bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic Factors for Carcinoma of the Male Breast
Authors: Gattuso Paolo , Reddy Vijaya B. , Green Linda K. , Castelli Melanie J. , Wick Mark R.
Published: November 2007

Male mammary carcinoma (MMC) affects approximately 1000 men in the United States each year. Aside from the impact of estrogen-receptor positivity on the clinical course of this tumor, relatively little information exists in published form on the ability of special pathologic studies to predict its biologic behavior. The authors analyzed 26 cases of invasive ductal MMC, comparing overall survival with tumor size, histologic grade (Page and Anderson), immunohistologic estrogen receptor protein status, DNA ploidy, expression of S 100 and gross cystic disease fluid proteins, and immunohisto chemically-detected amplification of the c-erbB-2 (HER-2/neu) oncoprotein. Tumor size and amplification of c-erbB-2 oncoprotein emerged as the statistically significant predictors in this group; MMCs of <2 cm had a more favorable prognosis than large tumors. Estrogen receptor protein was seen in 80% of cases; c-erbB-2 amplification was present in 35%; 80% were DNA-aneuploid; and S 100 and gross cystic disease fluid were observed in 38% and 62% of cases, respectively. The latter data are virtually identical to those on histologically similar tumors in women, but all except c-erbB-2 failed to achieve statistical prognostic value in this study. Substrata of histologic grades among MMCs were numerically too small to subject to statistical assessment. These findings suggest that no substantive differences exist between the pathologic features of male and female breast cancers. They also indicate that adjunctive laboratory studies are currently unhelpful in the prognostication of MMC. Int J Surg Pathol 2(3):199-206, 1995
Breast Frozen Section Outcome in the Community Hospital Setting
Authors: Caya James G.
Published: November 2007

The author presents a detailed analysis of 932 breast frozen sections performed at a Milwaukee, Wisconsin community hospital over a 54-month period. These 932 frozen sections came from a total of 857 women and 22 men (mean age 55.5 years and range 20.1-97.2 years). Frozen section diagnosis was deferred in 31 cases (3.3%) and dignostic accuracy for presence or absence of malignant neoplasia (excluding deferred diagnoses) was 99.2%, while strict diagnostic accuracy was 97.8%; one false positive case (pathologist judgement error) and six false negative cases (four sample and two pathologist judgment errors) were detected. Seventy-one of 324 positive frozen sec tions (21.9%) were followed by completion mastectomy. The author provides a de tailed histopathologic analysis, discusses pitfalls and limitations in breast frozen section diagnosis, and concludes that frozen section accuracy in an active community hospital setting can compare favorably with that observed at academic medical centers. Int J Surg Pathol 2(3):215-220, 1995
Transitional Cell Carcinoma of the Renal Pelvis With Symptomatic Ovarian Metastases
Authors: Oliva Esther , Musulen Eva , Prat Jaime , Young Robert H.
Published: November 2007

A 39-year-old woman underwent nephrectomy and ureterectomy for a transitional cell carcinoma involving the right renal pelvis and upper ureter. Four years later, the patient complained of vaginal spotting and abdominal pain. Bilateral adnexal masses were palpable on pelvic examination and a hysterectomy with bilateral salpingo oophorectomy was performed. The ovaries were both replaced by multicystic neo plasms measuring 10 and 12 cm in maximum dimension. Microscopic examination showed cysts lined by transitional cells, and nests of transitional cells permeated the intervening stroma. Prominent lymphatic and vascular invasion was also present. Tumor also filled the lumens of both fallopian tubes. Although only limited superficial invasion was demonstrated in the nephrectomy specimen, the features of the case strongly suggest that the ovarian tumors represent metastases from the transitional cell carcinoma of the renal pelvis. This represents only the third well documented case of clinically significant ovarian spread of this tumor. Problems that may be encountered in distinguishing between metastasis and an independent primary transitional cell ovarian tumor, (proliferative or malignant Brenner tumor, transitional cell carcinoma) are discussed. Int J Surg Pathol 2(3):231-236, 1995
Rhabdomyosarcoma Originating From an Ovarian Immature Teratoma
Authors: Amada Satoshi , Kuroiwa Shigekazu , Kamura Toshiharu , Okadome Masao , Nakano Hitoo , Tsuneyoshi Masazumi
Published: November 2007

