Deficiency of Testosterone Associates with the Substrate of Atrial Fibrillation in the Rat Model

Background: Since the prevalence of atrial fibrillation (AF) increases progressively with aging, especially in men, we hypothesized that testosterone might affect the occurrence of AF.
Methods and Results: We examined the electrophysiological properties of the atria in isolated-perfused hearts of sham-operated male (SM), female (SF), orchiectomized male with and without administration of testosterone (ORCH-T and ORCH), and ovariectomized female (OVX) Sprague-Dawley rats. An electrophysiological study revealed that repetitive atrial responses induced by electrical stimuli significantly increased in ORCH rats without changes in other electrophysiological properties and were abolished by administration of testosterone. To investigate the underlying mechanisms, we evaluated the expression level of calcium-handling proteins. In ORCH rats, the immunoreactive protein level of ryanodine receptor type 2 (RyR2) and sodium–calcium exchanger significantly increased as compared with SM and ORCH-T rats without alterations in the level of FK506-binding protein (FKBP12.6), sarcoendoplasmic reticulum Ca-ATPase, and phospholamban. Immunoprecipitation analysis demonstrated decreased binding of FKBP12.6 to RyR2 in ORCH rats, which was prevented by testosterone. In contrast, the expression levels of these proteins showed no significant differences between SF and OVX rats.
Conclusion: Deficiency of testosterone was arrhythmogenic in rat atria possibly through less binding of FKBP12.6 to RyR2, which could induce feasible calcium leakage from the sarcoendoplasmic reticulum. These results would explain, at least in part, the increase in the prevalence of AF in accordance with the decline of testosterone particularly in elderly men.     

Experimental Study About Removal of the Implanted Tined Polyurethane Ventricular Lead by Radiofrequency Waves Through the Lead

Polyurethane pacemaker leads are widely used nowadays. However, only a few studies have been done to investigate the fixation mechanism of polyurethane leads. To elucidate how pacemaker leads are fixed at the early phase after implantation, polyurethane-insulated tined ventricular leads were implanted in seven mongrel dogs. One to 4 months later, tips of the leads were anchored among the trabeculae and the distal part of the leads were encapsulated by whitish fibrous tissue. It was found that not organized thrombi, but cell reaction with various stages of inflammatory cells was responsible for forming the fibrous tissue. We attempted to remove the lead by delivering radiofrequency wave through the lead. However, no lead could be removed.     

Effects of Chronotropic Responsive Cardiac Pacing on Ventilatory Response to Exercise in Patients with Complete AV Block

To identify the effect of chronotropic responsive cardiac pacing on the ventilatory response to exercise, ten selected patients with complete atrioventricular block underwent paired cardiopulmonary exercise tests in fixed rate ventricular (WI) and dual chamber (DDD) or rate responsive ventricular (VVIR) pacing modes. Compared to VVI pacing, DDD or VVIR pacing increased peak oxygen uptake (P < 0.005) and augmented anaerobic threshold (P < 0.001), In eight patients, dyspnea was the major symptom limiting exercise with VAT pacing and this was markedly attenuated with DDD or VVIR pacing. In all patients, ventilation (VE) and the ratio of ventilation to CO₂ production (VE/VCO₂) were consistently higher with VVI pacing during exercise. To compare the response of the two pacing modes at the same workloads in an aerobic condition, we measured ventilatory variables 1 minute prior to the anaerobic threshold obtained with VVI pacing. When DDD or VVIR pacing was compared with VVI pacing, VE and VE/VCO₂ significantly decreased from 20.5 ± 5.3 L/min to 18.3 ± 5.0 L/min (P < 0.005) and from 35.9 ± 5.8 to 31.9 ± 5.0 (P < 0.003), respectively. Respiratory frequency rose significantly more with VVI pacing (P < 0.001) despite an unchanged tidal vohame. Although peak VE did not differ between the two pacing modes, VE/VCO₂ at the peak exercise increased significantly more with VVI pacing (P < 0.005). Respiratory frequency also rose more with VVI pacing (P < 0.005) and tidal volume did not change. This study suggests that chronotropic responsive cardiac pacing attenuates the exertional dyspnea by improving the ventilatory response to exercise as well as increasing the cardiac output in patients with complete atrioventricular block.     

