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A guinea pig heart Langendorif preparation was used in the present study to test the hypothesis that the coronary endothelium modulates coronary autoregulation through the production of nitric oxide (NO is an oversupply of oxygen, and diffusible metabolites are even more easily washed out of the heart. It is now clear that vascular endothelium modulates flow autoregulation. Mechanical denudation of the endothelium or endothelial injury by agents such as the combination of Evans blue plus irradiation by a heliumneon laser can enhance the myogenic response of isolated coronary8 and cerebral9 arteries. Endotheliumdependent relaxation factors, particularly nitric oxide (NO),10-12 participate in the setting of basal tone in many vascular beds, including the coronary circulation.'3-16 Competitively inhibiting the formation of NO from L-arginine, its natural precursor, 17,8 by means of analogues of L-arginine19 is an important tool for assessing the contribution of NO in vasodilator responses. Thus, Griffith and Edwards20 have shown that an isolated, buffer-perfused rabbit ear preparation that lacks the ability to autoregulate will develop the capacity to autoregulate under the combined influences of vasoconstriction by serotonin and the inhibition of NO production by NG-methyl-L-arginine.Our present article describes studies of isolated guinea pig hearts that test the hypothesis that NO modulates coronary autoregulation.Materials and Methods We used 28 Langendorff preparations from guinea pigs weighing 300-400 g. The perfusate consisted of (mM) NaCI 120, NaHCO3 27, KCI 3.7, MgSO4 0.64, CaCl2 1.3, sodium pyruvate 2.0, and glucose 5.0. The buffer was equilibrated with 95% 02-5% C02, warmed by guest on

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A Langendorff guinea pig heart preparation served for the assay of agonist potency of a series of 26 2-aralkoxyadenosines at the A1 and A2 receptors of, respectively, the atrioventricular node (conduction block) and coronary arteries (vasodilation). All of the analogues are weak agonists at the A1 receptor, requiring concentrations greater than 9 microM to cause second degree heart block. At the A2 receptor 2-phenethoxyadenosine is the most potent of the 2-phenylalkyladenosines. The activity of ring-substituted (F, Cl, CH3, and OCH3) 2-phenethoxyadenosines increases ortho less than meta less than para. The EC50s of coronary vasoactivity of several para-substituted analogues are in the subnanomolar range. The most potent analogue, 2-[2-(4-methylphenyl)ethoxy]adenosine 19, has an EC50 for coronary vasodilation of 190 pM and an A1/A2 selectivity ratio of 44,000. Aryl groups such as thienyl, indoloyl, or naphthyl also support A2 agonist activity. Although 2-oxoadenosine is 3 times more vasoactive than 2-aminoadenosine, the activities of the phenyl derivatives are markedly different; 2-phenoxyadenosine is 23 times weaker than 2-(phenylamino)adenosine (CV-1808).

