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Background: The clinical benefit of blood pressure (BP) reduction in individuals with diabetes has not been fully elucidated. We sought to identify the clinical impact of BP reduction on incident cardiovascular disease in people having diabetes and hypertension., Methods: We conducted a retrospective cohort study including 754,677 individuals (median age 47 years, 75.8 % men) with stage 1/stage 2 hypertension. Participants were categorized using fasting plasma glucose (FPG) at baseline as normal FPG (FPG < 100 mg/dL) (n = 517,372), prediabetes (FPG:100-125 mg/dL) (n = 197,836), or diabetes mellitus (FPG ≥126 mg/dL) (n = 39,469). The primary outcome was heart failure (HF), and the secondary outcomes included ischemic heart disease (IHD) including myocardial infarction and angina pectoris, and stroke., Results: Over a mean follow-up of 1111 ± 909 days, 18,429 HFs, 17,058 IHDs, and 8,795 strokes were recorded. Reduction in BP of< 120/80 mmHg at 1year was associated with a lower risk of developing HF (HR:0.77, 95% CI:0.72-0.82), IHD (HR:0.84, 95% CI:0.79-0.89), and stroke (HR:0.75, 95% CI:0.69-0.82) in individuals with normal FPG, whereas it was not associated with a risk of developing HF (HR:0.98, 95% CI:0.81-1.17) and stroke (HR:0.82, 95% CI:0.62-1.09) in those with DM. Interaction analyses showed that the influence of BP reduction on incident HF was attenuated with people with prediabetes or DM. A multitude of sensitivity analyses confirmed our results., Conclusions: The association of BP reduction with the risk of developing HF was attenuated with deteriorating glucose tolerance. The optimal management strategy for hypertensive people with prediabetes or DM for the prevention of developing cardiovascular disease (particularly HF) is needed to be established., (Copyright © 2022. Published by Elsevier Inc.)

Amlodipine reduces oxidative stress that decreases NO and adenosine release. This study was undertaken to examine whether amlodipine mediates coronary vasodilation and improves myocardial metabolism and contractility in ischemic hearts via either adenosine- or NO-dependent mechanisms. In open-chest dogs, amlodipine (2 mug kg per min) was infused at the minimum dose that caused maximal coronary vasodilation. The perfusion pressure was reduced in the left anterior descending coronary artery so that coronary blood flow (CBF) decreased by 50%. Amlodipine increased the difference of the adenosine level (VAD (Ado): 119+/-14 to 281+/-46 nM) and the nitrate+nitrite level (VAD (NOx): 7.8+/-1.3 to 16.1+/-1.1 muM) between coronary venous and coronary arterial blood, and also increased CBF (50+/-3 to 69+/-6 ml/100 g/min). These changes were partially reversed by either 8-sulfophenyeltheophylline (8SPT) or l(omega)-nitro arginine methyl ester (l-NAME), and were completely blocked by both 8SPT and l-NAME. The reduction of CBF increased VAD (8-iso-prostaglandin F(2alpha)), and this increase was reduced by amlodipine (10.8+/-1.1 to 5.0+/-0.5 pg/ml). In addition, pretreatment with superoxide dismutase mimicked the coronary effects of amlodipine and blunted the response to amlodipine administration. Amlodipine-induced coronary vasodilation via both adenosine- and NO-dependent mechanisms. Adenosine and NO may interact in ischemic hearts to mediate coronary vasodilation by amlodipine.

Background: Carvedilol is a beta-adrenoceptor blocker with a vasodilatory action that is more effective for the treatment of congestive heart failure than other beta-blockers. Recently, carvedilol has been reported to reduce oxidative stress, which may consequently reduce the deactivation of adenosine-producing enzymes and increase cardiac adenosine levels. Therefore, carvedilol may also have a protective effect on ischemia and reperfusion injury, because adenosine mediates cardioprotection in ischemic hearts., Methods and Results: In anesthetized dogs, the left anterior descending coronary artery was occluded for 90 minutes, followed by reperfusion for 6 hours. Carvedilol reduced the infarct size (15.0+/-2.8% versus 40.9+/-4.2% in controls), and this effect was completely reversed by the nonselective adenosine receptor antagonist 8-sulfophenyltheophylline (45.2+/-5.4%) or by an inhibitor of ecto-5'-nucleotidase (44.4+/-3.6%). There were no differences of either area at risk or collateral flow among the various groups. When the coronary perfusion pressure was reduced in other dogs so that coronary blood flow was decreased to 50% of the nonischemic level, carvedilol increased coronary blood flow (49.4+/-5.6 to 73.5+/-7.5 mL x 100 g(-1) x min(-1); P<0.05) and adenosine release (112.3+/-22.2 to 240.6+/-57.1 nmol/L; P<0.05) during coronary hypoperfusion. This increase of coronary blood flow was attenuated by either 8-sulfophenyltheophylline or superoxide dismutase. In human umbilical vein endothelial cells cultured with or without xanthine and xanthine oxidase, carvedilol caused an increase of ecto-5'-nucleotidase activity., Conclusions: Carvedilol shows a cardioprotective effect against ischemia and/or reperfusion injury via adenosine-dependent mechanisms.

