Munetoshi Matoba

Properties of G-protein modulated receptor-adenylyl cyclase system in myocardium of spontaneously hypertensive rats treated with adriamycin

Properties of the receptor--G protein--adenylyl cyclase system were studied in spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY) treated with adriamycin (ADR, 1 mg/kg per week) for 12 weeks. An identical dosing schedule caused a significantly greater decline in body weight gain and a marked elevation of plasma norepinephrine level in SHR than in WKY. A significant increase in the messenger RNA encoding Gi-alpha 2 was found in SHR+ADR group. The activity of the adenylyl cyclase stimulated by guanyliminodiphosphate [Gpp(NH)p] was decreased by 49% in SHR and 73% in SHR+ADR. However, stimulated activities of adenylyl cyclase by both sodium fluoride and forskolin remained unchanged. Functional level of stimulatory G-protein (Gs) as measured by reconstitution assay in sarcolemmal membrane was unaltered among different groups. Furthermore, the density of beta-adrenoceptor was significantly decreased without change of its affinity. Muscarinic receptors exhibited a three-site affinity distribution in SHR+ADR whereas other groups displayed only two-site affinity distribution. These results suggest that SHR exhibited a depressed myocardial adenylyl cyclase signaling system which may not be due to the functional uncoupling of beta-adrenoceptors from Gs but to the increased inhibitory G-protein (Gi) activity as demonstrated by the increased mRNA of Gi-alpha 2, increased inhibition of Gpp(NH)p-mediated adenylyl cyclase and the super high affinity for carbachol of the muscarinic receptors. Decreased beta-adrenoceptor density and functional alteration of Gi might be regarded as the predisposing factors for the increased susceptibility of myocardium of SHR to ADR.

Hemodynamic effects of dibutyryl cyclic AMP in congestive heart failure.

To evaluate the hemodynamic effects of dibutyryl cyclic AMP (DBcAMP) in congestive heart failure (CHF), right-sided cardiac catheterization was performed in 11 patients with CHF, and hemodynamic variables were investigated before and after infusion of various doses of DBcAMP at a rate of 0.025 to 0.2 mg/kg/min (mean 0.14 +/- 0.077 [standard deviation]). DBcAMP reduced total systemic vascular resistance index from 3,171 +/- 1,158 to 1,880 +/- 554 dynes s cm-5 X m2 (mean +/- standard deviation) and pulmonary arterial end-diastolic pressure from 23 +/- 13 to 20 +/- 11 mm Hg, and increased cardiac index from 2.24 +/- 0.60 to 3.41 +/- 1.02 liters/min/m2. Mean arterial blood pressure decreased from 91 +/- 14 to 84 +/- 13 mm Hg, and heart rate increased from 91 +/- 16 to 99 +/- 13 beats/min. The increase in cardiac index was accompanied by a proportional decrease in total systemic vascular resistance index in all patients except 1. In 8 patients the decrease in pulmonary arterial end-diastolic pressure was accompanied by an increase or no change in the left ventricular stroke work index. In 6 patients, DBcAMP was given in incremental doses of 0.05, 0.1, and 0.2 mg/kg/min every 20 minutes, and 5 of 6 patients tolerated the full dose and showed dose-related hemodynamic changes for the incremental doses of DBcAMP. These data suggest that DBcAMP has powerful vasodilating effects on resistance vessels in patients with CHF; hence, it can be a useful vasodilating agent for treatment of CHF.

Comparison of atorvastatin, pitavastatin and rosuvastatin for residual cardiovascular risk using non-fasting blood sampling.

Abstract Background: Low-density lipoprotein cholesterol (LDL-C) is a major cardiovascular risk. However, some patients show symptoms of coronary heart disease (CHD) even though their LDL-C is strictly controlled. Therefore, it is important to treat other risk factors. Methods: Some 129 outpatients with dyslipidemia who were treated with either atorvastatin 10 mg/day (ATO), pitavastatin 2 mg/day (PIT), or rosuvastatin 2.5 mg/day (ROS) were enrolled. After informed consent was obtained, these patients were switched to another statin. Lipid profiles and lipoprotein fraction by polyacrylamide gel electrophoresis (PAGE) were compared between before and after 3 months of treatment with non-fasting blood sample. Results: LDL-C did not show any significant changes after switching and was maintained around 2.59 mmol/L in all groups. High-density lipoprotein cholesterol (HDL-C) was significantly increased in group ATO→PIT (1.43→1.54 mmol/L, p = 0.0010) and ROS→PIT (1.46→1.57 mmol/L, p = 0.0004), and was significantly decreased in group PIT→ATO (1.44→1.36 mmol/L, p = 0.0290). Apolipoprotein A-I (Apo A-I) and preheparin lipoprotein lipase (LPL) mass showed similar changes in HDL-C. Changes in HDL-C showed a significant positive correlation with those in Apo A-I and preheparin LPL mass, and a little but significant negative correlation with changes in Lp(a) and intermediate density lipoprotein (IDL) fraction. Conclusions: ATO, PIT, and ROS have comparable effect on LDL-C lowering. Changes in HDL-C were similar to those in Apo A-I and preheparin LPL mass, and PIT was the most effective treatment in increasing HDL-C, Apo A-I, and preheparin LPL mass.

Effects of change in high-density lipoprotein cholesterol by statin switching on glucose metabolism and renal function in hypercholesterolemia

BACKGROUND Recent reports have suggested that high-density lipoprotein (HDL) is metabolically related to glucose metabolism and renal function. Statin administration clinically increases HDL cholesterol (HDL-C). OBJECTIVE To confirm that change in HDL-C by statin switching is associated with glucose metabolism and renal function in hypercholesterolemic patients. METHODS In hypercholesterolemic outpatients (n = 129) who had taken either statin, as atorvastatin, pitavastatin, or rosuvastatin and switched to another statin, the relationship of change in HDL-C to glycated hemoglobin and estimated glomerular filtration rate (eGFR) was assessed. RESULTS Change in HDL-C did not significantly correlate with change in HbA1c, eGFR calculated from creatinine (eGFRcre), and eGFR calculated from cystatin C (eGFRcys). The subjects were then divided into 2 groups by change in HDL-C: no change or decrease in HDL-C (HD group) and increase in HDL-C (HI group). In the HI group, apolipoprotein A-1 (Apo A-1) and eGFRs were significantly increased by statin switching. There were significant differences in changes in HDL-C, Apo A-1, lipoprotein lipase, glycated hemoglobin, and eGFR calculated from creatinine between the groups. In the patients with impaired glucose tolerance or diabetes, change in HbA1c was also significant between the groups. CONCLUSIONS Our data suggest that an increase in HDL-C due to statin switching is associated with improvement in glucose metabolism and renal function.