Tokuji Konishi

Effects of trapidil (triazolopyrimidine), a platelet-derived growth factor antagonist, in preventing restenosis after percutaneous transluminal coronary angioplasty

Trapidil (triazolopyrimidine), a platelet-derived growth factor antagonist, is a potential inhibitor of intimal proliferation after percutaneous transluminal coronary angioplasty (PTCA). To study its efficacy, 72 patients were randomized to receive Trapidil (600 mg/day orally for 1 week before PTCA and for 4 to 6 months after PTCA; n = 36) or aspirin and dipyridamole (aspirin, 300 mg/day, and dipyridamole, 150 mg/day; n = 36). At entry, both groups were comparable with regard to age, sex, dilated vessels, severity of pre-PTCA stenosis, residual stenosis after PTCA, and prevalence of coronary risk factors. Repeat coronary angiography was performed 6 months after PTCA. Restenosis, defined as the loss of at least 50% of the gain in luminal diameter accomplished by dilation, was present in seven patients (19.4%) in the trapidil group and 15 patients (41.7%) in the aspirin-dipyridamole group (p less than 0.05). The progression of stenosis in patients with less than 30% residual stenosis was significant in both groups. Furthermore, in the patients with residual stenosis of more than 30%, progression of stenosis was less in the trapidil group than in the aspirin-dipyridamole group. Thus trapidil was useful in preventing intimal proliferation after PTCA, especially in patients with more than 30% residual stenosis after PTCA.

Serial change of iodine-123 metaiodobenzylguanidine (MIBG) myocardial concentration in patients with dilated cardiomyopathy

Serial change of the metaiodobenzylguanidine iodine-123 (123I-MIBG) myocardial concentration was investigated in patients with dilated cardiomyopathy (DCM). Eight DCM patients and 6 control subjects were examined. After the injection of thallium-201 and 123I-MIBG, planar chest images were obtained simultaneously for both tracers in every 30–60 min over 5 h. Serial changes of myocardial uptake ratio (MUR) were compared for both tracers. In DCM, the initial MUR of 123I-MIBG did not differ significantly from that of the controls. The washout of 123I-MIBG from the myocardium, however, was significantly increased in DCM. In particular, the decrease in the early phase (15–45 min) was significantly larger in DCM than in the controls (21.2%±7.5% vs. 5.3%±4.0%, P <0.01), showing a significant negative correlation with the left ventricular ejection fraction (r = −0.72 P < 0.05). For 201TI, neither the initial MUR nor the washout rate different significantly between the two. Thus, an early rapid decrease of the 123I-MIBG myocardial concentration might characterize DCM and reflect the severity of this disease.

Isoenzymes of cyclic nucleotide phosphodiesterase in the human aorta : characterization and the effects of E4021

In extracts of the human aorta, five isoenzymes of cyclic nucleotide phosphodiesterase, namely, phosphodiesterase I, phosphodiesterase II, phosphodiesterase III, phosphodiesterase IV and phosphodiesterase V, were identified exclusively in the cytosolic fraction, and no phosphodiesterase activity was detected in the particulate fraction. Phosphodiesterase V and phosphodiesterase I were the major cGMP-hydrolyzing enzymes in the human aorta. A novel vasorelaxant, sodium 1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-yl ]piperidine-4- carboxylate sesquihydrate (E4021), relaxed prostaglandin F2 alpha-precontracted strips of human pulmonary artery with an ED50 value of 0.5 microM. E4021 potently and highly selectively inhibited the activity of phosphodiesterase V from human aorta with a Ki value of 2.4 nM. These results suggest that there is a unique distribution of phosphodiesterase isoenzymes in the human aorta and that inhibitors of phosphodiesterase V might be useful as a new type of vasodilator in the treatment of clinical disorders.

Isolated Congenital Left Ventricular Diverticulum in an Adult: A Case Report

A sixty-three-year-old man presented himself with atrial flutter and congestive heart failure. Cardiac catheterization revealed that left ventricular diverticulum was located on the anterobasal wall with narrow connection to the left ventricular cavity. Coronary angiography revealed normal coronary arteries. The patient had been asymptomatic until adult life with no other thoracoabdominal or cardiac anomalies. This is an extremely rare finding in the adult population.

