bluuebunny/crossref_metadata_2025_split huggingface dataset:
MEMBRANE TRANSPORT AS A DETERMINANT OF THE HEPATIC ELIMINATION OF DRUGS AND METABOLITES
Authors: Evans Allan M. 
Published: June 2007

SUMMARY1. The liver is ideally suited for the efficient uptake of drugs from sinusoidal blood. For most drugs, uptake into hepatocytes across the basolateral membrane occurs via passive diffusion, with minimal relaiance on carrier‐mediated transport systems. Often, this passive diffusion is so efficient that uptake is ratelimited by the delivery of the drug to the lvier (i.e. blood flow) rather than membrane transport per se2. For highly polar molecules, passive diffusion no longer represents an efficient mode of hepatocellular uptake and there is an increased reliance on carrier‐mediated transport systems. For these compounds, membrane transport may dictate the overall efficiency of hepatic elimination.3. Drug metabolites, particularly conjugated metabolites, such as sulphates and glucuronides, are invariably more polar than their precursors and are more likely to experience hepatocyte membranes as diffusional barriers. In the presence of such a barrier, the hepatocellular disposal of a locally formed metabolite will depend critically on the presence and activity of carrier‐mediated transport systems for sinusoidal efflux and biliary excretion. Transporters of current interest include P‐glycoproteins, which are responsible for the biliary excretion of a rage of organic cations, and the canalicular multispecific organic anion transporter.4. Intracellular trapping of hepatically formed metabolites, secondary to low membrane permeability, is clinically important as many metabolites are potentially hepatotoxic and/or capable of interfering with the hepatic transport of endogenous compounds or other durgs and metabolites. In addition, if the metabolite is unstable, intracellular accumulation can lead to the regeneration of the precursor and ‘futile cycling’ within hepatocytes.5. An increased understanding of the factors influencing the intracellular concentrations of drugs and hepatically formed metabolites in the lvier will improve our ability to specifically treat liver disorders, such as hepatocellular carcinoma and malaria, and minimize the risk of hepatotoxicity from drugs and other xenobiotics.
PERMEABILITY OF MYOCARDIAL CAPILLARIES TO HYDROPHILIC DRUGS: THE PARACELLULAR PATHWAY
Authors: Morgan Denis J. 
Published: June 2007

SUMMARY1. As the majority of drug molecules are relatively small and lipophilic, capillary uptake in those regions with a continuous endothelium, such as the heart, has generally been regarded as taking place by flow‐limited transcellular capillary transport. Little attention has been paid to myocardial paracellular capillary transport of hydrophilic drugs, despite efficient transport of hydrophilic solutes, such as sucrose, inulin and EDTA, by this route.2. The paracellular pathway is formed by the cleft between adjacent endothelial cells and its permeability properties are determined by the tight junction, a region of restricted diameter within the cleft. Paracellular capillary permeability is modulated by circulating macromolecules, such as albumin, by an unknown mechanism thought to involve the intra‐endothelial cell Ca2+ concentration.3. Studies in perfused rat heart have shown that capillary permeability of quinidine does not vary when perfusate pH is varied from 7.0‐8.0, suggesting that capillary transport involves the ionized as well as unionized moiety. Addition of albumin to the perfusion medium reduced quindine capillary permeability, which is consistent with paracellular transport of quinidine ions.4. Paracellular transport increases in capillary inflammation. Therefore, if there is significant paracellular transport of hydrophilic drugs, an increase in uptake of such drugs in areas of inflamed myocardium associated with acute myocardial infarction would be expected to result.
IRINOTECAN (CPT‐11): A BRIEF OVERVIEW
Authors: Rivory Laurent P. 
Published: June 2007

