bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiovascular and pharmacokinetic drug interactions between acute tirilazad mesylate and chronic nimodipine in conscious dogs
Authors: Humphrey Stephen J. , Weber Dennis J. , Smith Michael P. , Brown W. Patrick , Steenwyk Rick C. , Lund John E. 
Published: January 2005

AbstractIn support of prospective human tests, the cardiovascular, pharmacokinetic, and histopathologic drug interactions between the dihydropyridine calcium channel blocker nimodipine and the lipid peroxidase inhibitor tirilazad mesylate were examined in conscious beagle dogs. Chronic arterially cannulated dogs first received repeated oral doses of nimodipine (1 mg/kg q 4 h × 2 days) to establish its steady‐state pharmacokinetics prior to 30 min iv infusions of a citrate buffered vehicle (4 and 20 ml/kg) and tirilazad mesylate (6 and 30 mg/kg). Both vehicle and tirilazad infusions were very well tolerated in the placebo‐ and nimodipine‐pretreated dogs, and resulted in negligible changes in the plasma kinetics of the test agents. Nimodipine's phasic hypotensive response was largely unaffected by tirilazad, although its reflex tachycardia was moderately prolonged. Electrocardiographic and routine clinical parameters were within the range seen with the nimodipine plus citrate buffer combination. Plasma cholesterol, total lipids, and triglyceride levels increased slightly with tirilazad, independent of oral nimodipine therapy. Gross necropsy findings were limited to slight inflammatory liver changes in all dogs, which were attributed to the doses of heparin used to maintain catheter patency. This study demonstrates that in normal conscious dogs, standard and supratherapeutic iv doses of tirilazad mesylate can safely be combined with chronic oral nimodipine without untoward cardiovascular, pharmacokinetic, or histopathologic drug interactions. © 1993 Wiley‐Liss, Inc.
A new model to assess analgesic activity: Pain‐induced functional impairment in the rat (PIFIR)
Authors: López‐Muñoz Francisco J. , Salazar Luis A. , Castañeda‐Hernández Gilberto , Villarreal Julián E. 
Published: January 2005

AbstractA new experimental model to assess analgesic activity of both analgesic and non‐steroidal antiinflammatory drugs in described. It uses the unilateral intra‐articular knee injection of an uric acid suspension in mineral oil to produce acute inflammation, pain, and functional motor impairment. The model, named “pain‐induced functional impairment in the rat” (PIFIR) assesses analgesic activity by measuring the capacity to walk with the injured extremity. The procedure determines both the potencies of analgesic drugs and the time course of the effect. Analgesia of selected reference agents was followed for 4 h and the effect versus time curves were constructed. The area under the curve (effect versus time), an expression of the overall activity during the observation period, increased in a dose‐dependent manner. The area under the curve, Emax, TEmax, and ED50 of reference agents tested are reported. The PIFIR procedure was sensitive to opiate and nonopiate analgetics (nonsteroidal antiinflammatory drugs) and possibly steroidal antiinflammatory drugs. These characteristics make it suitable for screening purposes. © 1993 Wiley‐Liss, Inc.
Properties of recombinant adenosine receptors
Authors: Linden Joel , Tucker Amy L. , Robeva Anna S. , Graber Stephen G. , Munshi Ravi 
Published: January 2005

AbstractFour subtypes of adenosine receptors have been cloned in several laboratories. The receptors all interact with G proteins and span the plasma membrane 7 times. They range in size from 319 to 412 amino acids. Conservation of structure among 10 different receptor clones for various species suggests that ligand recognition sites involve amino acids in the 2, 3, and 7 transmembrane segments of receptors. Species differences in ligand binding to A1 receptors in tissues are very similar; for bovine receptors the affinity is R‐PIA ≫ NECA, for canine receptors NECA ≥ R‐PIA. Purified bovine A1 receptors functionally couple to the pertussis toxin sensitive recombinant G proteins, Gi1, Gi2, Gi3, and Go. © 1993 Wiley‐Liss, Inc.
Adenosine system in the heart
Authors: Belardinelli Luiz 
Published: January 2005