31P MR spectroscopy in hypertrophic cardiomyopathy: comparison with Tl-201 myocardial perfusion imaging.

Abnormal phosphate metabolism of the myocardium was evaluated in patients with hypertrophic cardiomyopathy (HCM) using 31P magnetic resonance (MR) spectroscopy. The results were compared with those from left ventricular function and thallium 201 (Tl-201) perfusion scintigraphy. Six normal volunteers and 19 patients with HCM were studied with a 1.5 T MR system. The spectra were localized to the myocardium using volume selection with the depth-resolved surface coil spectroscopy (DRESS) technique. Peak areas of 2,3-diphosphoglycerate (DPG), phosphodiesters (PDE), phosphocreatine (PCr), and beta-ATP were determined by fitting Gaussian functions to the phased spectra. The peak areas were corrected for contamination of blood adenosine triphosphate (ATP) and PDE. The corrected PCr/beta-ATP ratio in patients (1.07 +/- 0.10, mean +/- SE) was significantly lower compared with that in normal volunteers (1.71 +/- 0.13, p < .01). The PCr/beta-ATP ratio showed an abnormal decrease (< mean -2 SD of the controls) in 11 (58%) of 19 patients. The averaged PCr/beta-ATP ratio in 15 patients with normal left ventricular ejection fraction (LVEF) was 1.14 +/- 0.10, significantly lower than in healthy subjects. By contrast, the corrected PDE/PCr ratio in HCM did not differ significantly compared with that in healthy subjects (0.46 +/- 0.09 vs 0.36 +/- 0.09). The PDE/PCr ratio was abnormally elevated (> mean + 2 SD of the controls) in only four (21%) of the patients. On Tl-201 myocardial single-photon emission computed tomography (SPECT) imaging, the perfusion of the left ventricular wall looked normal in 6 and abnormal in 5 of 11 HCM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

IDENTIFICATION AND CHARACTERIZATION OF ISOENZYMES OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE IN HUMAN KIDNEY AND HEART, AND THE EFFECTS OF NEW CARDIOTONIC AGENTS ON THESE ISOENZYMES