Two cases of sleep-disordered breathing in climacteric

Abstract Two cases of sleep disordered-breathing in climacteric were reported. Polysomnography including esophageal pressure (Pes) measurement was performed. Case 1 was diagnosed as upper airway resistance syndrome. Case 2 was diagnosed as obstructive sleep apnea syndrome, while many episodes of upper airway resistance also existed. Hormone replacement therapy improved clinical symptoms, and in case 1, Pes nadir was improved but incidence of arousals which was induced by breathing disturbances was not significantly changed. Sleep disordered-breathing should be suspected as a cause of sleep disorder even in females, especially in climacteric age. Pes measurement and evaluation of arousals is required. Hormone replacement therapy may release the upper airway resistance.     

Stepped care medical treatment for cirrhotic ascites: Analysis of factors influencing the response to treatment

Abstract Thirty-two patients with liver cirrhosis and ascites were treated by stepped care diuretic treatment as follows: step 1, placed on a 35 mEq sodium diet; step 2, given 400 mg/day of potassium canrenoate in addition to step 1 treatment; step 3, given 40-80 mg/day of furosemide in addition to step 2 treatment. Eleven out of 32 patients (34.4%, group 1) and 12 of 21 patients (57.1%, group 2) lost their ascites at step 1 and step 2, respectively. The remaining nine patients (group 3) required step 3 treatment. Basal urinary sodium excretion and creatinine clearance were significantly lower and β₂-microglobulin was significantly higher in group 3 than those in groups 1 and 2. Elevation of basal plasma renin activity and norepinephrine was evident only in group 3. In group 1, urinary sodium excretion decreased after the treatment. In group 2, plasma α-atrial natriuretic polypeptide was lowered and plasma renin activity and norepinephrine were elevated after the treatment. These results suggest that basal renal function and plasma renin activity and norepinephrine levels are useful indices to predict the effect of ascites treatment and that responders to sodium restriction or potassium canrenoate may be in the state of vascular overflow, while non-responders to potassium canrenoate may be in the state of vascular underfilling. In summary, this stepped care treatment is safe without any side effects, although the diuretics themselves may lead to relative vascular underfilling.     

The female partner''s satisfaction with sildenafil citrate treatment of erectile dysfunction

BACKGROUND: Data on female partners' satisfaction are scarce, although there have been many articles on patient satisfaction after sildenafil citrate treatment. The aim of this study was to evaluate the satisfaction of female partners of patients receiving sildenafil citrate for their erectile dysfunction (ED) and to assess the female partners' sexual function. METHODS: Ninety-eight patients with ED were treated. Their female partners were asked to answer a questionnaire we have prepared to evaluate the efficacy of treatment, sexual satisfaction and changes in quality of life. It also included a question about female sexual function. From the results, the relationship between their female partner's satisfaction and efficacy of treatment, as well as female sexual function, were assessed. RESULTS: Thirty (31%) questionnaires were returned to us for analysis. Effectiveness of the treatment was acknowledged by 90% of the partners. An improvement in their partner's quality of life was noticed by 60% of the women. The majority (66.7%) of the female partners were satisfied with sildenafil citrate treatment and 20% were disappointed. Moreover, 20% of the female partners were concerned about adverse events. Regarding female sexual function, some form of sexual dysfunction affected 46.7% of the women. Furthermore, a significant number (P = 0.0230) of the female partners disappointed with the treatment had some kind of sexual dysfunction. CONCLUSIONS: The results indicated that female partners reported relatively high levels of treatment satisfaction. Female partners' sexual function and anxiety regarding adverse events should be evaluated when their satisfaction with sildenafil citrate treatment is poor despite an improvement of erectile function.     

