bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carvedilol: Molecular and Cellular Basis for Its Multifaceted Therapeutic Potential
Authors: Cheng Jianhua , Kamiya Kaichiro , Kodama Itsuo 
Published: August 2010

ABSTRACTCarvedilol is a unique cardiovascular drug of multifaceted therapeutic potential. Its major molecular targets recognized to date are membrane adrenoceptors (β1,β2, and α1), reactive oxygen species, and ion channels (K+and Ca2+). Carvedilol provides prominent hemodynamic benefits mainly through a balanced adrenoceptor blockade, which causes a reduction in cardiac work in association with peripheral vasodilation. This drug assures remarkable cardiovascular protection through its antiproliferative/atherogenic, antiischemic, antihypertrophic, and antiarrhythmic actions. These actions are a consequence of its potent antioxidant effects, amelioration of glucose/lipid metabolism, modulation of neurohumoral factors, and modulation of cardiac electrophysiologic properties. The usefulness of carvedilol in the treatment of hypertension, ischemic heart disease, and congestive heart failure is based on a combination of hemodynamic benefits and cardiovascular protection.
An Overview of SR121463, a Selective Non‐Peptide Vasopressin V2Receptor Antagonist
Authors: Gal C. Serradeil‐Le 
Published: August 2010

ABSTRACTSR121463 is a selective, orally active, non‐peptide antagonist of vasopressin (AVP) V2receptors with powerful aquaretic properties in various animal species and humans. SR121463 belongs to a new class of drugs, called aquaretics, which are capable of inducing free‐water excretion without affecting electrolyte balance. SR121463 displays high affinity for animal and human V2receptors and exhibits a remarkably selective V2receptor profile. SR121463 and [3H]SR121463 are used, therefore, as selective probes for characterization and labeling of V2receptors. In various functional studiesin vitro, SR121463 behaves as a potent antagonist. It inhibits AVP‐stimulated human renal adenylyl cyclase and dDAVP (1‐desamino, 8‐D arginine‐vasopressin)‐induced relaxation of rat aorta. SR121463 also behaves as an inverse agonist in cells expressing a constitutively activated human V2receptor mutant.In vitro, SR1 21463 rescued misfolded V2AVP receptor mutants by increasing cell surface expression and restoring V2function. In normally hydrated conscious rats, dogs and monkeys, SR121463, by either i.v. or p.o. administration, induced a dose‐dependent aquaresis with no major changes in urinary Na+and K+excretion (unlike classical diuretics). In cirrhotic rats with ascites and impaired renal function, a 10‐day treatment with SR121463 totally corrected hyponatremia and restored normal urine excretion. In a model of diabetic nephropathy in rats, SR121463 strongly reduced albumin excretion. SR121463 was also effective at extrarenal V2(or V2‐like) receptors involved in vascular relaxation or clotting factor releasein vitroandin vivo.In the rabbit model of ocular hypertension, SR121463 by either single or repeated instillation, decreased intraocular pressure. After acute and chronic administration to rats, dogs or healthy human volunteers, SR121463 was well absorbed and well tolerated. In all species studied the drug produced pronounced aquaresis without any agonist effect. Thus, SR121463 is a potent, orally active and selective antagonist at V2receptors with powerful aquaretic properties. It is a useful tool for further exploration of function of renal or extrarenal V2receptors. Pure V2receptor antagonists are likely to be therapeutically useful in several water‐retaining diseases such as hyponatremia, Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), congestive heart failure, liver cirrhosis, and other disorders possibly mediated by V2receptors (e.g., glaucoma).
Ibudilast: A Non‐selective PDE Inhibitor with Multiple Actions on Blood Cells and the Vascular Wall
Authors: Kishi Yukio , Ohta Seiko , Kasuya Natsuko , Sakita Shinya , Ashikaga Takashi , Isobe Mitsuaki 
Published: August 2010

