Kenji Kurosaki

Familial Isolated Noncompaction of the Left Ventricular Myocardium

Noncompaction of the ventricular myocardium (sometimes referred to as ‘spongy myocardium’) is believed to represent an arrest in endomyocardial morphogenesis. The gross anatomical appearance is characterized by numerous excessively prominent trabeculations and deep intertrabecular recesses. Distinct morphological features can be diagnosed on two-dimensional echocardiography. We present here a family of isolated noncompaction of the left ventricular myocardium, in which 5 affected individuals suggested the presence of some genetic abnormalities in this disorder.

Adenosine stimulates nitric oxide synthesis in vascular smooth muscle cells

OBJECTIVEnThe aim was to investigate the effects of adenosine on nitric oxide (NO) synthesis in vascular smooth muscle cells.nnnMETHODSnNO and cAMP synthesis was measured in confluent rat vascular smooth muscle cells in culture at passage 5-10, using Griess reagent and an enzyme immunoassay kit, respectively. The expression of inducible NO synthase mRNA was assayed by Northern blotting.nnnRESULTSnIncubation of cultures with interleukin-1 beta (10 ng/ml) for 24 h caused a significant increase in nitrite production. The interleukin-1 beta-induced nitrite production by vascular smooth muscle cells was significantly increased by adenosine or its stable analogue, 2-chloroadenosine, in a dose-dependent manner. The adenosine A2a receptor antagonist, KF17837, but not the A1 receptor antagonist, DPCPX, significantly inhibited 2-chloroadenosine-mediated nitrite production. The 2-chloroadenosine-mediated nitrite production by interleukin-1 beta-stimulated cells was accompanied by increased inducible NO synthase mRNA accumulation. In the presence of dibutyryl-cAMP (1 mM), interleukin-1 beta-induced nitrite accumulation was further increased, but the effect of 2-chloroadenosine was not additive or synergistic. Addition of 2-chloroadenosine dose-dependently increased intracellular cAMP levels of vascular smooth muscle cells.nnnCONCLUSIONSnThese results indicate that adenosine acts on A2 receptors and augments NO synthesis in interleukin-1 beta-stimulated vascular smooth muscle cells, at least partially through a cAMP-dependent pathway.

Assessment of coagulation and platelet activation in coronary sinus blood induced by transcatheter coronary intervention for narrowing of the left anterior descending coronary artery.

Influences of recently developed methods for coronary intervention on hemostasis in the coronary circulation are unclear. The objective of this study was to investigate changes in coagulation and platelet activation in the coronary circulation induced by percutaneous transluminal coronary angioplasty (PTCA). We studied 35 patients with coronary heart disease who underwent elective PTCA to isolated stenotic narrowing of left coronary arteries. Seven patients received only PTCA, 12 underwent percutaneous transluminal rotational atherectomy (PTRA), and 16 underwent stent implantation. Blood samples were drawn from the coronary sinus immediately before and after as well as 4 and 24 hours after PTCA. Plasma levels of tissue factor (TF), thrombin-antithrombin III complex, plasminogen activator inhibitor (PAI)-1, tissue plasminogen activator (t-PA), beta-thromboglobulin, and platelet factor 4 were measured by enzyme-linked immunosorbent assay. In all patients, TF levels in the coronary sinus blood showed significant increases 4 and 24 hours after PTCA and thrombin-antithrombin III complex levels showed significant increases 24 hours after PTCA. PAI-1 showed significant increases 24 hours after PTCA and t-PA showed significant increases 4 and 24 hours after PTCA. Changes in levels of these markers by PTCA were similar among the 3 groups. In PTRA, levels of beta-thromboglobulin and platelet factor 4, markers of platelet activation, increased immediately after the procedure and returned to baseline levels after 4 hours. PTCA induced increases in blood coagulation and fibrinolysis in the coronary circulation. PTRA caused a marked but transient activation of platelets. These changes may contribute to acute complications during the procedure.

Release of endothelin 1 and angiotensin II induced by percutaneous transluminal coronary angioplasty

Endothelial injury plays critical roles in acute and chronic complications after percutaneous transluminal coronary angioplasty (PTCA). We investigated coronary endothelial injury and the release of vasoactive substances induced by PTCA. We examined 44 patients with ischemic heart disease who underwent elective PTCA to isolated stenotic lesions in left coronary arteries. Eleven patients received balloon angioplasty (BA), 14 percutaneous transluminal rotational atherectomy (PTRA), and 19 stent implantation. Blood samples were drawn from the coronary sinus immediately before and after as well as 4 hr and 24 hr after PTCA. Plasma levels of endothelin (ET) 1, angiotensin (ANG) II, von Willebrand factor (vWF), and thrombomodulin (TM) were measured. Seven control subjects who underwent diagnostic coronary angiography (CAG) were used as controls. In all patients, ET‐1 levels in the coronary sinus blood significantly increased immediately after PTCA. ANG II levels and vWF activity showed significant increases 4 hr after PTCA. Changes in levels of these markers were similar among the BA, PTRA, and stent groups. TM levels were elevated in all groups of patients, including those simply undergoing diagnostic CAG. Changes in ET‐1, ANG II, and vWF levels in the coronary sinus reflect coronary endothelial injury induced by PTCA. Cathet. Cardiovasc. Intervent. 51:42–49, 2000.

