Morphologic evaluation and CYP11B2 IHC enabled the classification of cross-sectional image-negative hyperaldosteronism into MN and DH. Somatic mutations driving aldosterone overproduction are common in micronodules of MN, suggesting a histological entity possibly related to aldosterone-producing cell cluster development.

In this study, we examined the possibility that infarct-size limitation by repetitive preconditioning (PC) is achieved by activation of both protein kinase C (PKC) and tyrosine kinase. In addition, we assessed whether such kinase activation is triggered by angiotensin II type 1 (AT1) and alpha1-adrenergic receptors and whether sarcolemmal and mitochondrial adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels play roles as effectors of cardioprotection in the rat. Under pentobarbital anesthesia, myocardial infarction was induced by 20-min coronary occlusion and 3-h reperfusion in the rat. Infarct size was determined by tetrazolium and expressed as a percentage of area at risk (%IS/AR). PC with one cycle of 5-min ischemia/5-min reperfusion before 20-min ischemia significantly reduced %IS/AR from the control value of 49.4 +/- 2.0 to 35.4 +/- 2.8, and repetitive PC with two cycles of 5-min ischemia/5-min reperfusion further limited %IS/AR to 3.2 +/-0.9. Infarct-size limitation by single-cycle PC was completely abolished by a PKC inhibitor, staurosporine (100 microg/kg; %IS/ AR, 45.7 +/- 5.0). In contrast, the cardioprotection by repetitive PC was only partially blocked by staurosporine (%IS/AR, 19.8 +/- 2.4), another PKC inhibitor, polymyxin B (5 mg/kg; %IS/AR, 16.2 +/- 3.1), or a tyrosine kinase inhibitor, genistein (5 mg/kg; %IS/AR, 21.8 +/- 1.4). However, a combined injection of genistein and staurosporine additively inhibited protection of repetitive PC (%IS/AR, 36.4 +/- 1.7). Staurosporine, polymyxin B, or genistein alone did not modify %IS/AR in nonpreconditioned rat hearts. Infarct-size limitation by repetitive PC was not attenuated by pretreatment with a selective AT1-receptor blocker (CV11974, 10 mg/kg), prazosin (0.6 mg/kg; %IS/AR, 6.4 +/- 3.2 and 1.6 +/- 0.5, respectively). A selective blocker of mitochondrial K(ATP) channels, 5-hydroxydecanoate (3 mg/kg), completely abolished the cardioprotective effect (%IS/AR, 50.8 +/-3.5), but HMR1883 (3 mg/kg), a selective blocker of sarcolemmal K(ATP) channels, failed to inhibit the preconditioning effect (%IS/AR, 4.4 +/- 0.7). These findings suggest that repetition of PC provokes activation of both PKC and tyrosine kinase, leading to enhanced antiinfarct tolerance by opening of mitochondrial but not sarcolemmal K(ATP) channels. It is unlikely that activation of either AT1 or alpha1-adrenergic receptor alone is crucial to trigger preconditioning. Key Words: Tyrosine kinase-Genistein-Angiotensin II-alpha1-Adrenergic receptor-Sarcolemmal K(ATP) channel-Mitochondrial K(ATP) channel.

As compared with echocardiographic parameters of LA size and LA function, AEMI appears to be more useful for identifying PAF patients. AEMI may enable to detect high risk PAF patients, especially those categorized into low risk by CHADS2 score.

These findings suggest that opening of mitoK(ATP) channels before ischemia and during early ischemia, but not that upon reperfusion, is important for enhancement of myocardial tolerance against infarction.

To obtain insight into the role of the mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channel in ischemic preconditioning (PC), we aimed to clarify the mitoK(ATP) channel-dependent phase of PC in two PC protocols with different intervals between PC ischemia and an index ischemia. The possible contribution of mitoK(ATP) channel opening to protein kinase C activation in PC was also examined by Western blotting. Myocardial infarction was induced by 30-min coronary occlusion/2-h reperfusion in rat hearts in situ, and infarct size was expressed as a percentage of the area at risk (% IS/AR). PC was performed with 2 episodes of 5-min ischemia, and each heart was subjected to 30-min ischemia either 5 min or 20 min after PC. At 5 min after PC, both PKC-delta and -epsilon were translocated and the myocardium was protected against infarction (% IS/AR = 28.3 +/- 2.7 % vs. 72.7 +/- 2.2 in controls p < 0.05). Pretreatment with a selective mitoK(ATP) channel blocker, 5-hydroxydecanoate (5-HD, 10 mg/kg), abolished the cardioprotection but not PKC translocation by PC. At 20 min after PC, PKC translocation remained at the same level as that 5 min after PC, but the anti-infarct tolerance was attenuated (%IS/AR = 43.5 +/- 4.7 %). Injection of 5-HD after PC did not affect anti-infarct tolerance at 5 min after PC but abolished the protection at 20 min after PC without any effects on PKC. These results suggest that the mitoK(ATP) channel plays a role in triggering of PC in a PKC-independent manner and that the role of the mitoK(ATP) channel as a mediator of protection is detectable after, but not before, the PC effect starts to decay without a change in the level of PKC translocation in the rat heart.

