on lactate release by the constant-flow-perfused rat hindlimb were examined and compared with that by perfused mesenteric artery, incubated preparations of aortas, soleus and epitrochlearis muscles, and perifused soleus muscles. Infusion of vasopressin (0.5 nM), angiotensin II (5 nM), norepinephrine (50 nM), and methoxamine (10 microM) into the hindlimbs of 180- to 200-g rats increased the perfusion pressure by 112-167% from 30.4 +/- 0.8 mmHg, O2 consumption by 26-68% from 6.4 +/- 0.2 mumol.g-1 x h-1, and lactate efflux by 148-380% from 5.41 +/- 0.25 mumol.g-1 x h-1. Hindlimbs of 100- to 120-g rats responded similarly to angiotensin II. Isoproterenol (1 microM) had no effect on O2 uptake or perfusion pressure but increased lactate release by 118%. Nitroprusside (0.5 mM) markedly inhibited the vasoconstrictor-mediated increases in lactate release, perfusion pressure, and O2 consumption by the hindlimb but had no effect on isoproterenol-mediated lactate efflux. Serotonin (6.7 microM) increased lactate release from the perfused mesenteric artery by 120% from 5.48 mol.g-1 x h-1. Lactate release by incubated aorta was increased by angiotensin II (50 nM), isoproterenol (1 microM), and mechanical stretch. The increase mediated by angiotensin II was blocked by glycerol trinitrate (2.2 microM), which had no effect on lactate release by isoproterenol. Neither angiotensin II (5 nM) nor vasopressin (0.5 nM) increased lactate release from incubated soleus and epitrochlearis muscles; however, lactate release was increased by isoproterenol, and this increase was unaffected by glycerol trinitrate (2.2 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Pungent principles of ginger (Zingiber officinale) are thermogenic in the perfused rat hindlimb.

Crude extracts of both fresh and dry ginger induced the perfused rat hindlimb to consume oxygen in association with increases in perfusion pressure and lactate production. The principles responsible for these observations, the gingerols and shogaols, were isolated and tested for relative thermogenic activity. The gingerol homologues possessed greater molar potency than their shogaol counterparts. (6)-Gingerol was the most potent principle isolated, causing a mean maximal increase in oxygen consumption of 1.4 +/- 0.1 mumol/g/h (21%), an increase in lactate efflux of 4.7 +/- 0.6 mumol/g/h (87%) with a perfusion pressure increase of 7.7 +/- 0.7 mmHg (30%). Increases in alkyl chain length within each homologous series led to decreased molar potency. Specific nitro-vasodilation using glyceryl trinitrate demonstrated that thermogenesis was at least partly associated with vasoconstriction. Concurrent infusion of alpha or beta antagonists showed that neither adrenergic receptors nor secondary catecholamine release were responsible for the observed effects. Increasing doses of the ginger principles ultimately led to inhibition of steady state oxygen consumption, although perfusion pressure continued to increase. Removal of high ginger principle doses was followed by apparent increases in oxygen uptake unaccompanied by elevated perfusion pressure. As a consequence, the effective concentration ranges of the ginger principles were relatively narrow. The cause of high dose effects is as yet undetermined but may have been due in part to disruption of mitochondrial function.

Animals↗
PubMed1991

The apparent absence of serotonin-mediated vascular thermogenesis in perfused rat hindlimb may result from vascular shunting.

Vasoconstriction by norepinephrine, angiotensin II and vasopressin in the constant-flow perfused rat hindlimb is associated with increased oxygen uptake and has given rise to the concept of vascular thermogenesis. In the present study serotonin (5-hydroxytryptamine, 5HT) was found to inhibit oxygen uptake by up to 40% in a dose dependent manner whilst inducing vasoconstriction in this model, whereas norepinephrine increased oxygen consumption by up to 100% during vasoconstriction. This contrasted with the perfused isolated rat mesenteric artery arcade in which serotonin stimulated oxygen uptake by up to 130% in association with vasoconstriction in a dose dependent manner similar to the previously described norepinephrine induced vascular thermogenesis in this arterial preparation. In both perfusion systems, changes in pressure and oxygen uptake mediated by serotonin were completely blocked by ketanserin. These results and evidence from dye washout studies suggest that serotonin-mediated vascular thermogenesis, if it occurs in the constant-flow hindlimb, is masked by vascular shunting.

Animals↗
PubMed1991

Hypertension in obesity may reflect a homeostatic thermogenic response.

Systemic hypertension of mild to moderate degree is often associated with obesity. The hypothesis is that over-eating leads to increased sympathetic activity targeted at the peripheral vasculature as well as other tissues in an attempt (that in many cases may be futile) to stimulate facultative thermogenesis and burn-off the excess energy. This hypothesis represents an important modification of one proposed by Landsberg and is supported by: 1) recent observations that carbohydrate feeding to humans specifically increases muscle sympathetic vasoconstrictor activity in the peroneal nerve, and 2) studies with animal models in which active vasoconstriction in the limbs and elsewhere is associated with marked increases in oxygen consumption (energy expenditure).

Animals↗