The present study was done to identify and characterize the isoenzymes of cyclic nucleotide phosphodiesterase (PDE) and to determine their intracellular distribution in human kidney and heart. The in vitro effects of new cardiotonic agents, namely, NSP-805 (4,5-dihydro-5-methyl-6-[4-[(2-methyl-3-oxo-1-cyclopentenyl)amino] phenyl]-3(2H)-pyridazinone), TZC-5665 (6-[4-[2-[3-(5-chloro-2-cyanophenoxy)-2-hydroxypropylamino]-2-methylpropylamino]phenyl]-5-methyl-4,5-dihydro-3(2 H)-pyridazinone) and its metabolites, OPC-18790 ((±)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2-(1H)-quinolinone), MS-857 (4-acetyl-l-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone) and E-1020 (1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6yl)-3-pyridine carbonitrile hydrochloride monohydrate), on these human PDE isoenzymes were also investigated.PDE isoenzymes were separated from cytosolic and particulate fractions of homogenates of human kidney and heart by DEAE-Sepharose chromatography. PDE isoenzymes were identified by their elution characteristics, substrate specificities, sensitivities to regulation by effectors and by the use of isoenzyme-specific inhibitors.In a cytosolic fraction from kidney, Ca2+/calmodulin-dependent PDE (CaM-PDE), cyclic GMP-stimulated PDE (cGS-PDE), cyclic GMP-inhibited PDE (cGI-PDE) and two forms of cyclic AMP-specific PDE (cAMP-PDE) were resolved. One form of cAMP-PDE (cAMP-PDEα), which was eluted at a lower ionic strength than cGI-PDE during DEAE-Sepharose chromatography, was newly recognized in human tissues, though the other form (cAMP-PDEβ), which eluted later than cGI-PDE, had been previously isolated. Both of these cAMP-specific PDEs had similar properties in that they predominantly hydrolyzed cAMP with similar Km values for cAMP and were inhibited to almost equal extents by 3-isobutyl-l-methylxanthine (IBMX) but were hardly inhibited by cGMP. However, cAMP-PDEα was inhibited about 10 times more weakly (on the basis of IC50 values) by rolipram (4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone) and Ro 20-1724 (4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone than was cAMP-PDEβ. In a cytosolic fraction from heart ventricle, four distinct PDE isoenzymes, CaM-PDE, cGS-PDE, cGI-PDE and cAMP-PDEβ, were recognized. cAMP-PDEβ was the major component of the cAMP-hydrolyzing activity in the cytosolic fraction from human kidney, while CaM-PDE and cGI-PDE represented more than 90% of the total cAMP phosphodiesterase activity in the cytosolic fraction from human heart. In the particulate fractions from human kidney and heart, three activities, those of cGI-PDE and of two forms of cAMP-PDE, were identified. In kidney, cAMP/PDEα was the main cAMP-hydrolyzing PDE, while in heart cGI-PDE accounted for most of the activity. Furthermore, we evaluated the inhibitory effects on these human PDE isoenzymes of newly synthesized compounds with inotropic effects, namely, NSP-805, metabolites of TZC-5665 referred to as M-1 (6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone) and M-2 (6-(4-acetyl-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone), OPC-18790, MS-857 and E-1020. These drugs potently inhibited the activity of cGI-PDE and very weakly inhibited the activities of CaM-PDE and cGS-PDE. With respect to inhibitory effects on cardiac cAMP-PDEβ, there were some differences between the pyridazinone derivatives, for example NSP-805 and M-2, and the nonpyridazinone derivatives OPC-18790, MS-857 and E-1020. From the IC50 values, it was clear that the pyridazinone derivatives inhibited the activity of cGI-PDE at concentrations that were two to four orders of magnitude lower than that required for the inhibition of the activity of cAMP-PDEβ, while for the nonpyridazinone derivatives the difference was about one order of magnitude. The inhibition of the activity of human cardiac cGI-PDE by NSP-805, M2, OPC-18790, MS-857 and E-1020 was competitive with respect to cAMP with Ki values of 0.012, 0.32, 0.42, 1.3 and 0.15 μmol/l, respectively.These results suggest that there may be two isoforms of cAMP-PDE, which exist not only in the particulate fraction but also in the cytosolic fraction of human tissues, and that PDE inhibitors, which exert their cardiotonic effects by inhibiting cGI-PDE, have different selectivities with respect to the inhibition of the other human PDE isoenzymes.

Aneurysm of the left aortic sinus caused by Takayasu's arteritis: Compression of the left coronary artery producing coronary insufficiency

A 45 year old Japanese woman with an aneurysm of the left aortic sinus is described. The main trunk of the left coronary artery was displaced upward, and the proximal portion of the circumflex branch was markedly compressed and displaced posteriorly, causing subendocardial infarction and angina. The diagnosis of Takayasus arteritis was made based on: 1) age, sex and nationality of the patient; 2) inflammatory signs followed by weakness of the right radial pulse; and 3) typical angiographic findings. Five previously reported cases are reviewed.

Ca2+-dependent and Ca2+-independent vasorelaxation induced by cardiotonic phosphodiesterase inhibitors

