Sokichi Onodera

Absence of antioxidant effects of nifedipine and diltiazem on myocardial membrane lipid peroxidation in contrast with those of nisoldipine and propranolol

Both the production of active oxygen species and cellular damage due to concurrent lipid peroxidation are believed to be important factors in the pathogenesis of cardiovascular diseases and the ageing process. Since cardiovascular drugs are often administered over a long term, it might be advantageous if they reduced lipid peroxidation. There have been conflicting reports concerning the antiperoxidant effect of nifedipine. Therefore, we investigated whether nifedipine could inhibit lipid peroxidation in a nonenzymatic active oxygen-generating system, utilizing rat crude myocardial membranes, and compared its effect with those of propranolol, nisoldipine, and diltiazem. Nifedipine and diltiazem had no inhibitory effects on the lipid peroxidation of myocardial membranes. In contrast, nisoldipine and propranolol had a concentration-dependent antiperoxidant effect, with IC50 values of 28.2 and 50.1 microM, respectively. In addition, nisoldipine appeared to possess dual antiperoxidant mechanisms, involving both preventive and chain-breaking properties.

Down-regulation of protein kinase C potentiates atrial natriuretic peptide-stimulated cGMP accumulation in vascular smooth-muscle cells.

It has been reported that atrial natriuretic peptide (ANP) produces inositol phosphates and diacylglycerol in vascular smooth muscle cells (VSMC). The purpose of this study is to investigate whether diacylglycerol produced by ANP affects ANP-induced cyclic GMP (cGMP) accumulation through the activation of protein kinase C. Short-term (15 min) treatment of rat aortic VSMC with protein kinase C activating phorbol 12-myristate 13-acetate (PMA, 100 nM) decreased ANP (100 nM)-induced cGMP accumulation by 34.7% in the presence of IBMX (0.5 mM). However, the long-term (24 h) treatment to decrease the activity of protein kinase C led to an enhancement of the cGMP accumulation by 69.6% compared with that of control VSMC. There were no significant differences in Bmax and Kd for ANP and ANP-dependent particular guanylyl cyclase activity between long-term PMA-treated and control VSMC. In the present study, we show that the activation of protein kinase C attenuates the cGMP accumulation induced by ANP and that down-regulation of protein kinase C results in an enhancement of the cGMP accumulation. These data are consistent with the role of protein kinase C as a negative regulator in ANP-receptor/guanylyl cyclase pathway.

Effect of xamoterol in Shy-Drager syndrome.

BackgroundXamoterol, a cardioselective β1-adrenoceptor partial agonist, has been reported to be effective on postural hypotension. We investigated the effect of xamoterol in five patients with Shy-Drager syndrome (SDS) in relation to their prevailing sympathetic nerve activity and sensitivity of β-adrenoceptors and the change in circadian variation of blood pressure. Methods and ResultsAmbulatory blood pressure over 24 hours was monitored by noninvasive sphygmomanometer (model 5200, Spacelab). Plasma norepinephrine levels of SDS patients were significantly lower than that of normal subjects (n=5) both at rest (54±15 versus 178±83 pg/ml) and after 10-minute standing (74±24 versus 318±143 pg/ml). Infusion of isoproterenol (0.02 μg/kg/min) produced a mild rise of systolic blood pressure and tachycardia in normal subjects but resulted in marked hypotension and tachycardia in SDS subjects. After xamoterol administration (200 mg b.i.d.), systolic blood pressure and heart rate were significantly increased in the averages during the day; however, increases were more pronounced at night. In two of the five patients, the improvement in dizziness was large enough to enable them to increase their daily activities. ConclusionsOur observations suggest that 1) β1-selective, high intrinsic sympathomimetic activity of xamoterol increases blood pressure and heart rate in patients with SDS as a consequence of their prevailing β1-adrenoceptor hypersensitive state, and 2) blood pressure monitoring over 24 hours appears to have important advantages in evaluating the therapeutic effects on postural hypotension.

Prolonged period of global ischemia causes no change in the GTP-binding proteins in the isolated perfused rat heart

The response of the beta-adrenoceptor transduction system to global ischemia for 40 min was investigated in isolated working heart of rat. The enhancement of beta-adrenoceptors was not observed in the ischemic myocardium. A depression of forskolin-stimulated adenylate cyclase enzyme occurred with global ischemia, but no change in Gs or Gi2 was detected. Thus, the present in vitro ischemic heart model may not necessarily reflect the identical milieu induced by the in vivo myocardial ischemia.

