Increase In Coronary Blood Flow Research Articles

Role of superoxide anion in coronary endothelial dysfunction in type 2 diabetic mice

Coronary endothelial dysfunction leads to the increase in coronary blood flow and decrease in capillary density, and subsequently increases the incident of cardiac ischemia. Excess superoxide production (O2‐) has maladaptive effects on cellular functions in many tissues and organs. The objective of this study is to identify the role of O2‐ in coronary endothelial dysfunction in type 2 diabetic mice. Acetylcholine (ACh)‐induced relaxation (indicative of endothelium‐dependent relaxation) was significantly attenuated in diabetic coronary arteries (CAs) compared with control CAs. The pharmacological approach reveals that NO‐dependent relaxation, but not endothelial‐derived hyperpolarization‐dependent relaxation, is decreased in diabetic CAs. In the presence of Tempol (a O2‐scavenger), ACh‐induced relaxation in diabetic CAs is increased to the level seen in control CAs. In addition, mouse coronary endothelial cells (MCECs) isolated from diabetic mice exhibit significant increase in mitochondrial O2‐production and decrease in Mn‐SOD protein expression in comparison to those in control MCECs. These results suggest that the excess O2‐production in mitochondria attenuates the bioavailability of NO and subsequently decreases ACh‐induced relaxation in CAs in diabetic mice. This research was supported by grant DK083506.

Effects of the new potassium channel opener JTV-506 on coronary vessels in vitro and in vivo.

The vascular effects of JTV-506 ((-)-(3S,4R)-2.2-bis(methoxymethyl)- 4-[(1,6-dihydro-l-methyl-6-oxo-3-pyridazinyl)amino]-3-hydroxychroman+ ++-6- carbonitrile hemihydrate, CAS 170148-29-5), a new potassium channel opener, was evaluated in isolated coronary arteries and anesthetized dogs. JTV-506 (1 nmol/l-3 mumol/l) produced a concentration-dependent relaxation in porcine isolated epicardial large coronary arteries precontracted with KCl (30 mmol/l), phenylephrine (3 mumol/l), histamine (3 mumol/l), serotonin (5-HT; 300 nmol/l), prostaglandin F2 alpha (PGF2 alpha; 10 mumol/l), U-46619 (100 nmol/l), endothelin-1 (ET-1; 30 nmol/l) and Bay K-8644 (100 nmol/l). JTV-506 was 2.5-8.5 and 13.3-81.5 times more potent than levcromakalim (CAS 94535-50-9) and nicorandil (CAS 65141-46-0), respectively, but was less potent than nifedipine (CAS 21829-25-4). JTV-506 and levcromakalim produced almost a complete relaxation in arteries precontracted with various kinds of vasoconstrictor, except for KCl. In contrast, nifedipine produced about 80-90% relaxation in arteries, precontracted with PGF2 alpha, U-46619 and ET-1. Thus, this potassium channel opener can be characterized as an agonist-nonselective vasorelaxant. The relaxing effects of JTV-506 and levcromakalim on coronary arteries precontracted with 30 mmol/l KCl was competitively antagonized by 3 mumol/l glibenclamide, an ATP-sensitive potassium (KATP) channel blocker. In canine isolated epicardial large coronary arteries, 10 mumol/l JTV-506, 10 mumol/l levcromakalim, 100 mumol/l nicorandil and 0.1 mumol/l nifedipine eliminated 10 mmol/l 3,4-diaminopyridine-induced rhythmic contractions. In anesthetized dogs, when administered directly into the coronary artery, JTV-506 induced dose-dependent increases in coronary arterial diameter and coronary blood flow. These results suggest that JTV-506 elicits coronary vasorelaxation through activation of the KATP channel. It is expected that JTV-506 might be useful in the treatment of coronary vasospasm in angina pectoris.

Cardiovascular pharmacological studies on JTV-506, a new potassium channel opener. 1st communication: effects on myocardium and vasculature.

