Yoichi Miwa

HMG-CoA Reductase Inhibitor Has Protective Effects Against Stroke Events in Stroke-Prone Spontaneously Hypertensive Rats

Background and Purpose— Recent clinical studies suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert protective effects against nonhemorrhagic stroke. In a murine cerebral ischemia model produced by occlusion of the middle cerebral artery, statins were shown to reduce infarct size. However, the effect of statins on hypertension-based stroke is unknown. The purpose of this study is to clarify the effect of a statin on stroke in stroke-prone spontaneously hypertensive rats (SHR-SP), in which both cerebral hemorrhage and infarction occur. Methods— We treated SHR-SP chronically from 4 weeks of age with cerivastatin (2 mg/kg per day by gavage) or vehicle. The physiological parameters, the incidence of stroke-associated symptoms, and mortality were assessed. Results— At 14 weeks of age, the incidence (13±3% versus 37±8%;P <0.01) and the size of stroke (1.6±0.2 versus 2.2±0.1 arbitrary units;P <0.01) were significantly decreased by cerivastatin, although blood pressure and plasma cholesterol levels were not different. Moreover, stroke-associated symptoms and early mortality of SHR-SP were markedly reduced in the statin-treated group (mortality at the age of 15 weeks: 15% versus 50%;P <0.05). Statin treatment significantly reduced superoxide production from nonstroke parenchyma of brain and infiltration of inflammatory cells to the stroke lesions. Conclusions— Our data show that a high dose of statin exerts protection against hypertension-based stroke and ameliorates the disease severity via inhibition of superoxide production and modulation of inflammation in brain.

Serotonin-Induced Hypercontraction Through 5-Hydroxytryptamine 1B Receptors in Atherosclerotic Rabbit Coronary Arteries

Background — Augmented vasoconstriction to serotonin (5-hydroxytryptamine [5-HT]) in atherosclerotic vessels plays a crucial role in the development of myocardial ischemia. We investigated mechanisms for serotonin-evoked hypercontraction in atherosclerotic rabbit coronary arteries. Methods and Results — Contractile responses to serotonergic agents of endothelium-denuded coronary arteries from control and Watanabe heritable hyperlipidemic rabbits (WHHL) were examined. WHHL coronary arteries exhibited hypercontraction to 5-HT1–receptor agonists; the constrictor threshold concentrations and ED50 to serotonin, 5-carboxamidotryptamine, and sumatriptan in WHHL were significantly lower, and the Emax in WHHL to these agents were increased 55% to 59% above those of the control. Serotonin-evoked contractions in both groups were inhibited by GR127935 (5-HT1B/1D antagonist; 0.1 to 1 nmol/L) and pertussis toxin but not by ketanserin (5-HT2 antagonist; 0.01 to 1 &mgr;mol/L), suggesting that the hypercontraction is most likely mediated by 5-HT1B/1D receptors through a pertussis toxin–sensitive pathway. Furthermore, simultaneous measurements of [Ca2+]i and isometric tension of fura-2–loaded arteries revealed that the hypercontraction was concomitant with the augmented elevation of [Ca2+]i in the smooth muscle. The 5-HT1B mRNA levels in WHHL coronary arteries increased to 2.5-fold over those in control arteries, whereas neither 5-HT1D nor 5-HT2A mRNA was detected in either group. Conclusions — Atherosclerotic rabbit coronary arteries exhibited the enhancement in contraction and Ca2+ mobilization in response to serotonin. The 5-HT1B receptor, which is upregulated by atherosclerosis, most likely mediates the augmenting effects of serotonin.