Serum MCP-1 and VEGF Levels are not Affected by Inhibition of the Renin-Angiotensin System in Patients with Acute Myocardial Infarction

Monocyte chemoattractant protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) stimulate angiogenesis in ischemic tissues, and both of their expression are stimulated by angiotensin II. We measured the serum concentrations of MCP-1 and VEGF in patients with acute myocardial infarction (AMI) and investigated the effects of an early administration of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 receptor blocker (ARB) on their levels. Thirty-six patients with AMI were divided randomly into 3 therapeutic groups; the ACEI perindopril, the ARB candesartan and control (without perindopril and candesartan), and the drugs were administered within 36 hours after the onset of AMI. Peripheral blood mononuclear cells (PBMC) obtained from the patients were incubated for 24 hours. The levels of MCP-1 and VEGF in the serum and the supernatant of PBMC were measured by ELISA. The serum MCP-1 and VEGF levels in AMI patients at the time of admission were not significantly different from those in healthy control subjects, but both MCP-1 and VEGF levels in the patients were increased significantly after 7 days. There was no significant difference in the serum MCP-1 and VEGF levels among the 3 therapeutic groups. The production of MCP-1 and VEGF by PBMC was also increased in AMI patients compared with healthy control subjects, and there was also no difference in their production among the 3 therapeutic groups. In conclusion, circulating MCP-1 and VEGF levels and their production by PBMC are elevated during the course of AMI, and early administration of ACEI and ARB does not affect their levels.

Serotonin inhibits nitric oxide synthesis in rat vascular smooth muscle cells stimulated with interleukin-1.

We investigated the effects of serotonin (5-hydroxytryptamine; 5-HT) on nitric oxide (NO) synthesis in vascular smooth muscle cells. We measured the production of nitrite, a stable metabolite of NO, and the expression of inducible NO synthase protein in cultured rat vascular smooth muscle cells. Incubation of the cultures with interleukin-1beta (10 ng/ml) caused a significant increase in nitrite production. 5-HT inhibited nitrite production by interleukin-1beta -stimulated vascular smooth muscle cells in a concentration-dependent manner (10(-8)-10(-5) M). 5-HT-induced inhibition of nitrite production was accompanied by decreased inducible NO synthase protein accumulation in vascular smooth muscle cells. Addition of the 5-HT2 receptor antagonist ketanserin, but not the 5-HT1A receptor antagonist spiroxatrine, inhibited the effect of 5-HT. On the other hand, the 5-HT2 receptor agonist alpha-methyl-5-HT, but not the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin, decreased interleukin-1beta-induced nitrite production by vascular smooth muscle cells. 5-HT significantly increased protein kinase C activity in vascular smooth muscle cells, and the protein kinase C inhibitor calphostin C dose-dependently abolished the effect of 5-HT on nitrite production. After protein kinase C activity was functionally depleted by treatment of cells with phorbol 12-myristate 13-acetate for 24 h, the effect of 5-HT was abolished. These results indicate that 5-HT acts on 5-HT2 receptors and inhibits NO synthesis in interleukin-1beta-stimulated vascular smooth muscle cells at least partially through a protein kinase C-dependent pathway.

Effects of vesnarinone on nitric oxide synthesis in rat cardiac myocytes

OBJECTIVEnThe purpose of this study was to investigate the effects of vesnarinone on nitric oxide (NO) synthesis in cardiac myocytes.nnnMETHODSnWe measured the accumulation of nitrite, a stable oxidation product of NO synthase (iNOS) protein in cultured neonatal rat cardiac myocytes.nnnRESULTSnIncubation of the cultures with interleukin-1 beta (IL-1 beta; 10 ng/ml) and tumor necrosis factor alpha (TNF alpha; 10 ng/ml) caused a marked increase in nitrite production. Although vesnarinone by itself showed no effect on nitrite accumulation, it enhanced cytokine-induced nitrite production by cardiac myocytes in a dose-dependent manner. The effect of vesnarinone was completely abolished in the presence of NG-monomethyl-L-arginine or actinomycin D. The vesnarinone-induced nitrite production was accompanied by increased iNOS protein expression. In the presence of dibutyryl-cAMP, cytokine-induced nitrite accumulation was further increased, but the stimulatory effect on vesnarinone on nitrite accumulation was diminished. The effect of vesnarinone was also inhibited by Rp-8-Br-cAMPS, a competitive inhibitor of protein kinase A, in a dose-dependent manner.nnnCONCLUSIONSnThese findings indicate that vesnarinone increases NO synthesis in cytokine-stimulated cardiac myocytes, at least partially through a cAMP-dependent pathway.

Inhibition of the renin-angiotensin system: no effect on circulating macrophage colony-stimulating factor levels in acute myocardial infarction.

&NA; Macrophage colony‐stimulating factor, which induces proliferation and differentiation, and activation of monocytes and macrophages, plays an important role in the vulnerability of atheromatous plaques as well as the formation of atherosclerotic lesions. We measured serum concentrations of macrophage colony‐stimulating factor in patients with acute myocardial infarction and also investigated the effects of early administration of angiotensin‐converting enzyme inhibitor and angiotensin receptor blocker on circulating macrophage colony‐stimulating factor levels in these patients. The patients were divided randomly into 3 therapeutic groups; perindopril, candesartan, and control (without perindopril and candesartan) groups, and the drugs were administered within 24 to 36 hours after the onset of acute myocardial infarction. Serum macrophage colony‐stimulating factor concentrations in acute myocardial infarction patients at the time of admission were significantly higher than those in healthy control subjects. The macrophage colony‐stimulating factor levels in the patients decreased gradually after admission, but remained significantly higher than those in control subjects for 14 days. There were no significant differences in serum macrophage colony‐stimulating factor levels among the 3 therapeutic groups during this study period. In conclusion, circulating macrophage colony‐stimulating factor levels are elevated during the course of acute myocardial infarction, and inhibition of the renin‐angiotensin system by angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker does not affect these levels.