Kaname Kiuchi

Alpha-human atrial natriuretic peptide, carperitide, reduces infarct size but not arrhythmias after coronary occlusion/reperfusion in dogs.

Carperitide, a recombinant form of alpha-hANP, possesses potent diuretic, natriuretic, and vasodilatory activity, and inhibits the renin-aldosterone system and sympathetic nervous activity. However, its beneficial effects on ischemic myocardium have not been studied fully. We examined carperitides effects on infarct size, hemodynamics, and arrhythmia frequency in anesthetized dogs (n = 20) subjected to a 90-min coronary artery occlusion/6-h reperfusion protocol. Intravenous infusion of carperitide (0.2 microg/kg/min) commenced 15 min after occlusion and continued during occlusion/reperfusion. Ventricular fibrillation developed in two of 10 control versus three of 10 treated dogs (p = NS). Hemodynamics, collateral blood flow to the ischemic wall measured 10 min after occlusion, and extent of area at risk were comparable for the two groups. Infarct size/area at risk was smaller in treated than in control dogs (4.5 +/- 2.1% vs. 27.8 +/- 7.8%, respectively; p < 0.05). During occlusion, carperitide tended to increase collateral blood flow (+39%) and significantly decreased left ventricular systolic pressure (-13%) and end-diastolic pressure (-40%) compared with baseline. In control dogs, collateral blood flow tended to decrease (-8.3%), whereas most hemodynamic parameters did not change significantly with respect to baseline. The number of arrhythmias recorded during occlusion/reperfusion was similar in the two groups. Intravenous administration of carperitide limited infarct size, but did not reduce incidence of ventricular arrhythmias after 90-min coronary occlusion/6-h reperfusion in anesthetized dogs. Although the beneficial effects of carperitide may be attributable to concomitant changes in hemodynamics and collateral blood flow, the precise mechanisms require further investigation.

Long-term treatment with antipsychotic drugs in conventional doses prolonged QTc dispersion, but did not increase ventricular tachyarrhythmias in patients with schizophrenia in the absence of cardiac disease.

AbstractObjective: The aim of this study was to examine the hypothesis that long-term treatment with antipsychotic drugs in conventional doses prolongs QTc dispersion and increases ventricular tachyarrhythmias in patients with schizophrenia in the absence of cardiac disease. Methods: We measured QTc and QTc dispersion and ventricular tachyarrhythmias in 64 patients with schizophrenia, including 59 patients who received psychiatric medications, and five patients who did not receive psychiatric medications, and 45 healthy volunteers. None of the subjects had a history of cardiac disease or showed any abnormality in chest radiograph and transthoracic echocardiographic studies. None of the subjects had electrolyte abnormality. None of the subjects were taking drugs known to influence the QT interval, other than psychiatric medications. Results: QTc and QTc dispersion were significantly (P < 0.017) increased in patients who received psychiatric medications compared with patients who did not receive psychiatric medications, or with healthy volunteers [QTc: 0.442 (0.029), 0.418 (0.029), 0.417 (0.028) s, QTc dispersion: 0.054 (0.013), 0.038 (0.017), 0.038 (0.009) s]. Daily ventricular premature beats were 183 (689), 77 (23), and 86 (149), respectively. No ventricular tachycardia was observed. There were no correlation between QTc and QTc dispersion and ventricular premature beats. Conclusion: Long-term treatment with antipsychotic drugs in conventional doses prolonged both QTc and QTc dispersion in patients with schizophrenia, but did not increase ventricular tachyarrhythmias in patients with schizophrenia in the absence of cardiac disease. However, despite the negative findings, ventricular tachyarrhythmias may occur as a rare side-effect of antipsychotic drugs, particularly if a patient has additional risk factors.

Reduction of size of myocardial infarction with nicorandil, a new antianginal drug, after coronary artery occlusion in dogs

The effects of nicorandil, a new antianginal drug, on size of myocardial infarction were studied in anesthetized, open-chest dogs after left anterior descending coronary artery occlusion. To quantify the extent of the hypoperfused zone.99mTc-albumin microspheres were injected into the left atrium 1 min after occlusion. Fifteen minutes after occlusion, dogs were randomly assigned to a control group or a nicorandiltreated group that received immediately after assignments 100 μg/kg of nicorandil followed by a continuous infusion of 30 μg/kg/min for 6 h. Six hours after occlusion, the left ventricle was cut into 3 mm thick slices for triphenyltetrazolium chloride staining and autoradiography. The extent of the hypoperfused zone (26.1% ± 3.1% of the left ventricle in the control vs. 23.2% ± 3.7% in the treated group, mean ± SEM) was not different between the two groups. The ratio of the extent of myocardial necrosis to the extent of the hypoperfused zone was significantly smaller in the treated group (64.3% ± 7.2%. n = 7, p < 0.05) than in the control group (92.6% ± 9.2%, n = 7). Thus, nicorandil administered early after coronary artery occlusion reduced the size of myocardial infarction by 31%.