The combining of molecular biology and physiology is essential for the further development of cardiovascular medicine, and DNA microarray is a useful tool for assessing multiple gene expressions. A canine DNA microarray has been designed and tested. Approximately 60 cardiovascular-related genes were cloned from newly developed canine cDNA libraries and spotted on slides. Using the arrays, the gene expression profiles of canine myocardium in were analyzed 2 protocols: (1). ischemic myocardium by 50% reduction of the coronary blood flow, and (2). necrotic myocardium caused by coronary artery ligation. Three hours after 50% flow reduction, cardiovascular-related genes, including ecto-5'-nucleotidase, endothelin-1, PAI-1, and AT receptors, exhibited rapid alteration and there were many more altered genes than with the complete coronary occlusion. Irreversible ischemic damage without necrosis more strongly affected gene expressions in surviving myocardium than in fatally damaged myocardium. The canine DNA microarray is a useful tool for assessing the precise molecular events following changes in the pathophysiological conditions of the heart.

Celiprolol is a selective beta(1)-adrenoceptor antagonist with antihypertensive actions, which causes renal vasodilation by increasing tissue nitric oxide (NO) levels. The authors tested whether celiprolol increases coronary blood flow (CBF) by increasing cardiac NO release in the ischemic heart in vivo. In open-chest dogs, coronary perfusion pressure of the left anterior descending coronary artery was reduced so that CBF decreased to 60% of control levels, and thereafter, coronary perfusion pressure was maintained constant. Ten minutes after the reduction of coronary perfusion pressure, we infused celiprolol into the left anterior descending coronary artery and measured fractional shortening and lactate extraction ratio as indices of regional myocardial contractility and metabolism. CBF significantly increased from 51.5 mL/100 g/min +/- 1.9 to 67.0 mL/100 g/min +/- 5.1 20 minutes after celiprolol infusion without changes in coronary perfusion pressure, while fractional shortening and lactate extraction ratio increased. Celiprolol also increased cardiac NO release. The L omega-nitroarginine methyl ester, the inhibitor of NO synthase, attenuated the increases in CBF, fractional shortening, lactate extraction ratio, and cardiac NO release due to celiprolol. ICI 118551, a beta(2)-adrenoceptor antagonist, did not blunt the effects of celiprolol and a nonselective beta-adrenoceptor antagonist, propranolol, increased neither CBF nor cardiac NO release, indicating that the effect of celiprolol is independent of beta-adrenoceptor blockade. It was concluded that celiprolol mediates coronary vasodilation and improves myocardial ischemia through NO-dependent mechanisms.

Objectives: We examined whether the combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) synergistically mediates coronary vasodilation and improves myocardial metabolic and contractile dysfunction in ischemic hearts., Background: Either an ACE inhibitor or ARB mediates coronary vasodilation in ischemic hearts., Methods: In dogs with myocardial ischemia, we infused an ACE inhibitor (temocaprilat, 10 microg/kg/min) or ARB (RNH-6270, 10 microg/kg/min) into the coronary artery., Results: Perfusion pressure of the left anterior descending coronary artery was reduced from 104 +/- 8 to 42 +/- 2 mm Hg, so that coronary blood flow (CBF) decreased to one-third of the baseline value. Ten minutes after starting the infusion of temocaprilat, the cardiac bradykinin level increased (from 32 +/- 6 to 98 +/- 5 pg/ml). Coronary blood flow (29 +/- 2 to 44 +/- 3 ml/100 g/min) and the cardiac level of nitric oxide (NO) (7.8 +/- 1.9 to 17.5 +/- 3.2 microm) also increased, with these changes being attenuated by either N(omega)-nitro-L-arginine methyl ester or HOE140. RNH-6270 alone caused a modest increase in CBF (34 +/- 3 ml/100 g/min), with no increase in the cardiac NO or bradykinin levels. Both temocaprilat and RNH-6270 caused a further increase in both CBF (51 +/- 4 ml/100 g/min) and cardiac NO levels, without increasing the bradykinin level, and these changes were inhibited by HOE140. In the nonischemic heart, RNH-6270 augmented bradykinin-induced increases in CBF., Conclusions: The combination of an ACE inhibitor and ARB mediates greater increases in CBF and more potent cardioprotective effects through bradykinin-dependent mechanisms than either drug alone.

Atherosclerotic vascular diseases are expected to remain the major cause of mortality and morbidity globally well. Preventive measures by lifestyle changes(diet, exercise) will play an important role in retarding the onset of these diseases. The 4S, CARE and LIPID study demonstrated the efficacy of a statin on cardiovascular morbidity and mortality and on total mortality. The cardioprotective effect of statin is partially due to the cholesterol independent effect. Fibrate also decrease the mortality of patients with ischemic heart disease by improving the fiblolytic state. The association of a statin and a fibrate is reserved to specialized centers, however we should not forget the usefulness of diet.

Because many endogenous substances, including adenosine, contribute to the pathophysiology of ischemic hearts, the present study was designed to investigate the transcription responses of murine hearts to ischemia with or without administration of an inhibitor of adenosine receptor, 8-sulfophenyltheophylline (8SPT). Sixty minutes after ligation of the proximal site of the left coronary artery with (n=9) or without (n=9) 8SPT, the hearts were excised to obtain mRNA for cDNA array analysis. In 18,376 cDNA, 2 known genes were upregulated over 10-fold, and 11 known genes were upregulated 5.0-9.9-fold. 8SPT reduced the expressed gene to the control levels. Furthermore, 32 unknown genes were also upregulated over 5.0-fold. In contrast, 11 known genes were downregulated below 0.2-fold, and 64% of the downregulated genes were restored by 8SPT. The 7 unknown genes were downregulated to levels below 0.2-fold. Therefore, it was concluded that the cardiac expression of 24 known and 39 unknown genes was modulated by ischemic stress, and that these genes appeared to be related to the pathophysiology of the ischemic heart because endogenous adenosine modulated their expression.