ABSTRACTIbudilast (3‐isobutyryl‐2‐isopropylpyrazolo[1,5‐a]pyridine) is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It is widely used in Japan for improving prognosis and relieving symptoms in patients suffering from ischemic stroke or bronchial asthma. These clinical applications are based on the properties of ibudilast that inhibit platelet aggregation, improve cerebral blood flow and attenuate allergic reactions. The inhibition of platelet aggregation and vasodilatation by ibudilast may be due to synergistic elevation of intracellular cyclic nucleotides and release of nitric oxide (NO) or prostacyclin from endothelium, rather than direct inhibition of PDE5 or PDE3. Another important property of ibudilast is its antiinflammatory activity possibly associated with potent inhibition of PDE4. Combined with its relaxing effects on bronchial smooth muscle, antiinflammatory actvity of ibudilast could favorably influence pathophysiology of asthma by antagonizing chemical mediators triggering asthmatic attacks. Ibudilast was also reported to significantly attenuate inflammatory cell infiltration in the lumbar spinal cord in an animal model of encephalomyelitis. Future investigations should include effects of ibudilast on inflammatory reactions between endothelium and blood cells, which may initiate the development of atherosclerosis.
Gene Transfer Therapy in Vascular Diseases
Authors: McKay Mandi J. , Gaballa Mohamed A. 
Published: August 2010

ABSTRACTSomatic gene therapy of vascular diseases is a promising new field in modern medicine. Recent advancements in gene transfer technology have greatly evolved our understanding of the pathophysiologic role of candidate disease genes. With this knowledge, the expression of selective gene products provides the means to test the therapeutic use of gene therapy in a multitude of medical conditions. In addition, with the completion of genome sequencing programs, gene transfer can be used also to study the biologic function of novel genes in vivo.Novel genes are delivered to targeted tissue via several different vehicles. These vectors include adenoviruses, retroviruses, plasmids, plasmid/liposomes, and oligonucleotides. However, each one of these vectors has inherent limitations. Further investigations into developing delivery systems that not only allow for efficient, targeted gene transfer, but also are stable and nonimmunogenic, will optimize the clinical application of gene therapy in vascular diseases. This review further discusses the available mode of gene delivery and examines six major areas in vascular gene therapy, namely prevention of restenosis, thrombosis, hypertension, atherosclerosis, peripheral vascular disease in congestive heart failure, and ischemia. Although we highlight some of the recent advances in the use of gene therapy in treating vascular disease discovered primarily during the past two years, many excellent studies published during that period are not included in this review due to space limitations.The following is a selective review of practical uses of gene transfer therapy in vascular diseases. This review primarily covers work performed in the last 2 years. For earlier work, the reader may refer to several excellent review articles. For instance, Belalcazer et al. (6) reviewed general aspects of somatic gene therapy and the different vehicles used for the delivery of therapeutic genes. Gene therapy in restenosis and stimulation of angiogenesis in the cardiac muscle are discussed in reviews by several investigators (13,26,57, 74,83). In another review, Meyerson et al. (43) discuss advances in gene therapy for vascular proliferative disorders and chronic peripheral and cardiac ischemia.
AH‐1058: A Novel Cardioselective Ca2+Channel Blocker
Authors: Takahara Akira , Sugiyama Atsushi , Yoshimoto Ryota , Hashimoto Keitaro 
Published: August 2010

