Ichiro Nakae

Mechanism of the vasodilatory action of nicorandil on coronary circulation in dogs.

SummaryNicorandil possesses hybrid properties as a nitrate and a potassium (K) channel opener. We have previously reported that large coronary arteries responded to nicorandil at low plasma concentrations, while dilatation of small coronary arteries only occurred at higher plasma concentrations (above 200 ng/ml) in chronically instrumented dogs. In this study we examined the effects of intravenous nicroandil on epicardial coronary artery diameter (CoD) and coronary blood flow (CBF) in the absence and presence of glibenclamide, a K+ channel blocker, as well as the effects of nitroglycerin and cromakalim as reference drugs. The increase in CBF induced by nicorandil and cromakalim was significantly suppressed by glibenclamide. However, the increase in CoD induced by nicorandil and nitroglycerin was not suppressed by glibenclamide. These findings suggest that nicorandil-induced dilatation of the large coronary arteries was related to its nitrate action, while nicorandil-induced dilatation of the small coronary arteries was closely related to its effect as a K+ channel opener. In addition, the former response to nicorandil occurred at low concentrations, while the latter occurred at higher concentrations.

Absence of hemodynamic tolerance to nicorandil in patients with severe congestive heart failure

To evaluate whether hemodynamic tolerance develops to nicorandil, a nitrate and potassium channel opener, 14 patients with chronic heart failure (CHF) were treated with nicorandil and 11 were treated with nitroglycerin (GTN). Doses of GTN or nicorandil were titrated to achieve a > or = 20% reduction in pulmonary capillary wedge pressure (PCWP) within 1 hour, and the infusion was maintained at a constant rate for 24 hours. Both groups of patients had comparable hemodynamic parameters before drug infusions were started. The fall in PCWP was identical after 1 hour infusion of either GTN or nicorandil. In the GTN group, PCWP was not significantly different from the baseline value at 12 hours; however, in the nicorandil group, PCWP remained significantly lower than the preinfusion value for 24 hours. During the study period changes in plasma atrial natriuretic peptide (ANP) concentrations paralleled and correlated with changes in PCWP (r = 0.84, p < 0.001). These findings indicate that CHF patients develop hemodynamic tolerance to GTN within 12 hours of continuous infusion, but not to nicorandil, which remained hemodynamically effective during the 24-hour period of infusion. Furthermore, plasma ANP concentration may be a useful noninvasive index of hemodynamic tolerance during GTN or nicorandil therapy in patients with CHF.

Clinical features of myocardial triglyceride in different types of cardiomyopathy assessed by proton magnetic resonance spectroscopy: comparison with myocardial creatine.

BACKGROUND Myocardial lipid overstorage may produce cardiomyopathy, leading to dysfunction, but advanced heart failure may cause lipolysis via sympathetic nerve activation. In the failing heart, the creatine kinase system may also be impaired. The aims of this study were to assess myocardial triglyceride (TG) and creatine (CR) in different types of cardiomyopathy and to investigate whether they are related to the severity of cardiac dysfunction. METHODS AND RESULTS In patients with hypertrophic cardiomyopathy (HCM, n = 8), dilated cardiomyopathy (DCM, n = 12) or ischemic cardiomyopathy (ICM, n = 10), and normal subjects (NML, n = 22), myocardial TG and CR were evaluated using proton magnetic resonance spectroscopy. To assess cardiac sympathetic nerve activity, myocardial MIBG (a radioactive guanethidine analog) uptake was measured in DCM. Myocardial TG was significantly lower in hypertrophic cardiomyopathy (HCM) (1.92 ± 0.99 μmol/g), but higher in ICM (7.59 ± 4.36 μmol/g) than in NML hearts (4.05 ± 1.94 μmol/g). There was no significant difference in TG between DCM (4.84 ± 6.45 μmol/g) and NML. Myocardial CR in HCM (20.4 ± 8.4 μmol/g), DCM (14.8 ± 4.8 μmol/g), and ICM (19.4 ± 6.3 μmol/g) was significantly lower than that in NML hearts (27.1 ± 4.3 μmol/g). Overall, myocardial CR correlated positively with the severity of heart failure estimated by ejection fraction or myocardial BMIPP (a radioactive fatty acid analog) uptake, but TG did not. In DCM, myocardial TG correlated with body mass index, but not with MIBG uptake. CONCLUSIONS Myocardial TG may be related to the specific cause of disease rather than the severity of cardiac dysfunction. In contrast, myocardial CR reflects the severity of heart failure despite different pathoetiologic mechanisms of dysfunction. In DCM, myocardial TG may be affected by an overweight state rather than cardiac sympathetic nerve dysfunction. Thus, myocardial CR has a closer relationship to heart failure severity than does myocardial TG.