SUMMARY1. Irinotecan (also known as CPT‐11) is a water soluble, semi‐synthetic analogue of 20(S)camptothecin (CPT) with promising activity against a range of tumour types.2. As with all other active analogues of CPT, irinotecan causes cell toxicity by stabilizing a ternary complex between the nuclear enzyme topoisomerase I (topo I) and doublestranded DNA. This leads to replication fork‐arrest, double DNA strand breaks and, possibly, illegitimate recombination of vital genes.3. This activity is much greater for its metabolite SN‐38 and irinotecan is widely considered to be a prodrug of SN‐38.4. The anti‐topo I activity of CPT is stereoselective at C‐20 and irinotecan is synthesized from 20(S)CPT to ensure maximal activity. In aqueous solutions, the lacton ring of CPT under goes reversible and spontaneous hydrolysis to a ring‐opened and inactive carboxylate form. In patients, it has been shown that the lactone is the predominant form of SN‐38 in plasma, whereas the opposite is true for irinotecan.5. The transformation of irinotecan to SN‐38 is catalysed by carboxylesterases. However, this conversion appears relatively inefficient in man.6. Irinotecan and SN‐38 show evidence of other metabolic reactions (type I and II), some of which could be subject to pharmacogenetic variablity.7. Therapy with irinotecan is associated with unusual toxicities, such as an acute cholinergic‐like syndrome and delayed onset diarrhoea. Although the mechanism for the diarrhoea remains to be defined, the cholinergic toxicity appears to be due to an inhibition of acetylcholinesterase.
POTASSIUM CHANNELS IN VASCULAR SMOOTH MUSCLE
Authors: Brayden Joseph E. 
Published: June 2007

SUMMARY1. Regulation of smooth muscle membrane potential through changes in K+ channel activity and subsequent alterations in the activity of voltage‐dependent calcium channels is a major mechanism of vasodilation and vasoconstriction, both in normal and pathophysiological conditions. The contribution of a given K+ channel type to this mechanism of vascular regulation depends on the vascular bed and species examined.2. Multiple K+ channels are present in most vascular smooth muscle cells and these different K+ channels play unique roles in regulating vascular tone. Voltage‐dependent K+ (Kv) channels are activated by depolarization, may contribute to steady state resting membrane potential and are inhibited by certain vasoconstrictors. Calcium‐activated K+ (KCa) channels oppose the depolarization associated with intrinsic vascular tone and are activated by some endogenous vasodilators. Small‐conductance, apamin‐sensitive KCa channels may be activated by endothelium‐derived hyperpolarizing factor. ATP‐sensitive K+ (KATP) channels are activated by pharmacological and endogenous vasodilators. Inward rectifier K+ (Kir) channels are activated by slight changes in extracellular K+ and may contribute to resting membrane potential.3. Membrane potential and diameter are determined, in part, by the integrated activity of several K+ channels, which are regulated by multiple dilator and constrictor signals in vascular smooth muscle.
EVIDENCE FOR A RENOMEDULLARY VASODEPRESSOR HORMONE
Authors: Thomas Collen J. , Woods Robyn L. , Evans Roger G. , Alcorn Daine , Christy Irene J. , Anderson Warwick P. 
Published: June 2007

SUMMARY1. Recent physiological experiments have established that increasing the perfusion pressure of the kidney causes the release of a vasodepressor substance from the renal medulla.2. The substance is not a platelet activating factor, a prostaglandin or nitric oxide and the vasodepressor response to increased renal perfusion pressure is not due simply to inhibition of renin release.3. The mechanisms by which the renomedullary vasodepressor substance lowers arterial pressure remain to be determined. Sympathoinhibition may account for part of the response, but the hypotension still occurs in autonomic ganglion blocked animals.4. The source of the substance appears to be the renomedullary interstitial cells, though the control of the production and release of the substance remain to be determined.5. The substance may be a lipid but it is yet to be fully isolated and identified.6. The threshold for release of the substance appears to be close to normal resting arterial blood pressure.7. Despite strong evidence that the renal medulla releases a vasodepressor hormone in response to increased renal perfusion pressure, much is still to be determined regarding the physiology of this hormone and its involvement in the aetiology of hypertension.
NEUROHUMORAL ACTIVATION IN HEART FAILURE: ROLE OF PARAVENTRICULAR NUCLEUS
Authors: Patel Kaushik P. , Zhang Kun 
Published: June 2007

SUMMARY1. A number of neurohumoral processes are activated in heart failure (HF), including an increase in the plasma concentration of noradrenaline.2. Few studies have been performed to examine the role of the central nervous system (CNS) in the activation of sympathetic outflow during HF. In the present paper we review the limited studies performed to examine the role of the CNS in the activation of sympathetic outflow, with particular emphasis on our recent study that examined the activity of discrete regions of the brain as assessed by histological localization and photodensitometric quantification of the metabolic enzyme hexokinase during HF.3. There were significant increases in hexokinase activity in the parvocellular (pPVN) and magnocellular (mPVN) divisions of the paraventricular nucleus of the hypothalamus and in the locus coeruleus (LC) in rats with HF. No changes in hexokinase activity were observed in the median preoptic area, supraoptic nucleus (SON) or posterior hypothalamus.4. We conclude that HF is associated with changes in specific areas in the brain and that alterations in the activation of neurons in the pPVN, mPVN and LC are likely to be related to alterations in vasopressin production, blood volume regulation and sympathoexcitation observed in the HF state.
OESTROGEN AND ENDOTHELIAL CELL ANGIOGENIC ACTIVITY
Authors: Schnaper H William , McGowan Kelly A. , Kim‐Schulze Seunghee , Cid Maria C. 
Published: June 2007