ABSTRACTThe pharmacologic profile of a cyproheptadine‐related compound, 4‐(5H‐dibenzo[a,d]cyclohepten‐5‐ylidene)‐1‐[(E)‐3‐(3‐methoxy‐2‐nitro)phenyl‐2‐propenyl]piperidine hydrochloride (AH‐1058), was assessed in variousin vivoandin vitromodels. In guinea pig cardiomyocytes, AH‐1058 effectively suppressed L‐type Ca2+channel currents without affecting other ion channel or ion exchange currents. In rat cerebral cortical membranes AH‐1058 appears to bind preferentially to L‐type Ca2+channels at phenylalkylamine‐ and benzothiazepine‐binding sites. In canine isolated, blood‐perfused heart preparations, AH‐1058 exerted negative inotropic, dromotropic, and chronotropic and weak coronary vasodilator effects. In halothane‐anesthetized dogs, AH‐1058 suppressed ventricular contractility and decreased blood pressure and cardiac output. Total peripheral vascular resistance was hardly affected by the drug, suggesting thatin vivoAH‐1058 can selectively suppress cardiac, as compared to peripheral vascular, function. In conscious dogs, by intravenous administration AH‐1058 reduced systolic blood pressure and maximal upstroke velocity of the left ventricular pressure, while it increased heart rate in a dose‐dependent manner. The drug did not affect diastolic blood pressure, which is quite different from cardiovascular properties of well‐known Ca2+channel blockers, verapamil and diltiazem. This unique cardiovascular profile of AH‐1058 is expected to be useful in the treatment of certain pathological processes such as the obstructive hypertrophic cardiomyopathy, vasovagal syncope, dissecting aortic aneurysm, and ventricular arrhythmias, in which selective inhibition of the ventricular Ca2+channels is essential for drug therapy.
A Review of HNS‐32: A Novel Azulene‐l‐Carboxamidine Derivative with Multiple Cardiovascular Protective Actions
Authors: Tanaka Yoshio , Shigenobu Koki 
Published: August 2010

ABSTRACTHNS‐32 [N1,N1‐dimethyl‐N2‐(2‐pyridylmethyl)‐5‐isopropyl‐3,8‐dimethylazulene‐1‐carboxamidine] (CAS Registry Number: 186086‐10‐2) is a newly synthesized azulene derivative. Computer simulation showed that its three dimensional structure is similar to that of the class Ib antiarrhythmic drugs, e.g., lidocaine or mexiletine. HNS‐32 potently suppressed ventricular arrhythmias induced by ischemia due to coronary ligation and/or ischemia‐reperfusion in dogs and rats. In the isolated dog and guinea pig cardiac tissues, HNS‐32 had negative inotropic and chronotropic actions, prolonged atrial‐His and His‐ventricular conduction time and increased coronary blood flow. In the isolated guinea pig ventricular papillary muscle, HNS‐32 decreased maximal rate of action potential upstroke (V̇max) and shortened action potential duration (APD). These findings suggest that HNS‐32 inhibits inward Na+and Ca2+channel currents. In the isolated pig coronary and rabbit conduit arteries, HNS‐32 inhibited both Ca2+channel‐dependent and ‐independent contractions induced by a wide variety of chemical stimuli. HNS‐32 is a potent inhibitor of protein kinase C (PKC)‐mediated constriction of cerebral arteries. It is likely to block both, Na+and Ca2+channels expressed in cardiac and vascular smooth muscles. These multiple ion channel blocking effects are largely responsible for the antiarrhythmic and vasorelaxant actions of HNS‐32. This drug may represent a novel approach to the treatment of arrhythmias.
Cardiovascular Properties of Yangambin, a Lignan Isolated from Brazilian Plants
Authors: Tibiriçá Eduardo 
Published: August 2010

ABSTRACTYangambin was initially selected from a number of lignans isolated from Brazilian plants for its ability to antagonize Platelet‐Activating Factor (PAF, 1‐O‐hexadecyl‐2‐acetyl‐sn‐glyceryl‐3‐phosphorylcholine)‐induced biological effects. Subsequently it was shown that, besides its antagonistic properties at PAF receptors, yangambin also prevents the cardiovascular collapse observed during anaphylactic and endotoxic/septic shocks, as well as the vascular and cardiac hyporesponsiveness to catecholamines in endotoxic shock. It is suggested that this naturally occurring compound could be of potential interest in the adjunctive management of the above mentioned pathologies. In the present article, we review the main studies investigating the pharmacological properties of yangambin related to the cardiovascular function.
Transforming Growth Factor‐β:A Promising Target for Anti‐Stenosis Therapy
Authors: Chamberlain J. 
Published: August 2010