We tested the hypothesis that cellular acidosis modulates the production of nitric oxide (NO) in ischemic hearts. In canine hearts, we decreased coronary blood flow (CBF) to one third of the control by reduction of coronary perfusion pressure (105+/-3 to 41+/-5 mmHg), and thereafter we maintained CBF constant (89.8+/-1.6 to 30.0+/-0.5 ml/100 g/min) with an intracoronary administration of either saline, atropine, rauwolscine, HOE140, 8-sulfophenyltheophylline (8SPT), NaHCO3, or HOE642 (the inhibitor of Na+/H+ exchange). The cardiac NO levels defined as the differences of the nitrate and nitrite levels between coronary venous and arterial blood increased in the saline administration (2.9+/-0.2 to 12.7+/-1.7 micromol/l), and the extents of increases were identical in the condition of either saline, atropine, rauwolscine, HOE140 or 8SPT administration. In the condition with either NaHCO3 or HOE642, the increases in the cardiac NO levels were blunted (4.5+/-0.7 and 4.8+/-0.4 micromol/l, respectively). Cyclic GMP content of epicardial coronary artery in the ischemic area increased, which was also attenuated by either NaHCO3 or HOE642. We confirmed the acidosis-induced NO production in a more severe ischemic myocardium, and also showed that cellular acidosis produced by infusion of HCl increased NO production in non-ischemic myocardium. We conclude that cellular acidosis and subsequent activation of Na+/H+ exchanges modulate production of endogenous NO in canine ischemic myocardium., (Copyright 2001 Academic Press.)

Angiotensin converting enzyme (ACE) inhibitors inhibit the degradation of bradykinin and contribute to accumulation of bradykinin and NO, both of which may be beneficial for diseased hearts. To test this idea, we administered imidaprilat and cilazaprilat, respectively to the canine ischemic myocardium. In the open chest dogs with low constant coronary perfusion pressure (CPP, from 104 +/- 3 to 42 +/- 3 mmHg), coronary blood flow (CBF, 91 +/- 1 to 32 +/- 2 ml/100 g/min), fractional shortening (FS), and lactate extraction ratio (LER) decreased. Either imidaprilat or cilazaprilat increased CBF, FS, and LER with increases in cardiac bradykinin and NO levels. The beneficial effects of ACE inhibitors were blunted by either L-NAME (an inhibitor of NO synthase) and HOE140 (an inhibitor of bradykinin receptors), respectively. ACE inhibitors, on the other hand, are reported to attenuate the severity of myocardial stunning, which effect is partially attributable to bradykinin- and NO-dependent mechanisms. Further, ACE inhibitors limited infarct size following coronary occlusion and reperfusion. This infarct size-limitation was blunted by either L-NAME and IBTX (the antagonist of K(Ca) channels). Bradykinin is also reported to close K(Ca) channels. Thus, we concluded that ACE inhibitors attenuate both reversible and irreversible myocardial cellular injury via bradykinin/NO-dependent mechanisms. In experimental and clinical settings, the cardioprotective effects of ACE inhibitors on the diseased heart may be attributable to these mechanisms.

ATP generates nitric oxide (NO) via activation of P2y receptors, and is degraded to adenosine. This study was undertaken to examine whether ATP causes coronary hyperemic flow via purinoceptors-, NO- and adenosine-dependent mechanisms, and attenuates the severity of contractile and metabolic dysfunction in the ischemic myocardium. In the non-ischemic canine hearts, the infusions of ATP into the coronary artery dose-dependently increased coronary blood flow. The levels of adenosine and end-product of NO in coronary venous blood over the arterial blood also increased. This hyperemic flow was partially attenuated by either 8-sulfophenyltheophylline (8SPT) or L(omega)-nitro arginine methyl ester (L-NAME), and completely blocked by the treatment with 8SPT, L-NAME and suramin (SRM). During myocardial ischemia, exogenous ATP increased coronary blood flow, and attenuated myocardial metabolic and contractile dysfunction, which was completely blunted by the treatment with 8SPT, L-NAME and SRM. We conclude that exogenous ATP increases coronary blood flow in the non-ischemic and ischemic myocardium mainly via either NO- or adenosine-dependent mechanisms.

5-Amino-4-imidazole carboxamide (AICA) riboside increases adenosine release in ischemic myocardium, suggesting that AICA riboside improves contractile dysfunction. In 49 open-chest dogs, contractile function assessed by fractional shortening (FS) was observed 3 h after the onset of reperfusion following 15 min of occlusion of the left anterior descending coronary artery. During reperfusion, the treatment with AICA riboside increased adenosine concentration in the coronary venous blood (536+/-44 vs. 281+/-21 pmol/ml at 3 min of reperfusion, p<0.001) and peak coronary hyperemic flow (367+/-13 vs. 300+/-21 ml/100 g per min, p<0.001) when compared with the untreated group. FS at 3h of reperfusion increased in the AICA riboside group (21.1+/-2.3 vs. 12.8+/-0.6% in the untreated group, p<0.001). AICA riboside increased myocardial ecto-5'-nucleotidase activity. Administration of adenosine also augmented coronary hyperemic flow and increased FS to the levels of the AICA riboside group. Either 8-phenyltheophylline (an antagonist of adenosine receptors) or alpha,beta-methylene-adenosine 5'-diphosphate (an inhibitor of ecto-5'-nucleotidase) completely abolished the increased coronary hyperemic flow and improvements of myocardial contractile function due to AICA riboside. Thus it was concluded that AICA riboside improves the contractile dysfunction that follows a brief period of ischemia via adenosine-dependent mechanisms.

