Coronary effects of nicorandil in comparison with nitroglycerin in chronic conscious dogs

The effects of nicorandil (0.2 mg/kg, IV) and nitroglycerin (15 micrograms/kg, IV) on large and small coronary arteries were compared in conscious dogs instrumented with ultrasonic crystals and electromagnetic flow meters in the circumflex coronary artery. Nicorandil dilated the large coronary arteries to the same extent, but with a longer duration of action than nitroglycerin. The small coronary arteries dilated for a very short period of time with nitroglycerin, but dilated markedly with nicorandil. The dilatory action of nicorandil on large coronary arteries persisted after the action on the small coronary artery fell to the control value, indicating that the dilatory action on the large coronary arteries is due to the direct relaxing effect on smooth muscle and is not the result of the flow-dependent effect. The measurement of the plasma concentration of nicorandil after incremental infusions of the agent showed that the dilation of the small coronary artery took place at only a very high level (above 200 ng/ml). On the other hand, the large coronary arteries responded to nicorandil at a much lower concentration (about 100 ng/ml, the clinically effective plasma concentration of nicorandil) than the small coronary resistance arteries. In conclusion, whereas nicorandil possesses a dilatory action on both large and small coronary arteries, in a clinical setting, with a daily dosage of 15-30 mg, part of the beneficial effects of nicorandil may be the result of a dilation of the large coronary arteries and may be due to the fact that a coronary steal phenomenon does not occur after nicorandil administration.     

麝香保心丸对心力衰竭大鼠肺脏肾上腺素受体表达的影响

目的探讨麝香保心丸对心力衰竭大鼠肺脏α_(1A)-肾上腺素受体(α_(1A)-AR)和β_1、β_2肾上腺素受体(β-AR)表达水平的变化。方法选择Wistar大鼠54只,随机分为对照组(A组,10只)、假手术组(B组,10只)、心力衰竭模型对照组(C组,9只)、阳性药物对照组(D组,9只)、麝香保心丸小剂量组(E组,9只)和麝香保心丸大剂量组(F组,9只)。超声心动图检测用药前后大鼠心功能,采用Western blot测定各组大鼠肺组织α_(1A)-AR和β_1-AR、β_2-AR蛋白表达水平。结果用药前,A组与B组大鼠LVEF比较,差异无统计学意义(P>0.05);与B组比较,C、D、E、F组大鼠LVEF明显降低(P<0.01)。用药后与C组比较,F组大鼠LVEF明显改善;与B组比较,C组大鼠α_(1A)-AR、β_1-AR蛋白明显降低,β_2-AR蛋白明显升高;与C组比较,D、E、F组大鼠α_(1A)-AR、β_1-AR、β_2-AR蛋白明显升高(P<0.05,P<0.01)。结论麝香保心丸能改善心肌梗死后心力衰竭大鼠的心脏功能,肾上腺素受体表达水平的变化,有利于维持心力衰竭时肺脏的通气/血流比值,进而对心力衰竭起到有益的治疗作用。     

Regulation of large coronary arteries by beta-adrenergic mechanisms in the conscious dog

We examined, in conscious dogs, the effects of beta-adrenergic stimulation on measurements of left circumflex coronary arterial diameter and blood flow and on calculations of late diastolic coronary resistance (LDCR) and left circumflex coronary internal cross-sectional area (CSA). Isoproterenol (0.1 microgram/kg) initially decreased mean arterial pressure by 25 +/- 2% (mean +/- SEM), and LDCR by 62 +/- 4%, and increased heart rate by 82 +/- 10%, left ventricular (LV) dP/dt by 79 +/- 12%, and mean coronary blood flow by 85 +/- 5%, while CSA rose slightly. The peak effects on CSA (24 +/- 2%) occurred later, along with decreases in mean arterial pressure (7.4 +/- 1.0%) and LDCR (25 +/-5.3%) and increases in coronary blood flow (14 +/- 2%), LV dP/dt (12 +/- 3%), and heart rate (24 +/- 4%). Pirbuterol (1.0 microgram/kg) induced changes that were qualitatively similar to those induced by isoproterenol. Prenalterol (20 micrograms/kg), a cardioselective beta 1-adrenergic receptor agonist, did not affect mean arterial pressure, but increased heart rate by 40 +/- 5%, LV dP/dt by 72 +/- 10%, mean coronary blood flow by 34 +/- 11%, and CSA by 26 +/- 3%, and decreased LDCR by 29 +/- 5+. Isoproterenol and pirbuterol, but not prenalterol, increased coronary sinus O2 content and decreased A-VO2 difference. After beta 1-adrenergic receptor blockade with atenolol (1 mg/kg), prenalterol no longer induced significant effects, whereas isoproterenol and pirbuterol decreased mean arterial pressure similarly to what was observed prior to blockade, but did not increase LV dP/dt, and induced attenuated increases in mean coronary blood flow, CSA, and decreases in LDCR. Thus, in the intact, conscious animal, large coronary arteries are regulated by beta-adrenergic mechanisms. Surprisingly, a major fraction of large coronary arterial dilation appeared to be either directly or indirectly due to beta 1-adrenergic receptor mechanisms, although beta 2-adrenergic effects were also significant.     