SUMMARY1. Increasing evidence suggests that oestrogens protect women from cardiovascular disease during their reproductive years. Although most studies by others have examined the effect of oestrogen on vascular smooth muscle cells, we have evaluated the effect of oestrogen on the angiogenic behaviour of endothelial cells.2. Oestrogen enhances endothelial cell attachment, proliferation, migration and organization into capillary‐like structures in vitro. In vivo, oestrogen augments experimental angiogenesis.3. As the same endothelial cell behaviours that are important in angiogenesis in small vessels are also important in the healing response to injury of large vessels, it is likely that the effect of oestrogen on these endothelial cell functions contributes significantly to the cardioprotective effects of oestrogen in women.
INDOMETHACIN DAMAGE TO RAT GASTRIC MUCOSA IS MARKEDLY DEPENDENT ON LUMINAL pH
Authors: Elliott Susan L , Ferris Rebekah J , Giraud Andrew S , Cook Gregory A , Skeljo Maryanne V , Yeomans Neville D 
Published: June 2007

SUMMARY1. There is good evidence that acid is a prerequisite for aspirin induced gastric mucosal damage; however, there is inconsistent information available for non‐salicylate NSAID. The present study examines the effect of gastric luminal pH on indomethacin‐induced gastric mucosal damage.2. Macroscopic gastric mucosal damage induced by indomethacin (40 mg/kg) or vehicle, administered intraduodenally to male pylorus‐ligated rats (n= 5–10/group), was assessed at four different levels of luminal pH (2,4,5.5 and 7) by means of digital planimetry.3. There was a marked difference in the extent of damage induced by indomethacin at the different luminal pH levels (P= 0.001). There was no difference between the percentage of haemorrhagic lesions at pH 2 and 4 (P>0.05), nor between pH 5.5 and 7 (P>0.05). However, the damage at the high levels of luminal acidity (pH 2 and 4) was strikingly different from that at pH 5.5 and 7 (P<0.05).4. Gastric mucosal damage induced by indomethacin, a non‐salicylate NSAID, is augmented by the presence of high concentrations of acid in the gastric lumen. The main finding, that indomethacin injury is markedly less above pH 4, may have clinical implications in the prevention of NSAID‐induced mucosal injury.
ALTERED REACTIVITY OF THE INFERIOR VENA CAVA TO NORADRENALINE AND ACETYLCHOLINE FOLLOWING THE BLOCKADE OF EDRF‐BIOSYNTHESIS WITH NG‐NITRO‐l‐ARGININE METHYL ESTER
Authors: Schwarzacher Severin , Krejcy Kurt , Ferber Wolfgang , Weidinger Franz 
Published: June 2007

SUMMARY1. Endothelium‐derived relaxing factor (EDRF) has been shown to influence arterial tone, but controversial results have been obtained studying veins. The present study was performed to determine the importance of EDRF for the inferior vena cava in the rabbit and whether blockade of the synthesis of EDRF with NG‐nitro‐l‐arginine methyl ester may influence the reactivity of the inferior vena cava to noradrenaline.2. The inferior vena cava was excised in six New Zealand white rabbits and 12 rings were prepared for organ bath studies. Concentration‐response curves were constructed for acetylcholine (10−9‐10−4mol/L) and noradrenaline (10−9‐10−4mol/L) before and following the administration of NG‐nitro‐l‐arginine methyl ester.3. All rings showed concentration‐dependent relaxation to acetylcholine (mean maximum: 57 ± 9%) following precon‐traction with noradrenaline (EC50: 10−6mol/L). Following NG‐nitro‐l‐arginine methyl ester, this dilation was significantly reduced to a mean maximum relaxation of 13 ± 6% (P<0.01).4. Contraction of the inferior vena cava to increasing doses of noradrenaline reached a maximum of 5.8 ± 2.8 g before NG‐nitro‐l‐arginine methyl ester (basal tension 1.0 ± 0.5 g). NG‐nitro‐l‐arginine methyl ester did not affect basal tension, but the constrictor response to noradrenaline was enhanced significantly to a maximum of 9.1 ± 3.8 g (P<0.01).5. Although it cannot be ascertained definitively from the present results, it is suggested that EDRF is mediating vasodilation of the inferior vena cava and that this vasoactive agent may also contributes significantly to the modulation of the reactivity to catecholamines.
Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: ROLE OF AT1 RECEPTORS IN THE CENTRAL CONTROL OF SYMPATHETIC VASOMOTOR FUNCTION
Authors: Head Geoffrey A 
Published: June 2007