Efficacy and safety of laparoscopic surgery for pheochromocytoma

OBJECTIVE: Laparoscopic surgery for primary aldosteronoma and Cushing's syndrome is well established. We report on our experiences with laparoscopic adrenalectomy for pheochromocytoma, and assess the efficacy and safety of the laparoscopic approach. METHODS: Between April 1998 and April 2003, a total of 23 patients underwent laparoscopic adrenalectomy for pheochromocytoma at Chiba University Hospital and Yokohama Rosai Hospital, Japan. We compared the surgical outcomes of these patients with those of 106 patients with adrenal tumors due to other pathologies who underwent laparoscopic adrenalectomy during the same period. RESULTS: The mean tumor size of pheochromocytoma was 4.96 cm. Mean operative time was 192.7 min, and mean estimated blood loss was 130 mL. Neither mean operative time nor mean estimated blood loss was greater for patients with pheochromocytoma. Intraoperative hypertension (systolic blood pressure > 180 mmHg) occurred in 39.1% (9/23) of patients with pheochromocytoma. During the follow-up period, there were no mortalities or recurrences of endocrinopathy. CONCLUSIONS: Laparoscopic adrenalectomy for pheochromocytoma is a safe and minimally invasive procedure.     

Pharmacokinetic behaviour in polymorphonuclear leucocytes of N,N-dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]benzopyrano[2,3-b]-pyridine-7-acetate (Y-23023), a new prodrug type of antiinflammatory agent,and indomethacin after oral administrations in rats

Abstract— N,N-Dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]-benzopyrano[2,3-b]pyridine-7-acetate (Y-23023) is a prodrug developed as a new non-steroidal anti-inflammatory drug (NSAID). Y-23023 is rapidly hydrolysed to an active metabolite, α,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid (M₁) following its absorption and then exhibits a strong anti-inflammatory activity. We have examined the pharmacokinetic behaviour in polymorphonuclear leucocytes (PMNs) of M₁ and of indomethacin after oral administration to rats of Y-23023 and indomethacin, respectively. Y-23023 was rapidly absorbed, producing a mean C_max (1·13 μg mL^?1) of M₁ after 1 h in plasma. Indomethacin was less rapidly absorbed, producing a mean C_max (3·38 μg mL^?1) after 3 h in plasma. The mean AUC of M₁ and indomethacin in plasma were 5·45 μg h mL^?1 and 22·49 μg h mL^?1, respectively. The mean t_max, C_max and AUC of M1 in PMNs were 1 h, 11·1 ng (41 pmol)/10⁸ cells and 58·6 ng (164 pmol) h/10⁸ cells, respectively. The same parameters for indomethacin in the PMNs were 3 h, 15·4 ng (57 pmol)/10⁸ cells and 95·2 ng (266 pmol) h/10⁸ cells, respectively. The PMNs/plasma ratio of M₁ was about 2·8 times that of indomethacin. These results indicate that the association of M₁, an active metabolite of Y-23023, from blood to the PMNs is greater than that of indomethacin.     

Enzymatic Hydrolysis of Zenarestat 1-O-Acylglucuronide

Abstract— Zenarestat, (3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-y1) acetic acid, an aldose reductase inhibitor is metabolized mainly to the glucuronide in rat and man. The glucuronide was purified from urine of volunteers after ingestion of zenarestat. The structure of the glucuronide was confirmed by LC-MS and NMR as 1-O-acyl-β-glucuronide. This compound was unstable at physiological pH, being converted to its structural isomers and the aglycone with half-life of 25 min at pH 7·4 and 37°C in aqueous solution. Enzymatic hydrolysis of the glucuronide was studied in urine, blood and tissues. β-Glucuronidase in human urine contributed little to the hydrolysis of the glucuronide, while in rat urine at pH 6, it was degraded by β-glucuronidase and the formation of zenarestat was clearly faster than its formation in buffer at pH 6. In both rat and human blood, these reactions were accelerated by albumin, although rat red blood cells may also contribute. The rate of degradation was not affected by red blood cell membrane, haemoglobin, globulin, esterases or β-glucuronidase. Arylesterase in rat liver, arylesterase and acetylcholinesterase in the kidney, and β-glucuronidase in both tissues may contribute. Thus, enzymatic degradation of zenarestat 1-O-acyl-β-glucuronide is dependent not only on pH and temperature but also on species and the type of tissue or body fluid.