Left ventricular systolic/diastolic function evaluated by quantitative ECG-gated SPECT: comparison with echocardiography and plasma BNP analysis

Objective: The aim of this study was to evaluate the left ventricular (LV) functional parameters calculated using quantitative electrocardiography (ECG)-gated myocardial perfusion single photon emission computed tomography (QGS). In addition to LV systolic parameters, diastolic parameters were compared with those by ultrasound echocardiography (UCG) and also with plasma B-type natriuretic peptide (BNP) concentrations.Methods: We examined 46 patients with various forms of heart disease. By the QGS data with 16 framing data acquisition using technetium (Tc)-99m methoxyisobutylisonitrile (MIBI) perfusion, we calculated the following parameters: LV end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), peak filling rate (PFR), filling rate during the first third of the filling time ( 1/3FR) and first third filling fraction ( 1/3FF). By UCG, we measured mitral early to atrial (E/A) wave velocity ratio and pulmonary venous inflow systolic/diastolic (S/D) ratio as diastolic functional parameters. Plasma BNP concentrations were also measured.Results: There was a significant correlation between LVEDV, ESV and EF measured by QGS and UCG (EDV, r = 0.71, p < 0.001; ESV, r = 0.82, p < 0.001; EF, r = 0.75, p < 0.001). The PFR, 1/3FR and 1/3FF obtained by QGS correlated positively with E/A ratio (PFR, r = 0.54, p < 0.001; 1/3FR, r = 0.61, p < 0.001; 1/3FF, r = 0.42, p < 0.01) and negatively with S/D ratio (PFR, r = -0.40, p < 0.01; 1/3FR, r = -0.38, p < 0.05; 1/3FF, r = -0.39, p < 0.01) obtained by UCG. Plasma BNP concentrations in EF < 50% patients were greater than those in EF ≥ 50% patients (335.2 ± 60.2 vs. 101.2 ± 41.3 pg/m/, p < 0.01, both n = 17). Plasma BNP levels were also compared between higher and lower 1/3FF patients matched for LVEF. Plasma BNP concentrations in 1/3FF < 35% patients were significantly greater than those in 1/3FF ≥ 35% patients (312.9 ± 62.5 vs. 120.5 ± 32.8 pg/m/, p < 0.05, both n = 14).Conclusions: The degree of LV systolic and diastolic dysfunctions evaluated by QGS correlated with that by UCG or BNP. The QGS functional parameters offer useful information regarding cardiac failure.

Coronary effects of diadenosine tetraphosphate resemble those of adenosine in anesthetized pigs: involvement of ATP-sensitive potassium channels.

Diadenosine tetraphosphate (Ap4A) is an adenine nucleotide with vasodilatory properties. We examined the effects of Ap4A on coronary circulation in comparison with those of adenosine, its metabolite, in anesthetized pigs. Left atrial (LA) infusion of Ap4A at increasing doses of 100, 200, and 300 micrograms/kg/min increased coronary blood flow (CBF) and decreased systemic blood pressure (BP) and coronary vascular resistance (CVR). Ap4A had no effect on large epicardial coronary artery diameter (CoD). Likewise, LA infusion of adenosine at doses of 150 and 300 micrograms/kg/min increased CBF and decreased BP and coronary vascular resistance (CVR) but did not affect CoD. Therefore, the vasodilatory effects of Ap4A and adenosine were predominant in small coronary resistance vessels and negligible in large coronary arteries. Pretreatment with glibenclamide (2 mg/kg, intravenously, i.v.), a specific blocker of ATP-sensitive potassium channels (KATP), attenuated alterations of CBF, BP, and CVR induced by Ap4A and by adenosine. In contrast, treatment with cromakalim (0.5 microgram/kg/min i.v.), an activator of KATP, enhanced the coronary effects of Ap4A and adenosine. Therefore, the opening of KATP in the pig coronary circulation is involved in the in vivo vasodilatory effects of Ap4A and adenosine. Treatment with 8-phenyltheophylline (8-PT, 4 mg/kg i.v.), an adenosine receptor antagonist, suppressed CBF increases induced by Ap4A (20 micrograms/kg/min, intracoronarily, i.c.) and adenosine (5 micrograms/kg/min i.c.) by 68 and 90%, respectively. These findings suggest that the in vivo coronary effects of Ap4A are largely caused by the opening of KATP through rapid degradation to adenosine to activate adenosine receptors.