Objectives: This study was undertaken to examine whether a dihydropyridine Ca channel blocker, benidipine, increases cardiac NO levels, and thus coronary blood flow (CBF) in ischemic hearts., Background: Benidipine protects endothelial cells against ischemia and reperfusion injury in hearts., Methods and Results: In open chest dogs, coronary perfusion pressure (CPP) of the left anterior descending coronary artery was reduced so that CBF decreased to one-third of the control CBF, and thereafter CPP was maintained constant (103+/-8 to 42+/-1 mmHg). Both fractional shortening (FS: 6.1+/-1.0%) and lactate extraction ratio (LER: -41+/-4%) decreased. Ten minutes after the onset of an intracoronary infusion of benidipine (100 ng/kg/min), CBF increased from 32+/-1 to 48+/-4 ml/100g/ min during 20 min without changing CPP (42+/-2 mmHg). Both FS (10.7+/-1.2%) and LER (-16+/-4%) also increased. Benidipine increased cardiac NO levels (11+/-2 to 17+/-3 nmol/ml). The increases in CBF, FS, LER and cardiac NO levels due to benidipine were blunted by L-NAME. Benidipine increased cyclic GMP contents of the coronary artery of ischemic myocardium (139+/-13 to 208+/-15 fmol/mg protein), which was blunted by L-NAME., Conclusion: Thus, we conclude that benidipine mediates coronary vasodilation and improves myocardial ischemia through NO-cyclic GMP-dependent mechanisms.

We examined whether nisoldipine, a calcium (Ca) channel blocker, increases coronary blood flow (CBF) without decreasing aortic blood pressure (AoP) with ischemic and nonischemic hearts, and whether the presence of cellular acidosis in ischemic myocardium contributes to the augmentation of coronary vasodilation due to nisoldipine. In 42 dogs, coronary perfusion pressure (CPP) was reduced so that CBF decreased to 60% of the baseline, and CPP was maintained constant thereafter. First, we administered nisoldipine into a systemic vein in the ischemic and nonischemic hearts. Second, nisoldipine was administered into the canine coronary artery of the ischemic myocardium, with and without administration of either sodium bicarbonate (NaHCO3), sodium hydroxide (NaOH), or amiloride. Nisoldipine (0.25-4.0 mg/kg, i.v.) increased CBF by 59% in the ischemic myocardium more than the nonischemic myocardium (by 34%) without reducing AoP. The infusion of nisoldipine (40 ng/kg/min, IC) increased CBF markedly by about 55% in the ischemic myocardium with increases in fractional shortening (FS; 11 +/- 2% to 21 +/- 2%) and lactate extraction ratio (LER; -19 +/- 4% to 15 +/- 2%). Increases in CBF, FS, and LER were markedly attenuated during administration of nisoldipine with concomitant administration of either NaHCO3 or NaOH. Furthermore, the extent of increases in CBF (54 +/- 2 mL/100 g/min), FS (13 +/- 2%), and LER (-17 +/- 4%) were also markedly attenuated due to the concomitant treatment with amiloride. We conclude that myocardial cellular acidosis plays an important role in mediating coronary vasodilation affected by nisoldipine in the ischemic myocardium. H+ may modulate the property of voltage-dependent Ca channels via Na(+)-H+ exchange.

Since angiotensin-converting enzyme (ACE) produces angiotensin II in the heart, ACE inhibitors may prevent coronary vasoconstriction and increase coronary blood flow. On the other hand, since ACE inhibitors also inhibit kininase II which results in reduced degradation of bradykinin, ACE inhibitors may increase cardiac nitric oxide (NO) levels via stimulation of bradykinin receptors. This study was undertaken to test whether ACE inhibitors increase the cardiac NO levels and coronary blood flow in the ischemic myocardium. In 34 open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the left carotid artery. When either imidaprilat or cilazaprilat of 3 microg/kg/min was infused into the bypass tube for 10 min after reduction of coronary blood flow due to partial occlusion of the bypass tube, coronary blood flow increased from 31 +/- 1 to either 45 +/- 5 or 43 +/- 4 ml/100 g/min despite no changes in coronary perfusion pressure (43 +/- 2 mmHg). During an infusion of either imidaprilat or cilazaprilat, bradykinin and the end-products of NO (nitrate + nitrite) concentrations of coronary venous blood were markedly increased, which were attenuated by either HOE-140 (an inhibitor of bradykinin receptors) or by N(omega)-nitro-L-arginine methyl ester (an inhibitor of NO synthase). We also observed increases in cardiac bradykinin and NO levels due to either imidaprilat or cilazaprilat in the low constant coronary blood flow condition. It is concluded that ACE inhibitors can increase cardiac NO levels via the accumulation of bradykinin in the ischemic myocardium.