ABSTRACTTransforming growth factor‐β (TGF‐β) is the general name for a family of cytokines which have widespread effects on many aspects of growth and development. The TGF‐β isoforms are produced by most cell types and exert a wide range of effects in a context‐dependent autocrine, paracrine or endocrine fashion via interactions with distinct receptors on the cell surface. TGF‐β is involved in the wound healing process and, thus plays a significant role in the formation of a restenotic lesion after percutaneous transluminal coronary angioplasty (PTCA) or stenting. Perhaps because of its wide‐ranging effects, TGF‐β is usually released from cells in a latent form, and its activation and signaling are complex. Manipulation of the TGF‐β1, TGF‐β2, and TGF‐β3 isoforms by inhibiting their expression, activation, or signaling reduces scarring and fibrosis in animal models. However, to date, few have reached clinical trial. This review summarizes current knowledge on the activation and signaling of TGF‐β, and focuses on the anti‐TGF‐β strategies which may lead to clinical applications in the prevention of restenosis following PTCA or stenting.
Bopindolol: Pharmacological Basis and Clinical Implications
Authors: Nagatomo Takafumi , Hosohata Yoshiaki , Ohnuki Toshio , Nakamura Takashi , Hattori Kaoru , Suzuki Jun , Ishiguro Masaji 
Published: August 2010

ABSTRACTBopindolol, a non‐selective antagonist of β1‐ and β2‐adrenoceptors (ARs), has been found by pharmacological, molecular biological techniques and molecular modeling to have several unique properties. Bopindolol produces sustained blockade of β1‐ and β2‐ARs, has intrinsic sympathomimetic as well as membrane stabilizing actions, inhibits renin secretion, and interacts with 5‐HT receptors. Also, our recent molecular modeling studies identified possible interaction sites between bopindolol and beta‐AR subtypes. The reviewed studies support our findings that bopindolol is non‐selective for β1‐ and β2‐ARs, has low affinity for β3‐AR subtype and has pharmacological properties that are likely to be beneficial in the treatment of cardiovascular diseases.
UR‐3216: A Manageable Oral GPIIb/IIIa Antagonist
Authors: Baba Kosuke , Aga Yasuhiro , Nakanishi Takayuki , Motoyama Takahiro , Ueno Hitoshi 
Published: August 2010

ABSTRACTUR‐3216, a prodrug, is a novel, selective, and orally active platelet surface glycoprotein GPIIb/IIIa) receptor antagonist. The most important property of UR‐3216 is the very tight binding of its active metabolite to platelets (Kifor resting platelets is <1 nM). UR‐2992, the active form of UR‐3216, binds to platelets for a long period of time, while the unbound drug is rapidly cleared. Therefore, after an initial loading dose of 0.1 mg/kg, only once daily repeated low maintenance doses of UR‐3216 (<0.05 mg/kg p.o.) are required. This regimen maintains a high level of inhibition of platelet aggregation and, due to a small peak‐to‐trough ratio, severe bleeding is avoided. The therapy with UR‐3216 is easy to manage, because it has low peak‐to‐trough ratio and high efficacy (>80% inhibition of platelet aggregation). In addition, UR‐3216 does not produce excessive bleeding or thrombocytopenia and does not interact with abciximab. UR‐3216 is excreted mostly in bile, so that it will not accumulate in patients with chronic renal dysfunction. UR‐2316 has the following abciximab‐like features: (a) its half‐lives for residence on platelets, inhibition of platelets aggregation and bleeding time prolongation are 60 to 80 h, 24, and 2 h, respectively; (b) its receptor binding occupancy is similar to that of abciximab (Mab1 is inhibited and Mab2 is unaltered). In conclusion, UR‐3216 is a promising, orally active GPIIb/IIIa antagonist for the treatment of cardiovascular diseases.
Basic Experimental Studies and Clinical Aspects of Gadolinium Salts and Chelates
Authors: Adding L. Christofer , Bannenberg Gerard L. , Gustafsson Lars E. 
Published: August 2010