The effects of JTV-506 ((-)-(3S,4R)-2,2-bis(methoxymethyl)-4-[(1,6-dihydro-1-methyl-6-oxo-3- pyridazinyl)amino]-3-hydroxychroman-6-carbonitrile hemihydrate, CAS 170148-29-5), a novel coronary vasodilator, on hemodynamics, cardiac function and cardiac oxygen consumption were evaluated in anesthetized dogs. In anesthetized, open-chest dogs, JTV-506 (0.3-10 micrograms/kg i.v.) induced a marked increase in coronary blood flow in a dose dependent manner, while at these doses it had smaller effects on vertebral and mesenteric blood flow and almost no effect on renal blood flow. JTV-506 (1-10 micrograms/kg i.v.) showed a tendency to decrease oxygen consumption of the heart and elevate myocardial oxygen pressure without cardiac suppression. Effects of JTV-506 on hemodynamics and the respiratory system following i.v. administration (0.3-300 micrograms/kg) were investigated in spontaneously breathing anesthetized dogs. The effective dose to induce hemodynamic changes was more than 3 micrograms/kg. JTV-506 did not have a crucial influence on electrocardiogram. JTV-506 caused marked increase in coronary blood flow and myocardial oxygen pressure with slight change in blood pressure. It is concluded that JTV-506 is a potent vasodilator, with particularly pronounced effect on vasculature of the heart. These results suggest that JTV-506 may be useful in the treatment of angina pectoris.

Selective action of metoprolol to attenuate regadenoson-induced tachycardia in conscious dogs

BackgroundRegadenoson is a coronary vasodilator that causes tachycardia via activation of the sympathetic nervous system. We determined whether β1-adrenergic blockade can attenuate tachycardia without significantly reducing coronary vasodilation induced by regadenoson. Methods and ResultsHemodynamics and coronary blood flow (CBF) were measured in conscious dogs. Baseline CBF and heart rate (HR) were 42 ± 2 mL/min and 87 ± 8 bpm (mean ± SEM), respectively. Regadenoson (1, 2.5, and 5 μg/kg) increased peak CBF by 129 ± 10, 149 ± 7, and 174 ± 10 mL/min and HR by 48 ± 6, 67 ± 5, and 85 ± 11 bpm, respectively, (all P < .05 vs baseline). In the presence of metoprolol (1.5 mg/kg), the peak increases in CBF caused by these three doses of regadenoson were reduced by only 11 ± 7%, 10 ± 4%, and 21 ± 2% (P = NS, <.05, and <.05 vs regadenoson alone), respectively, whereas the regadenoson-induced tachycardia was significantly reduced by 55 ± 8%, 55 ± 4%, and 52 ± 5% (all P < .05). In the presence of metoprolol, the duration of the regadenoson-induced increase in CBF was reduced, but the duration of the 2-fold increase in CBF caused by 5 μg/kg regadenoson was still nearly 6 minutes. Conclusionβ1-Adrenergic blockade with metoprolol attenuated the regadenoson-induced increase in HR more than the increase in CBF.

CD34 + Autologous Human Stem Cells in Treating Refractory Angina

See related article, pages 428–436 The article by Losordo et al1 in this issue of Circulation Research is an important addition to the relatively small body of literature in clinical cardiac stem cell therapy. Although the number of patients in the trial by Losordo et al is fairly small, only a handful of similarly sized trials have been published.2–4 In the recent past, the merit of performing clinical trials of cardiac cell therapy was debated in the literature.5,6 However, the study of regenerative cardiac medicine continues to move forward, despite the fact that opponents have highlighted the many challenges in the field, focusing mainly on the lack of mechanistic data. Nevertheless, other questions, such as the best cell type, cell dose, and delivery modality, are beginning to be answered. The performance of larger-scale studies is now being proposed. Interestingly, a large phase III trial of autologous bone marrow mononuclear cells (ABMMNCs) is ready to be initiated in Europe (Oral presentation by Anthony Mathur, PhD; June 2011, Eighth International Symposium on Stem Cell Therapy and Cardiovascular Innovations, Madrid, Spain). Most clinical trials in cardiac cell therapy have been performed with ABMMNCs. Although the use of this mixed cell population may be considered a relatively broad or less sophisticated approach, ABMMNCs continue to be used because of the previous success with this approach. However, investigators are also seeking new, possibly more potent cell types in bone marrow subpopulations, such as aldehyde dehydrogenase bright (ALDHbr) cells7 (characterized by a common enzyme), mesenchymal cells (a single bone marrow cell population), or as in the trial by Losordo et al, CD34+ …

