bluuebunny/crossref_metadata_2025_split huggingface dataset:
KINETIC ASPECTS OF DRUG DISPOSITION IN THE LUNGS
Authors: Upton Rn , Doolette Dj 
Published: March 2003

1. The pharmacokinetic role of the lungs has been extensively studied usingin vitropreparations, but this information has not been well integrated into many systemic pharmacokinetic models.2. The lung is characterized by short diffusion distances, extremely high relative perfusion and heterogeneous cell types. Anionic and neutral lipophilic drugs have relatively small distribution volumes in the lungs due to their low lipid content. Cationic lipophilic drugs can accumulate in the lungs, probably due to trapping in mitochondria and lysosomes, forming very slowly eluting pools.3. Drug metabolism in the lungs is possible, but not universal. The lung, generally, has a low activity for many of the metabolic enzymes found in the liver, although this activity is relatively more inducible. The resultant drug extraction would be ‘enzyme limited’, variable and flow dependent.4. Double indicator studies of first‐pass lung kinetics can characterize short‐term distribution in the lungs, but not longer‐term distribution or metabolism; the converse applies for studies of drug concentration gradients across the lungs. No single study or model has adequately defined the short‐ and long‐term kinetics of drugs in the lungs.5. Drug clearance in the lungs can contribute to an apparent total body clearance in excess of hepatic blood flow and cardiac output. The lung is a first pass filter for any drug administered on the venous side of the circulation and can act as a ‘capacitor’ that damps the first‐pass concentration peak in the blood after intravenous bolus injection.
OPIOID RECEPTOR SIGNALLING MECHANISMS
Authors: Connor Mark , Christie MacDonald J 
Published: March 2003

1. Three pharmacological types of opioid receptors, μ, δ and κ, and their corresponding genes have been identified. Although other types of opioid receptors have been suggested, their existence has not been established unequivocally. A fourth opioid receptor, ORL1, which is genetically closely related to the others, has also been isolated. ORL1 responds to the endogenous agonist nociceptin (orphanin FQ) and displays a pharmacological profile that differs greatly from μ, δ and κ receptors.2. All opioid receptors mediate many of their cellular effects via activation of heterotrimeric G‐proteins. The μ, δ and κ receptors are all capable of interacting with the pertussis toxin‐sensitive G‐protein α‐subunits Gi1, Gi2, Gi3, Go1, Go2 and the pertussis toxin‐insensitive Gz and G16. None of the opioid receptors interacts substantially with Gs and μ receptors do not activate Gq, G11, G12, G13 or G14.3. Differential coupling of different opioid receptors to most types of G‐proteins is marginal. The μ, δ and κ receptors appear to preferentially activate Go and Gi2 over other pertussis toxin‐sensitive G‐proteins, although there is evidence that μ receptors show some preference for Gi3. δ Receptors couple more efficiently to G16 than do μ or κ receptors.4. There is some evidence that opioid receptors, particularly μ and ORL1 receptors, can also couple to cellular effectors in a G‐protein‐independent manner.5. In general, the consequences of activation of any of the opioid receptors in a given cell type depend more on the profile (stoichiometry) of the G‐proteins and effectors expressed than on the type of opioid receptor present in the cell. Notions that different types of opioid receptors intrinsically couple preferentially to one type of effector rather than another should, therefore, be discarded.
HYPERTENSION MECHANISMS CAUSING STROKE
Authors: Johansson Barbro B 
Published: March 2003

