bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACE Inhibitors and Renal Vascular Responses in the Spontaneously Hypertensive Rat
Authors: Hollenberg Norman K. , Guidi Ettore 
Published: November 2007

Background: Substantial evidence has accumulated for the intrarenal generation of func tionally important quantities of angiotensin II (Ang II). To assess the possibility that Ang II generation occurs beyond a barrier to diffusion from the vascular compartment, six angiotensin-converting enzyme (ACE) inhibitors varying widely in their lipid solubility were employed in the spontaneously hypertensive rat (SHR) and their normotensive con trols (WKY). The biological end points were renal blood flow and its response to Ang II. Results: Two ACE inhibitors, ramipril and captopril, induced a larger increase in renal blood flow and enhanced the renal vascular response to Ang II substantially more than did enalapril and lisinopril. The two prodrugs, enalapril and ramipril, which are substantially more lipophilic than the respective active drugs, enalaprilat and ramiprilat, showed equiva lent responses. The partial agonist saralasin virtually abolished the renal vasodilator response to ramipril. The pattern of response was similar in WKY, but the responses were substantially smaller. Conclusions: The results support the concept that a functionally important compartment for intrarenal Ang II formation exists in the healthy rat and that this process is amplified in the SHR.
A Multicenter Study Evaluating the Effects of Sevoflurane on Renal Function in Patients With Renal Insufficiency
Authors: McGrath Brian J. , Hodgins Lewis R. , DeBree Ashley , Frink Edward J. , Nossaman Bobby D. , Bikhazi George B. 
Published: November 2007

Background: This multicenter study was undertaken to compare the effect of sevoflurane with that of isoflurane on renal function in 26 patients with pre-existing renal insufficiency. Sevoflurane undergoes hepatic metabolism, with release of inorganic fluoride. Elevated flu oride levels have been associated with renal impairment in patients undergoing methoxyflu rane anesthesia raising concerns about the nephrotoxic potential of sevoflurane. Methods : Patients were ASA II or III class, with renal insufficiency defined by a preopera tive serum creatinine concentration of 1.5-3.0 mg/dl. A standardized anesthetic regimen was used consisting of intravenous induction with propofol, vecuronium for muscle relax ation, and fentanyl for analgesia. Patients were randomized to receive either isoflurane or sevoflurane with 100% oxygen. Blood samples were obtained preoperatively and at 24, 48, and 72 h postoperativety for renal/electrolyte determinations. Blood samples for plasma flu oride measurement were obtained preoperatively. Results: Plasma fluoride levels were significantly higher in patients receiving sevoflurane at all measurement points from 0 to 72 h postanesthesia. Mean peak fluoride concentration was 33.4 μM. The maximum fluoride value measured was 51.2 μM. There were no signifi cant differences in postoperative serum creatinine values at any time between patients receiving sevoflurane or isoflurane. Conclusions: Sevoflurane metabolism produces elevations in plasma fluoride concentra tions relative to isoflurane. Despite the increase in plasma fluoride levels, the administration of sevoflurane to patients with renal insufficiency did not produce any adverse effects on renal function as measured by serum creatinine concentration when compared with isoflurane.
Effect of β-Adrenoceptor Antagonists on Phospholipid N-Methylation Activities of Cardiac Sarcolemma
Authors: Panagia Vincenzo , Taira Yuji , Bryson Gregory L. , Tappia Paramjit S. , Dhalla Naranjan S. 
Published: November 2007