The use of the appetite suppressant agents aminorex and fenfluramine derivatives has been reported as a risk factor for the development of pulmonary hypertension. A 29-year-old female developed pulmonary hypertension suspected to be due to an amphetamine-like appetite suppressant agent, mazindol ((+/-)-5-(p-chlorophenyl)-2,5-dihydro-3H-imidazo [2,1-a] isoindol-5-ol). She was admitted to Sapporo Medical University Hospital with dyspnea due to severe pulmonary hypertension. Twelve months prior to admission, she had taken mazindol continuously for a period of 10 weeks. As yet, her pulmonary hypertension has not completely improved. This is the first reported case of mazindol-associated pulmonary hypertension, which developed after a long latent interval, and it suggests that mazindol is also a risk factor for the development of pulmonary hypertension, making long-term follow-up necessary for patients taking this anorectic agent.

This study examined whether chronic inhibition of the angiotensin-converting enzyme (ACE) lowers the threshold of preconditioning (PC) and potentiates cardio-protection of subthreshold PC. Rabbits were orally administered either 0.5 mg/kg/day temocapril or placebo for 14 days and were randomly subjected to subthreshold PC (i.e., PC with 2 minutes ischemia/5 minutes reperfusion) or no PC before a 30-minute coronary artery occlusion and a 3-hour reperfusion. The size of the infarct was determined by tetrazolium staining and was expressed as the percent of the area at risk (%IS/AR). At the end of the experiment, the lungs were sampled for a tissue ACE activity assay. There was no significant difference in %IS/AR among the rabbits given placebo alone, placebo plus 2 minutes PC, and temocapril alone (%IS/AR = 59.5 +/- 5.8%, 43.6 +/- 3.7%, and 56.7 +/- 7.1%, respectively). However, %IS/AR was significantly reduced in the group that received temocapril and 2 minutes PC before infarction (%IS/AR = 35.4 +/- 4.8%, P < 0.05 vs. placebo control and temocapril control). The lung tissue ACE activity did not differ in the placebo-treated rabbits with and without PC (12.6 +/- 2.8 vs. 13.7 +/- 2.0 nmol/g protein/min) but was suppressed in temocapril-treated rabbits despite 2 minutes PC (0.9 +/- 0.1 vs. 1.5 +/- 0.2 nmol/g protein/min, both P < 0.05 vs. placebo-treated groups). The present results suggest that chronic inhibition of ACE is beneficial for potentiating the anti-infarct effect of subthreshold PC.

This study was designed to determine whether inhibition of neutral endopeptidase 24.11 (NEP) reduces infarct size and enhances protection afforded by ischemic preconditioning (PC) by elevation of the tissue bradykinin (BK) level in the heart in situ. In experiments to determine a dose of thiorphan (Thio) that inhibits NEP activity in the rabbit, infusion of Thio at a rate of 15 micro g/kg per min was found to be NEP-selective, since it increased the extent and duration of hypotension after BK injection (50 ng/kg and 100 ng/kg, i.v.) but did not inhibit pressor response to angiotensin I (100 ng/kg and 500 ng/kg, i.v.). Infusion of Thio at a rate of 25 micro g/kg per min blunted pressor response to angiotensin I by 30%, suggesting this dose partially inhibits angiotensin-converting enzyme activity. In the second series of experiments, myocardial infarction was induced by 30-min coronary occlusion and 3-h reperfusion in rabbits. In untreated controls, infarct size as a percentage of area at risk (%IS/AR) was 50.1+/-4.1%, and infusion of Thio at 15 micro g/kg per min and 25 micro g/kg per min failed to limit infarct size (54.3+/-4.0% and 50.1+/-2.8%, respectively). However, these doses of Thio significantly reduced %IS/AR when combined with PC with 2-min ischemia to 25.7+/-3.3% and 19.7+/-3.1%, respectively, although this submaximal PC protocol alone did not achieve significant cardioprotection (%IS/AR=35.6+/-4.0%). This effect of Thio on PC was abolished by pretreatment with icatibant (2 micro g/kg), a BK B(2) receptor blocker. The results of the present study suggest that NEP inhibition does not increase anti-infarct tolerance of the myocardium but significantly enhances cardioprotection of PC via a B(2) receptor-mediated mechanism.