Contribution of IKCa channels to the control of coronary blood flow

The purpose of this investigation was to elucidate the contribution of intermediate conductance calcium-activated potassium channels (IK(Ca)) to the regulation of coronary blood flow in vivo. We hypothesized that IK(Ca) channels modulate coronary arteriolar resistance at rest and contribute to vasomotor responses to changes in coronary perfusion pressure and/or in response to cardiac ischemia. Experiments were conducted in open-chest anesthetized dogs in the absence and presence of IK(Ca) channel inhibitor, TRAM-34 (1 μg/min, intracoronary), and the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine-methyl ester (L-NAME) (150 μg/min, intracoronary). We found that administration of the potent SK(Ca) and IK(Ca) channel agonist NS309 dose-dependently increased coronary blood flow and that inhibition of IK(Ca) channels with TRAM-34 attenuated this response by ∼90%. The increase in coronary blood flow to NS309 was also decreased ∼100% by the inhibition of NO production with L-NAME. Multiple linear regression analysis demonstrated that TRAM-34 diminished the autoregulatory capability of the coronary circulation at coronary pressures ranging from 60 to 120 mmHg. However, inhibition of IK(Ca) channels did not affect coronary vasodilation in response to a transient 15 s coronary artery occlusion (i.e. reactive hyperemia). Our data reveal that IK(Ca) channels are functionally expressed in the coronary circulation and that activation of these channels produces marked coronary vasodilation in vivo, primarily via increases in endothelial NO production. In addition, IK(Ca) channels modestly contribute to changes in coronary vascular resistance in response to alterations in coronary perfusion pressure but do not contribute to the reactive hyperemic response following a brief coronary artery occlusion.

Contribution of IKCa Channels to the Control of Coronary Blood Flow

The purpose of this investigation was to determine the role of intermediate conductance calcium‐activated potassium channels (IKCa) in regulating coronary arteriolar resistance at rest, in response to changes in coronary perfusion pressure, and during cardiac ischemia. Experiments were conducted in open‐chest anesthetized dogs in the presence of IKCa channel inhibitor, TRAM‐34 (1 μg/min, ic), or the nitric oxide (NO) synthase inhibitor, L‐NAME (150 μg/min, ic). Administration of the SKCa and IKCa channel agonist NS309 dose‐dependently increased coronary blood flow and inhibition of IKCa channels with TRAM‐34 attenuated this response by ~ 90%. The increase in coronary blood flow with NS309 was also decreased ~100% by L‐NAME. In addition, TRAM‐34 diminished the autoregulatory capability of the coronary circulation at pressures ranging from 60 – 120 mmHg. However, inhibition of IKCa channels did not affect coronary reactive hyperemia. Our data reveal that IKCa channels are functionally expressed in the coronary vasculature and that activation of these channels produces marked coronary vasodilation in vivo, primarily via increases in endothelial NO production. In addition, IKCa channels modestly regulate vascular resistance in response to alterations in coronary perfusion pressure but do not modulate coronary vasodilation in response to cardiac ischemia. Support 10PRE4230035, HL092245

Direct Vasorelaxation by a Novel Phytoestrogen Tanshinone IIA Is Mediated by Nongenomic Action of Estrogen Receptor Through Endothelial Nitric Oxide Synthase Activation and Calcium Mobilization