AbstractThe adenosine system in the heart consists of three components : (1) a mechanism formation, (2) a receptor‐effector coupling system, and (3) a mechanism for degradation. Selective pharmacological modification of this system with drug such as nucleoside uptake inhibitors osine. The action of adenosine in the heart are mediated by specific cell surface receptors of at least two subtypes. The A1 receptor subtype mediates the actions of adenosine that decrease O2 consumption (e.g, slowing of heart rate), whereas the A2 receptor subtype mediates the well‐known coronary vasodilatory effects of adenosine and thereby increases O2 supply. Adenosine formation is increased when O2 demand exceeds O2 supply. Thus, in the heart adenosine may serve as a negative‐feedback signal to adjust myocardial balance between O2 supply and consumption. In this brief review we describe the cardiovascular effects of adenosine, its mechanism(s) of action, and metabolism. © 1993 Wiley‐Liss, Inc.
Mechanism of the negative dromotrophic effect of adenosine 5′‐triphosphate in the guinea pig heart in vivo
Authors: Xu Jiang , Wang Li , Hurt Carl , Pelleg Amir 
Published: January 2005

AbstractTo test the hypothesis that the vagus nerve does not play a major mechanistic role in the cardiac electrophysiologic action of adenosine 5′‐triphosphate (ATP), the negative dromotropic actions of the nucleotide and adenosine on atrioventricular (AV) nodal conduction were quantitated in an in vivo guinea pig model. Anesthetized animals were divided into three groups. In group 1, ATP and adenosine (0.1–10.0 μmol/kg, iv) were given at random as a rapid bolus during right atrial pacing (paced cycle length 220–270 msec). This protocol was repeated following the administration of atropine (0.2 mg/kg, iv) followed by propranolol (1 mg/kg, iv). In group 2, ATP and adenosine (1.6 μmol/kg, iv) were given in the absence and presence of the selective A1‐adenosine receptor antagonist, N6‐endonorbornan‐2‐yl‐9‐methyladenine (N‐0861, 30 μmol/kg, iv), and in group 3, ATP and adenosine were given as in group 2 but instead of N‐0861, an adenosine transport blocker, dipyridamole (250 μg/kg, iv), was used. Standard lead I and II electrocardiogram, right atrial, right ventricular, and His bundle electrogram as well as systemic arterial blood pressure were continuously monitored and recorded. AV nodal conduction time was quantitated as AH interval. ATP and adenosine were equipotent in suppressing AV nodal conduction. For example, maximal AH interval following the highest dose of ATP and adenosine was 102 ± 10 and 112 ± 7 msec, respectively. These effects were not significantly altered by either muscarinic cholinergic or β‐adrenergic blockade. Furthermore, N‐0861 attenuated and dipyridamole enhanced the effects of ATP and adenosine similarly. It was concluded that the electrophysiologic action of ATP in the guinea pig AV node in vivo is independent of the vagus nerve and mediated by its degradation to adenosine and the action of the latter on A1‐adenosine receptors. © 1993 Wiley‐Liss, Inc.
Mechanism of the effector function of adenosine in asthma and rhintis
Authors: Crimi Nunzio , Polosa Riccardo , Mistretta Antonino 
Published: January 2005

AbstractAdenosine, a purine nucleoside which may be formed following immunological activation, may act as an autacoid by modulating the function of a variety of cells. In asthmatic and rhinitic subjects, but not in normals, exposure to adenosine causes marked responses, which are markedly reduced by pretreatment with histamine‐H1 receptor antagonists. Although the mechanism by which adenosine induces changes in the function of the lower and upper airways are not clear this form of provocation of the airways may serve as a convenient tool in investigating the characteristic pathophysiological changer of asthma and rhinitis. © 1993 Wiley‐Liss, Inc.
Nucleoside transport inhibition for cardioprotection: New perspectives for the clinic
Authors: Van Belle Herman 
Published: January 2005

AbstractIn this review the role of adenosine, produced in the myocardium in response to ischemia, as a “natural defense” system is briefly summarized. In contrast with exogenous adenosine or adenosine agonists, interference with adenosine metabolism will restrict the action of endogenous adenosine to when and where it is produced (site and event specificity). In this respect, Nucleoside transport inhibition seems to be the preferred strategy because of a dual effect, namely, attenuation of catabolism during ischemia and delay of the washout upon reperfusion. In a variety of experimental studies in animals, nucleoside transport inhibition has been documented to afford marked cardioprotection. Failure in humans thus far may be due to the shortcomings of the few existing drugs. The development of draflazine, a new transport inhibitor with a more appropriate pharmacokinetic profile may open new perspectives for therapy based on this concept. © 1993 Wiley‐Liss, Inc.
Adenosine outflow from hippocampal slices evoked by ischemic‐like conditions: Effect of the excitatory amino acid antagonists
Authors: Pedata Felicita , Latini Serena , Pazzagli Marta , Pepeu Giancarlo 
Published: January 2005