rogression of coronary atherosclerosis and rupture of unstable plaque are key processes in acute myocardial infarction (AMI). The extent of coronary artery disease has been well documented as a major prognostic factor in patients with AMI. Prevention and evaluation of the progression of atherosclerotic plaque volume is thus essential to both reduce cardiac events and estimate prognosis after AMI.Evidence that supplementation with n-3 polyunsaturated fatty acids prevents atherosclerosis-related cardiovascular risk has been accumulating. 1,2 More recently, a large randomized study demonstrated that eicosapentaenoic acid (EPA) is effective in preventing major coronary events in patients with hyperlipidemia. 3 Dysfunction of the vascular endothelium, fatty streak formation and fibrous cap formation are processes in the formation of atherosclerotic lesions that are regulated by the action of vasoactive molecules, growth factors, cytokines, and lipid metabolites. Several studies have demonstrated that supplementation with n-3 polyunsaturated fatty acids attenuates the exaggerated platelet aggregation induced by various stimuli, 4,5 attenuates the action of growth factors and cytokines, 5-7 reduces the serum triglyceride concentration, 8,9 and increases high-density lipoprotein levels. 8 There are several methods of evaluating coronary atherosclerotic lesions. Coronary angiography is widely used as the gold-standard to determine coronary stenosis, but it can only detect a luminal reduction in stenosis, collateral patterns and the presence of dense calcification of the coronary arteries, not plaque quantity. Coronary angioscopy and intravascular ultrasound (IVUS) can provide information about plaque characteristics to some extent, 10-14 but the observation areas are somewhat restricted and the methods are quite invasive. Multidetector spiral computed tomography (MDCT) with high slice numbers is now providing sufficient time and spatial resolution power to detect coronary atherosclerosis. 15,16 Its reliability in the determination of coronary plaque morphology has been recently demonstrated by studies using IVUS and histopathologic studies. 17,18 The advantages of MDCT are that it is relatively noninvasive compared with intracoronary angioscopy and IVUS, and has sufficient stability for observation of the entire coronary tree. Indeed, at present, MDCT is thought to be 1 of the best methods of evaluating coronary plaque characteristics.Based on these lines of evidence, we hypothesized that serum n-3 polyunsaturated fatty acid levels would correlate with the extent of coronary atherosclerotic lesions. The Background The relationship between serum fatty acid levels and the extent of coronary plaques and calcification was examined in patients with acute myocardial infarction (AMI). Methods and ResultsThe serum levels of the n-3 polyunsaturated fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) and the n-6 polyunsaturated fatty acids (arachidonic acid (AA) and dihomogamma-linolenic acid (DGLA)) were det...

A Langendorff guinea pig heart preparation served for the assay of agonist activity of a series of 24 2-alkoxyadenosines at the A1 and A2 adenosine receptors of, respectively, the atrioventricular node (conduction block) and coronary arteries (vasodilation). Activities are low at the A1 receptor and do not show a clear relationship to the size or hydrophobicity of the C-2 substituent. All the analogues are more potent at the A2 receptor, activity varying directly with the size and hydrophobicity of the alkyl group. The most potent analogue in this series, 2-(2-cyclohexylethoxy)adenosine has an EC50 of 1 nM for coronary vasodilation and is 8700-fold selective for the A2 receptor.

The reaction of aliphatic aldehydes and ketones with 2-hydrazinoadenosine under relatively mild conditions (at room temperature or in refluxing methanol) formed 2-(N'-alkylidenehydrazino)-adenosines, 5-22, in good yields. Two kinds of adenosine receptors regulate cardiac and coronary physiology. In supraventricular tissues an A1AR coupled to muscarinic K channels mediates the negative chronotropic, dromotropic, and inotropic actions of adenosine, and an inhibitory A1AR coupled to adenylate cyclase mediates the "antiadrenergic" action of adenosine. One or more kinds of A2 receptors mediate coronary vasodilation. Bioassays employing a guinea pig heart Langendorff preparation showed that 5-22 weakly retard impulse conduction through the AV node (negative dromotropic effect), but several analogues were very active coronary vasodilators. The coronary vasoactivity of the (n-alkylidene- and of the (isoalkylidenehydrazino)adenosines paralleled the length of the alkyl chain, the EC50s of the of the most active n-pentylidene (8) and isopentylidene (18) congeners being 1 nM. The EC50s of the cyclohexylmethylene (9), cyclohexylethylidene (10), and cyclohex-3-enylmethylene (12), analogues were likewise < 1 nM, but the cyclohex-1-enylmethylene congener 12 was 10 times less active than 9. The unselective adenosine receptor antagonist 8-(p-sulfophenyl)theophylline (0.1 mM) raised the EC50s of the negative dromotropic effects of 8, 9, and 18 by 5-28-fold and the EC50s of coronary vasodilation of 22-90-fold. Catalytic reduction of 9 increased the hydrophobicity and changed the UV spectrum, suggesting reduction of the --CH = N-- bond. The product darkened on exposure to air and so was not characterized further. A new method for preparing 2',3',5'-tri-O-acetyl-2,6-dichloropurine riboside, a precursor in the synthesis of 2-hydrazinoadenosine, consists of the addition of tert-butyl nitrite to a mixture of 2',3',5'-tri-O-acetyl-6-chloroguanosine and CuCl in CHCl3 saturated with Cl2.

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