Salvia miltiorrhiza (Danshen) has been widely used in China and other Asian countries for treating various cardiovascular diseases resulting from its ability to improve coronary microcirculation and increase coronary blood flow. Tanshinone IIA (Tan IIA), the major active lipophilic ingredient responsible for the beneficial actions of Salvia miltiorrhiza, has been shown to induce vasodilation in coronary arteries. Because our recent study identified Tan IIA as a new member of the phytoestrogens, we hypothesized that its action might be mediated by estrogen receptor (ER) in vascular endothelial cells. The aim of the present study was to assess whether cardiovascular protection exerted by Tan IIA is mediated by the ER signal pathway and whether the genomic or nongenomic action of ER is involved within arteries and vascular endothelial cells. The effect of Tan IIA on blood vessels was investigated by vascular ring assay using endothelium-intact and endothelium-denuded rat aortas. Similar to estrogen, Tan IIA caused an nitric oxide- and endothelium-dependent relaxation, which was blocked by ER antagonist ICI 182,780. Primary cardiac microvascular endothelial cells were used as a model to study the cellular and molecular mechanisms of Tan IIA-induced vasorelaxation. We demonstrate that Tan IIA is capable of activating the estrogen receptor signal pathway, leading to increased endothelial nitric oxide synthase gene expression, nitric oxide production, ERK1/2 phosphorylation, and Ca mobilization. Collectively, these effects contribute to Tan IIA's vasodilative activity effects of y ER antagonist Cnt of cardiovascular diseases. Our findings support a continued effort in discovering and developing novel phytoestrogens as an alternative hormone replacement therapy for safer and more effective treatment of cardiovascular diseases.

Cardioprotective effects of hydrogen sulfide

The gaseous mediator hydrogen sulfide (H 2S) is synthesized mainly by cystathionine γ-lyase in the heart and plays a role in the regulation of cardiovascular homeostasis. Here we first overview the state of the art in the literature on the cardioprotective effects of H 2S in various models of cardiac injury. Subsequently, we present original data showing the beneficial effects of parenteral administration of a donor of H 2S on myocardial and endothelial function during reperfusion in a canine experimental model of cardiopulmonary bypass. Overview of the literature demonstrates that various formulations of H 2S exert cardioprotective effects in cultured cells, isolated hearts and various rodent and large animal models of regional or global myocardial ischemia and heart failure. In addition, the production of H 2S plays a role in myocardial pre- and post-conditioning responses. The pathways implicated in the cardioprotective action of H 2S are multiple and involve K ATP channels, regulation of mitochondrial respiration, and regulation of cytoprotective genes such as Nrf-2. In the experimental part of the current article, we demonstrate the cardioprotective effects of H 2S in a canine model of cardiopulmonary bypass surgery. Anesthetized dogs were subjected hypothermic cardiopulmonary bypass with 60 min of hypothermic cardiac arrest in the presence of either saline (control, n = 8), or H 2S infusion (1 mg/kg/h for 2 h). Left ventricular hemodynamic variables (via combined pressure—volume-conductance catheter) as well as coronary blood flow, endothelium-dependent vasodilatation to acetylcholine and endothelium-independent vasodilatation to sodium nitroprusside were measured at baseline and after 60 min of reperfusion. Ex vivo vascular function and high-energy phosphate contents were also measured. H 2S led to a significantly better recovery of preload recruitable stroke work ( p < 0.05) after 60 min of reperfusion. Coronary blood flow was also significantly higher in the H 2S group ( p < 0.05). While the vasodilatory response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly higher increase in coronary blood flow in the H 2S-treated group ( p < 0.05) both in vivo and ex vivo. Furthermore, high-energy phosphate contents were better preserved in the H 2S group. Additionally, the cytoprotective effects of H 2S were confirmed also using in vitro cell culture experiments in H9c2 cardiac myocytes exposed to hypoxia and reoxygenation or to the cytotoxic oxidant hydrogen peroxide. Thus, therapeutic administration of H 2S exerts cardioprotective effects in a variety of experimental models, including a significant improvement of the recovery of myocardial and endothelial function in a canine model of cardiopulmonary bypass with hypothermic cardiac arrest.