Background: Some β-adrenoceptor antagonists exert a negative inotropic action by affect ing Ca2+ fluxes in the myocardial cell as a consequence of their interaction with sarcolem mal and sarcoplasmic reticular membranes. This action may be caused by their effects on the cliemicophysical properties of membrane phospholipids. Because phosphatidylethanolamine (PE) N-methylation can influence the chemicophysical properties of membranes, these agents may affect PE N-methylation. This study was undertaken to examine the effects of pro pranolol, acebutolol, and atcnolol on PE N-methylation in rat heart sarcolemma (SL). Methods and Results: Sarcolemmal membrane was isolated from rat hearts by the hypo- tonic shock LiBr method. Incorporation of radiolabeled methyl groups from S-adenosyl-L- methionine was assayed at three catalytic sites involved in the PE N-methylation reaction in the presence and absence of these drugs. A biphasic effect of propranolol at site I was notcd; low concentrations (10-8 M) enhanced the total N-methylation. whereas high con centrations (106 -10-3 M) were inhibitory. Accbutolol (10-9-10 -3 M) depressed methyl group incorporation in SL at site II in a dose-dependent manner, whereas atenolol showed no effect. Propranolol also exerted a biphasic effect on sarcoplasmic reticular (SR) methyla tion at site I, whereas accbutolol depressed the SR enzyme activity at site II and atenolol had no effect. The mitochondrial methyltransferase activities at sites I. II, and III were unal tered by any of these drugs. Conclusions: It is suggested that propranolol and acebutolol alter SL and SR PE N-methyl transferase activity at site I and site II, respectively, either by affecting the enzyme directly or by changing the physicochemical properties of the membrane.
Analysis of Vasodepressor Responses to Nociceptin and Nociceptin Analogs in the Systemic Vascular Bed of the Anesthetized Rabbit In Vivo
Authors: Champion Hunter C. , Bivalacqua T.J. , Rauchwarger A. , McWilliams S.M. , McNamara D.B. , Kadowitz Philip J. 
Published: November 2007

Background : The heptadecapeptide nociceptin, also known as Orphanin FQ, is a recently discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL 1. Methods and Results: In the present study, responses to nociceptin, [Tyr1]-nociceptin, noci ceptin-(2-17), nociceptin-(1-11), and nociceptin-(1-7) were compared in the systemic vascu lar bed of the rabbit. Nociceptin and [Tyr1]-nociceptin induced dose related decreases in systemic arterial pressure (SAP) when injected in doses of 1-30 nmol/kg intravenous (IV); in terms of relative vasodepressor activity, [Tyr1]-nociceptin and nociceptin were similar in potency. However, nociceptin-(2-17), nociceptin-(1-11), and nociceptin-(1-7) had no effect on SAP when injected in doses up to 30 nmol/kg IV. The decreases in SAP in response to nociceptin and [Tyr1]-nociceptin were not altered by the opioid receptor antagonist naloxone at a time when depressor responses to methionine-enkephalin were reduced significantly. Conclusions: The results of the present study show that vasodepressor responses to noci ceptin and [Tyr1]-nociceptin arc mediated by the activation of a naloxone-insensitive opioid receptor and arc not dependent on the presence of Phc at the N-terminus of the nociceptin sequence. Moreover, the present results show that nociceptin-(2-17). nociceptin-(1-11), and nociccptin-(1-7) do not after SAP in the rabbit, indicating that peptide chain length is important for the expression of vasodepressor activity.
Effects of Sotalol on the Circadian Rhythmicity of Heart Rate and QT Intervals With a Noninvasive Index of Reverse-Use Dependency
Authors: Sharma Param P. , Sarma Jonnalagedda S.M. , Singh Bramah N. 
Published: November 2007

Background: The effects of sotalol on the 24-hour profile of the QT interval relative to that of the heart rate (HR) may be helpful in determining the time course of the drug's action in controlling cardiac arrhythmias. This has not been previously determined. Thus, the objec tive of the current study was to evaluate the influence of the drug on the circadian rhyth micity of HR and QT intervals from Holter recordings in ambulatory patients. Reverse-use dependency (RUD) of sotalol was also studied noninvasively from Holter recordings.Methods and Results: Holter recordings of 18 patients with ventricular arrhythmias were analyzed before and after 3-7 days of treatment with sotalol. We developed and used a sig nal processing system. A new noninvasive index to evaluate RUD was defined and applied to sotalol as a test agent. Sotalol significantly reduced HR from 76.9 ± 3.2 to 60.0 ± 1.1 (P < .001). The mean QT interval increased from 393 ± 11 ms to 489 ± 9 ms, whereas the mean normalized QT (QTc) interval increased from 415 ± 5 ms to 487 ± 5 ms (P < .001) during the drug treatment. Circadian rhythmicity of RR interval was abolished, but the circadian rhythms of the QT and QTc intervals were maintained during continuous treatment with sotalol. This finding is in contrast to amiodarone, which abolished the circadian rhythmicity of QTc interval while maintaining that of RR interval. RUD index was increased from 0.13 ± 0.08 to 0.24 ± 0.10 (P < .001) after sotalol, consistent with increased RUD with sotalol.Conclusions: The effects of sotalol on the circadian rhythmicity of HR and QTc interval are dissociated. They are in direct contrast to those reported for amiodarone, a difference that may be of clinical significance. The RUD index introduced here provides a noninvasive parameter for comparing short-term as well as long-term effects of class III antiarrhythmic drugs on RUD.
Review : Sotalol: Current Status and Expanding Indications
Authors: Singh Bramah N. 
Published: November 2007