Effects of nicorandil and nipradilol on ischemic myocardium in perfused rat heart

We examined the effect of nicorandil and nipradilol on the ischemic myocardium in the isolated perfused rat heart. The heart was perfused by the working heart technique with an afterload pressure of 60 mm Hg and with a left atrial filling pressure of 9 mm Hg. Ischemia was induced for 20 min by lowering the afterload pressure. The afterload pressure was raised to 60 mm Hg again during reperfusion. Ischemia decreased the pressure-rate product, coronary flow, adenosine triphosphate level and creatine phosphate level, and increased the lactate level. Reperfusion could not restore the pressure-rate product nor the adenosine triphosphate level completely. Nicorandil (5 x 10(-5) and 1.5 x 10(-4) M) or nipradilol (10(-5), 5 x 10(-5) and 1.5 x 10(-4) M) was introduced 5 min before ischemia. Nipradilol preserved the levels of adenosine triphosphate and creatine phosphate after 20 min of ischemia and increased the extent of recovery of the pressure-rate product during reperfusion, whereas nicorandil did not. Nipradilol, but not nicorandil, can protect the myocardium against ischemic damage.

Efficacy of long-term treatment with nipradilol, a nitroester-containing beta-blocker, in patients with mild-to-moderate essential hypertension

The effects of long-term treatment with nipradilol, a nitroester-containing beta-blocker, on casual and 24-hour blood pressures were studied in 70 patients with mild-to-moderate essential hypertension. Antihypertensive effects of nipradilol on casual blood pressure were observed in 68% of patients. Nipradilol reduced pulse rates, but no bradycardia was observed. The usefulness of nipradilol in the present study was 65%. The results of ambulatory blood pressure monitoring indicated that nipradilol reduced systolic blood pressure more than diastolic blood pressure, and reduced blood pressure during waking more than during sleep. These results suggest that nipradilol is a safe and useful long-term antihypertensive drug in both young and older patients with mild-to-moderate essential hypertension. When administered twice daily, nipradilol is effective throughout a 24-hour period.

Hemoglobin Kansas found in a patient with polycythemia

SummaryA 62-year-old woman, long suspected of having heart disease, was admitted to our hospital for thorough examination. Her hemoglobin level was 17.7 g/dl and her 2.3-DPG level was 8.90 μM/ml RBC. The patient proved to have polycythemia, hemoglobin Kansas, and diabetes mellitus. To our knowledge, this is the third case of hemoglobin Kansas in the world.

Transient pulsus alternans induced by isosorbide dinitrate: echocardiographic and hemodynamic evidence of reduced venous return--a case report.

Transient pulsus alternans was induced by isosorbide dinitrate (ISDN) in a patient with postmyocarditis congestive heart failure under diuretic therapy. The severity and duration of pulsus alternans depended on the dose of ISDN. According to the echocardiographic and hemodynamic examinations, the superimposed preload reduction caused by ISDN combined with decreased blood volume owing to diuretic therapy most likely contributed to the development of pulsus alternans.

Leiomyosarcoma of the Inferior Vena Cava Causing Budd-Chiari Syndrome—A Case Report

A forty-eight-year-old Japanese woman with leiomyosarcoma of the inferior vena cava presenting as Budd-Chiari syndrome is reported. A large tumor orig inating from the venous wall grew into the lumen, obstructing the hepatic vein, and extended up to the right atrium. Although this is a very rare tumor, care should be taken in order to make an early diagnosis and manage the condition effectively.

Effects of a β-agonist and antagonist on the pulmonary circulation and the pulmonary pressor response to 5-HT

We investigated the effects of beta-agonist and antagonist (isoproterenol, propranolol) on the pulmonary circulation and on the pulmonary pressor response to 5-HT in an isolated canine lung lobe. The pulmonary vessels were dilated by isoproterenol at doses up to 200 micrograms, but were constricted by alpha-adrenoceptor stimulation at relatively high doses. The mechanism by which isoproterenol inhibited the 5-HT response is probably related to the stimulation of beta-adrenoceptors at the lower doses and to the stimulation of alpha-adrenoceptors at the higher doses. Propranolol alone had no effect on pulmonary vascular tone, but inhibited the 5-HT response markedly at doses high, possibly by directly blocking the 5-HT receptors.