1. Although it is well established that hypertension is the main risk factor for stroke, the complexity of cerebrovascular problems related to hypertension is not generally appreciated.2. Hypertension can cause stroke through many mechanisms. A high intraluminal pressure will lead to extensive alteration in endothelium and smooth muscle function in intracerebral arteries. The increased stress on the endothelium can increase permeability over the blood–brain barrier and local or multifocal brain oedema. Endothelial damage and altered blood cell–endothelium interaction can lead to local thrombi formation and ischaemic lesions. Fibrinoid necrosis can cause lacunar infarcts through focal stenosis and occlusions. Degenerative changes in smooth muscle cells and endothelium predisposes for intracerebral haemorrhages. Furthermore, hypertension accelerates the arteriosclerotic process, thus increasing the likelihood for cerebral lesions related to stenosis and embolism originating from large extracranial vessels, the aortic arch and from the heart.3. Adaptive structural changes in the resistance vessels, while having the positive effect of reducing the vessel wall tension, have the negative consequence of increased peripheral vascular resistance that may compromise the collateral circulation and enhance the risk for ischaemic events in connection with episodes of hypotension or distal to a stenosis.4. Hypertension is clearly a risk factor for vascular dementia. All the mechanisms referred to above may be important.
Olanzapine Transfer By Human Placenta
Authors: Schenker S , Yang Y , Mattiuz E , Tatum D , Lee M 
Published: March 2003

SUMMARY1. The present study assessed the human transplacental transport of olanzapine, a new antipsychotic drug effective in the treatment of schizophrenia.2. Using the normal‐term placenta perfused single cotyledon system, we show that: (i) 5–14% of labelled olanzapine crosses from the maternal to foetal compartments in 4 h; (ii) transport depends significantly on binding characteristics, especially of albumin; (iii) no oxidative metabolites of olanzapine appear in the placental perfusate over 4 h; and (iv) approximately 17% of olanzapine, on average, is converted to the glucuronide, which is transferred by the placenta at a rate slightly slower than the parent drug.
EVIDENCE FOR A COMMON DEFECT ASSOCIATED WITH PRESSURE IN THE AORTA OF TWO HYPERTENSIVE RAT STRAINS
Authors: Chamiot‐Clerc Ph , Colle  , Legrand  , Sassard  , Safar  , Renaud  
Published: March 2003

1. Thoracic aortas of normotensive (Wistar‐Kyoto (WKY) and Lyon normotensive (LN)) and hypertensive (spontaneously hypertensive rats (SHR) and Lyon hypertensive (LH)) rats from two groups (Japanese (WKY rats and SHR) and Lyon (LN and LH rats)) were compared using organ chambers. Changes in endothelium and smooth muscle reactivity to noradrenaline (NA), carbamylcholine and Nω‐nitro‐
L‐arginine (
L‐NNA) were analysed to distinguish between changes in reactivity that are associated with the presence of hypertension and those that are dependent on group (Japanese vs Lyon).2. Aortas of hypertensive rats had lower pD2 values for NA than aortas from normotensive rats. These differences were associated with hypertension (P < 0.005 and P < 0.01) and group (P < 0.005 and P < 0.005) in presence or absence of endothelium, respectively, whereas no difference was seen in the maximal developed tension in response to NA.3. Aortas also differed by a reduced ability to relax in response to carbamylcholine in hypertensive rats; this effect is hypertension (P < 0.05) and group (P < 0.005) dependent, without any change in carbamylcholine pD2 values.4. Changes in maximum developed tension in the presence of L‐NNA were found to be endothelium dependent and pressure and group independent. Furthermore, the change in tension induced by
L‐NNA appears significantly more pronounced in SHR than in LH rats (P < 0.05).5. These results indicate that the common defect associated with hypertension appears to be linked to the endothelium through α‐adrenoceptors and muscarinic receptors in both the Japanese and Lyon groups. However, SHR differs markedly from LH rats by having a higher developed tension in response to NA, this increased tension being counterbalanced by the release of nitric oxide, as observed in the presence of L‐NNA.
ROLE OF INDUCIBLE NITRIC OXIDE SYNTHASE IN TRANSPLANT ARTERIOSCLEROSIS
Authors: Lee Paul C , Shears Larry L Shears , Billiar Timothy R 
Published: March 2003