Background: 17Beta-estradiol increases the production of nitric oxide (NO) and prostacyclin and opens Ca2+-activated K+ (K(Ca)) channels. Whether these effects of 17beta-estradiol reduce infarct size and the incidence of ventricular arrhythmia was investigated in dogs subjected to myocardial ischemia and reperfusion., Methods and Results: Infarct size was measured in open-chest dogs after 90 minutes' occlusion of the left anterior descending coronary artery and a subsequent 6 hours of reperfusion. Infusion of 17beta-estradiol into the coronary artery was initiated 10 minutes before coronary occlusion and continued until after 1 hour of reperfusion, with the exception of the occlusion period. The difference in NO concentration between coronary venous and arterial blood 10 minutes after the onset of reperfusion was significantly greater in dogs treated with 17beta-estradiol (10 ng x kg(-1) x min(-1)) than in control animals. Infarct size (13.1+/-3.0% versus 43.7+/-5.4% of the area at risk) and the incidence of ventricular arrhythmia during ischemia and reperfusion periods were significantly reduced in the 17beta-estradiol group. Both N(G)-nitro-L-arginine methyl ester (an inhibitor of NO synthase) and iberiotoxin (a blocker of K(Ca) channels) reduced both the infarct size-limiting effect (infarct size, 29.3+/-3.0% and 31.7+/-2.1%, respectively) and the antiarrhythmic effect of 17beta-estradiol; indomethacin (an inhibitor of cyclooxygenase) did not attenuate the beneficial effects of 17beta-estradiol., Conclusions: 17Beta-estradiol reduced both myocardial infarct size and the occurrence of ischemia- and reperfusion-induced ventricular arrhythmias, which appear to be mediated by NO and the opening of K(Ca) channels in canine hearts.

Estrogen induces the generation of nitric oxide (NO) and produces coronary vasodilation by opening the Ca2+-activated K+ (K[Ca]) channels. The hypothesis that 17beta-estradiol produces NO and activates K(Ca) channels during coronary hypoperfusion was investigated. In open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the left carotid artery. 17beta-Estradiol was infused into the bypass tube for 20 min after coronary blood flow was reduced by partial occlusion of the bypass tube. 17beta-Estradiol increased the difference in NO concentrations between the coronary venous and arterial blood as well as coronary blood flow. The lactate extraction ratio and pH of coronary venous blood were both also increased by 17beta-estradiol, indicating a reduction in myocardial anaerobic metabolism. Whereas the increase in the coronary arteriovenous difference in NO concentration was completely attenuated by N(G)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of NO synthase), the increase in coronary blood flow induced by 17beta-estradiol was only partially attenuated by L-NAME. The combination of L-NAME and iberiotoxin (a blocker of high-conductance K(Ca) channels) completely abolished the coronary vasodilatory effect of 17beta-estradiol. The data indicate that during coronary hypoperfusion in canine hearts, 17beta-estradiol increases coronary blood flow and improves metabolic dysfunction by increasing NO release and opening K(Ca) channels.

We tested the hypothesis that myocardial extracellular acidosis during early reperfusion limits infarct size. The left anterior descending coronary artery was perfused with blood through a bypass tube in dogs. We occluded the bypass tube for 40 (protocol I; n = 24 hearts) and 90 min (protocol II; n = 36 hearts). In protocols I and II, we infused one group of hearts with HCl (60 micrograms.kg-1.min-1) for 60 min after the onset of reperfusion (the metabolic acidosis group), and another group of hearts were ventilated with 3 liters of 70% O2-30% CO2 mixed with room air 10 min before the onset of reperfusion for 70 min (the respiratory acidosis group). pH in the coronary venous blood and myocardial pH during reperfusion in the metabolic and respiratory acidosis groups were lower than those in the control groups. Infarct sizes in the metabolic (16.4 +/- 2.5 and 22.3 +/- 2.5%) and respiratory (16.7 +/- 2.6 and 22.3 +/- 2.5%) acidosis groups in protocols I and II, respectively, were smaller than those in the control groups (33.1 +/- 3.0 and 40.6 +/- 4.1%, respectively). Thus we conclude that temporary acidosis during reperfusion limits infarct size.

Background: Endothelium-dependent hyperpolarizing factor relaxes vascular smooth muscles by opening the Ca(2+)-activated K+ (KCa) channels. The role of the opening of KCa channels in coronary vasodilation during myocardial ischemia was investigated., Methods and Results: The left anterior descending coronary arteries of open-chest dogs were perfused with blood through an extracorporeal bypass tube from the carotid artery. Intracoronary administration of bradykinin increased coronary blood flow (CBF) in dogs treated with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase; this effect was completely inhibited by the KCa channel blocker iberiotoxin. In dogs treated with L-NAME, the bypass tube was occluded to reduce CBF to one third of the baseline value, after which coronary perfusion pressure was maintained constant. Intracoronary administration of iberiotoxin for 20 minutes further decreased CBF (from 33 +/- 2 to 19 +/- 2 mL.100 g-1.min-1, P < .01), fractional shortening, and lactate extraction ratio during coronary hypoperfusion. Bradykinin was released, and the bradykinin receptor antagonist HOE-140 blocked the effects of iberiotoxin on coronary hemodynamic and metabolic parameters during myocardial ischemia. Although the combination of L-NAME and the adenosine receptor antagonist 8-sulfophenyltheophylline reduced reactive hyperemic flow after 20 seconds of coronary occlusion, the additional presence of iberiotoxin resulted in a further decrease in this parameter., Conclusions: The opening of KCa channels in response to endogenous bradykinin contributed to coronary vasodilation and reduced contractile and metabolic dysfunction during myocardial ischemia in open-chest dogs.