Value of Cardiac Ultrafast Computed Tomography for Detecting Right Atrial Thrombi in Chronic Atrial Fibrillation

We evaluated the accuracy of cardiac ultrafast computed tomography in diagnosing atrial thrombi in 70 patients with chronic atrial fibrillation, and identified the predictors of atrial thrombi from among clinical, echocardiographic, and ultrafast computed tomographic features. Ultrafast computed tomography identified 11 atrial thrombi in 9 patients: 4 patients had thrombi in the left atrium, 3 in the right, and 2 in both. Transthoracic echocardiography detected only 4 left atrial thrombi, and enlargement of the left or right atrium was associated with atrial thrombi (p <0.05).

Inhibition of nitric oxide synthesis reduces coronary blood flow response but does not increase cardiac contractile response to β-adrenergic stimulation in normal dogs

Whether the nitric oxide (NO) system constitutively present in the normal myocardium and resistance coronary vessels regulates basal cardiac contractility and coronary blood flow (CBF), as well as their responses to beta-adrenergic stimulation in intact heart, remains controversial. We examined the effects of low and high doses of NG-nitro-L-arginine methyl ester (L-NAME) (10 and 100 mu g/kg/min for 10 min), an NO synthase inhibitor, as well as D-enantiomer administered into left circumflex (LCX) artery on responses of left ventricular (LV) dP/dt, regional wall thickening in LCX region and LCX blood flow to graded intracoronary doses of isoproterenol (ISO 0.002-0.016 mu g/kg/min) in normal dogs. Intracoronary L-NAME, which was associated with dose-related reductions in acetylcholine (ACh)-induced coronary vasodilation, significantly reduced baseline LCX blood flow and its response to ISO. However, L-NAME did not change baseline LV contractility as assessed by LV dP/dt and regional wall thickening, nor did it increase its response to ISO. D-Enantiomer was ineffective in reducing baseline LCX blood flow as well as its response to ISO. These results indicate that constitutive NO formation in the vasculature contributes to basal coronary vascular tone as well as resistance adjustments during beta-adrenergic stimulation. However, NO formation in the normal myocardium did not influence basal cardiac contractility; nor did it increase cardiac response to beta-adrenergic stimulation.

Effects of a Thromboxane Synthetase Inhibitor, Y-20811, on Infarct Size, Neutrophil Accumulation, and Arrhythmias After Coronary Artery Occlusion and Reperfusion in Dogs

To examine effects of a new thromboxane synthetase inhibitor, Y-20811, on infarct size, neutrophil accumulation, and arrhythmias, coronary artery was occluded for 90 min and reperfused for 6 h in anesthetized dogs. Y-20811 administered intravenously (i.v.) 30 min before occlusion decreased serum thromboxane B2 (TBX2) formation by 98% 30 min later and by 79% at 6 h after reperfusion. Ventricular fibrillation (VF) developed in 1 of 15 control and 3 of 10 treated dogs during occlusion (p = NS), whereas after reperfusion it occurred in 7 of 14 control and none of seven treated dogs (p < 0.05). The number of arrhythmias during the first hour of reperfusion was significantly reduced in treated dogs (134 ± 74 beats/min in control vs. 14 ± 4 beats/min in treated dogs, p < 0.05). Hemodynamics, area at risk, and collateral flow to the ischemic region were similar for the two groups. The extent of myocardial necrosis was 28.0 ± 10.0% (n = 7) of the area at risk in control dogs and 27.6 ± 6.2% (n = 7) in treated dogs (p = NS). The relation between the ratio of myocardial necrosis to area at risk and collateral flow was similar. The degree of neutrophil accumulation did not differ but correlated with infarct size (r = 0.85). Thus, Y-20811 reduced reperfusion arrhythmias but failed to limit infarct size and neutrophil accumulation after coronary artery occlusion/reperfusion in dogs.

Sustained beneficial effects of gallopamil (D600) on size of myocardial infarction 24 hours after coronary artery occlusion in dogs

To examine whether gallopamil (D600), a methoxy derivative of verapamil, has sustained beneficial effects on the ischemic myocardium, its effects on the size of myocardial infarction determined 6 hours (protocol 1) and 24 hours (protocol 2) after left anterior descending coronary artery occlusion were compared in anesthetized, open-chest dogs. To quantify the extent of the hypoperfused zone, Tc-99m- or In-111-albumin microspheres were injected into the left atrium 1 minute after occlusion. Fifteen minutes after occlusion, dogs were randomly assigned to a control group or a gallopamil-treated group that received immediately after assignment 0.08 mg/kg of gallopamil followed by a continuous infusion of 0.2 mg/kg/hr for 6 hours. Six or 24 hours after occlusion, the left ventricle was cut into 3 mm thick slices for triphenyltetrazolium chloride staining and autoradiography. There were no differences in the extent of the hypoperfused zone among the four groups. In both protocols 1 and 2 the ratio of the extent of myocardial necrosis to the extent of the hypoperfused zone was significantly smaller in the treated groups (56.7 +/- 6.7% [n = 8], p less than 0.01 and 72.3 +/- 5.3% [n = 6], p less than 0.05 for protocols 1 and 2, respectively) than in the control groups (100.7 +/- 6.0% [n = 7] and 95.2 +/- 4.3% [n = 5] for protocols I and II, respectively). Thus gallopamil administered early after coronary artery occlusion had beneficial effects on the ischemic myocardium, which were sustained for at least 24 hours after the onset of infarction.