Visual assessment of coronary artery stenosis with electrocardiographically-gated multislice computed tomography.

Background: With faster image acquisition times and thinner slice widths, multislice detector computed tomography (MSCT) allows visualization of human coronary arteries. Significantly improved image quality, with high resolution and new software for three-dimensional post-processing, has made non-invasive examination of the cavities within human body possible. Objective: The aims of this study are to evaluate the diagnostic accuracy of ECG-gated MSCT for the detection of significant coronary artery stenosis and occlusions. Methods: In 25 patients (19 male and 6 female aged 65 ± 9 years) with suspected obstructive coronary artery disease, ECG-gated MSCT angiography was performed with an 8-slice MSCT scanner. Visual coronary arteries were simulated in three coronary arteries. Conventional coronary angio-graphies were performed in all patients. And coronary lesions in MSCT were estimated by two observers, who did not know the results of the coronary angiography. Results: Current MSCT allows visual coronary artery with good image quality. The overall sensitivity for diagnosing significant coronary stenosis were 75.0%, the specificity was 95.6%. The positive and negative predictive values were 84.9 and 92.2%, respectively. The accuracy of MSCT for detecting coronary stenosis is the highest in the left main tranck and left anterior descending coronary artery, and lowest in the circumflex coronary artery. Conclusion: MSCT was feasible for the detection of coronary artery stenosis.

Prognostic value of ECG-gated thallium-201 single-photon emission tomography in patients with coronary artery disease.

Background: The phenomenon of reversible impairment in LV function has been well described and is known as myocardial stunning.Objective: Thallium-201 myocardial perfusion gated SPECT was used to evaluate myocardial stunning and its incremental prognostic value in patients with coronary artery disease.Patients and Methods: Fifty-six patients (aged 63 ±11 years) with coronary artery disease were included in this study. All subjects underwent exercise thallium scintigraphy. ECG-gated SPECT was obtained both at post-stress (10 minutes after the injection of 111 MBq of thallium at the time of peak exercise) and at rest (180 minutes). The left ventricular ejection fraction (LVEF) and end-systolic and end-diastolic volume (ESV, EDV) were determined by a quantitative gated SPECT (QGS) program.Results: Follow-up was complete in all patients (mean 569 days). The magnitude of the depression of post-stress LVEF relative to the rest LVEF was correlated with the severity of ischemia (p < 0.05). The group with a median LVEF of more than 45% had a significantly higher event-free rate (p < 0.01).Conclusion: Assessment of post-stress left ventricular function by gated-SPECT provides incremental prognostic information and is useful in predicting cardiac events in patients with suspected or definite coronary artery disease.

Vasorelaxing effects of atrial and brain natriuretic peptides on coronary circulation in heart failure.