ABSTRACTGadolinium is a lanthanide that has in recent years become more commonly present in our society. Organic chelates of gadolinium are increasingly used as contrast agents for the imaging of body fluids. Although adverse reactions to these agents are uncommon, it is known that gadolinium salts can bring about a wide variety of changes in physiology. Gadolinium chloride is widely used experimentally as an inhibitor of stretch‐activated ion channels and physiological responses of tissues to mechanical stimulation. It is also employed as a selective inhibitor of macrophagesin vivo. In this review, the known biochemical actions of gadolinium are brought together with itsin vivopharmacology and toxicology.
Angiotensin Receptor Blockers and the Kidney: Possible Advantages over ACE Inhibition?
Authors: Cooper Mark E. , Webb Randy L. , de Gasparo Marc 
Published: August 2010

ABSTRACTThis review deals with similarities and differences between the effects of ACE inhibitors and AT1‐receptor blockers in the kidney. Specific receptor blockade has demonstrated that the beneficial effects of AT1blockers arise from two mechanisms: the reduction of the AT1receptor mediated response and the increase in plasma levels of Ang II through the AT1‐receptor blockade, which leads to increased stimulation of the AT2receptor (the so‐called yin‐yang effect). Both ACE inhibition and AT1‐receptor blockade provide significant renal protection in the majority of experimental animal models of kidney diseases. AT1receptor blockade may offer additional clinical benefits over ACE inhibitor treatment, particularly in the kidney, where AT1‐receptor blockade does not cause the fall in glomerular filtration rate seen with ACE inhibitor treatment. A number of long‐term clinical studies currently running should show the real value of this new class of compounds in the management of hypertension and associated cardiorenal diseases.
Endothelin Antagonism with Bosentan: Current Status and Future Perspectives
Authors: Ono Koh , Matsumori Akira 
Published: August 2010

ABSTRACTEndothelin receptor antagonist have been proposed for the treatment of a variety of disorders in which the endothelins may act as pathogenic mediators, such as hypertension, congestive heart failure, and cerebral vasospasm. Bosentan is a nonpeptide competitive antagonist, which can be a good tool for studying the endothelin system. It is specific for the endothelin system and blocks the actions of endothelin at both mammalian receptors (A and B). Bosentan has recently moved into Phase III clinical trial. This review will attempt to overview the experimental and clinical effects of bosentan.SUMMARYET receptor antagonists, such as bosentan, produce beneficial effects in various pathological conditions. Bosentan, as a mixed ETA/ETBreceptor antagonist, may be of particular benefit in heart failure and cerebral vasospasm where ETBreceptors are upregulated. For some clinical indications bosentan should be evaluated more vigorously in further controlled clinical trials.
Potential Use of β3‐Adrenoceptor Antagonists in Heart Failure Therapy
Authors: Moniotte Stéphane , Balligand Jean‐Luc 
Published: August 2010

ABSTRACTRecently, a functional, negatively inotropic, β3‐adrenoceptor was characterized in the human heart. Several studies now suggest that this receptor might play an important role in the pathophysiology of heart failure, by counterbalancing the effects of a β1and β2‐stimulation. Therefore, this review summarizes the rationale and effects of β‐adrenergic blockade in chronic heart failure and specifically addresses the question of the potential use of β3‐adrenoceptor antagonists in the treatment of heart failure and other pathophysiological conditions associated with a decreased cardiac contractility.
Brain Natriuretic Peptide (Nesiritide) in the Treatment of Heart Failure
Authors: Bettencourt Paulo 
Published: August 2010