Background: The role of antiarrhythmic drug therapy continues to undergo major changes. The change is necessitated by the advent of invasive interventional procedures, such as catheter ablation of arrhythmias and the use of implantable devices for sensing and termi nating life-threatening ventricular arrhythmias and symptomatically troublesome supraven tricular arrhythmias. Many conventional and time-honored drugs, such as sodium channel blockers, have been found either to be ineffective or to have the potential to produce seri ous proarrhythmic reactions. Attention is therefore focused on compounds that prolong repolarization and reduce sympathetic stimulation. Two compounds, amiodarone and sotalol, have emerged as prototypes of drugs of the future. Methods and Results: This review focuses on sotalol for controlling supraventricular and ventricular tachyarrhythmias. Sotalol is a major antiarrhythmic agent that combines potent class III action with nonselective β-blocking properties. The drug's pharmacokinetics is sim ple. Its elimination half-life is 10-15 hours, the drug being excreted almost exclusively by the kidneys. Sotalol's pharmacokinetics allows development of optimal dosing for initiation of therapy relative to changes in creatinine clearance with further dose adjustment by mon itoring the QT interval on the surface electrocardiogram. The compound exerts broad- spectrum antiarrhythmic actions in supraventricular and ventricular arrhythmias. It prevents inducible ventricular tachycardia (VT) and ventricular fibrillation (VF) in approximately 30% of patients with a higher figure for the suppression of spontaneously occurring arrhyth mias documented on Holter recordings. Conclusions: The major role of sotalol is in the management of VT/VF often in conjunction with an implantable cardioverter/defibrillator, in which context it lowers the defibrillation threshold. Sotalol is superior to class I agents, especially in VT/VF and in survivors of car diac arrest. Sotalol has emerged as a major antifibrillatory compound for the control of life- threatening ventricular arrhythmias as the main indication. Data have indicated its poten tial for the maintenance of stability of sinus rhythm in patients with atrial fibrillation and flutter after electrical conversion and in preventing their occurrence in a variety of clinical settings.
Prevention of Vascular Apoptosis in Myocardial Infarction by Losartan
Authors: Sharma Sushil K. , Chapman Donald , Temsah Rana , Netticadan Thomas , Brasil David P. , Dhalla Naranjan S. 
Published: November 2007

Background: Previous studies have demonstrated the occurrence of apoptosis in cardiomyo cytes in different types of cardiovascular diseases. This report provides the first evidence for the presence of vascular apoptosis in myocardial infarction induced in rats by occluding the coronary artery for 7 weeks. Methods and Results: Apoptosis was characterized by DNA fragmentation, upregulation of caspase-3, downregulation of poly (ADP-ribose) polymerase (PARP), increased c-fos mRNA expression and caspase-3/PARP ratio in aortic vascular smooth muscle cells. The results show apoptotic changes in 10-25% of the aortic vascular cells after myocardial in farction ; these alterations were prevented after treating the 3-week operated animals with an angiotensin II receptor antagonist, losartan (25 mg/kg/day; intraperitoneal) for 4 weeks. Cultured rat aortic smooth muscle cells exposed to 10 nmol/L angiotensin II for 48 hours also exhibited apoptotic changes, which were inhibited by 10 nmol/L losartan. Conclusions: These results suggest that vascular apoptosis occurs in myocardial infarction, and this may be due to an increase in the circulating levels of angiotensin II.
Increased Intramural Retention After Local Delivery of Molecules with Increased Binding Properties: Implications for Regional Delivery of Pharmacologic Agents
Authors: Wilensky Robert L. , Mehdi Khawar , Sowinski Kevin M. , Sang Hong Baek  , March Keith L. 
Published: November 2007

