Comparative effect of clinidipine and quinapril on left ventricular mass in mild essential hypertension.

The aim of this study was to compare the regressive effect of clinidipine on left ventricular mass (LVM) with that of quinapril. Sixty patients with mild essential hypertension aged more than 39 years were randomly allocated to two groups to receive cilnidipine (10 mg; n = 30) or quinapril (10 mg; n = 30). The patients underwent echocardiography before and 12 months after drug treatment. Sixteen patients in each group underwent 123I-metaiodobenzylguanidine (MIBG) cardiac imaging before and 12 months after drug treatment. In both groups systolic and diastolic blood pressures significantly decreased to similar levels. In the clinidipine group, both end-diastolic and end-systolic diameters and posterior wall thickness significantly decreased, while only end-systolic diameter significantly decreased in the quinapril group. However, LVM (206 +/- 36 g to 189 +/- 40 g, p < 0.02 for the quinapril group, 195 +/- 60 g to 171 +/- 48 g, p < 0.004 for the clinidipine group) and the LVM index (127 +/- 20 g/m2, to 116 +/- 20 g/m2, p < 0.02 for the quinapril group, 121 +/- 32 g/m2 to 106 +/- 24 g/m2 p < 0.003 for the clinidipine group) significantly decreased in both groups. Regarding MIBG imaging, in the cilnidipine group, the heart-to-mediastinum ratio significantly increased (p < 0.02) and the washout rate significantly decreased (p < 0.02) after drug treatment. In contrast, there were no significant changes in MIBG parameters in the quinapril group. Clinidipine produced a greater decrease in LVM in essential hypertension than quinapril, probably due to the long-term suppression of the cardiac sympathetic nervous system. Clinidipine is useful for hypertensive patients with left ventricular hypertrophy and may improve their prognosis.

Diffuse and severe left ventricular dysfunction induced by epicardial coronary artery spasm.

Endothelial dysfunction and effectiveness of treatment of calcium antagonists are suggestive of coronary artery spasm as an underlying disorder in dilated cardiomyopathy (DCM). The aim of this study is to determine whether or not the epicardial coronary artery spasm can induce severe cardiac dysfunction like DCM. Thirty-four consecutive patients with angiographically normal coronary arteries and diffuse left ventricular hypokinesis whose causes had been unknown underwent acetylcholine provocation test and left ventricular biopsy. Eight patients were excluded according to the clinical and laboratory data and biopsy findings suggesting myocarditis or other systemic diseases. According to the results of the acetylcholine provocation test, 17 patients were finally diagnosed as having DCM, and nine patients (35% of the study patients), who had acetylcholine-induced diffuse and multivessel coronary spasm, were diagnosed as having DCM-like vasospastic angina pectoris (VSA). Clinical and cardiac catheterization data including hemodynamics and biopsy findings were similar between the two groups except that left ventricular end-systolic volume was significantly greater in DCM than in DCM-like VSA. After the acetylcholine provocation test, DCM patients received both a beta blocker and an angiotensin-converting enzyme inhibitor, and DCM-like VSA patients received antianginal drugs. In echocardiographic findings at predischarge and those after 6-month drug treatment, both DCM-lke VSA and DCM showed significant reduction in end-diastolic and end-systolic diameters and significant increase in fractional shortening and ejection fraction, whereas changes in ejection fraction and fractional shortening were significantly greater in DCM-like VSA than those in DCM. Epicardial coronary artery spasm can induce diffuse and severe left ventricular dysfunction like DCM in VSA. Although antianginal drugs markedly improve left ventricular function of these patients, only the acetylcholine provocation test can identify DCM-like VSA.

Cardiac sympathetic dysfunction contributes to left ventricular remodeling after acute myocardial infarction.