Effects of inosine on reperfusion injury after cardiopulmonary bypass

ObjectiveInosine, a break-down product of adenosine has been recently shown to exert inodilatory and anti-inflammatory properties. Furthermore inosine might be a key substrate of pharmacological post-conditioning. In the present pre-clinical study, we investigated the effects of inosine on cardiac function during reperfusion in an experimental model of cardioplegic arrest and extracorporal circulation.MethodsTwelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or inosine (100 mg/kg, n = 6). Left ventricular end-systolic pressure volume relationship (ESPVR) was measured by a combined pressure-volume-conductance catheter at baseline and after 60 minutes of reperfusion. Left anterior descendent coronary blood flow (CBF), endothelium-dependent vasodilatation to acetylcholine (ACh) and endothelium-independent vasodilatation to sodium nitroprusside (SNP) were also determined.ResultsThe administration of inosine led to a significantly better recovery (given as percent of baseline) of ESPVR 90 ± 9% vs. 46 ± 6%, p < 0.05. CBF and was also significantly higher in the inosine group (56 ± 8 vs. 23 ± 4, ml/min, p < 0.05). While the vasodilatatory response to SNP was similar in both groups, ACh resulted in a significantly higher increase in CBF (58 ± 6% vs. 25 ± 5%, p < 0.05) in the inosine group.ConclusionsApplication of inosine improves myocardial and endothelial function after cardiopulmonary bypass with hypothermic cardiac arrest.

Contribution of Adenosine A2A and A2B Receptors to Ischemic Coronary Dilation: Role of KV and KATP Channels

This study was designed to elucidate the contribution of adenosine A(2A) and A(2B) receptors to coronary reactive hyperemia and downstream K(+) channels involved. Coronary blood flow was measured in open-chest anesthetized dogs. Adenosine dose-dependently increased coronary flow from 0.72 ± 0.1 to 2.6 ± 0.5 mL/minute/g under control conditions. Inhibition of A(2A) receptors with SCH58261 (1 μm) attenuated adenosine-induced dilation by ∼50%, while combined administration with the A(2B) receptor antagonist alloxazine (3 μm) produced no additional effect. SCH58261 significantly reduced reactive hyperemia in response to a transient 15 second occlusion; debt/repayment ratio decreased from 343 ± 63 to 232 ± 44%. Alloxazine alone attenuated adenosine-induced increases in coronary blood flow by ∼30% but failed to alter reactive hyperemia. A(2A) receptor agonist CGS21680 (10 μg bolus) increased coronary blood flow by 3.08 ± 0.31 mL/minute/g. This dilator response was attenuated to 0.76 ± 0.14 mL/minute/g by inhibition of K(V) channels with 4-aminopyridine (0.3mm) and to 0.11 ± 0.31 mL/minute/g by inhibition of K(ATP) channels with glibenclamide (3 mg/kg). Combined administration abolished vasodilation to CGS21680. These data indicate that A(2A) receptors contribute to coronary vasodilation in response to cardiac ischemia via activation of K(V) and K(ATP) channels.