Cyclical coronary flow reductions in conscious dogs equipped with ameroid constrictors to produce severe coronary narrowing

Summary In conscious dogs equipped with ameroid constrictors to produce gradual coronary occlusion, coronary flow velocity was monitored prior to complete occlusion when coronary constriction was severe (resting flow velocity reduced by 10–50% from control recordings made 7–10 days after ameroid implantation). In six of the ten dogs, we observed spontaneous cyclical variations in coronary flow velocity, characterized by gradual reduction in flow followed by very abrupt restoration of flow. The cyclic coronary flow reductions were observed between 20 and 31 days after ameroid implantation. These changes in flow bear striking similarity to those observed by previous investigators using anesthetized, open-chest canine preparations, in which the role of platelets was clearly demonstrated. Consequently, we hypothesize that spontaneous platelet aggregation and de-aggregation within the severely narrowed coronary lumen (enclosed by the ameroid constrictors) could account for our observations.Supported by Specialized Center of Research on Ischemic Heart Disease HL-17682 from the National Heart, Lung, and Blood Institute     

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

Summary Nicorandil 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.     

Diameter of coronary arteries in 36 species of mammalian from mouse to giraffe

Summary Systematic quantitative investigations were performed in the coronary arteries of 102 hearts of 36 mammal species with an overall more than tenthousandfold difference of their heart weight. After postmortem coronary angiography with a filling pressure of 100 mm Hg x-rays were taken, and the widest diameters of the coronary artery stems were determined. We found a nearly linear correlation between diameter of a standardized coronary artery and virtual diameter of heart, but the increase in diameter of coronary arteries exceeded somewhat that of the diameter of heart especially for heart weights surmounting 100 g. Perhaps relative enlargement of coronary arteries in the bigger hearts contributes to the prevention of large increase of blood flow velocity.This study was supported by a research grant of the Deutsche Forschungsgemeinschaft 282/8     

Cardiac alpha- and beta-adrenergic receptor alterations in diabetic cardiomyopathy

Summary The effect of chronic experimental diabetes on the adrenergic receptors in the rat heart was investigated. Diabetes was induced by streptozotocin (65 mg/kg; i.v.) administration, animals were sacrificed 8 weeks later, and positive as well as negative dF/dt values were determined in isolated papillary muscle preparations. Stimulation of the contractile force generation by isoproterenol and methoxamine was attenuated in diabetic preparations. Beta-and alpha-adrenergic receptor bindings were determined in cardiac membranes by employing³H-dihydroalprenolol and³H-dihydroergocryptine respectively. Reduced number of beta- and alpha-receptor binding sites without changes in the affinity constants were observed in diabetic myocardium. Such a decrease in alpha- and beta-receptor density in the heart may account for the depressed contractile responsiveness to adrenergic stimuli in diabetic cardiomyopathy.

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Zusammenfassung Es wurde der Einfluß eines chronischen, experimentellen Diabetes auf die adrenergen Rezeptoren des Rattenherzens untersucht. Diabetes wurde durch Streptozotocin (65 mg/kg i.v.) erzeugt. Die Untersuchungen wurden 8 Wochen nach Verabreichung durchgeführt. Es wurden positive und negative dF/dt-Werte (Geschwindigkeit der Kraftentwicklung) von isolierten Papillarmuskeln bestimmt. Die durch Isoproterenol und Methoxamin gesteigerte Kraftentwicklung war bei Ratten mit Diabetes vermindert. Die Bindungseigenschaften von Beta-und Alpha-rezeptoren in den Membranen des Herzens wurden mit Hilfe von³H-dihydroalprenolol und³H-dihydroergocryptin bestimmt. Im diabetischen Myokard war die Zahl der Beta- und Alpharezeptor-Bindungsstellen vermindert, nicht jedoch die Affinitätskonstanten. Die verringerte Beta- und Alpharezeptoren-Dichte im Herz könnte für die verminderte Ansprechbarkeit der Mechanik auf adrenerge Reize bei der diabetischen Kardiomyopathie verantwortlich sein.