1. Ischaemic preconditioning (IP) protects the myocardium against irreversible ischaemic injury by activating protein kinase C (PKC). The mechanism by which PKC protects the myocardium is unknown. We have shown that PKC increases the activity of ecto-5'-nucleotidase (ecto-5'-N) and thereby the production of adenosine in cardiomyocytes which may protect the myocardium against ischaemia-reperfusion injury in vivo. 2. The objective of this study was to elucidate the possible role of PKC-induced activation of ecto-5'-N in the cardioprotection associated with IP in the canine heart. 3. IP increased the activities of both ecto-5'-N and PKC, and minimized ischaemic damage (infarct size: 7.5 +/- 1.8 vs. 42.3 +/- 2.8%, P < 0.01 vs. the control group). Treatment with the PKC activator (4 beta-phorbol 12-myristate-13-acetate) also reduced infarct size (13.5 +/- 2.9%, P < 0.01 vs. the control group). 8-Sulfophenyltheophylline (an antagonist of adenosine receptors) or alpha,beta-methyleneadenosine 5'-diphosphate (an inhibitor of ecto-5'-N) eliminated the cardioprotective effect of the PKC activator (infarct size: 36.6 +/- 3.9 and 34.7 +/- 4.2%, respectively), suggesting that PMA limits infarct size by increasing the activity of ecto-5'-N and the adenosine level. 4. The PMA-induced cardioprotection was blunted by GF109203X (an inhibitor of PKC, infarct size: 36.2 +/- 3.1%), but not by pretreatment with dexamethasone (infarct size, 14.2 +/- 2.6%). 5. We conclude that the PMA- and IP-induced cardioprotection is attributable to phosphorylation and activation of ecto-5'-N.

Objectives: This study was undertaken to examine whether nitric oxide released in ischemic myocardium decreases the coronary vascular resistance and attenuates the severity of contractile and metabolic dysfunction., Background: Endothelium-derived relaxing factor, recently identified as nitric oxide, is a potent relaxant of coronary smooth muscle., Methods: The left anterior descending coronary artery was perfused through an extracorporeal bypass tube placed in the carotid artery in 56 open chest dogs. After hemodynamic stabilization, we occluded this bypass tube to decrease coronary blood flow to one third of the control flow. Thereafter, we maintained a constant coronary perfusion pressure (40.9 +/- 3.1 mm Hg)., Results: Under ischemic conditions, the coronary arteriovenous differences in nitrate and nitrite (end products of nitric oxide) increased (from 3.5 +/- 0.4 [mean +/- SEM] to 12.9 +/- 2.1 mumol/liter, p < 0.01). NG-Monomethyl L-arginine (3 micrograms/kg body weight per min, intracoronary) decreased the coronary arteriovenous differences in nitrate and nitrite (5.0 +/- 0.9 mumol/liter, p < 0.05) and coronary blood flow (from 29.8 +/- 0.5 to 18.1 +/- 1.1 ml/100 g per min, p < 0.001). Fractional shortening (from 3.7 +/- 1.0 to -1.3 +/- 0.7%, p < 0.001) and lactate extraction ratio (from -44.0 +/- 4.1 to -59.2 +/- 4.9%, p < 0.005) of the perfused area also decreased. These values were restored by the concomitant administration of L-arginine. Blood flow to the endomyocardium was decreased relative to the epimyocardium. A reduction in coronary blood flow and worsening of myocardial contractile and metabolic functions due to the administration of NG-monomethyl L-arginine during ischemia were observed in denervated hearts. A reduction in coronary blood flow in ischemic myocardium was observed with the administration of NW-nitro-L-arginine methyl ester as well, although neither NW-nitro-L-arginine methyl ester nor NG-monomethyl L-arginine changed coronary blood flow and myocardial contractile and metabolic functions in the nonischemic myocardium. The cyclic guanosine monophosphate content of epicardial coronary artery increased due to myocardial ischemia; this increase was attenuated with NG-monomethyl L-arginine treatment., Conclusions: We conclude that endogenous nitric oxide predominantly decreases the coronary vascular resistance of ischemic endomyocardium, thereby improving myocardial contractility and metabolic function.

Background: We have reported that myocardial ischemia increases nitric oxide (NO) production. Several lines of evidence suggest that NO reduces myocardial contraction. Therefore, we tested whether endogenous NO decreases the inotropic response of the ischemic myocardium and whether endogenous NO is beneficial in the metabolic function of ischemic myocardium., Methods and Results: The left anterior descending coronary artery was perfused with blood from the left carotid artery in 72 dogs. An infusion of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, did not affect fractional shortening (FS) under nonischemic conditions. After reduction of perfusion pressure so that coronary blood flow decreased to 60% of the control value, FS of the perfused area decreased, and intravenous infusion of isoproterenol increased FS. Before and during intravenous infusion of isoproterenol under conditions of coronary hypoperfusion, FS was significantly increased in the L-NAME group compared with the untreated group. Both lactate extraction ratio and the pH in coronary venous blood were significantly lower in the L-NAME-treated group than in the untreated group during coronary hypoperfusion. Infusion of L-arginine prevented the effects of L-NAME in the ischemic myocardium., Conclusions: These results indicate that endogenous NO reduces myocardial contractile function and improves myocardial metabolic function in the ischemic heart. The myocardial energy-sparing effect as well as coronary vasodilation due to NO may be beneficial to the ischemic myocardium.