To investigate the role of the cardiac sympathetic nervous system in left ventricular remodelling, 50 patients with first-time acute myocardial infarction (AMI) and patency of the infarct-related artery after reperfusion underwent quantitative iodine-123 metaiodobenzylguanidine (MIBG) imaging at 4 days and 4 weeks (n=42), and quantitative technetium-99m tetrofosmin imaging at 2 days after AMI. They also underwent both ventriculography and coronary angiography on admission and about 4 weeks after AMI. On the basis of left ventricular end-systolic volume (LVESV), patients were divided into two groups. Patients with LVESV dilatation (n=20) had a significantly lower ejection fraction (P<0.003) and a significantly higher severity score of 99mTc-tetrofosmin (P<0.04), and total severity (P<0.01), delta extent (P<0.007) and delta severity (P<0.0008) scores of MIBG than patients without LVESV dilatation (n=30). delta severity score of MIBG was directly correlated with change in LVESV at 4 weeks (r=0.63, P<0.0001). Stepwise linear discriminant function analysis showed that delta severity score of MIBG (P<0.0002) was the only discriminator of LVESV dilatation. Patients with LVESV dilatation had higher regional washout rates in both the infarct and the non-infarct zones than patients without such dilatation. Furthermore, no MIBG parameters changed significantly between 4 days and 4 weeks after AMI. In reperfused AMI, delta severity score of MIBG was related to the degree of ventricular dilatation and was the only powerful discriminator of ventricular dilatation. These results suggest that cardiac sympathetic nervous abnormality might contribute to left ventricular remodelling in reperfused AMI. MIBG imaging may allow identification of reperfused AMI patients at high risk for left ventricular remodelling.

Scintigraphic assessment of regional cardiac sympathetic nervous system in patients with single-vessel coronary artery disease.

In coronary artery disease, the cardiac sympathetic nervous system is closely associated with myocardial ischemia. I-123 metaiodobenzylguanidine (MIBG) imaging allows us to assess the cardiac sympathetic nervous system regionally. One-hundred and eleven patients with single-vessel disease underwent regional quantitative analysis of MIBG imaging before successful percutaneous transluminal coronary angioplasty (PTCA), and repeat angiography 6 months after PTCA. Based on the results of the follow-up left ventriculogram, patients were divided into 3 groups: 39 angina pectoris (AP), 48 prior myocardial infarction without asynergy (MI without asynergy) and 24 prior myocardial infarction with asynergy (MI with asynergy). AP and MI without asynergy had significant correlations between uptake parameters and regional washout in the territory of diseased vessels, among which the severity score in AP was the most closely correlated with regional washout (r = 0.79, p < 0.0001). These correlations disappeared in MI with asynergy. To compare regional MIBG parameters in the territory of the diseased vessel as well as in the territories of the other major coronary arteries among the 3 groups, we examined MIBG parameters in 57 patients with left anterior descending artery (LAD) disease selected from among the study patients. Regional washout in the territory of the LAD was significantly higher in the MI without asynergy group than in the other two groups. The left circumflex artery (LCX) region showed significantly reduced MIBG uptake and an increased extent score in the MI with asynergy group compared with the AP group, although only a difference in the extent score existed between the MI with asynergy group and the AP group in the right coronary artery (RCA) region. In addition, the global ejection fraction before PTCA showed a significant negative correlation with each regional washout rate. In this way, regional quantitative analysis of MIBG imaging can detect the regional differences in the cardiac sympathetic nervous system in coronary artery disease, which may be associated with the degree of regional left ventricular dysfunction due to myocardial ischemia.

Pseudoxanthoma elasticum with dipyridamole-induced coronary artery spasm: a case report.

In patients with pseudoxanthoma elasticum, severe organic coronary artery stenosis often occurs without coronary risk factors. However, this report presents the case of a 49-year-old woman with pseudoxanthoma elasticum who had coronary artery spasm with an angiographically normal coronary artery. In addition, coronary artery spasm was provoked with dipyridamole thallium-201 cardiac imaging.

Effects of amlodipine and cilnidipine on cardiac sympathetic nervous system and neurohormonal status in essential hypertension.