SUMMARY1. Transplant arteriosclerosis is a major obstacle to long‐term allograft survival. Nitric oxide (NO) has been implicated as a mediator in the development of this disease.2. We and others have shown that inducible nitric oxide synthase (iNOS) is up‐regulated in allografts with transplant arteriosclerosis. Despite the acute cytotoxic effects produced by high levels of NO, a chronic increase in NO availability is protective against neointimal hyperplasia, mainly by suppressing the inflammatory cell recruitment and neointimal smooth muscle cell accumulation.3. Currently, we have the technology to directly transfer the iNOS gene to allografts. We have demonstrated that this exciting strategy is feasible and therapeutic and may improve the long‐term survival and function of allografts. Future challenges include optimizing the methods and the vectors of gene delivery.
Myoendothelial Electrical Coupling In Arteries And Arterioles And Its Implications For Endothelium‐Derived Hyperpolarizing Factor
Authors: Coleman Harold A , Tare Marianne , Parkington Helena C 
Published: March 2003

SUMMARY1. Considerable progress has been made over the past decade in evaluating the presence of electrical coupling between the endothelial and smooth muscle layers of blood vessels, prompted, in part, by ultrastructural evidence for the presence of myoendothelial junctions.2. In a variety of vessels ranging in size from conduit arteries down to small arterioles, action potentials have been recorded from endothelial cells that were associated with constriction of the vessels and/or occurred in synchrony with and were indistinguishable from action potentials recorded from the smooth muscle. From these results, it is now firmly established that myoendothelial electrical coupling occurs in at least some blood vessels.3. Spread of hyperpolarizing current from the endothelium to the smooth muscle is the most likely explanation of the smooth muscle hyperpolarization attributed to endothelium‐derived hyperpolarizing factor. Because this hyperpolarization can evoke considerable relaxation of the smooth muscle, myoendothelial electrical coupling has important implications for endothelial regulation of the contractile activity of blood vessels.
Alzheimer’s Disease And Inflammation: A Review Of Cellular And Therapeutic Mechanisms
Authors: Halliday Glenda , Robinson Stephen R , Shepherd Claire , Kril Jillian 
Published: March 2003

SUMMARY1. Of the neurodegenerative diseases that cause dementia, Alzheimer’s disease (AD) is the most common. Three major pathologies characterize the disease: senile plaques, neurofibrillary tangles and inflammation. We review the literature on events contributing to the inflammation and the treatments thought to target this pathology.2. The senile plaques of AD consist primarily of complexes of the β‐amyloid protein. This protein is central to the pathogenesis of the disease.3. Inflammatory microglia are consistently associated with senile plaques in AD, although the classic inflammatory response (immunoglobulin and leucocyte infiltration) is absent. β‐Amyloid fragments appear to mediate such inflammatory mechanisms by activating the complement pathway in a similar fashion to immunoglobulin.4. Epidemiological studies have identified a reduced risk of AD in patients with arthritis and in leprosy patients treated with anti‐inflammatory drugs. Longitudinal studies have shown that the consumption of anti‐inflammatory medications reduces the risk of AD only in younger patients (< 75 years).5. There is a considerable body of in vitro evidence indicating that the inflammatory response of microglial cells is reduced by non‐steroidal anti‐inflammatory drugs (NSAID). However, no published data are available concerning the effects of these medications on brain pathology in AD.6. Cyclo‐oxygenase 2 enzyme is constitutively expressed in neurons and is up‐regulated in degenerative brain regions in AD. Non‐steroidal anti‐inflammatory drugs may reduce this expression.7. Platelets are a source of β‐amyloid and increased platelet activation and increased circulating β‐amyloid have been identified in AD. Anti‐platelet medication (including NSAID) would prevent such activation and its potentially harmful consequences.8. Increased levels of luminal β‐amyloid permeabilizes the blood–brain barrier (BBB) and increases vasoconstriction of arterial vessels, paralleling the alterations observed with infection and inflammation. Cerebral amyloidosis is highly prevalent in AD, compromising the BBB and vasoactivity. Anti‐inflammatory medications may alleviate these problems.
Carbonic Anhydrase I Inhibition By Nitric Oxide: Implications For Mediation Of The Hypercapnia‐Induced Vasodilator Response
Authors: Puscas Ioan , Coltau Marcela , Domuta Gabriela , Baican Michael , Puscas Carmen , Pasca Radu 
Published: March 2003