Lysophosphatidylcholine Inhibits Receptor-Mediated Ca2+ Mobilization in Intact Endothelial Cells of Rabbit Aorta

We have previously reported that lysophosphatidylcholine (LPC), which accumulates in oxidized LDL and atherosclerotic arteries, inhibits endothelium-dependent relaxation and modulates Ca2+ regulation in cultured bovine aortic endothelial cells. To test the effect of LPC on endothelium-dependent relaxation and endothelial Ca2+ regulation in intact vessels, we simultaneously measured both isometric tension and endothelial cytosolic free Ca2+ concentration ([Ca2+]i), using fura 2, in intact endothelial cells of aortic strips isolated from rabbits. In the aortic strips precontracted with phenylephrine, cumulative addition of acetylcholine (ACh) dose dependently induced endothelium-dependent relaxation, with an increase in endothelial [Ca2+]i, and positive correlation was obtained between these two parameters. LPC (2 to 20 mumol/L) inhibited both ACh (3 mumol/L)-induced endothelium-dependent relaxation and an increase in endothelial [Ca2+]i in a dose-dependent manner. On the other hand, phosphatidylcholine (20 mumol/L) affected neither ACh-induced endothelium-dependent relaxation nor an increase in endothelial [Ca2+]i. LPC had no effect on endothelium-independent relaxation and a decrease in smooth muscle [Ca2+]i induced by nitroglycerin. Thus, the inhibitory effect of LPC on endothelium-dependent relaxation is due to the inhibition of agonist-induced Ca2+ mobilization in vascular endothelial cells, which is an essential step in the synthesis of endothelium-derived relaxing factor.

Augmented receptor-mediated Ca2+ mobilization causes supersensitivity of contractile response to serotonin in atherosclerotic arteries.

We have previously reported that atherosclerotic arteries obtained from Watanabe heritable hyperlipidemic (WHHL) rabbits exhibit a marked increase of contractile response to serotonin (5-hydroxytryptamine [5-HT]) and ergonovine and that these augmented contractile responses to specific agonists may play an important role in the pathogenesis of vasospasm. In the present study, we investigated whether supersensitivity to 5-HT in atherlosclerotic arteries was due to an increase in 5-HT receptor-mediated Ca2+ mobilization or to an increase in Ca2+ sensitivity of the contractile elements. We measured simultaneously both isometric tension and [Ca2+]i in fura 2-loaded aortic smooth muscle strips from control and WHHL rabbits. Muscle tension in the high K+ (72.7 mmol/L)-stimulated states and [Ca2+]i in both resting and high K(+)-stimulated states did not differ between control and WHHL rabbits. In atherosclerotic aortas from WHHL rabbits, the dose-response curves of both tension and [Ca2+]i for 5-HT were shifted to the left at lower threshold concentrations and one-half maximally effective dose. The maximum response of contraction produced by 5-HT in WHHL rabbits was augmented compared with that in control rabbits (123 +/- 17% versus 33 +/- 7% of the 72.7 mmol/L K(+)-induced contraction, P < .001). The maximum response of [Ca2+]i produced by 5-HT was also augmented in WHHL rabbits compared with control rabbits (29 +/- 4% versus 10 +/- 0.9% of the 72.7 mmol/L K(+)-induced [Ca2+]i, P < .001). In contrast, the responses of contraction and [Ca2+]i to phenylephrine were similar between control and WHHL rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Isolated ACTH deficiency presenting with severe myocardial dysfunction

We present a case of isolated adrenocorticotropic hormone (ACTH) deficiency complicated by acute adrenal crisis and severe myocardial dysfunction. A 54-year-old woman developed consciousness disturbance, hypoglycemia, hyponatremia, and rhabdomyolysis. Initial echocardiographic examinations on the sixth hospital day revealed marked right-sided atrial and ventricular dilatation and severe tricuspid regurgitation. A computed tomography scan for pulmonary embolism was negative. On the 14th hospital day, she became dyspneic and hypotensive. Repeated echocardiographic examinations demonstrated diffuse and severe hypokinesis of the left ventricle. The previous right-sided chamber dilatation became less apparent. Congestive heart failure and severe hypotension were refractory to catecholamines, while she was eventually diagnosed as having acute adrenal crisis due to isolated ACTH deficiency. Hydrocortisone replacement therapy was started, and echocardiographic examinations revealed that the left ventricular dysfunction completely returned to normal in the following eight days. Severe myocardial dysfunction is an uncommon but serious complication of acute adrenal insufficiency. The present case was unique in that diffuse left ventricular dysfunction was preceded by right ventricular dysfunction.