N-Type calcium channel antagonists may suppress sympathetic activity. The purpose of this study was to assess the effects of amlodipine and cilnidipine on the cardiac sympathetic nervous system and the neurohormonal status of essential hypertension. 123I-metaiodobenzylguanidine (MIBG) cardiac imaging was performed and blood samples were taken to determine plasma renin activity and plasma norepinephrine concentration before and 3 months after drug administration in 47 patients with mild essential hypertension. Twenty-four of the patients were treated with 5 to 10 mg/d of amlodipine; the other 23 were treated with 10 to 20 mg/d of cilnidipine. For comparison, 12 normotensive subjects were also studied. No significant differences were found in the basal characteristics between the 2 hypertensive groups. In both hypertensive groups, both the systolic and diastolic blood pressures were significantly reduced to similar levels 3 months after drug treatment. Before the drug treatment, the 2 hypertensive groups had a significantly higher washout rate and lower heart-to-mediastinum (H/M) ratio compared with the normotensive subjects. The H/M ratio significantly increased (P<0.05) in combination with a decreased washout rate (P<0.02) after drug treatment in the cilnidipine group. In the amlodipine group, a significant decrease in washout rate (P<0. 04) was noted, without an increase in the H/M ratio. However, no significant changes were found in plasma renin activity and plasma norepinephrine concentration in either group. Thus, in patients with essential hypertension, cilnidipine suppressed cardiac sympathetic overactivity and amlodipine had a little suppressive effect. Cilnidipine may provide a new strategy for treatment of cardiovascular diseases with sympathetic overactivity.

Coordinate interaction between ATP-sensitive K+ channel and Na+, K+-ATPase modulates ischemic preconditioning.

BACKGROUND: We reported that digoxin abolishes the infarct size (IS)-limiting effect of ischemic preconditioning (IPC). Because ATP-sensitive K+ (KATP) channels are involved in IPC, we studied whether Na+,K+-ATPase and KATP channels functionally interact, thereby modulating IPC. METHODS AND RESULTS: Rabbits received 30 minutes of coronary artery occlusion followed by 3 hours of reperfusion. IPC was elicited by 5 minutes of occlusion followed by 10 minutes of reperfusion. The IS, expressed as a percentage of the area at risk, was 40.2+/-2.8% in control and 39.8+/-5.0% in digoxin pretreatment rabbits. Both IPC and pretreatment with cromakalim, a KATP channel opener, reduced IS to 11.8+/-1.8% and 13.4+/-2.6% (P<0. 05 versus control). Digoxin abolished the reduction in IS induced by IPC (33.5+/-3.3%), whereas it did not change that induced by cromakalim (18.8+/-3.0%). In patch-clamp experiments, digoxin was found to inhibit the opening of KATP channels in single ventricular myocytes in which ATP depletion had been induced by metabolic stress. In contrast, digoxin had little effect on the channel opening induced by cromakalim. Moreover, the inhibitory action of digoxin on channel activities was dependent on subsarcolemmal ATP concentration. CONCLUSIONS: The IS-limiting effect of IPC is modulated by an interaction between KATP channels and Na+,K+-ATPase through subsarcolemmal ATP.

Effects of alkaline protease or restrictocin deficient mutants of Aspergillus fumigatus on human polymorphonuclear leukocytes.

Several substances including proteases and restrictocin have been suggested as candidates for virulence determinants in invasive pulmonary aspergillosis. However, the roles of such substances are not well understood. This study compared the in vitro suppressive effects of Aspergillus fumigatus culture filtrates (ACFs), on the functions of human polymorphonuclear leukocytes (PMNLs), the principal cells in the host defence against aspergillus hyphae, from a clinically isolated wild-type and isogenic mutant strains which lack production of elastolytic alkaline protease (Alp) and/or restrictocin. ACFs were obtained by culturing conidia of each strain in Medium- 199 at 37 degrees C for 5 days. ACFs of the wild-type significantly (p<0.01) suppressed chemotaxis, superoxide anion (O2-) release and PMNL-mediated hyphal damage, compared with the control (Medium-199). ACFs of the mutant strains that lack Alp or restrictocin significantly (p<0.01) suppressed chemotaxis and O2(-)-release, but did not suppress hyphal damage, compared with the control. The wild-type significantly (p<0.01) suppressed chemotaxis of PMNLs compared with the mutant strains lacking Alp or restrictocin, whereas there were no significant differences in suppression of O2(-)-release and hyphal damage by PMNLs. ACF of a mutant strain that lacks both Alp and restrictocin had much less activity, but significantly (p<0.01) suppressed chemotaxis of PMNLs compared with the control. In conclusion, alkaline protease and restrictocin may play roles in the suppressive effect of Aspergillus fumigatus culture filtrates on the functions of human polymorphonuclear leukocytes. Other antiphagocytic substances produced by Aspergillus fumigatus remain to be identified.

KATP channels are common mediators of ischemic and calcium preconditioning in rabbits.