AbstractThe effect of amino acid receptor antagonists on adenosine and inosine outflow evoked by 5 or 10 min ischemia‐like conditions “in vitro” (glucose‐free Krebs solution gassed with 95% N2/5% CO2) was investigated on rat hippocampal slices. The viability of the slices after ischemia was evaluated by extracellular recording of the evoked synaptic responses in the CA1 region. The NMDA receptor antagonist D(−)‐2‐amino‐7‐phosphonoheptanoic acid (D‐AP7 100 μM) and the non‐NMDA receptor antagonist 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX 10 μM) did not significantly decrease the adenosine and inosine outflow evoked by ischemia. The glutamate uptake blocker dihydrokainate (500 μM) also did not affect the outflow of adenosine and inosine. It is concluded that ischemia‐like conditions “In vitro” evoke and adenosine and inosine outflow, through a mechanism which does not involve excitatory amino acids. © 1993 Wiley‐Liss, Inc.
Manipulation of endogenous adenosine affects seizure susceptibility
Authors: Murray Thomas F. , Zhang Ge , Franklin Paul H. 
Published: January 2005

AbstractA1 adenosine receptors in rat prepiriform cortex (PPC) play an important role in the inhibition of bicuculline methiodide (BMI)‐induced convulsions. In the present study, we evaluated the manipulation of endogenous adenosine in this brain area as a strategy to effect seizure suppression. All compounds evaluated were unilaterally microinjected into the PPC. Focal administration of 5′NH25′dADO and dilazep were found to be highly efficacious as anticonvulsants with respective ED50 values of 2.6±0.8, and 5.6±1.6 nmol. In contrast, 2′DCF was both less potent and less efficacious. These results suggest that accumulation of endogenous adenosine may contribute to seizure suppression, and that adenosine kinase and adenosine transport may play a pivotal role in the regulation of extracellular levels of adenosine in the CNS. © 1993 Wiley‐Liss, Inc.
Cellular mechanisms underlying the excitatory actions of ATP in vascular smooth muscle
Authors: Kennedy Charles 
Published: January 2005

AbstractIt is now clear that noradrenaline (NA) is not the sole excitatory cotransmitter in perivascular sympathetic nerves, as both adenosine 5′‐triphosphate (ATP) and neuropeptide Y (NPY) are co‐stored with NA in synaptic vesicles and co‐released during nerve stimulation. The relative contribution of these compounds to neurogenic contractions is dependent upon the species, vessel and parameters of stimulation studied. Stimulation of the perivascular nerves evokes excitatory junction potentials (ejps) which, in most vessels are resistant to α‐adrenoceptor antagonists. The ejps are mediated by ATP, as they are selectively abolished by desensitisation of the P2x‐purinoceptor by α,β‐MeATP or by the selective P2‐antagonist, suramin. In many vessels a component of the neurogenic contraction also shows resistance to β‐adrenoceptor blockade but can be inhibited by α,β‐MeATP or suramin. In the limited number of vessels studied to date, ATP has been found to act via several ionic mechanisms, including an increasing in a non‐specific, cationic current and an increase in a chloride current. These currents appear to have a variable distribution and are not all present in all vessels. This may allow vessels a differential response to ATP depending on their function. However, the distribution, role and relative importance of these effects is not yet known. As well as its direct contractile effects, ATP also interacts in a synergistic manner with NA and NPY. The mechanisms which underlie these effects are unclear but may involve an increase in the current through L‐type calcium channels. Clearly, vascular neurotransmission is not the simple process previously envisaged. © 1993 Wiley‐Liss, Inc.
ACE inhibition versus angiotensin II, AT1 receptor antagonism: A review of effects on intimal lesion formation in animal models of vascular injury, restenosis, and atherosclerosis
Authors: Prescott Margaret Forney , Sawyer Wilbur K. 
Published: January 2005