SUMMARY1. At present, CO2 is considered to be the most important factor in regulating cerebral blood flow by modification of the interstitial fluid and extracellular pH, but the mechanism by which hypercapnia produces vasodilation is still controversial. In the present paper we investigated the effect of hypercapnia on carbonic anhydrase (CA) activity. We also studied the combined effects of CO2 with either indomethacin or an L‐arginine analogue on CA activity.2. Nine groups of 12 rabbits each were established. Groups 1–4 were ventilated with a mixture of 10% CO2, 21% O2 and 69% N2 for 20, 60, 120 and 180 min. Group 5 rabbits received 15 mg/kg bodyweight, i.v., indomethacin and, after 1 h, were ventilated with a mixture of 10% CO2, 21% O2 and 69% N2 for 2 h. Group 6 animals were ventilated with a mixture of 10% CO2, 21% O2 and 69% N2 for 2 h and then received indomethacin. Group 7 rabbits received 100 mg/kg bodyweight, i.v., NG‐monomethyl‐L‐arginine (L‐NMMA) and, after 1 h, were ventilated with a mixture of 10% CO2, 21% O2 and 69% N2 for 2 h. Group 8 rabbits were ventilated for 2 h with a mixture of 10% CO2, 21% O2 and 69% N2 and were then administered L‐NMMA. Group 9 rabbits received L‐NMMA treatment concomitant with ventilation for 2 h with a mixture of 10% CO2, 21% O2 and 69% N2. In all groups, the erythrocyte CA activity was measured, as well as PaCO2 before and after ventilation or treatment.3. The present study shows that CO2 reduces CA I activity down to complete inhibition and antagonizes the activating effects of indomethacin and L‐NMMA on this isozyme. Our data prove that nitric oxide‐ and prostaglandin‐induced CA I inhibition is involved in the vasodilation produced by hypercapnia. These results suggest that, due to subsequent pH changes, CA I is directly implicated in the modulation of vascular processes in the organism.
Chemistry And Biological Effects Of Dietary Phenolic Compounds: Relevance To Cardiovascular Disease
Authors: Morton Lincoln W , Caccetta Rima Abu‐Amsha , Puddey Ian B , Croft Kevin D 
Published: March 2003

SUMMARY1. There has been considerable recent interest in the possibility that increased intake of dietary anti‐oxidants may protect against cardiovascular disease. This is partly due to the knowledge that oxidative events in vivo may play a role in the pathogenesis of atherosclerosis.2. While dietary anti‐oxidants, such as vitamins E and C, have received considerable attention in this regard, relatively little is known about a similar anti‐oxidant role for plant‐derived polyphenolic compounds, such as the flavonoids and phenolic acids. A review of the distribution, bioavailability and biological activity of these compounds suggests that they may have a physiological role as anti‐oxidants.3. Human trials on the anti‐oxidant effects of beverages rich in polyphenolics, such as red wine, fruit juice or tea, have been limited and results are, at present, inconclusive. This is due, in part, to poor methodologies available to measure oxidative damage in vivo.4. There is a sound rationale for considering polyphenolics as important contributors to the dietary anti‐oxidant intake derived from fruits and vegetables. However, continuing research is needed using appropriate biomarkers of oxidant damage in vivo before these compounds can be conclusively considered as dietary anti‐oxidants with nutritional benefit.
Role Of Brain Angiotensin Ii In The Somatosensory Induced Antinatriuresis In The Anaesthetized Rat
Authors: Huang Chunlong , Johns Edward J 
Published: March 2003