Calcium preconditioning (CPC), like ischemic preconditioning (IPC), reduces myocardial infarct size in dogs and rats. ATP-sensitive potassium (KATP) channels induce cardioprotection of IPC in these animals. To determine whether KATP channels mediate both IPC and CPC, pentobarbital sodium-anesthetized rabbits received 30 min of coronary artery occlusion followed by 180 min of reperfusion. IPC was elicited by 5 min of occlusion and 10 min of reperfusion, and CPC was elicited by two cycles of 5 min of calcium infusion with an interval period of 15 min. Infarct size expressed as a percentage of the area at risk was 38 +/- 3% (mean +/- SE) in controls. IPC, CPC, and pretreatment with a KATP channel opener, cromakalim, all reduced infarct size to 13 +/- 2, 17 +/- 2, and 12 +/- 3%, respectively (P < 0.01 vs. controls). Glibenclamide, a KATP channel blocker administered 45 min (but not 20 min) before sustained ischemia, attenuated the effects of IPC and CPC (31 +/- 4 and 41 +/- 6%, respectively). Thus KATP channel activation appears to contribute to these two types of cardioprotection in rabbits.

Effects of Aspergillus fumigatus culture filtrate on antifungal activity of human phagocytes in vitro.

BACKGROUND: Aspergillus fumigatus can colonise the airways and the lungs with localised underlying conditions and occasionally invade the surrounding lung tissues even in subjects without systemic predisposing factors, presumably by escaping the local host defences. The aim of this study was to investigate the effects of A fumigatus culture filtrate (ACF) on the activities of human phagocytes--inhibition of germination of A fumigatus spores by alveolar macrophages (AMs) and hyphal damage by polymorphonuclear leucocytes (PMNs)--which are the critical host defences against A fumigatus. METHODS: Spores were incubated with AMs at a ratio of 1:1 in a medium containing different concentrations of ACF for 10 hours at 37 degrees C. Spore germination was visualised with light microscopy and the inhibition rate was calculated. The percentage of hyphal damage caused by PMNs pretreated with various concentrations of ACF was measured by a colorimetric tetrazolium metabolic assay. RESULTS: The inhibition rate of spore germination by AMs cultured with medium alone (control) was 90 (0.8)% whereas that by AMs cultured with the medium containing 10% ACF was significantly (p < 0.05) reduced to 41.7 (4.6)%. ACF suppressed the inhibition of spore germination in a dose dependent manner without altering the phagocytosing activity against the spores. The percentage of hyphal damage caused by PMNs pretreated with medium-199 (control) was 78.1 (2.3)% compared with 65.3 (2.8)% when PMNs were pretreated with 50% ACF (p < 0.05). CONCLUSIONS: A fumigatus releases biologically active substance(s) which suppress the inhibition of spore germination by AMs and also suppress PMN mediated hyphal damage, and thus may contribute to the pathogenicity of this fungus.

Inhibition of sarcolemmal Na+,K+-ATPase activity reduces the infarct size-limiting effect of preconditioning in rabbit hearts.

BACKGROUND: The inhibition of sarcolemmal Na+,K+-ATPase activity is closely related to ischemic myocardial cell injury. However, the involvement of this enzyme in preconditioning has not been determined. METHODS AND RESULTS: We assessed the effect of ischemia on sarcolemmal Na+,K+-ATPase activity. Control and preconditioned rabbits were subjected to 0, 10, 20, 30, and 60 minutes of coronary occlusion. Ten to 60 minutes of ischemia reduced Na+,K+-ATPase activity, whereas preconditioning preserved the activity of this enzyme only during the first 20 minutes of ischemia. To determine whether the preservation of Na+,K+-ATPase activity in the early phase of ischemia contributed to limiting the infarct size, additional rabbits underwent 30 minutes of occlusion followed by 3 hours of reperfusion with or without pretreatment with digoxin, an inhibitor of Na+,K+-ATPase. Infarct size in animals pretreated with digoxin in the absence of preconditioning did not differ from that in controls. It was markedly reduced by preconditioning, whereas digoxin reduced the infarct size-limiting effect. Moreover, preconditioning increased sarcolemmal Na+-Ca2+ exchange activity in rabbits subjected to 20 minutes of ischemia, whereas digoxin diminished this increase. CONCLUSIONS: Preconditioning preserves the ischemia-induced reduction in sarcolemmal Na+,K+-ATPase activity in the early phase of ischemia in rabbit hearts. Inhibition of Na+,K+-ATPase activity reduces the infarct size-limiting effect of preconditioning with a loss of increased Na+-Ca2+ exchange activity, implying that this preservation is responsible for the cardioprotective effect of preconditioning.