We report a rare case with unique histologic findings in the extra-abdominal metastases from an ovarian immature teratoma in a 33-year-old Japanese woman. The primary ovarian tumor was a grade 2 immature teratoma that contained a small aggregate of recognizable rhabdomyoblasts in addition to other immature and mature teratomatous elements. After three courses of chemotherapy, metastatic tumors were identified in the para-aortic area and a right cervical lymph node. Histologically, the para-aortic tumor was predominantly a typical embryonal rhabdomyosarcoma with minor foci of mature teratoma, whereas the cervical tumor consisted only of mature teratomatous elements without any evident immature elements. Int J Surg Pathol 2(3):245-250, 1995
Review : Pharmacological Management of Atrial Fibrillation: An Update
Authors: Hohnloser Stefan H. , Li Yi-Gang , Bender Birgit , Grönefeld Gerian
Published: November 2007

Therapy of atrial fibrillation remains difficult in many patients. There is increasing awareness that antiarrhythmic drug therapy instituted to maintain sinus rhythm after successful cardio version of atrial fibrillation may pose a substantial risk to the patient. Therefore, results of prospective randomized trials are needed to allow a more evidence-based approach to the treatment of this common arrhythmia. Two recently published studies have shown superiority of amiodarone over conventional antiarrhythmic drugs in maintaining sinus rhythm. The largest such study published today, the Canadian Trial in Atrial Fibrillation (CTAF), has randomized 403 patients to amiodarone or to sotalol or propafenone. At the end of the observation period, amiodarone-treated patients were significantly more likely to remain in sinus rhythm than conventionally treated patients. A number of new antiarrhythmic drugs, mainly class III substances, are currently developed for the treatment of atrial fibrillation or atrial flutter. Ibutilide has recently been released for intravenous administration, attempting pharmacological cardioversion of atrial fibrillation/atrial flutter. It has been evaluated in a number of prospective trials, which showed a higher conversion rate in patients with atrial flutter. Dofetilide is another new compound developed mainly for maintenance of sinus rhythm after restoration of sinus rhythm. It has been evaluated in two prospective, random ized, placebo-controlled trials; moreover, analysis of the DIAMOND trials showed effec tiveness of dofetilide in maintaining sinus rhythm in patients with depressed left ventricular function without increased mortality when compared with placebo. Finally, several ongoing studies compare the therapeutic strategy of controlling ventricular rate in atrial fibrillation compared with the strategy of maintaining sinus rhythm. These trials will help to optimize therapy in atrial fibrillation, the most commonly encountered arrhythmia.
Nitric Oxide Synthesis Inhibition and Role of P-selectin in Leukocyte Adhesion to Vascular Tissues
Authors: Yang B.C. , Mehta P. , Mehta J.L.
Published: November 2007

Background: This study was designed to examine the role of P-selectin expression in leuko cyte adhesion to endothelium caused by inhibition of nitric oxide synthesis.

Methods and Results: Rat aortic rings were treated with the nitric oxide synthesis inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) for 2 hours. Parallel sets of aortic rings were pretreated with the nitric oxide precursor L-arginine or posttreated with a specific mono clonal antibody against P-selectin. Some rings were used for determination of vasoreactivity in response to norepinephrine and acetylcholine, while other rings were incubated with autol ogous unlabeled leukocytes or Biotin-FITC labeled leukocytes for 30 minutes. Leukocyte adhesion to vascular endothelium was determined by scanning electron microscopy. L-NAME enhanced the contractile response in response to norepinephrine, suppressed the relaxant response to acetyleholine, promoted leukocyte adherence to the endothelium and resulted in P-selectin expression on the aortic endothelium. Pretreatment of aortic rings with L-arginine reversed the L-NAME-mediated changes in vasoreactivity in response to nore pinephrine and acetyleholine and attenuated the L-NAME-enhanced leukocyte adhesion to endothelial intima. P-selectin treatment, on the other hand, had no effect on L-NAME-medi ated changes. Intrtperitoneal administration of L-NAME resulted in a significant decrease in plasma nitrite level, a small, but significant, increase in lung and spleen myeloperoxidase activity, and a significant increase in leukocyte deposition in lung and spleen. The L-NAME- mediated increase in myelopcroxidase activity and leukocyte deposition in the spleen, but not in the lungs, was abolished by treatment of rats with the P-selectin antagonist CY 1503 administered 30 minutes prior to L-NAME.