SUMMARY1. The present study set out to explore the importance of angiotensin (Ang)II in the brain in allowing the somatosensory system to cause a reflex renal nerve‐mediated reduction in renal sodium and water excretion.2. In chloralose–urethane‐anaesthetized rats receiving saline i.c.v. (2 μL + 1 μL/h), the administration of capsaicin (0.5 mg, s.c.) increased blood pressure by 14% (P < 0.001) and, while renal perfusion pressure was regulated at an unchanged level, neither renal blood flow (RBF) nor glomerular filtration rate was changed. However, urine flow and absolute and fractional sodium excretion was reduced between 29 and 38% (P < 0.05–0.01). All variables had returned to control levels 30 min later.3. The administration of captopril (40 μg + 20 μg/h i.c.v.) decreased blood pressure and sodium excretion by 6 and 17%, respectively (both P < 0.05). Under these conditions, capsaicin s.c. increased blood pressure by 9% (P < 0.05); however, with renal perfusion pressure regulated at a constant level, neither renal haemodynamics nor water nor sodium excretion were changed.4. A final group of animals received AngII (100 ng + 50 ng/h) concomitantly with captopril i.c.v., which increased blood pressure, RBF and urine flow, absolute and fractional sodium excretions by 8 (P < 0.05), 22 (P < 0.001) and 52–149% (P < 0.05–0.01), respectively. Capsaicin given s.c. under these conditions increased blood pressure by 6% (P < 0.05) and, while renal perfusion pressure was maintained at an unchanged value and renal haemodynamics remained constant, urine flow and absolute and fractional sodium excretion were reduced by 35–38% (all P < 0.05).5. These data show that for the somatosensory system to induce a reflex increase in renal sympathetic nerve activity sufficient to cause an antinatriuresis and antidiuresis, the presence of AngII is necessary in the brain. How AngII exerts this facilitatory action within the central nervous system remains to be investigated.
Chronotropic And Vasodilatory Responses To Adenosine And Isoproterenol In Mouse Heart: Effects Of Adenosine A1 Receptor Overexpression
Authors: Headrick John P , Gauthier Naomi S , Morrison R Ray , Matherne G Paul 
Published: March 2003

SUMMARY1. Chronotropic and vasodilatory effects of adenosine receptor activation with 2‐chloroadenosine (2‐ClAdo) and β‐adrenoceptor activation with isoproterenol were studied in wild‐type murine hearts and transgenic hearts overexpressing the A1 adenosine receptor.2. Treatment of wild‐type hearts with 2‐ClAdo induced bradycardia (pEC50 6.4±0.2) and vasodilatation (pEC50 7.9±0.1; minimal resistance 2.2±0.2 mmHg/mL per min per g). The A1 receptor‐mediated bradycardia was 20‐fold more sensitive in transgenic hearts (pEC50 7.7±0.2), whereas coronary vasoactivity of 2‐ClAdo was unaltered (pEC50 7.6±0.1).3. β‐Adrenoceptor stimulation with isoproterenol increased heart rate (pEC50 8.5±0.2; maximal rate 594±23 b.p.m.) and produced vasodilation (pEC50 8.7±0.1; minimal resistance 1.7±0.2 mmHg/mL per min per g) in wild‐type hearts. Treatment with 10 IU/mL adenosine deaminase increased the magnitude of the tachycardia (maximal rate 653±27 b.p.m.) without altering potency (pEC50 8.5±0.1). Antagonism of A1 receptors with 10 nmol/L 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX) produced a comparable increase in the magnitude of the chronotropic response (maximal rate 695±26 b.p.m.) without altering potency (pEC50 8.3±0.1).4. Isoproterenol‐mediated vasodilatation was unaltered by transgenic A1 receptor overexpression. Overexpression of A1 receptors significantly reduced the maximal heart rate during β‐adrenoceptor stimulation by 35% (to 381±28 b.p.m.) without altering potency (pEC50 8.4±0.2). At 10 nmol/L, DPCPX increased the magnitude of the chronotropic response to isoproterenol in transgenic hearts (maximal heart rate 484±36 b.p.m.) without altering potency (pEC50 8.3±0.2).5. The data show that transgenic A1 receptor overexpression selectively sensitizes the cardiovascular A1 receptor response and that A1 receptor activation by endogenous adenosine depresses the magnitude, but not potency, of the β‐adrenoceptor‐mediated chronotropic response in mouse heart. The A1 receptor‐mediated depression of β‐adrenoceptor responsiveness is non‐competitive (reduced response magnitude with no change in sensitivity). This indicates that A1 receptor activation non‐competitively inhibits effector mechanisms activated by β‐adrenoceptors (e.g. adenylate cyclase) and/or A1 receptors activate unrelated but opposing mechanisms. This inhibitory response may have physiological importance during periods of sympathetic stimulation of cardiac work.
Nitric Oxide As A Metabolic Regulator During Exercise: Effects Of Training In Health And Disease
Authors: Kingwell Bronwyn A 
Published: March 2003