K(ATP) channels contribute to the cardioprotection of preconditioning independent of anaesthetics in rabbit hearts.

The contribution of ATP sensitive potassium (K(ATP)) channels to the infarct-size limiting effect of preconditioning is considered to be anaesthetic-dependent in the rabbit heart. It has previously been reported that ischaemic preconditioning prevents ischaemia-induced reductions in activities of sarcolemmal adenylate cyclase (AC) and Na+, K(+)-ATPase. Anaesthetic dependency of the role of K(ATP) channels in the preservation of these enzyme activities, induced by ischaemic preconditioning, as well as that induced by activation of A1-adenosine receptors, was examined in rabbits anaesthetized with either pentobarbital or ketamine-xylazine and subjected to 20 min of regional ischaemia. Adenylate cyclase and Na+, K(+)-ATPase activities were lower in the ischaemic than in the non-ischaemic region of the hearts in control rabbits, but not in animals subjected to ischaemic preconditioning, or those pretreated with the A1-adenosine receptor agonist R(-)-N6-(2-phenylisopropyl) adenosine. The protective effects of both ischaemic preconditioning and A1-adenosine receptor activation were prevented by 6 mg/kg, but not 3 mg/kg, of the K(ATP) channel blocker, glibenclamide, in rabbits anaesthetized with pentobarbital, while these effects were prevented by 3 mg/kg of the blocker in rabbits anaesthetized with ketamine-xylazine. Moreover, K(ATP) channel opener, cromakalim, prevented the ischaemia-induced decreases in enzymatic activities in rabbits subjected to either type of anaesthesia. Thus, although the antagonistic effect of glibenclamide is blunted under pentobarbital, compared to ketamine-xylazine anaesthesia, K(ATP) channels contribute to preservative actions independent of the type of anaesthesia in the rabbit heart.

Murine model of invasive pulmonary aspergillosis following an earlier stage, noninvasive Aspergillus infection.

Aspergillus spp. occasionally cause invasive pulmonary aspergillosis following noninvasive infection in patients with underlying bronchopulmonary disorders regardless of their systemic immunological conditions. We developed a murine model of invasive pulmonary aspergillosis following an earlier stage, noninvasive Aspergillus infection. BALB/c mice were inoculated intratracheally with agarose beads containing Aspergillus fumigatus conidia. Two weeks after inoculation, half of the mice were immunosuppressed with cortisone acetate. During a 4-week observation period, the survival rate of infected immunosuppressed mice was significantly lower (P < 0.01) than that of infected nonimmunosuppressed mice. The number of CFU in the lungs gradually decreased in the nonimmunosuppressed mice, whereas a time-related significant increase (P < 0.05) of CFU was demonstrated in the immunosuppressed mice. In the lungs of the nonimmunosuppressed mice, there was marked accumulation of neutrophils, lymphocytes, and macrophages (in this order) around the agarose beads in the bronchi. Aspergillus hyphae were surrounded by the inflammatory cells and did not invade the lung parenchyma. In contrast, in the immunosuppressed mice, Aspergillus hyphae proliferated markedly and invaded the lung parenchyma after immunosuppression. In this model, the two-dimensional extents of the lesions were also evaluated with an image-processing system. Time-related increase of the area of peribronchial necrotic lesions was significant (P < 0.05) after immunosuppression. This model should therefore be useful for investigating the pathophysiology of noninvasive Aspergillus infection and invasive pulmonary aspergillosis and also for clarifying the mechanism of conversion to the invasive disease from the noninvasive stage.

Suppressive effects of Aspergillus fumigatus culture filtrates on human alveolar macrophages and polymorphonuclear leucocytes.