     

乙酰胆碱对犬冠状动脉循环和心电活动的影响

本研究对２２条犬，在建立颈总动脉向左冠脉回旋支（ＬＣＸ）供血的模型基础上，进行刺激右侧迷走神经（ＲＶ）。ＬＣＸ内注射乙酰胆硷（Ａｃｈ）、硝酸甘油（ＮＧ）、去甲肾上腺素（ＮＥ）等实验，观察冠脉灌注压（ＣＰＰ）、冠脉平均血流量（ＣＢＦ）及ＥＣＧ的变化。结果表明:刺激ＲＶ和冠脉（ＣＡ）内注射Ａｃｈ对心脏频率、传导和心肌收缩力的抑制作用，随刺激强度和注射剂量的增加而加强；小剂量ＮＧ可直接扩张ＣＡ，使ＣＢＦ增加，大剂量Ａｃｈ可能诱发ＣＡ痉挛和严重心律失常，并使ＣＰＰ和ＣＢＦ降低。     

Effects of endothelin-1 on epicardial coronary tone,coronary blood flow,ECG-ST change and regional wall motion in anesthetized dogs

Summary The effects of intracoronaryadministrated endothelin-1 on coronary hemodynamics and regional myocardial function were studied in anesthetized open-chest dogs. Epicardial coronary diameter (CoD) and coronary blood flow (CBF) were measured by a sonomicrometer of 10 MHz piezoelectric crystals and an electromagnetic flow probe on the left circumflex coronary artery (LCX). Regional wall motion was sonomicrometrically measured at regions supplied by the LCX and left anterior descending artery (LAD) and electrocardiograms were recorded. Endothelin-1, administered as a bolus injections into the LCX via an intracoronary cannula, in a dose-dependent manner reduced COD and CBF. The extent of the reduction of COD and CBF at a dose of 300 pmol was 12.3±1.5% (P<0.01) and 86±5% (p<0.01), respectively, of the control. The extent of CBF reduction and deterioration of systolic wall motion were linearly related with the dosage of endothelin-1. ST-elevation (lead II) and fatal ECG abnormalities, including complete atrioventricular block or ventricular fibrillation, were observed with doses above 60 and 100 pmol, respectively. Coronary angiography revealed that filling defects of dye were propagated from the third or distal branches to those of more proximal arteries when the doses of endothelin-1 were cumulatively infused into the LCX. Accordingly, lethal myocardial ischemia induced by endothelin-1 is produced by critical obstruction of rather small coronary vessels.Part of the study was supported by Grants-in-Aid for Scientific Research (Nos. 02454259, 02404045) from the Ministry of Education, Science, and Culture, Japan, and a Research Grant for Cardiovascular Disease (1S-1) from the Ministry of Health and Welfare, Japan.     

Arrhythmogenic dose of acetylstrophanthidin unchanged by beta-sympathomimetics in conscious dogs

Summary The enhanced arrhythmogenic risk of combined treatment with cardiac glycosides and beta-sympathomimetics is referred in some textbooks, but only a few detailed studies on in vivo models are available. We therefore investigated this problem in conscious dogs in an intraindividual study. We determined the dose of acetylstrophanthidin (intravenous infusion of 5 mcg/kg per min), which provoked ventricular premature beats with and without concomitant treatment with the partial betaagonistic compounds doxaminol (3 mg/kg p.o.), prenalterol (0.4 or 1.0 mg/kg p.o) or isoprenaline (0.31±0.100 mcg/kg per min). In some dogs a coronary artery was narrowed in order to reduce the coronary blood supply. The arrhythmogenic dose of acetylstrophanthidin was nearly the same in all the groups investigated (range from 52.1±5.66 to 59.9±3.23 mcg/kg). Whereas the arrhythmogenic dose of acetylstrophanthidin was unchanged by beta-sympathomimetics, the combination of the glycoside and each of the beta-agonistic drugs increased the contractile force more than did either single compound.We therefore conclude that the arrhythmogenic risk of the combination of glycosides and betasympathomimetics may be — at least in experimental models — less than has been suggested in the past.     