We investigated whether loss of myocardial protection after ischemic preconditioning (IP) is related to the extent of deactivation of activated ecto-5'-nucleotidase. The coronary arteries of mongrel dogs were occluded four times for 5 min separated by 5 min of reperfusion (IP). Five (IP1), 30 (IP2), 60 (IP3), and 120 min (IP4) after the fourth 5-min coronary occlusion or after a corresponding nonischemic period (control groups), the coronary arteries were occluded for 90 min followed by 6 h of reperfusion. The infarct size-limited effect of IP gradually disappeared in the IP2 (21.6 +/- 3.9%) and IP3 (33.8 +/- 3.6%) groups compared with the IP1 group (8.3 +/- 1.6%) and returned to the control level in the IP4 group (39.9 +/- 5.2%). The increased ecto-5' -nucleotidase activity due to the IP procedure decreased according to the order of IP1 to IP4 groups. Infarct size was inversely correlated with ecto-5'-nucleotidase activity (P < 0.001). An inhibitor of ecto-5'-nucleotidase blunted the infarct size-limiting effect of IP. The infarct size-limiting effect of IP decreased as the activation of ecto-5'-nucleotidase was blunted. These results suggest that ecto-5'-nucleotidase activity plays a key role in the cardioprotection of IP.

This study was undertaken to test whether a brief period of ischemia affects the coronary pressure-flow relationship during reduction of coronary perfusion pressure (CPP). The left anterior descending coronary artery was cannulated and perfused with blood from the left carotid artery in 40 open-chest dogs. Coronary blood flow (CBF) was measured during intracoronary administrations of papaverine and adenosine. The coronary pressure-flow relationship was assessed during transient reduction of CPP from 100 to 30 mmHg. Coronary hyperemic flow due to adenosine and papaverine was attenuated 30 min after transient 10- and 15-min periods of ischemia. In the group of transient 10-min ischemia, both fractional shortening (FS) and CBF returned to the preischemic values at 30 and 60 min of reperfusion; however, marked decreases in CBF (35 +/- 5 vs. 56 +/- 4 ml.100 g-1.min-1 at CPP = 60 mmHg, P < 0.01) during graded reductions in CPP were observed. The endomyocardial blood flow was reduced relative to the control condition. Furthermore, both FS (6 +/- 1 vs. 14 +/- 1% at CPP = 60 mmHg, P < 0.01) and lactate extraction ratio (-41 +/- 15 vs. 1 +/- 6% at CPP = 60 mmHg, P < 0.05) were decreased. The downward shift of the CPP-CBF relationship and the deterioration of myocardial contractile and metabolic function during reduction of CPP were restored 60 min after the onset of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Aminophylline blocks adenosine receptors and increases levels of plasma catecholamines. We investigated the effect of aminophylline on myocardial ischemia by varying its severity and attempted to identify the mechanism by which aminophylline modulates myocardial ischemia in the canine model., Methods and Results: In 41 open-chest dogs, the left anterior descending coronary artery was cannulated and perfused with blood through a bypass tube from the left carotid artery. When coronary blood flow (CBF) was reduced to 80% of the control, aminophylline increased fractional shortening (FS) from 11.0 +/- 0.4% to 18.5 +/- 1.7% (P < .05) and lactate extraction ratio (LER) from 7.5 +/- 0.1% to 13.6 +/- 1.0% (P < .01). The endocardial to epicardial flow ratio (Endo/Epi ratio) of regional myocardium was also increased. Release of adenosine was increased compared with the nonischemic condition (7 +/- 3 versus 28 +/- 5 pmol/mL). Prazosin, an alpha 1-adrenoceptor antagonist, blunted the aminophylline-induced improvement in contractile and metabolic function. Administration of 8-phenyltheophylline, a selective antagonist of adenosine receptors, did not increase FS, LER, or the Endo/Epi ratio when CBF was reduced to 80% of control. When CBF was reduced to 60% of control, aminophylline did not change the metabolic and contractile function. In contrast, when CBF was reduced to 33% of control, release of adenosine was increased markedly (243 +/- 19 pmol/mL) and aminophylline induced decreases in FS, LER, and Endo/Epi ratio similar to those observed with 8-phenyltheophylline., Conclusions: Aminophylline had opposite effects on the ischemic myocardium depending on the severity of ischemia. It improved mild ischemia but worsened severe ischemia. The beneficial effect of aminophylline was attributable to alpha 1-adrenoceptor stimulation, which improves endomyocardial flow in the ischemic myocardium. The deleterious effect was attributable to the aminophylline-induced blockade of adenosine receptors.