Aspergillus spp., especially A. fumigatus (Af) can colonize the airways and the lungs with localized underlying conditions and further invade the surrounding lung tissues, even in subjects without systemic predisposing factors, presumably by escaping the local host defences. To clarify the mechanisms of colonization and invasion of Af, we investigated the in vitro effects of Af culture filtrates (ACFs) on the functions of human alveolar macrophages (AMs), and polymorphonuclear leucocytes (PMNs). ACFs were obtained by culturing clinically isolated Af in Medium-199 at 37 degrees C for 5 days. In the study of phagocytosis of Af conidia by human AMs, 52% of AMs ingested conidia during a 60 min incubation period in Medium-199. However, the percentage decreased to 24% when incubated with a final concentration of 30% ACF in Medium-199. With respect to the antichemotactic activity on human PMNs, 3% ACF was sufficient for significant suppression, and 30% ACF completely inhibited the migration of PMNs. In addition, phorbol myristate acetate (PMA)-induced O2- release from PMNs was significantly suppressed in Medium-199 which included 12.5% ACF or more. The antichemotactic activity of ACF was partially abolished by trypsin or chicken egg ovomacroglobulin. When ACF was separated into two fractions (molecular weight > 10 and < 10 kDa) by dialysis and centrifugation through CL-LGC filters, both fractions retained the antichemotactic activity. We conclude that Af produce several antiphagocytic factors, which can be responsible for the colonization of Af in the bronchopulmonary tissues and allow this species to invade surrounding lung tissues in pulmonary aspergillosis by suppressing local host defences.

Bronchial mucoid impaction due to the monokaryotic mycelium of Schizophyllum commune.

We report, to our knowledge, the first case of mucoid impaction of the bronchi due to a hypersensitivity reaction to the monokaryotic mycelium of Schizophyllum commune. The patient was hospitalized because of mild asthma attacks, persistent cough, peripheral eosinophilia, and "gloved finger" shadows on a chest roentgenogram. Bronchoscopic examination disclosed mucoid impactions that consisted of accumulations of eosinophils, Charcot-Leyden crystals, and nondichotomously branched hyphae in B3, B9, and B10 of the left lung. Cultures of the mucous plugs and sputum samples yielded white, felt-like mycelial colonies that were later identified as the monokaryotic mycelium of S. commune by use of mating tests with established monokaryotic and dikaryotic strains of S. commune. The results of tests for serum antibody to S. commune cytosol antigen were positive. Repeated bronchoscopies for performing bronchial toilet were effective in removing the mucous plugs and relieving the patient's symptoms. We suggest that the monokaryotic mycelium of S. commune should be considered as one of the fungi that can cause hypersensitivity-related lung diseases.

Aspergillus culture filtrates and sputum sols from patients with pulmonary aspergillosis cause damage to human respiratory ciliated epithelium in vitro.

Aspergillus species frequently colonize lower respiratory tracts and lungs with localized underlying conditions (healed tuberculous cavity, cystic fibrosis, bronchiectasis, etc.) even in subjects without systemic predisposing factors. We investigated the in vitro effects of culture filtrates of Aspergillus species and sputum sols from patients with pulmonary aspergillosis on ciliary beat frequency (CBF) and epithelial integrity of human respiratory ciliated epithelium. Culture filtrates of 25 clinically isolated fungi (16 Aspergillus fumigatus, three Aspergillus niger, one Aspergillus flavus, three Candida albicans, and two Cryptococcus neoformans) were obtained by culturing the fungi in Medium-199 at 37 degrees C for 7 days, and five sputum sols were obtained from patients with pulmonary aspergillosis infected by A. fumigatus. During 6 h experiments using a photometric technique, 14 out of 16 A. fumigatus culture filtrates caused progressive and significant reduction in CBF associated with marked epithelial disruption, whilst the culture filtrates of A. niger and A. flavus caused minor epithelial damage without slowing of CBF, and Medium-199 alone (Control) showed neither epithelial damage nor slowing of CBF. All of the sputum sols also caused significant slowing of CBF as well as epithelial disruption. Culture filtrates of C. albicans and Cr. neoformans had no effects on human respiratory epithelium. We conclude that Aspergillus species, especially A. fumigatus release a factor (or factors) which causes damage to respiratory epithelium and slows CBF, and that these factors may contribute to the colonization of the lower respiratory tracts by the Aspergillus species and may possibly contribute to the further proliferation and spread of the lesions in pulmonary aspergillosis.