Formation of large coronary arteries by cardiac progenitor cells

Coronary artery disease is the most common cause of cardiac failure in the Western world, and to date there is no alternative to bypass surgery for severe coronary atherosclerosis. We report that c-kit-positive cardiac progenitor cells (CPCs) activated with insulin-like growth factor 1 and hepatocyte growth factor before their injection in proximity of the site of occlusion of the left coronary artery in rats, engrafted within the host myocardium forming temporary niches. Subsequently, CPCs divided and differentiated into endothelial cells and smooth muscle cells and, to a lesser extent, into cardiomyocytes. The acquisition of vascular lineages appeared to be mediated by the up-regulation of hypoxia-inducible factor 1alpha, which promoted the synthesis and secretion of stromal-derived factor 1 from hypoxic coronary vessels. Stromal-derived factor 1 was critical in the conversion of CPCs to the vascular fate. CPCs formed conductive and intermediate-sized coronary arteries together with resistance arterioles and capillaries. The new vessels were connected with the primary coronary circulation, and this increase in vascularization more than doubled myocardial blood flow in the infarcted myocardium. This beneficial effect, together with myocardial regeneration attenuated postinfarction dilated myopathy, reduced infarct size and improved function. In conclusion, locally delivered activated CPCs generate de novo coronary vasculature and may be implemented clinically for restoration of blood supply to the ischemic myocardium.     

Inotropic reserve and histological appearance of hibernating myocardium in conscious pigs with ameroid-induced coronary stenosis

Inotropic reserve, demonstrated with administration of sympathomimetic amines, is characteristic of hibernating myocardium. The goal of this study was to determine whether inotropic reserve was present following chronic coronary artery constriction in the pig, which is one potential model of hibernating myocardium. The effects of isoproterenol were examined in five conscious pigs 21±2.1 days after ameroid implantation on the left circumflex coronary artery on measurements of left ventricular (LV) pressure, LV dP/dt, and regional wall thickening in the ameroid-dependent zone (posterior wall) and contralateral non-ischemic zone (anterior wall). Isoproterenol, 0.1 g/kg/min, increased LV dP/dt by 96±11%, heart rate by 43±13 beats/min, and normalized systolic wall thickening, slightly, but not significantly more in the ameroid-dependent zone (+1.57±0.31 mm) than in the contralateral non-ischemic zone (+1.04±031 mm), although the baseline wall thickening was reduced significantly in the ameroid-dependent zone. This occurred at a time when baseline myocardial blood flow was preserved and myocardial perfusion in the ameroid-dependent zone was derived in part from the native coronary circulation and also through collateral channels. Two weeks later histological evidence of lesions characteristics of hibernating myocardium, i.e., myofibrolysis and increased glycogen deposition, were observed. Thus, these histological changes and the confluence of chronically depressed regional function and residual inotropic reserve in the conscious pig with chronic ameroid-induced coronary constriction support this model for further study of hibernating myocardium.Supported in part by USPHS grants HL 33065, 33107 and 38070     

急性实验性冠状动脉狭窄时血栓和微血栓的形成

目的:探讨急性冠状动脉狭窄与血栓和微血栓的关系。方法: 将实验犬用微米缩窄器造成冠脉左回旋支定量狭窄,形成心电图ST段下移组（A组）与ST段抬高组（B组）,经60 min缺血后观察冠脉血流量变化和冠状窦内血管活性物质的变化,并做血管组织病理学检查。结果: A组冠脉血流量轻度下降,B组冠脉血流量严重下降;A、B两组的血小板聚集功能、乳酸和血栓素B2(TXB2)增加,血小板生长因子1α(PGF1α)、纤维连接蛋白和纤维蛋白原减少;两组间上述指标无明显差异;病理组织学检查揭示,冠脉急性狭窄后出现血管内皮细胞的损伤、血小板的聚集、附壁血栓的形成以及微循环内以红色血栓与白色血栓组成微血栓形成。A、B两组的上述病理改变无显著差异。结论: 实验性急性冠脉狭窄可以引起心电图ST段下移和抬高不同变化,并造成冠脉内皮的损伤、血栓和微血栓的形成,这在不稳定心绞痛发病机制中起了重要作用。