AbstractWe recently demonstrated that the angiotensin converting enzyme inhibitor (ACEi) benazepril reduced balloon‐induced lesion formation solely by inhibiting smooth muscle cell (SMC) migration, whereas the Ang II, AT1 antagonist losartan reduced lesion formation by inhibiting both SMC migration and proliferation [Prescott et al. (1991): Am J Pathol 139:1291–1296.]. We thus proposed that in order for both SMC migration and proliferation to be reduced by ACEi treatment, a dose must be selected which is greater than the dose necessary to reduce blood pressure. Recent evidence that ACEi prevention of early intimal lesion formation following balloon injury can be reversed by simultaneous administration of the bradykinin antagonist, Hoe 140 [de‐Blois et al. (1992): Circulation 86 [Suppl I]:I‐226.] raises the possibility that low doses of ACEi treatment may be sufficient to inhibit lesion formation via mechanisms independent of effects on Ang II production but that high doses of ACEi treatment are necessary to prevent the local formation of Ang II. The present review therefore analyzes the results of ACEi treatment on lesion formation following balloon catheterization, vascular stenting, or angioplasty. Effects on lesion formation are correlated with the importance of SMC migration vs. proliferation in the specific model employed. In addition, we present evidence to support our speculation that ACEi reduction of both atherosclerosis and restenotic lesions in the hypercholesterolemic rabbit is primarily due to inhibition of monocyte emigration into the vessel wall and is independent of effects on SMC migration or proliferation. Finally, we present preliminary results from our efforts to develop a rabbit angioplasty model in which macrophage‐derived foam cells are not the primary component of either the initial “atherosclerotic” lesion or the restenotic lesion post‐angioplasty. © 1993 Wiley‐Liss, Inc.
Is there a functional cardiovascular role for AT2 receptors?
Authors: Keiser Joan A. , Major Terry C. , Lu Gina H. , Davis Leslie S. , Panek Robert L. 
Published: January 2005

AbstractThe presence of at least two major subtypes of mammalian angiotensin II (Ang II) receptors has been convincingly demonstrated with the use of selective non‐peptide receptor ligands. Subtype selective peptide ligands have also been identified. The role of AT1 receptors in mediating angiotensin II‐induced vascular smooth muscle contraction, aldosterone secretion and a host of other responses has been well documented. However, the role of the AT2 receptor has remained an enigma. The purpose of the studies presented here was to examine the potential role of AT2 receptors in cardiovascular responses in young animals in which the AT2 receptor predominates, and to examine Ang II responses in animals chronically treated with an AT2 receptor ligand. Ang II receptor binding assays and Ang II contractile responses were assessed in aortic tissue from neonatal rats; aortic binding was compared to liver binding in tissues from the same animals. Although AT2 receptors were expressed in neonatal aorta, the AT2 selective ligand PD 123319 had no effect on Ang II‐induced contractile responses in aortic rings from these neonatal rats. In adult rats acute administration of PD 123319 failed to inhibit Ang II‐induced increases in blood pressure; however, in rats treated for 10–12 days with PD 123319 Ang II‐induced pressor responses were inhibited roughly 40% compared to vehicle treated control rats. These data demonstrate that the AT2 receptor in the neonate may not play a role in Ang II induced vascular tone. However, there may be some resetting or interaction of Ang receptor subtypes in adults rats chronically exposed to an AT2 receptor ligand such that Ang‐II pressor responses are impaired. © 1993 Wiley‐Liss, Inc.
Captopril decreases accelerated atherosclerosis in hypertensive one kidney one clip rats fed cholesterol
Authors: Kowala Mark C. 
Published: January 2005

AbstractThe effect of captopril treatment on early atherosclerosis was determined in cholesterol‐fed rats with acute renovascular hypertension. Three groups were established: normotensive rats, hypertensive one kidney one clip (1K1C) rats, and 1K1C rats treated with 27 mg/kg/day of captopril. Animals in the 3 groups received chow containing 4% cholesterol and 1% cholic acid. Cholesterol feeding and drug treatment were started immediately following surgery, then after 1 or 2 weeks, mean arterial pressure, heart rate, and plasma lipids were measured; and the thoracic aorta was perfused with formalin. One or 2 weeks after surgery, mean arterial pressure increased by 17% to 22% in the 1K1C group compared to the normotensive animals. Captopril decreased blood pressure in the 1K1C rats by 22% to 25% compared to the hypertensive 1K1C group. In the 3 sets of rats, plasma cholesterol was similarly elevated from 109 to 531 mg/dl. Early atherosclerosis and endothelial cell proliferation in the thoracic aorta were quantified from en face specimens that were stained with hematoxylin and oil red O. Compared to the normotensive group, hypertensive 1K1C rats (1 and 2 weeks) had a 463% to 647% increase in the number of subendothelial macrophage‐foam cells/mm2. In 1K1C rats, foam cell accumulation was dense and widespread compared to a focal distribution of leukocytes in normotensive animals. Endothelial cell mitoses increased by 444% in hypertensive 1K1C rats at 1 week compared to the normotensive group. One or 2 weeks of captopril treatment of 1K1C rats reduced macrophage‐foam cells/mm2 by 62% to 72% compared to the hypertensive 1K1C group. Captopril decreased the rate of endothelial cell mitoses in 1K1C rats (1 week) by 62% compared to the hypertensive animals. The results indicate that macrophage‐foam cell accumulation was accelerated in the hypertensive 1K1C rats, and this was accompanied by an increased rate of endothelial cell turnover. Captopril lowered blood pressure, decreased the number of foam cells and inhibited the proliferation of arterial endothelial cells in 1K1C rats. © 1993 Wiley‐Liss, Inc.
Pharmacological and mechanistic aspects concerning the use of heparin and β‐cyclodextrin tetradecasulfate for the treatment of vascular restenosis
Authors: Reilly Christopher F. , Fujita Tsuneo , McFall Rosemary C. , Stabilito Inez I. , Eng Wai‐Si , Johnson Robert G. 
Published: January 2005