Background: Catheter-based local vascular delivery results in concentrated quantities of pharmaceutical agents or genes into focal areas of the arterial wall. However, intramural retention is short and has reduced the potential efficacy of this approach. It was postulated that agents that possess increased intramural binding would show increased intramural reten tion. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) were models of agents with increased cellular and extracellular matrix binding properties. Methods and Results: The delivery efficiency and intramural retention of 2 mL of saline containing I125 labeled PDGF (n = 35 arteries) and bFGF (n = 24) were compared with albumin (n = 21) after local delivery into porcine coronary arteries. Animals were sacrificed at three or more prespecified timepoints: immediately after delivery, 1 day, or 3 days after delivery and if necessary at 5 or 7 days to document prolonged retention. Autoradiograms of the arterial sections were evaluated for the extent of delivery. Delivery efficiency, defined as the amount leaving the catheter and retrieved from the arterial wall, was 0.60% ± 0.42% for albumin, 1.98% ± 0.88% for PDGF ( P = .001), and 0.31% ± 0.11% for bFGF. The calculated intramural half-life of albumin was 7.4 hours, 56.2 hours for PDGF, and 14.9 hours for bFGF ( P = .0001 for PDGF). Infusate covering >50% of the medial area was observed in 85% of arteries immediately after delivery. Although myocardial delivery was similar for albumin, PDGF, and bFGF, myocardial retention was significantly longer for bFGF ( P < .001). Conclusions: Molecules that exhibit preferential intramural binding show a longer intra mural residence duration than solutes without such binding properties. In addition, delivery and subsequent prolonged retention in the myocardium can be obtained by local delivery via the arterial lumen of solutions with preferential binding properties.
Persistence of Atrial Fibrillation After Its Induction— Importance of the Duration and Dispersion of Atrial Refractoriness and Electrical Remodeling
Authors: Rahme Marc M. , Cotter Bruno , Leistad Elisabeth , Subudhayangkul Suppachok , Wadhwa Manish , Ungab GilAnthony , Feld Gregory K. 
Published: November 2007

Background: The electrophysiologic mechanisms of the persistence of atrial fibrillation (AF) after its initiation are not well understood. Therefore, the electrophysiologic charac teristics of the right atrium were evaluated in an acute, pacing-induced model of AF in the pig in order to identify parameters associated with persistence of AF. Methods and Results: AF was induced by rapid atrial pacing in 30 anesthetized, open- chest, juvenile pigs. Sustained (S) AF was defined as that lasting > 10 minutes, nonsustained (NS) AF <10 minutes but >30 seconds, and no (N) AF <30 seconds. Activation mapping and programmed stimulation (S1S1 = 200 ms) was performed at 56 electrodes on the right atrial free wall, to determine ERP (mean and minimum), dispersion of refractoriness (ERPdisp, ELEdisp), conduction velocity (CV), wavelength, AF cycle length (mean of 10 beats), and AF cycle length/time (electrical remodeling). SAF was induced in 10 pigs, NSAF in 9, and NAF in 11. AF cycle length was shorter in SAF and/vs NS vs NAF ( P < .001). Mean ERP (107 ± 9 and/vs 122 ± 5 vs 142 ± 9, P < .001) and wavelength (7 ± 1 and/vs 9 ± 1 vs 11 ± 1, P < .001) were shorter in SAF and/vs NSAF vs NAF. Minimum ERP was shorter in SAF and NSAF vs NAF ( P < .001). CV at cycle lengths of 200 and 150 msec was not different between groups. Dispersion of ERP was greater in SAF and/vs NSAF vs NAF (8 ± 1 and/vs 11 ± 1 vs 19 ± 4, P < .001). Conclusions: Persistence of AF correlated with shorter ERP and wavelength, and greater dispersion of ERP and electrical remodeling. There was no correlation with CV.
Recurrent Torsades de Pointes After Sotalol Therapy for Symptomatic Paroxysmal Atrial Fibrillation in a Patient with End-Stage Renal Disease
Authors: Rizza Christina , Valderrabano Miguel , Singh Bramah N. 
Published: November 2007

Background: In recent years there has been an increase in the use of class III antiarrhyth mic drugs such as sotalol, amiodarone, and the so-called pure class III compound for the control of cardiac arrhythmias. It appears there has been a corresponding increase in the frequency of torsades de pointes (TdP). Methods and Results: The case reported here, a patient on daily renal dialysis for end-stage renal disease, has important implications for class III agents, which are excreted largely by the kidneys. A relatively low dose of sotalol administered for the prevention of recurrences of atrial fibrillation, with a fast ventricular response producing angina, led to modest increases in the QT interval and moderate bradycardia. This culminated in the development of TdP, which deteriorated into ventricular fibrillation, from which the patient could be resuscitated with considerable difficulty. Dialysis after the occurrence of TdP led to further and striking prolongation of the QT interval associated with numerous episodes of TdP for several days before control was achieved. The atrial fibrillation and recurrences of TdP were eventually controlled with oral amiodarone. Conclusions: This case emphasizes that in the absence of significant renal function, use of sotalol may not be safe because drug accumulation may not be controlled adequately with renal dialysis. In view of this, in patients with end-stage renal disease, the use of sotalol for arrhythmia control appears contraindicated and alternative agents, the excretion of which does not occur by the renal route, should be used.
The Effect of Agmatine on Ischemic and Nonischemic Isolated Rat Heart
Authors: Greenberg Shai , Finkelstein Ariel , Gurevich Jacob , Brazowski Eliau , Rosenfeld Faina , Shapira Itchak , George Jacob , Laniado Shlomo , Keren Gad 
Published: November 2007