SUMMARY1. Accumulating animal and human data suggest that nitric oxide (NO) is important for both coronary and peripheral haemodynamic control and metabolic regulation during performance of exercise.2. While still controversial, NO of endothelial origin is thought to potentiate exercise‐induced hyperaemia, both in the peripheral and coronary circulations. The mechanism of release may include both acetylcholine derived from the neuromuscular junction and vascular shear stress.3. A splice variant of neuronal nitric oxide synthase (NOS), nNOSμ, incorporating an extra 34 amino acids, is expressed in human skeletal muscle. In addition to being a potential modulator of blood flow, skeletal muscle‐derived NO is an important regulator of muscle contraction and metabolism. In particular, recent human data indicate that NO modulates muscle glucose uptake during exercise, independently of blood flow.4. Exercise training in healthy individuals promotes adaptations in the various NO systems, which can increase NO bioavailability through a variety of mechanisms, including increased NOS enzyme expression and activity. Such adaptations likely contribute to increased exercise capacity and protection from cardiovascular events.5. Cardiovascular risk factors, including hypercholesterolaemia, hypertension, diabetes and smoking, as well as established disease, are associated with impairment of the various NO systems. Given that NO is an important signalling mechanism during exercise, such impairment may contribute to limitations in exercise capacity through inadequate coronary or peripheral blood delivery and via metabolic effects.6. Exercise training in individuals with elevated cardiovascular risk or established disease can increase NO bioavailability and may represent an important mechanism by which exercise training provides benefit in the setting of secondary prevention.
Antihypertensive Effect Of Cattle Bone Collagen‐Derived Peptides In Ovariectomized Stroke‐Prone Spontaneously Hypertensive Rats
Authors: Mizutani K , Ikeda K , Ishikado A , Kawai Y , Yamori Y 
Published: March 2003

SUMMARY1. The effect of food collagen, cattle bone collagen‐derived (CBC) peptides, on ovariectomy induced increases in blood pressure was examined in stroke‐prone spontaneously hypertensive rats (SHRSP).2. Long‐term administration of CBC peptides to ovariectomized SHRSP suppressed the hypertension compared with ovariectomized SHRSP fed standard chow.3. The CBC peptides showed an inhibitory activity (IC50 = 40 μg/mL) for angiotensin I‐converting enzyme (ACE) in vitro. Furthermore, pre‐incubation of CBC peptides with gastrointestinal proteases did not change this inhibitory activity of CBC for ACE.4. These results indicate that CBC peptides may prevent increases in blood pressure in ovariectomized SHRSP by a possible mechanism of an inhibitory action against ACE.