Intracoronary gastrin 17 increases cardiac perfusion and function through autonomic nervous system, CCK receptors, and nitric oxide in anesthetized pigs

The release of gastrointestinal hormones has been reported to modulate reflex cardiovascular responses caused by gastric distension, although the role played by gastrin 17 is as yet unknown. The present study was therefore planned to determine the primary in vivo effect of gastrin 17 on coronary blood flow and cardiac function and the involvement of autonomic nervous system, CCK1/2 receptors, and nitric oxide (NO). In 40 anesthetized pigs, gastrin 17 was infused into the left anterior descending coronary artery at constant heart rate and arterial blood pressure. In 35 of the 40 pigs, the mechanisms of the observed hemodynamic responses were analyzed by repeating gastrin 17 infusion after autonomic nervous system and NO blockade, and after specific CCK receptors agonists/antagonists administration. Intracoronary gastrin 17 administration caused dose-related increases of both coronary blood flow and cardiac function. The intracoronary co-administration of CCK33/pentagastrin and gastrin 17 potentiated the coronary effects observed when the above agents were given alone (P <0.05). The potentiation of the cardiac response was observed only with the co-administration of pentagastrin and gastrin 17 (P <0.05). Moreover, blockade of muscarinic cholinoceptors (intravenous atropine) and of α-adrenoceptors (intravenous phentolamine) did not abolish the hemodynamic responses to gastrin 17. The cardiac and vascular effects of the hormone were prevented by blockade of β-adrenoceptors (intravenous atenolol and butoxamine), CCK1/2 receptors (intracoronary lorglumide and CAM-1028), and NO synthase (intracoronary Nω-nitro-l-arginine methyl ester). In conclusion, gastrin 17 primarily increased coronary blood flow and cardiac function through the involvement of CCK receptors, β-adrenoceptors, and NO release.

Effect of Heart tablets on cardiac hemodynamics and myocardial oxygen consumption in anesthetized dogs

To observe the pharmacological effects of Heart tablets on cardiac function and its mechanism, the effects on cardiac hemodynamics and myocardial oxygen consumption in anesthetized dogs were observed. Observe the effect of Heart tablets on coronary blood flow, cardiac output, myocardial oxygen consumption and other indicators in normal anesthetized dogs. The Heart tablets can increase femoral arterial blood pressure, while no effect is found on the heart rate, standard II ECG PR interval, QRS interval, QT interval, T wave and other parameters. The tablets can expand coronary artery and peripheral vessel, increase coronary blood flow, lower coronary resistance and increase cardiac blood supply capacity, improve left ventricular function, ameliorate cardiovascular adaptability, increase dp/dt(max), enhance myocardial activity and have a positive regulatory role in heart. At the meantime raise the cardiac output and stroke volume were raised, so that blood pressure can be increased, while the total peripheral resistance was decreased. The coronary vein sinus oxygen content were significantly increased and myocardial oxygen consumption index and myocardial oxygen utilization were reduced. The tablets can adjust and improve the cardiovascular system.

Crystalloid versus red blood cell-containing medium in the Langendorff-perfused isolated heart preparation

The isolated heart model is widely used for the assessment of coronary vascular response under various experimental conditions. As medium perfusate influences oxygenation conditions, coronary vascular response and myocardial consumption performance may differ between isolated hearts perfused with from with Krebs-Henseleit solution or Krebs-Henseleit mixed with red blood cells (KH-RBC). Coronary vascular response to endothelium-dependent and independent vasodilators as well as myocardial performance and oxygen consumption to isoproterenol infusion were compared in isolated rabbit hearts perfused with Krebs-Henseleit or KH-RBC. Krebs-Henseleit perfusate was equilibrated with 95% oxygen and 5% carbon dioxide, KH-RBC (haemoglobin 8.0 +/- 1.1 g.dl) with 20% oxygen, 5% carbon dioxide, and 75% nitrogen. The perfusion pressure was kept constant so that coronary blood flow (CBF) varied with coronary resistance. Data are mean +/- SD. Bradykinin induced a greater increase in CBF in KH-RBC-perfused hearts than in Krebs-Henseleit-perfused hearts (263 +/- 78 versus 134 +/- 35% of baseline, P < 0.001). Sodium nitroprusside induced a greater increase in CBF in KH-RBC-perfused than in Krebs-Henseleit-perfused hearts (257 +/- 70 versus 174 +/- 31% of baseline, P < 0.001). The increases in myocardial performance and in oxygen consumption induced by isoproterenol were greater with KH-RBC-perfused hearts than in Krebs-Henseleit-perfused hearts. A greater myoglobin release was observed in Krebs-Henseleit-perfused hearts. Endothelium-dependent and independent coronary flow responses are increased in KH-RBC-perfused hearts. Moreover, metabolic control of CBF is altered in Krebs-Henseleit-perfused hearts. Such differences should be taken into account when pharmacologic responses of anaesthetic agents are studied.