Objective: The natural polyamines play a protective role during ischemic injury. We stud ied the effects of agmatine on ischemic and nonischemic isolated rat hearts.Methods: Thirty-one rats were randomly assigned to one of four experimental groups. Six teen rats were injected with saline (group 1, n = 9; group 3, n = 7), and 15 rats were injected with 100 mg/kg of agmatine (group 2, n = 8; group 4, n = 7). Injections were given twice: 24 hours and 1 hour before the experiment. Using the modified Langendorf model, rat hearts were perfused with Krebs-Henseleit solution for 105 minutes during phase 1 of the experi ment (groups 1 and 2). During phase 2, hearts were exposed to 45 minutes of global ischemia (groups 3 and 4).Results: During phase 1, no statistically significant differences were observed between the agmatine and the control groups. During phase 2, agmatine caused a significant increase in left ventricular pressure ( P < .003). At the end of reperfusion, P(max) was 111 % ± 10% from the baseline levels versus only 82% ± 5% in the control group. After 20 minutes of reper fusion, dP/dt (first-time derivative of the ventricular pressure) in the agmatine group reached full recovery of 106% ± 12% versus only 64% ± 14% in the saline group ( P = .059). Agmatine also caused a significant increase in coronary flow rate ( P < .004) through out the reperfusion period. Quantitative immunohistochemical staining disclosed reduced cell damage in the agmatine-treated hearts ( P < .02) versus the control group.Conclusion: Agmatine injection given before induced ischemia improves hemodynamic recovery by mechanisms that may be attributed to its vasodilatory properties.
Relative Effects of α- and γ-Tocopherol on Low-Density Lipoprotein Oxidation and Superoxide Dismutase and Nitric Oxide Synthase Activity and Protein Expression in Rats
Authors: Dayuan Li  , Saldeen Tom , Romeo Francesco , Mehta Jawahar L. 
Published: November 2007

Background: Increasing evidence suggests that vitamin E prevents the progression of ath erosclerosis by inhibiting platelet aggregation, monocyte adhesion. and improving plaque stability and vasomotor function. Recently, controversy has arisen as to the relative effects of α- and γ-tocopherol in modulating some mediators of atherosclerosis. Methods and Results: We examined the effects of α- and γ-tocopherol on constitutive nitric oxide synthase (cNOS) and superoxide dismutase (SOD) activity and protein expression in rats. Sprague-Dawley rats were fed regular chow or chow mixed with α- or γ-tocopherol (100 mg/kg/ day) for 7 to 10 days. Plasma α- and γ-tocopherol levels, low-density lipoprotein (LDL) oxida tion, and cNOS and SOD activity and protein expression were measured. Plasma α-tocopherol levels were significantly increased ( P < .01 vs control), but γ-tocopherol levels fell ( P < .01 vs control) in rats fed α-tocopherol. Plasma γ-tocopherol levels were increased ( P < .01 vs con trol), and α-tocopherol levels did not change in rats fed γ-tocopherol. Both α- and γ-tocopherol feeding decreased the rate of LDL oxidation induced by phorbol 12-myristate 13-acetate (PMA)-stimulated leukocytes ( P < .01 vs control). Both α- and γ-tocopherol increased SOD activity in plasma and arterial tissues as well as Mn SOD and Cu/Zn SOD protein expression in arterial tissues (all P < .01 vs control). γ-Tocopherol was more potent than α-tocopherol in all these effects ( P < .05). Both a- and γ-tocopherol increased NO generation and cNOS activity (all P < .05 vs control). However, only γ-tocopherol increased cNOS protein expression. Conclusions: These observations indicate that whereas both α- and γ-tocopherol exert important effects on determinants of oxidation and vasomotor function, effects of dietary α-tocopherol supplementation in vivo are less pronounced than those of γ-tocopherol supplementation.