Cardiotonic agents that belong to a group of phosphodiesterase inhibitors--vesnarinone, amrinone, enoximone, pimobendan, MS-857 and E-1020--inhibited the 35 mM KCl- and 10(-7) M norepinephrine-induced contractions of helical strips from rat thoracic aorta in a concentration-dependent manner. In the absence of extracellular Ca2+, 10(-7) M phorbol 12,13-dibutyrate caused a sustained contraction of the muscle strip without an increase in intracellular Ca2+ level ([Ca2+]i). The phorbol 12,13-dibutyrate-induced contractions in Ca2+(-)free buffer were also inhibited by the cardiotonic phosphodiesterase inhibitors. A cyclic GMP-inhibited cyclic nucleotide phosphodiesterase was partially purified from rat aorta and the activity of the phosphodiesterase was inhibited by the cardiotonic agents. The inhibitory effect of these agents on the KCl-, norepinephrine-and phorbol 12,13-dibutyrate-induced contractions showed good correlations to the concentrations of the agents producing 50% inhibition (IC50) of cyclic GMP-inhibited cyclic nucleotide phosphodiesterase. Vesnarinone inhibited the norepinephrine-induced contraction with a decrease in [Ca2+]i, but inhibited the phorbol 12,13-dibutyrate-induced contraction in Ca(2+)-free buffer without significant changes in [Ca2+]i. Dibutyryl cyclic AMP and NKH477 also inhibited the phorbol 12,13-dibutyrate-induced contraction in Ca(2+)-free buffer without significant changes in [Ca2+]i. The six cardiotonic phosphodiesterase inhibitors increased the cyclic AMP contents of the muscle strips. These results suggest that the inhibitory actions of these cardiotonic phosphodiesterase inhibitors on cyclic GMP-inhibited cyclic nucleotide phosphodiesterase may cause vasorelaxation through a decrease in [Ca2+]i and an inhibitory effect on a Ca(2+)-independent contractile process (or a decrease in Ca(2+)-sensitivity of contractile elements).

Contractile actions of endothelin-1 in isolated helical strips from rat pulmonary artery : potentiation of serotonin-induced contraction

Summary: Endothelin-1 (ET-1) caused a concentration-dependent contraction of helical strips from rat pulmonary arteries. Removal of endothelial cells did not change the response to ET-1. ET-1 (10-8M) induced a small contraction of the arterial strips in the absence of extracellular Ca2+ (31.0% of the contraction in the presence of extracellular Ca2 + ). Pretreatment of pulmonary arterial strips with 6 x 10-11M ET-1 potentiated the serotonin-induced contraction (10-7-3 x 10-6 M), but showed no significant effect on KCl-induced contraction. The ET-1-induced potentiation of the response to serotonin was prevented by nordihydroguaiaretic acid (3 x 10-6M), quinacrine (10-6M), and AA861 (10_6M), but not by in-domethacin (10-7M) and baicalein (10-6M). These results suggest that ET-1 may cause pulmonary hypertension through a direct vasoconstrictor action and potentiation of serotonin-induced contraction, which may involve the 5-lipoxygenase pathway.

Contraction of rat thoracic aorta strips by endothelin‐1 in the absence of extracellular Ca2+

1 Endothelin‐1 (ET‐1) caused a concentration‐dependent contraction of helical strips from rat thoracic aorta in the absence of extracellular Ca2+. The Ca2+‐depleted muscle strips, prepared by three repeated applications of 10−2 m caffeine or 10−6 m noradrenaline in Ca2+‐free buffer, were contracted by 10−8 m ET‐1 in the same manner as non‐treated strips. 2 In the absence of extracellular Ca2+, 10−7 m phorbol 12‐myristate 13‐acetate (PMA), an activator of protein kinase C, induced a small but sustained contraction of the rat thoracic aorta strips within 60 min. Preincubation of the strips with 10−7 m PMA for 60 min in Ca2+‐free buffer, did not affect the 10−8 m ET‐1‐induced contraction, but decreased the 5 × 10−8 m phorbol 12,13‐dibutyrate (PDB)‐, or the 10−7 m PMA‐induced contraction, and potentiated the contraction induced by 10−8 m urotensin II. Preincubation with 10−8 m ET‐1 (which induced maximum contraction) for 25 min in Ca2+‐free buffer did not change the subsequent contraction induced by PMA (10−7 m) or urotensin II (10−8 m) but gave a somewhat lower maximum tension than in non‐treated strips. 3 Calyculin‐A, a potent inhibitor of phosphatase, also induced a contraction of the Ca2+‐depleted muscle strips in Ca2+‐free buffer. Preincubation of the strips with ET‐1 (10−8 m) or PMA (10−7 m) decreased the calyculin‐A (3 × 10−8 m)‐induced contraction. 4 These results suggest that ET‐1 may induce phosphorylation of an unknown protein either without an increase in myoplasmic Ca2+ concentration or, alternatively, with mobilization of intracellular Ca2+ from noradrenaline‐ and caffeine‐insensitive Ca2+ sources, through a mechanism different from that of phorbol ester.