Scavenging free radicals improves endothelial dysfunction in human coronary arteries in vivo

The effect of a novel free radical scavenger, edaravone, on coronary endothelial dysfunction was examined in patients who had no significant stenosis of coronary arteries, to elucidate the role of free radicals on coronary endothelial dysfunction. The coronary blood flow (CBF) responses to acetylcholine (ACh) were measured by quantitative coronary arteriography and the intracoronary Doppler technique before and after the administration of edaravone. Twenty-four patients were divided into two groups on the basis of CBF responses to ACh; those with "attenuated" (%Delta CBF < 300%, n = 12) and "normal" (%Delta CBF > 300%, n = 12) flow responses. An intracoronary infusion of edaravone significantly improved ACh-induced increases in CBF in patients with attenuated flow responses; however, edaravone had no effect in those with normal flow responses (36.8% +/- 7.3% vs 0.0% +/- 5.1%, P < 0.01). The plasma levels of nitric oxide compounds (NOx) in the attenuated response group were lower than those in the normal group (35.7 +/- 2.3 vs 49.4 +/- 6.2 muM, P < 0.01) and correlated with the magnitude of CBF improvement by edaravone (r = 0.566, P < 0.01). The plasma level of malondialdehyde and 4-hydroxynonenal, which indicates the level of oxidative stress, in the attenuated group was higher than that in the normal group (6.9 +/- 0.9 vs 3.3 +/- 0.5 muM, P < 0.01) and correlated with the magnitude of CBF improvement by edaravone (r = 0.854, P < 0.01). A free radical scavenger improved the ACh-induced CBF response in patients with coronary atherosclerosis in vivo. Therefore, the current results suggest that scavenging free radicals has a beneficial effect for patients with coronary endothelial dysfunction.

Coronary endothelial dysfunction is associated with a reduction in coronary artery compliance and an increase in wall shear stress

ObjectiveEndothelial dysfunction is associated with arterial stiffness in large arteries. The purpose of this study was to investigate the association between coronary endothelial dysfunction, coronary artery compliance and wall shear...

Assessment of Coronary Flow Parameters by Transesophageal Echocardiography in Patients with Isolated Coronary Artery Ectasia: Effect of Intravenous Nitroglycerin

We sought to assess coronary flow parameters in patients with isolated coronary artery ectasia (CAE) as compared to subjects with normal coronaries. Consecutively, we enrolled 30 patients with ectasia of the left anterior descending (LAD) coronary artery (study group), and 10 subjects with normal coronaries (control group). All patients underwent transesophageal echocardiography to visualize the LAD. Spectral recordings of proximal LAD flow velocities were made and velocity time integrals were calculated. The diameter of the proximal LAD was measured and LAD blood flow was calculated. Nitroglycerin (0.3 mg) was administered intravenously and measurements were repeated 5 minutes later. The mean age of the whole series was 48.6 ± 8 years, 39 (97.5%) being males. A significantly higher baseline systolic, diastolic, and total coronary blood flow was found in the study group as compared to the control group (46.1 ± 34.3 vs. 23.1 ± 8.2, 123.9 ± 73.3 vs. 68.1 ± 21.6, 170.1 ± 97.9 vs. 91.1 ± 26.8 cm(3) /min, respectively, P < 0.05 for all). Within the study group, nitroglycerin administration caused a significant decrease in peak diastolic velocity; systolic, diastolic, and total velocity time integrals; and both diastolic and total coronary blood flow (P < 0.05 for all). Meanwhile, within the control group, nitroglycerin administration caused a significant increase in the total coronary blood flow (P < 0.05). Patients with CAE have higher resting coronary blood flow in comparison with subjects with normal coronaries. Intravenous nitroglycerin administration causes significant reduction of coronary blood flow in ectatic coronary arteries.