Conclusions: These observations indicate that a reduction in nitric oxide synthesis enhances leukocyte adhesion to aortic endothelium and in visceral tissues. While P-selectin expression is evident in some of the experimental models of leukocyte adhesion to endothelium under conditions of nitric oxide inhibition, the role of P-selectin expression remains unclear.
Antiarrhythmic and Arrhythmogenic Actions of Varying Levels of Extracellular Magnesium: Possible Cellular Basis for the Differences in the Efficacy of Magnesium and Lidocaine in Torsade de Pointes
Authors: Takanaka Chiei , Ogunyankin Kofo O. , Sarma J.S.M. , Singh Bramah N.
Published: November 2007

Background: In recent years, there has been an increasing use of antiarrhythmic drugs that act predominantly by prolonging myocardial repolarization. An inevitable electrophysiologic con sequence of these drugs is the development of torsade de pointes as a proarrhythmic reaction. Both intravenous lidocaine and magnesium sulphate have been used in the acute control of such a proarrhythmia. Their electrophysiologic mechanisms in this setting are not well defined.

Methods and Results: Using the standard microelectrode techniques, the effects of magne sium (Mg) and lidocaine on action potential duration (APD), and on barium-induced sponta neous action potentials, were studied in canine Purkinje fiber preparations. The objective was to clarify the direct and indirect effects of magnesium on triggered activities due to early afterdepolarizations. Superfusion in media with 0.1 mM Mg and 2.5 mM K produced more pronounced increases in APD measured at -20mV repolarization time [APD20] than those in a solution with 5 mM K. This effect was further enhanced at lower stimulation frequencies. The striking prolongation of APD20 by solutions with low potassium concentrations dimin ished as the Mg concentration was increased. In solutions with 2.5 mM K, Mg produced con centration-dependent decreases in APD20. This effect was greater at lower stimulation fre quencies. Lidocaine at 4.0 × 10-5 M produced a marked shortening of the APD in the entire voltage range. On barium-induced automaticity, Mg markedly suppressed the spontaneous firing frequency of the abnormal automaticity in a concentration-dependent manner. With 10 mM Mg, such action potentials appeared only sporadically. Magnesium also decreased the amplitude and the maximum upstroke velocity of these action potentials. In contrast, lido caine at 4.0 × 10-5 M exhibited no significant effects on action potentials due to barium- induced abnormal automaticity, or on additional depolarizations developing from the repolar ization phase of these action potentials.

Conclusions: The data indicate that (i) hypomagnesemia may be arrhythmogenic when com bined with hypokalemia and bradycardia leading to a prolongation of the plateau phase of the action potential, (ii) magnesium administration may suppress triggered activities mainly by a direct inhibition of the development of triggered potentials, and (iii) lidocaine may suppress triggered potentials only indirectly by preventing the development of early afterdepolariza tions due to the shortening effect on the APD. These findings are consistent with the clinical observation of a high incidence of torsade de pointes in the setting of hypokalemia and hypo magnesemia induced by a chronic diuretic therapy. They are also consistent with the marked effectiveness of intravenous Mg relative to the inconsistent clinical effects of lidocaine in controlling torsade de pointes.
Mechanical Ablation of Concealed Left Lateral Bypass Tract
Authors: Altamirano Jaime , Wachsner Robin , Gallik Donna
Published: November 2007

A 50-year-old man with hypertension had been treated for supraventricular tachycardia with several medications for nine years. In 1990, he was started on amiodarone but a year later he developed side effects causing discontinuation of amiodarone. Because of his recurrent episodes of palpitations associated with near syncope, chest pain and shortness of breath, he underwent an electrophysiology study in 1992 that showed orthodromic AVRT with the pres ence of a concealed left-sided accessory bypass tract. Scheduled for radiofrequency ablation the following day, after catheters were placed and during mapping of the lateralmitral annu lus, his tachycardia stopped abruptly without further inducability. Isoproterenol infusion dur ing atrial and ventricular stimulation also failed to induce his original tachycardia. A year later, the patient presented with palpitations that felt different than his previous experiences. Work-up at that point only revealed a parasystolic focus on a 24-hour ECG monitoring with out any form of supraventricular tachycardia. This represents a very unusual case by which the left lateral accessory pathway was mechanically ablated with catheter manipulation. This led to the disappearance of the orthodromic tachycardia that was easily induced before due to the activity of his parasytolic focus. The latter continued for the following four years but the patient has had no recurrences of his tachycardia.
Adrenergic-dependent Effect of Adenosine-induced Ventricular Fibrillation in the Isolated Rabbit Heart
Authors: Friedrichs Gregory S. , Chi Liguo , Park James L. , Lucchesi Benedict R.
Published: November 2007

Background: The present study examined the contributory role of endogenous cate cholamines in adenosine-induced ventricular fibrillation in isolated rabbit hearts.