ABSTRACTOver the last decade brain natriuretic peptide (BNP) emerged as a cardiac hormone of clinical interest in diagnosis, prognosis and treatment of patients with Heart Failure (HF). The diagnostic potential of BNP is now well established both in patients with suspected HF as well as in patients with asymptomatic left ventricular systolic dysfunction. The prognostic information obtained from BNP levels in HF and acute myocardial infarction patients seems even more promising.Nesiritide is a synthetic peptide, homologous to endogenous BNP. It is a balanced vasodilator with diuretic and natriuretic properties. It decreases the elevated levels of neurohormones resulting from activation of the sympathetic and renin‐aldosterone systems in HF. The results of clinical trials involving more than 2000 patients with decompensated HF are now available. In these trials nesiritide was administered by single or repeated bolus injections, as well as by sustained infusions.Nesiritide has been shown to produce a potent, dose‐related vasodilator effect that is rapid in onset and sustained during infusion. Balanced vasodilation is reflected by decreases in systemic vascular resistance, pulmonary artery wedge pressure and right atrial pressure. No tachyphylaxis has been observed in these trials. Efficacy of nesiritide in the treatment of decompensated HF has been demonstrated. Trials comparing nesiritide with conventional treatment of decompensated HF showed that nesiritide compares favorably to standard agents. The safety profile has been excellent with a dose‐dependent hypotension as the major side effect. Ventricular arrhythmia was not more frequent in patients treated with nesiritide than with placebo. Thus, nesiritide appears to be useful as a first‐line agent in the treatment of patients with decompensated HF.
BQ‐788, A Selective Endothelin ETBReceptor Antagonist
Authors: Okada Megumu , Nishikibe Masaru 
Published: August 2010

ABSTRACTWe describe characteristics of a selective endothelin (ET) ETBreceptor antagonist, BQ‐788 [N‐cis‐2,6‐dimethylpiperidinocarbonyl‐L‐γ‐methylleucyl‐D‐1‐methoxycarbonyltryptophanyl‐D‐norleucine], which is widely used to demonstrate the role of endogenous or exogenous ETsin vitroandin vivo. In vitro, BQ‐788 potently and competitively inhibited125I‐labeled ET‐1 binding to ETBreceptors in human Girrardi heart cells (hGH) with an IC50of 1.2 nM, but only poorly inhibited the binding to ETAreceptors in human neuroblastoma cell line SK‐N‐MC cells (IC50, 1300 nM). In isolated rabbit pulmonary arteries, BQ‐788 showed no agonistic activity up to 10 μ and competitively inhibited the vasoconstriction induced by an ETB‐selective agonist (pA2, 8.4). BQ‐788 also inhibited several bioactivities of ET‐1, such as bronchoconstriction, cell proliferation, and clearance of perfused ET‐1. Thus, it is confirmed that BQ‐788 is a potent, selective ETBreceptor antagonist.In vivo, in conscious rats, BQ‐788, 3 mg/kg/h, i.v., completely inhibited a pharmacological dose of ET‐1‐ or sarafotoxin6c (S6c) (0.5 nmol/kg, i.v.)‐induced ETBreceptor‐mediated depressor, but not pressor responses. Furthermore, BQ‐788 markedly increased the plasma concentration of ET‐1, which is considered an index of potential ETBreceptor blockadein vivo.In Dahl salt‐sensitive hypertensive (DS) rats, BQ‐788, 3 mg/kg/h, i.v., increased blood pressure by about 20 mm Hg. It is reported that BQ‐788 also inhibited ET‐1‐induced bronchoconstriction, tumor growth and lipopolysaccharide‐induced organ failure. These data suggest that BQ‐788 is a good tool for demonstrating the role of ET‐1 and ETBreceptor subtypes in physiological and/or pathophysiological conditions.