Background: Angiotensin-converting enzyme (ACE) produces angiotensin II, causing vasoconstriction of coronary arteries and reduction of coronary blood flow. The present study was undertaken to test the hypothesis that an ACE inhibitor increases coronary blood flow and improves myocardial metabolic and contractile functions of ischemic myocardium., Methods and Results: In 65 open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the left carotid artery. When cilazaprilat (3 micrograms/kg per minute) was infused into the bypass tube for 10 minutes after reduction of coronary blood flow due to partial occlusion of the bypass tube, coronary blood flow increased from 30 +/- 1 to 43 +/- 2 mL/100 g per minute despite there being no changes in coronary perfusion pressure (43 +/- 1 mm Hg). The ratio of myocardial endocardial flow to epicardial flow increased during an infusion of cilazaprilat. Both fractional shortening and lactate extraction ratio of the perfused area were increased (fractional shortening: 4.1 +/- 0.6% to 8.9 +/- 0.6%, P < .001; lactate extraction ratio: -55.7 +/- 3.3% to -36.7 +/- 3.9%, P < .001). During an infusion of cilazaprilat, the bradykinin concentration of coronary venous blood was markedly increased. The increased coronary blood flow due to cilazaprilat was attenuated by HOE-140 (an inhibitor of bradykinin receptors; coronary blood flow: 35 +/- 2 mL/100 g per minute), and by N omega-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase; coronary blood flow: 34 +/- 2 mL/100 g per minute). Intracoronary administration of bradykinin mimicked the beneficial effects of cilazaprilat. Cyclic GMP content of the coronary artery was increased by cilazaprilat compared with the untreated condition in the ischemic myocardium. In the denervated hearts, the increased coronary blood flow due to cilazaprilat was not attenuated. On the other hand, CV11974, an inhibitor of angiotensin II receptors, slightly increased coronary blood flow to 34 +/- 2 from 30 +/- 1 mL/100 g per minute., Conclusions: We conclude that an inhibitor of ACE can increase coronary blood flow and ameliorate myocardial ischemia, primarily due to accumulation of bradykinin and production of nitric oxide from the ischemic myocardium. Inhibition of angiotensin II production due to inhibition of ACE partially contributes to coronary vasodilation in the ischemic myocardium.

The difference in end-products of the nitric oxide, i.e., nitrate-plus-nitrite, in the coronary arterial and venous blood was increased during coronary hypoperfusion of the canine heart (12.8 +/- 0.6 vs. 2.2 +/- 0.2 microM at the baseline). Norepinephrine from sympathetic nerve endings in the heart is released due to ischemic stress, however the relation of norepinephrine with nitric oxide is unknown during ischemia. Neither beta- or alpha 2-adrenoceptor antagonists attenuated the release of nitric oxide during coronary hypoperfusion. An intracoronary infusion of an alpha 1-adrenoceptor antagonist attenuated the release of nitric oxide during coronary hypoperfusion (5.3 +/- 0.4 microM), and the attenuation of alpha 1-adrenoceptor activity further decreased coronary blood flow during hypoperfusion. These findings suggest that alpha 1-adrenoceptor activity contributes to the mechanisms whereby nitric oxide is released from the ischemic myocardium.

Coronary arteriovenous difference in stable end-products of nitric oxide metabolism, nitrate and nitrite, was increased in ischemic canine hearts. In accordance with the reduction of coronary blood flow by 40, 67, 80 and 100%, the plasma nitrate+nitrite concentration increased from 3.2 +/- 0.6 to 8.7 +/- 1.3, 12.5 +/- 1.8, 15.9 +/- 2.7, and 20.2 +/- 2.3 microM, respectively. The plasma nitrate+nitrite concentrations were further elevated during reperfusion. Administration of NG-nitro-L-arginine methyl ester decreased the production of both nitrate+nitrite and coronary blood flow; the former was restored by the concomitant administration of L-arginine. These findings suggest that the increases in the nitric oxide production result from the action of nitric oxide synthase during myocardial ischemia and reperfusion, decreasing coronary vascular resistance and attenuating myocardial ischemia.

This study was undertaken to examine whether 5-amino-4-imidazolecarboxamide (AICA) riboside (acadesine), which augments adenosine release in ischemic myocardium, further attenuates ischemic injury after acute coronary microembolization. The left anterior descending coronary artery was cannulated and perfused with blood from the left carotid artery in 46 dogs, and coronary blood flow (CBF) of the perfused area was measured. In 12 dogs, 15-microns microspheres (5.0 x 10(4)/ml) were injected repeatedly until CBF approached zero. Changes in CBF, fractional shortening, lactate extraction ratio, and adenosine release were measured with and without administration of AICA riboside. In the control group (n = 7), CBF increased to 154 +/- 11 ml.100 g-1.min-1 at 16-30% of total coronary embolization, and adenosine release was 6.1 +/- 1.0 nmol.100 g-1.min-1. Administration of AICA riboside (n = 5) enhanced coronary hyperemia (187 +/- 8 ml.100 g-1.min-1, P < 0.05), adenosine release (11.9 +/- 0.9 nmol.100 g-1.min-1, P < 0.001), and myocardial adenosine content (0.434 +/- 0.069 vs. 0.118 +/- 0.019 nmol/mg wet wt, P < 0.01) and attenuated decreases in fractional shortening and lactate extraction ratio. AICA riboside preserved myocardial tissue ATP content of the embolized area. The administrations of 8-phenyltheophylline (n = 12) and alpha,beta-methyleneadenosine 5'-diphosphate (n = 10) abolished the beneficial effects of AICA riboside. Furthermore, AICA riboside increased ectosolic and cytosolic 5'-nucleotidase activity of the embolized myocardium (n = 12). Thus we conclude that AICA riboside attenuates contractile and metabolic dysfunction by enhancing adenosine release via activation of ectosolic 5'-nucleotidase and inducing local hyperemia in acute coronary microembolization.