Chronic direct stimulation of adenylyl cyclase induces cardiac desensitization to catecholamine and beta-adrenergic receptor downregulation in rabbits.

Chronic stimulation of beta-adrenergic receptors (βARs) induces βAR downregulation. However, it is not known whether continuous activation of adenylyl cyclase without direct stimulation of βARs leads to receptor downregulation. This study investigated the effects of chronic stimulation of adenylyl cyclase with colforsin, on hemodynamic variables, and on myocardial βAR density. In all, 55 rabbits received intravenous colforsin (1.6 μg/kg/min, n = 20), isoproterenol (ISO; 0.4 μg/kg/min, n = 16), or saline (n = 19) for two weeks. After chronic drug administration, responses of systolic (Δ% peak LV +dP/dt) and diastolic function (Δ% peak LV −dP/dt), and heart rate (Δ% heart rate), to acute administration of ISO (0.05 to 0.2 μg/kg/min) or colforsin (5 to 20 nmol/kg/min) were decreased compared to those before chronic administration. βAR density in the colforsin group (69.8 ± 13.8 fmol/ml protein) was less than that in the saline group (79.8 ± 15.0 fmol/ml protein, P < 0.05), but was greater than that in the ISO group (56.3 ± 8.4 fmol/ml protein, P < 0.05). Thus, chronic direct stimulation of adenylyl cyclase elicited systolic and diastolic functional desensitization to βAR stimulation or adenylyl cyclase stimulation, and myocardial βAR downregulation.

Does the Extent of the Zone at Risk after Coronary Artery Occlusion Influence the Percentage of the Zone that Evolves to Infarction

To examine whether the extent of the zone at risk for infarction after coronary artery occlusion influences the percentage of the zone that evolves to necrosis in the absence of intervention, 99mTc-labeled albumin microspheres were injected into the left atrium 1 min after coronary occlusion in 34 dogs. Six hours after occlusion, the left ventricle was cut into 3-mm-thick slices for triphenyltetrazolium chloride staining and autoradiography. The extent of myocardial necrosis and hypoperfused zone was measured by planimetry and expressed as a percentage of the total volume of the left ventricle. The extent of myocardial necrosis and hypoperfused zone varied widely from 8 to 40% and 14 to 43% of the left ventricle, respectively. However, there was a close correlation between infarct size (IS, percent of left ventricle) and the extent of hypoperfused zone (HZ, percent of left ventricle): IS = 0.89x (HZ) - 0.21 (r = 0.909, SEE = 3.02, p less than 0.01). The ratio of infarct size to the extent of hypoperfused zone was 87.9 +/- 2.3%. Dogs with large hypoperfused zones (greater than or equal to 30% of the left ventricle) had a significantly greater ratio of infarct size to the extent of the hypoperfused zone (95.3 +/- 2.4%, n = 11, p less than 0.05) than dogs with small hypoperfused zones (less than 30% of the left ventricle; 84.3 +/- 3.0%, n = 23). Moreover, the ratio was greater than or equal to 90% in all but one dog (91%) with large hypoperfused zones, but in only 10 of 23 dogs (43%) with small hypoperfused zones (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Initial Changes in β-Adrenergic Receptor Function during Development of Rapid Ventricular Pacing-Induced Heart Failure

Current knowledge of the pathogenesis of myocardial failure is derived mainly from studies of chronic or end-stage failing hearts. However, the mechanisms responsible for early changes in contractile function prior to the onset of severe congestive heart failure and the accompanying complications such as fibrosis might be more important, especially for creating therapeutic strategies to reverse the process of heart failure. The canine model of rapid pacing-induced heart failure is ideal for these studies because there is a progressive impairment in cardiac function, with initial cardiac dysfunction prior to development of a large dilated heart and severe congestive heart failure [1–6]. Since this occurs in the absence of significant hypertrophy or fibrosis, it makes the interpretation of data less complicated. This model of pacing-induced failure is also characterized by decreased responsiveness to β-adrenergic receptor stimulation, as seen with chronic human heart failure [7–8]. Furthermore, this action can be observed early in the cardiac dysfunction stage. Therefore, the goal of this chapter is to review data from our laboratory concerning the early changes in the β-adrenergic-receptor-G-protein-adenylyl-cyclase signal transduction system induced by rapid ventricular pacing prior to the onset of heart failure [1–3].