SUMMARY

In a number of species, high concentrations of angiotensin II (AngII) receptors have been found in the rostral ventrolateral medulla (RVLM) in the hindbrain, which is an important region involved in the modulation of sympathetic vasomotor tone. The present review describes studies in which the contribution of angiotensin receptors in the brainstem to cardiovascular regulation, in particular sympathetic vasomotor reflexes, has been examined in conscious and anaesthetized rabbits.
In conscious rabbits, fourth ventricular infusions of AngII produced dose‐dependent pressor responses as doses 400 times less than equipressor intravenous doses. Chronic baroreceptor denervation increased the sensitivity to AngII by 1000‐fold. Administration of prazosin i.v. blocked the pressor response, suggesting that the mechanism involved sympathetic vasoconstriction.
The pattern of haemodynamic changes in response to AngII injected into the fourth ventricle (4V) involved decreased total peripheral conductance and mesenteric conductance, but a rise in hindlimb conductance. Sinoaortic denervation changed the hindlimb fall in conductance to an increase, suggesting that muscle vasomotor pathways were particularly inhibited by baroreceptor feedback mechanisms.
In anaesthetized rabbits, infusion of AngII into the RVLM increased blood pressure and transiently increased resting renal sympathetic nerve activity. The renal sympathetic baroreflex curves were shifted to the right and the upper plateau of the sympathetic reflex increase was markedly increased.
The pressor actions of 4V AngII were blocked by administration of a peptide antagonist injected into the RVLM or by the angiotensin AT1 antagonist losartan injected into the 4V. These results suggest that mainly AT1 receptors are involved and that the RVLM is a likely candidate site for the modulation of the renal sympathetic baroreflex.
Losartan administration into the 4V in conscious rabbits increased resting renal sympathetic tone and enhanced renal sympathetic baroreflex and chemoreflexes.
Our studies suggest that there are sympathoexcitatory AT1 receptors in the RVLM accessible to AngII from the cerebrospinal fluid. In addition, an AT1 receptor pathway normally inhibits the sympathoexcitation produced by baroreceptor unloading or chemoreceptor activation. The effect of losartan suggests that there is greater tonic activity within the sympathoinhibitory pathways. These two actions suggest that angiotensin receptors in the brainstem modulate sympathetic responses to specific afferent inputs, thus forming part of a potentially important mechanism for the integration of characteristic autonomic response patterns.
AUTORADIOGRAPHIC LOCALIZATION OF ACTIVE RENIN IN THE JUXTAGLOMERULAR APPARATUS OF THE DOG KIDNEY: EFFECTS OF SODIUM INTAKE
Authors: Zhuo Jialong , Anderson Warwick P , Song Keifu , Mendelsohn Frederick AO 
Published: June 2007

SUMMARY1. The effects of dietary sodium intake on active renin binding in the juxtaglomerular apparatus (JGA) of superficial and juxtamedullary cortex of the dog kidney were examined by quantitative in vitro autoradiography using a radiolabelled renin inhibitor [125I]‐H77, which has high affinity for dog renin.2. Changes in sodium intake resulted in marked alterations of active renin binding in the radiolabelled JGA. In comparison with the control kidney (190.8 ± 7.7 Bq/mm3), a higher density of binding occurred in the labelled JGA of sodiumdepleted kidney (277.7 ± 6.2 Bq/mm3), while a lower density of binding was found in the labelled JGA of sodium‐loaded kidney (99.3 ± 7.4 Bq/mm3).3. Active renin binding in the labelled JGA was significantly higher in superficial JGA than in their juxtamedullary counterparts, irrespective of sodium intake.4. Pre‐incubation with trypsin (0.5mg/mL), a procedure known to activate prorenin, markedly increased active renin binding in the labelled JGA of control (+∼ 35%; P < 0.01), and sodium‐loaded kidneys (+∼ 75%; P < 0.01), but had little effect on binding in the labelled JGA of the sodium‐depleted kidney (± 5–10%; NS). The proportions of active renin as a percentage of total renin were 60, 75 and 95% in the labelled JGA of sodium‐loaded, control, and sodium‐depleted kidneys, respectively.5. Emulsion microscopic autoradiography revealed that the binding was exclusively localized in the JGA, including the afferent and efferent arterioles, macula densa and extraglomerular mesangium. Labelling extended to the interlobular arteries in sodium depleted kidney.6. These results indicate that autoradiography combined with the in vitro binding of radiolabelled renin inhibitors may provide a useful tool to measure active and prorenin renin and thereby study the physiological regulation of renin in the kidney.
EFFECT OF STEADY SHEAR STRESS ON FLUID FILTRATION THROUGH THE RABBIT ARTERIAL WALL IN THE PRESENCE OF MACROMOLECULES
Authors: Karmakar Nivedita , Dhar Promila 
Published: June 2007

