Keisuke Takeda

Anti-arrhythmic effects of (-)-carnitine chloride and its acetyl analogue on canine late ventricular arrhythmia induced by ligation of the coronary artery as related to improvement of mitochondrial function

1 Using the two‐stage coronary ligation method, first described by Harris, (1950), anti‐arrhythmic effects (AAE) of (‐)‐carnitine chloride (LCC) and acetyl (‐)‐carnitine chloride (ALCC) were studied in conscious unrestrained dogs in comparison with those of disopyramide (D). Two‐stage ligation of the coronary artery resulted in a significant decrease in the myocardial free carnitine content. 2 Intravenous administration of LCC (300 mg kg−1) and D (5 mg kg−1) suppressed the ventricular arrhythmia induced by coronary ligation after 24 hours. ALCC (300 mg kg−1) was found to be less potent. 3 An improvement of the mitochondrial function (respiratory control index (RCI) and oxidative phosphorylation rate (OPR)) was noted with LCC and ALCC and there was a linear correlation between AAE expressed as reduction of arrhythmic ratio and improvement in the OPR, whereas there was no improvement in mitochondrial function after D. 4 Plasma carnitine concentration was increased after administration of LCC, attaining the value of around 8 mm at 10 min after 300 mg kg−1. At 60 min, the plasma carnitine concentration was still about half as high as at 10 min. After ALCC, both acetyl carnitine and free carnitine were found in the plasma. The concentration of the former was decreased after attaining a peak value of around 0.2 mm at 10 min, while the plasma concentration of free carnitine was gradually increased. 5 The anti‐arrhythmic effects of LCC and ALCC were ascribed to the improvement of mitochondrial oxidative phosphorylation, while effects other than the improvement of the mitochondrial activity were suggested as mechanisms of anti‐arrhythmic effects of D.

Parathyroid hormone‐related peptide‐producing non‐familial pheochromocytoma in a child

We experienced a case of parathyroid hormone‐related peptide (PTHrP)‐producing pheochromocytoma, which was found in a 12‐year‐old boy with hypercalcemia. The leading symptom was abdominal pain, and severe hypertension and tachycardia were noticed at the initial visit. His medical and familial histories were unremarkable. Laboratory examinations showed hypercalcemia (3.3 mmol/L of serum‐calcium). Computed tomography showed a heterogeneous mass measuring 5.0 cm in the right adrenal gland, which had abnormal uptake with 123‐I metaiodobenzylguanidine scintigraphy. Serum/urine catecholamines were highly elevated, and serum PTHrP also increased (1.4 pmol/L). The patient underwent laparoscopic right adrenalectomy. The tumor was histologically diagnosed as typical pheochromocytoma and the expression of PTHrP was confirmed with immunohistochemistry. The serum PTHrP level was normalized after surgery. He was free of disease postoperatively for 12 months. There has been no described pediatric patient with PTHrP‐producing pheochromocytoma. We showed evidence that the present tumor is a complex neoplasm involving various neuroendocrine activities with the dual‐lineage differentiation.

Effects of drugs on the cerebral circulation of the dog in relation to the cerebral oxygen consumption

1 Drug effects were studied on the cerebral circulation by measuring the sagittal sinus outflow in the anaesthetized dog following the method of Michenfelder and by monitoring cerebral oxygen consumption. Systemic aortic pressure, heart rate and spinal fluid pressure were also studied. 2 Since dilatation of cerebral vessels was observed in nearly all the preparations after inhalation of CO2, it was thought that gross extracerebral contamination was virtually eliminated in this preparation. A close correlation was observed between the oxygen consumption of the brain as a whole and the sagittal sinus outflow (r = 0.93, P < 0.001); therefore it became feasible to differentiate the direct effects of drugs on cerebral blood vessels from indirect ones attributable to changes in the cerebral oxidative metabolism. 3 Sodium pentobarbitone (5 mg kg−1, i.v.), reduced the cerebral venous outflow and caused a decrease in the oxygen consumption. Pentylenetetrazol (30 mg kg−1 i.v.) and bemegride (5 mg kg−1 i.v.) produced an increase in the blood flow and a corresponding increase in the cerebral oxygen consumption. Thus, it was concluded these substances had no direct effects on the cerebral blood vessels. 4 Acetazolamide (10 mg kg1, i.v.), a carbonic anhydrase inhibitor, produced a marked and sustained vasodilatation after a latent period of 0.5–1 min. There was no increase in the cerebral oxygen consumption. A similar pattern was seen after CO2 had been inhaled. Methylergometrine and dihydroergotamine (20 μg kg−1 i.v.) induced a prolonged vasoconstriction of the cerebral vascular bed without any changes in the oxygen consumption of the brain. Therefore this method can discriminate between indirect or direct effects of drugs on cerebral vascular outflow.