Muscle Metaboreflex‐Induced Coronary Vasoconstriction Limits Left Ventricular Performance‐Blood Flow Relationship

Raising myocardial work elicits coronary vasodilation. However, during dynamic exercise with muscle metaboreflex activation (MMA), a rise in sympathetic activity increases cardiac performance as well as induces alpha‐1 adrenergic mediated coronary vasoconstriction. Thus, the increase in coronary blood flow (CBF) is restrained by limited vasodilation. We tested whether this limited increase in CBF during MMA acts to functionally limit increases in left ventricular (LV) performance. Using chronically instrumented dogs we assessed the relationship between left ventricular function and blood flow during exercise and MMA before and after alpha‐1 adrenergic blockade (prazosin 50–100μg/kg). Coronary vascular conductance (CVC) was plotted as a function of cardiac power. Preload recruitable stroke work (PRSW) was assessed vs. CBF. We found that after alpha‐1 blockade the relationship between CVC and cardiac power was shifted upwards with an increase in slope such that MMA elicited greater increases in CVC per increase in cardiac power. Furthermore, PRSW increased linearly with increases in CBF independent of alpha blockade. We conclude that during MMA sympathetic vasoconstriction limits increases in CBF which restrains increases in cardiac contractility and the ability to increase cardiac power. NIH HL‐55473 and HL‐095819.

Efficacy of the Non-Adenosine Analogue A1 Adenosine Receptor Agonist (BR-4935) on Cardiovascular Function after Cardiopulmonary Bypass

We tested the hypothesis that pharmacological preconditioning with a newly developed, potent non-adenosine analogue A1AdoR agonist (BR-4935) improves biventricular cardiac and endothelial function after cardiopulmonary bypass. Twelve anesthetized dogs underwent cardiopulmonary bypass. Dogs were divided into two groups: group 1 (n = 6) received saline vehicle, group 2 (n = 6) received BR-4935 before cardiopulmonary bypass. Biventricular hemodynamic variables were measured using a combined pressure-volume conductance catheter. Coronary blood flow, ATP content, malondialdehyde and myeloperoxidase levels and vasodilatative responses to acetylcholine and sodium nitroprusside were also determined. Administration of the A1AdoR agonist led to a significantly better recovery of left and right ventricular systolic function after 60 minutes of reperfusion. Although the vasodilatative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary blood flow in the BR-4935 group. In addition, the ATP content was significantly higher in the same group. Furthermore, malondialdehyde and myeloperoxidase levels significantly decreased in the A1AdoR group. Pharmacological preconditioning with a new, potent non-adenosine analogue A1AdoR agonist improves biventricular function recovery and endothelial function after hypothermic cardiac arrest.

Regadenoson

Regadenoson is an adenosine A(2A) receptor agonist approved for use as a pharmacologic stress agent for radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress. Regadenoson causes a rapid increase in coronary blood flow, which is sustained for a short duration. In two phase III trials in patients with known or suspected coronary artery disease who were indicated for pharmacologic stress myocardial perfusion imaging, the agreement rate (in detecting reversible perfusion defects) between sequential adenosine-regadenoson scan images was noninferior to that between sequential adenosine-adenosine scan images. Regadenoson, compared with adenosine, was associated with a faster and greater peak increase in heart rate, but a slower return to baseline. The SBP and DBP decreased slightly with both agents; recovery to baseline levels was again faster with adenosine than with regadenoson. Regadenoson appeared to be generally well tolerated, with most adverse events beginning soon after administration and resolving within approximately 15 minutes. No unexpected treatment-emergent ECG changes occurred with regadenoson in the phase III trials.