SUMMARY1. Transport properties of the arterial wall in general and endothelial cells in particular are known to be sensitive to fluid flow generated shear stress.2. The effect of steady wall shear stress was studied in vitro on transmural water filtration in the presence of a control perfusate (10mg/mL bovine serum albumin) and a test perfusate (50 mg/mL Dextran 500). The latter is a macromolecule with certain physical properties comparable to those of the circulating low density lipoproteins. Dextran 500 is a neutral polysaccharide carrying no charge groups.3. Male rabbits were anaesthetized with sodium pentobarbital and one of the common carotid arteries was cannulated and excised.4. Fluid flux across the artery wall was measured at a constant transmural pressure (150 cm H2O) in the presence and absence of luminal flow of the perfusate.5. Luminal flow produced an average increase by 21% in the filtration flux relative to its value under static conditions with 10 mg/mL bovine serum albumin in the perfusate. In the presence of 50 mg/mL Dextran 500 in the perfusate an average reduction by 36% was observed in fluid flux when luminal flow was imposed in the artery.6. The increase in flux with the control perfusate may be due to a structural alteration of the glycocalyx fibre matrix caused by flow imposed shear stress. The observed decrease in flux with 50 mg/mL Dextran 500 may be accounted for by the deformation of the dextran polymer chains when subjected to shear stress. Although intact molecules are likely to be excluded by the glycocalyx, parts of the chain may insert themselves in the network and enhance the steric exclusion of water. Also, decreased hydration of the medial interstitium may increase medial resistance to fluid transport.
IBUDILAST REDUCES INTRACELLULAR CALCIUM ELEVATION INDUCED BY IN VITRO ISCHAEMIA IN GERBIL HIPPOCAMPAL SLICES
Authors: Yanase Hisato , Mitani Akira , Kataoka Kiyoshi 
Published: June 2007

SUMMARY1. A microfluorometry was carried out to investigate the effect of 3‐isobutyryl‐2‐isopropylpyrazolo[1,5‐a]pyridine (ibudilast) on changes in levels of intracellular calcium concentration ([Ca2+]i) induced by in vitro ischaemia in the CA1 field of gerbil hippocampal slices.2. When slices, loaded with a calcium ion sensitive dye (rhod‐2) were exposed to a glucose‐free physiological medium equilibrated with a 95% N2/5% CO2 gas mixture (standard in vitro ischaemia), a large [Ca2+]i elevation was detected approximately 5 min after the beginning of in vitro ischaemia.3. When slices were perfused with the in vitro ischaemic medium containing 43 μmol/L ibudilast, a [Ca2+]i elevation was still observed; however, the extent of the increase in [Ca2+]i was significantly depressed in all subregions of the hippocampal slices.4. The extent of this inhibitory effect of ibudilast on the in vitro ischaemia‐induced [Ca2+]i elevation was in a similar range as those of Ca2+ blockers, including (+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cycloheptan‐5,10‐imine maleate (MK‐801), flunarizine and dantrolene.5. Similar [Ca2+]i increases in the CA1 field were induced by a Ca2+‐free in vitro ischaemia, a high concentration of KCl or by specific agonists for glutamate receptor subtypes (N‐methyl‐d‐aspartate (NMDA), (s)‐alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA) and kainate); these increases were also depressed with 43 μmol/L ibudilast present in the perfusion medium.6. These results indicate that ibudilast may act by depressing the Ca2+ accumulation during and shortly after ischaemia, a possible pharmacological action of ibudilast that leads to the amelioration of ischaemic injury in the central nervous system.