Methods and Results: Cardiac catecholamine depletion was induced in eleven rabbits by the administration of 6-hydroxydopamine (2 x 30 mg/kg, every 12 hours intramuscularly). Hearts were removed 24 hours later, and subjected to 12 minutes of hypoxic perfusion fol lowed by 40 minutes of reoxygenation while heart rate was maintained with atrial pacing. One of six, and one of five hearts from 6-hydroxydopamine treated rabbits developed ventric ular fibrillation during hypoxia-reoxygenation when exposed to 3,7-dimethyl-1-propar gylzanthine (DMPX) (10 μM) + adenosine (ADO) (1 μM) and DMPX (10 μM) + ADO (10 μM), respectively. In hearts from a control group, not exposed to 6-hydroxydopamine, ven tricular fibrillation developed in each of five (100% incidence) hearts when perfused in the presence of DMPX (10 μM) + ADO (10 μM) ( P < .05). Nadolol (1 μM), a β-adrenoceptor antagonist, decreased the incidence of ventricular fibrillation (30%) in a separate group of DMPX (10 μM) + ADO (10 μM) treated hearts (n = 6, P < .05 vs DMPX + ADO treated hearts). To ensure catecholamine depletion. spontancously beating isolated hearts from vehi cle and 6-hydroxydopamine treated rabbits were perfused under normoxic conditions while exposed to increasing concentrations of tyramine ( 1, 3, 10 mM) and the change in heart rate was determined. A concentration-related, positive chronotropic response to tyramine was obtained in hearts from the vehicle treated group that was absent in hearts from 6-hydroxy dopamine treated rabbits or hearts perfused in the presence of nadolol.

Conclusions: The results demonstrate that inhibition of the cardiac adenosine A2 receptor, unmasks an adenosine A1 receptor profibrillatory effect that is dependent upon endogenous cardiac catecholamines and β-adrenoreceptor activation during myocardial hypoxia-reoxy genation.
Electrocardiographic Changes and Mortality Due to Myocardial Infarction in Rats With or Without Imidapril Treatment
Authors: Ren Bin , Lukas Anton , Shao Qiming , Guo Min , Takeda Nobuakira , Aitken Randy M. , Dhalla Naranjan S.
Published: November 2007

Background: Various angiotensin-converting enzyme inhibitors are known to improve heart function and prolong survival in patients and animals after myocardial infarction. Because myocardial infarction is known to induce arrhythmias, this study tested the hypoth esis that early treatment with the angiotensin-converting enzyme inhibitor imidapril reduces mortality during acute myocardial infarction because of protective effects against arrhythmogenesis.

Methods and Results: Rats were randomly divided into four groups: sham control, myocar dial infarction, sham plus imidapril, and myocardial infarction plus imidapril. Myocardial infarction was produced by ligation of the left anterior descending coronary artery. Treated rats received imidapril (1 mg/kg/day) through a gastric tube beginning 1 hour after coronary occlusion; control rats received tap water. Electrocardiograms (ECGs) were recorded 1, 3, 7, and 21 days postocclusion. Infarct size and scar weight were determined at 21 days in the myocardial infarction groups with and without imidapril treatment. ECGs of untreated rats showed ST-segment changes, abnormal Q waves, premature ventricular complexes, and QTc prolongation 1-21 days after coronary occlusion. Total mortality in 21 days averaged 35% in untreated rats; mortality within 48 hours was 30%. On the other hand, imidapril-treated rats showed fewer ST-segment changes, fewer abnormal Q waves, and a decreased inci dence of premature ventricular complexes after coronary occlusion; the ST-segment and QTc interval returned to basal values within 1 week after occlusion. Imidapril treatment did not affect the ECG pattern in sham-treated control animals. Total mortality in the imidapril- treated group in 21 days after infarction was 22.5%; mortality within 48 hours was 20% ( P < .05 compared with the untreated infarction group). Infarct size and scar weight caused by coronary occlusion did not differ in the untreated and imidapril-treated groups. Conclusions: Early treatment with imidapril markedly decreases mortality in rats after acute myocardial infarction. The lower mortality is not associated with a decrease in infarct size but is consistent with a protective effect of the drug against arrhythmogenesis.
Formation of Reactive Oxygen Species in Various Vascular Cells During Glyceryltrinitrate Metabolism
Authors: Dikalov S. , Fink B. , Skatchkov M. , Sommer O. , Bassenge E.
Published: November 2007