AbstractAberrant smooth muscle cell (SMC) growth within the intimal tissues of the arterial wall plays a major role in the development of restenosis which commonly occurs following coronary bolloon angioplasty. Studies from several laboratories have demonstrated that heparin reduced neointimal formation in response to balloon denudation in vivo and that heparin also inhibits the growth and migration of cultured SMC in vitro. In this paper, data will be presented demonstrating that heparin markedly inhibits neointimal thickening and bromodexyuridine incorporation into newly synthesized DNA in a fully characterized rat model of arterial injury. Heparin treatment begun at the time of angioplasty and continued for as little as 2–4 days resulted in substantial inhibiton of neointimal formation 14 days later. The relevance of the rat model to human restenosis and the positive and negative aspects concerning the use of heparin and heparin‐like molecules for the treatment of vascular restenosis will be discussed. In addition, we will show that heparin recognizes specific binding sites on the surface of cultured aortic SMC which is a feature possibly associated with the anti‐proliferative mechanism of action of heparin. Finally, a highly sulfated cyclic polysaccharide, β‐cyclodextrin tetradecasulfate (S‐β‐CD), was found to significantly inhibit neointimal formation in the rat model of arterial injury. S‐β‐CD retains several positive aspects but lacks some of the negative features associated with the chronic use of heparin for the treatment of vascular restenosis. © 1993 Wiley‐Liss, Inc.
Novel signal transduction targets in cardiovascular disease: Role of platelet‐derived growth factor in vascular smooth muscle cell proliferation
Authors: Molloy Christopher J. 
Published: January 2005

AbstractProliferation and directed migration of vascular smooth muscle cells (VSMCs) are important components in such processes as hypertension‐induced vascular remodeling, vascular restenosis, and atherosclerosis. However, the cellular mechanisms involved in the control of VSMC growth and migration at the tissue level remain largely undefined. Platelet‐derived growth factor (PDGF) has been identified as one of the most potent endogenous VSMC mitogens/chemoattractants. PDGF consists of disulfide‐linked polypeptide dimers composed of two distinct gene products, designated A‐chain and B‐chain. These are assembled as either heterodimers (e.g., AB) or homodimers (e.g., AA, BB). Two distinct PDGF‐receptor genes have been identified, designated α and β. Elevated vascular expression of PDGF‐A and ‐B chains and PDGF‐receptors has been observed in cardiovascular disorders and their related animal models, including restenosis and atherosclerosis. For example, in the rat ballon‐injury model, infusion of PDGF greatly increases intimal thickening and migration of VSMC [Jawien et al. (1992): J Clin Invest 89:507–511]. Furthermore, in a similar model, PDGF‐neutralizing antibodies significantly reduce intimal thickening following balloon injury [Ferns et al. (1991): Science 253:1129–1132]. Thus, PDGF may have a pivotal role in the pathophysiology of hyperproliferative vascular diseases. Pharmacological antagonism of PDGF can be directed at distinct cellular sites, related to the biochemical signaling pathways involved in PDGF‐initiated signal transduction. These include inhibition of ligand binding to high‐affinity surface receptors, inhibition of activated PDGF‐receptor tyrosine kinases, interruption of intracellular PDGF‐receptor‐protein interactions, and inhibition of secondary signaling enzymes. Future development of specific PDGF antagonists will allow precise elucidation of the role of this potent growth factor in cardiovascular diseases. © 1993 Wiley‐Liss, Inc.