Natriuretic peptide (NP) receptor has been postulated to be downregulated under a high concentration of atrial NP (ANP) in congestive heart failure (CHF), but limited information is available on how the vascular functional responsiveness to NPs is altered in coronary circulation during CHF. We assessed the relaxant effects of ANP, brain NP (BNP), and other vasodilators in isolated coronary arteries obtained from dogs with and without severe CHF induced by rapid right ventricular pacing. In CHF dogs, plasma ANP and cGMP concentrations were elevated compared with control dogs. In CHF arteries the relaxant effects of ANP and BNP (10-8 and 10-7 mol/l) were suppressed compared with control arteries. Nitroglycerin, nitric oxide, 8-bromo-cGMP, and beraprost sodium produced similar concentration-response curves in both arteries. The addition of 10-7 mol/l ANP increased the level of tissue cGMP in control arteries, but not in CHF arteries. We conclude that there was a specific reduction in the relaxant effects of ANP and BNP in isolated coronary arteries in severe CHF dogs, which suggests the possibility of the downregulation of NP receptors coupled to guanylate cyclase.Natriuretic peptide (NP) receptor has been postulated to be downregulated under a high concentration of atrial NP (ANP) in congestive heart failure (CHF), but limited information is available on how the vascular functional responsiveness to NPs is altered in coronary circulation during CHF. We assessed the relaxant effects of ANP, brain NP (BNP), and other vasodilators in isolated coronary arteries obtained from dogs with and without severe CHF induced by rapid right ventricular pacing. In CHF dogs, plasma ANP and cGMP concentrations were elevated compared with control dogs. In CHF arteries the relaxant effects of ANP and BNP (10(-8) and 10(-7) mol/l) were suppressed compared with control arteries. Nitroglycerin, nitric oxide, 8-bromo-cGMP, and beraprost sodium produced similar concentration-response curves in both arteries. The addition of 10(-7) mol/l ANP increased the level of tissue cGMP in control arteries, but not in CHF arteries. We conclude that there was a specific reduction in the relaxant effects of ANP and BNP in isolated coronary arteries in severe CHF dogs, which suggests the possibility of the downregulation of NP receptors coupled to guanylate cyclase.

Augmentation Index and Pulse Wave Velocity as Indicators of Cardiovascular Stiffness

The authors examine the clinical significance of radial augmentation index (rAI) and brachial-ankle pulse wave velocity (baPWV). In 78 hypertensive patients, rAI correlates inversely with pulse rate (PR; r = −0.57, P < .001), but baPWV does not. A weak correlation between rAI and systolic blood pressure (SBP) is observed (r = 0.28, P < .05). rAI has no significant correlation with diastolic blood pressure (DBP). In contrast, baPWV correlates positively with both SBP (r = 0.54, P < .001) and DBP (r = 0.43, P < .001). In 56 of these patients, baPWV correlates with the diastolic parameters—the mitral E/A ratio (r = —0.35, P < .01), pulmonary vein S/D ratio (r = 0.41, P < .01), and deceleration time (r = 0.28, P < .05)—by echocardiography, but AI.P75 (rAI corrected for PR 75 bpm because of PR dependence) does not. Therefore, for detection of diastolic dysfunction, baPWV may be more sensitive than rAI.

Effects of intravenous nicorandil on coronary circulation in humans : Plasma concentration and action mechanism

We investigated the cardiovascular profile of nicorandil, an antianginal agent, in humans. Pharmacologically, nicorandil acts as both an adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channel opener and a nitrate. We examined which of these mechanistic components has a predominant vasodilatory effect at clinical doses. Fourteen patients underwent cardiac catheterization. The effects of the continuous intravenous infusion of nicorandil (12 mg/45 min) were examined in angiographically normal coronary arteries. Coronary vascular resistance was calculated from coronary artery diameter and coronary blood flow velocity measured using an intravascular Doppler catheter. We compared the hemodynamic responses to nicorandil with those to the intracoronary injection of nitroglycerin (250 microg) and papaverine (12 mg). The epicardial coronary arteries responded to nicorandil at the lowest plasma concentration examined (dilation of +14.0 +/- 3.3% at approximately 170 ng/ml), whereas dilation of the coronary resistance arteries (i.e., a decrease in coronary vascular resistance) took place only at higher concentrations (>200 ng/ml). Nitroglycerin caused no further changes in coronary artery diameter or coronary vascular resistance. Papaverine caused no further increase in coronary artery diameter, but markedly decreased coronary vascular resistance (1.6 +/- 0.3 to 0.4 +/- 0.1 mm Hg/ml/min; p < 0.05). Nicorandil significantly decreased pulmonary capillary wedge pressure (i.e., reduced cardiac preload) at a plasma level of >200 ng/ml, but did not change either systemic or pulmonary vascular resistance. Thus nicorandil preferentially dilated epicardial coronary arteries rather than coronary resistance arteries, and had a stronger effect on preload than on afterload. These changes in human coronary hemodynamics suggest that the nitrate actions of nicorandil as a coronary vasodilator predominate over those as a K(ATP) opener.