Background: Anti-ischemic therapy with organic nitrates as nitric oxide (NO) donors is complicated by the induction of tolerance. When nitrates are metabolized to release NO, there is a considerable coproduction of reactive oxygen species (superoxide radical and per oxynitrite) in vessels leading to inactivation of NO, to diminished cyclic quanosine mono phosphate production in smooth muscle cells (SMC), to impaired vasomotor responses to the endothelium-derived relaxation factor (EDRF), and to formation of nitrotyrosine as a marker of glyceryltrinitrate (GTN)-induced formation of peroxynitrite. The aim of the study was to analyze in vitro the formation of superoxide radicals and of peroxynitrite in GTN-treated endothelial and smooth muscle cells and in washed ex vivo platelets using electron spin resonance and spin-trapping techniques.

Methods and Results: Using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as a spin trap, it was shown that in platelets, smooth muscle, and endothelial cells incubated acutely for 15 minutes with 0.5 mM GTN, the rate of generation of reactive oxygen species (ROS) was twice as high as under control conditions. Using the new spin-trap 2H-imidazole-1-oxide (TMIO), a GTN-induced peroxynitrite formation was detected in SMC and in platelets incubated with 0.5 mM GTN for 15 minutes. Spin-trap 1-hydroxy-3-carboxy-pyrrolidine (CP-H) was used to estimate the rate of ROS formation in platelets incubated for 15 min utes with 0.5 mM GTN; the rate amounted to 14.6 ± 1.1 nM/min/mg protein compared with 4.0 ± 0.4 nM/min/mg protein in controls. The rate of ROS formation in SMCs was substan tially increased (240 ± 16%) after initiation of GTN tolerance by treatment of the cells in culture with 100 μM GTN for 24 hours.

Conclusions: GTN increases the formation of superoxide radicals in endothelial cells, SMCs, and platelets. Peroxynitrite is formed during GTN metabolism in vascular cells and may contribute to the development of tolerance. A decrease in the nitrate-induced inhibi tion of platelet aggregation during GTN tolerance is associated with oxidative actions of ROS formed in platelets during GTN metabolism.
Effect of Nifedipine on the Steady-State Pharmacokinetics and Pharmacodynamics of Irbesartan in Healthy Subjects
Authors: Marino M.R. , Hammett J.L. , Ferreira I. , Ford N.F. , Uderman H.D.
Published: November 2007

Background: In clinical practice, nifedipine has the potential to alter the pharmacokinetics, and therefore possibly the pharmacodynamics and efficacy or safety, of irbesartan. The objectives of the current study were to determine the effects of concomitant administration of nifedipine on the steady-state pharmacokinetics and pharmacodynamics of irbesartan in 12 healthy subjects.

Methods and Results: This was an open-label, randomized, crossover study. Each subject received irbesartan 300 mg once daily for 4 days in one period and irbesartan 300 mg once daily plus long-acting nifedipine (Procardia XL, Pratt Pharmaceuticals, New York, NY) 30 mg once daily for 4 days in the other period. The order of treatment periods was random ized, and a minimum 7-day washout phase separated the two periods. Steady state was achieved by day 3. On day 4, no significant differences were observed between the two treatments with respect to maximum concentration of irbesartan at the end of the dosing interval (Cmax) or the area under the plasma concentration versus time curve during a dos ing interval (AUCtau) of irbesartan. Steady-state Cmax and AUCtau met the criteria for bioequivalence when irbesartan was administered alone or with nifedipine. On day 4, mean plasma renin activity was somewhat higher at every point but one when irbesartan was administered with nifedipine; however, no significant difference was observed between the two treatments in mean 24-hour AUC values. On day 4, there was a modest overall decrease from baseline in mean blood pressure for both treatments. No significant differences were observed between the two treatments in mean 24-hour AUC values for seated diastolic or systolic blood pressure. No serious adverse events were reported.

Conclusions: Concomitant administration of nifedipine 30 mg with irbesartan 300 mg for 4 days in healthy subjects (1) does not alter the steady-state pharmacokinetic parameters of irbesartan, (2) results in Cmax and AUCtau values for irbesartan that meet the criteria for bioequivalence, and (3) is well tolerated.
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.