Retroperitoneal disorders associated with IgG4-related autoimmune pancreatitis

IgG4-related autoimmune pancreatitis is frequently accompanied by relevant lesions in the genitourinary tract and retroperitoneal organs, which cause various clinical problems, ranging from non-specific back pain or bladder outlet obstruction to renal failure. The diagnosis of IgG4-related retroperitoneal fibrosis requires a multidisciplinary approach, including serological tests, histological examination, imaging analysis, and susceptibility to steroid therapy. Radiological examinations are helpful to diagnose this condition, but surgical resection is occasionally unavoidable to exclude malignancy, particularly for patients with isolated retroperitoneal involvement. Steroid therapy is the treatment of choice for this condition, the same as for other manifestations of IgG4-related disease. For patients with severe ureteral obstruction, additional ureteral stenting needs to be considered prior to steroid therapy to preserve the renal function. Some papers have suggested that IgG4-related disease can affect male reproductive organs including the prostate and testis. IgG4-related prostatitis usually causes lower urinary tract symptoms, such as dysuria and pollakisuria. Patients sometimes state that corticosteroids given for IgG4-related disease at other sites relieve their lower urinary tract symptoms, which leads us to suspect prostatic involvement in this condition. Because of the limited number of publications available, further studies are warranted to better characterize IgG4-related disease in male reproductive organs.

Adrenergic Receptor Effects and Antihypertensive Actions of β -Adrenoceptor-Blocking Agents with Ancillary Properties

SummaryThe acute antihypertensive effects and possible underlying mechanisms of 3 β-adrenergic-blocking drugs with α-blocking activity, i.e. labetalol, nipradilol and arotinolol, were studied in conscious spontaneously hypertensive rats (SHR) and compared with the effects of prazosin, propranolol and hydralazine. Prazosin produced a dose-dependent antihypertensive effect which paralleled inhibition of the pressor response to phenylephrine. Labetalol (30 mg/kg), nipradilol (30 and 100 mg/kg) and arotinolol (30 and 100 mg/kg) also produced a fall in blood pressure. However, inhibition of the pressor response to phenylephrine was not seen in association with the antihypertensive effect after the lower dose of nipradilol and arotinolol. Propranolol (100 mg/kg) did not lower blood pressure. These results suggest that a mechanism(s) other than an α-adrenergic-blocking effect plays a role in the acute antihypertensive effects produced by the lower dose of nipradilol and arotinolol.

Contraction of the large conductance coronary artery produced by acetylcholine in the mini pig

In the mini pig, acetylcholine reduced the coronary blood flow and constricted the large coronary artery. These effects were abolished by atropine, but not by phentolamine, suggesting that cholinergic mechanisms may be involved in coronary artery vasoconstriction.

Dihydrotestosterone synthesis pathways from inactive androgen 5α-androstane-3β,17β-diol in prostate cancer cells: Inhibition of intratumoural 3β-hydroxysteroid dehydrogenase activities by abiraterone

Intratumoural dihydrotestosterone (DHT) synthesis could be an explanation for castration resistance in prostate cancer (PC). By using liquid chromatography-mass spectrometry, we evaluated the intratumoral DHT synthesis from 5α-androstane-3β,17β-diol (3β-diol), which is inactive androgen metabolized from DHT. 3β-diol had biochemical potential to be converted to DHT via three metabolic pathways and could stimulate PC cell growth. Especially, 3β-diol was not only converted back to upstream androgens such as dehydroepiandrosterone (DHEA) or Δ5-androstenediol but also converted directly to DHT which is the main pathway from 3β-diol to DHT. Abiraterone had a significant influence on the metabolism of DHEA, epiandrosterone and 3β-diol, by the inhibition of the intratumoural 3β-hydroxysteroid dehydrogenase (3β-HSD) activities which is one of key catalysts in androgen metabolic pathway. The direct-conversion of 3β-diol to DHT was catalysed by 3β-HSD and abiraterone could inhibit this activity of 3β-HSD. These results suggest that PC had a mechanism of intratumoural androgen metabolism to return inactive androgen to active androgen and intratumoural DHT synthesis from 3β-diol is important as one of the mechanisms of castration resistance in PC. Additionally, the inhibition of intratumoural 3β-HSD activity could be a new approach to castration-resistant prostate cancer treatment.