Decrease In Coronary Perfusion Pressure Research Articles

Oxygen-sensing pathways below autoregulatory threshold act to sustain myocardial oxygen delivery during reductions in perfusion pressure.

The coronary circulation has an innate ability to maintain constant blood flow over a wide range of perfusion pressures. However, the mechanisms responsible for coronary autoregulation remain a fundamental and highly contested question. This study interrogated the local metabolic hypothesis of autoregulation by testing the hypothesis that hypoxemia-induced exaggeration of the metabolic error signal improves the autoregulatory response. Experiments were performed on open-chest anesthetized swine during stepwise changes in coronary perfusion pressure (CPP) from 140 to 40mmHg under normoxic (n = 15) and hypoxemic (n = 8) conditions, in the absence and presence of dobutamine-induced increases in myocardial oxygen consumption (MVO2) (n = 5-7). Hypoxemia (PaO2 < 40mmHg) decreased coronary venous PO2 (CvPO2) ~ 30% (P < 0.001) and increased coronary blood flow ~ 100% (P < 0.001), sufficient to maintain myocardial oxygen delivery (P = 0.14) over a wide range of CPPs. Autoregulatory responsiveness during hypoxemia-induced reductions in CvPO2 were associated with increases of autoregulatory gain (Gc; P = 0.033) but not slope (P = 0.585) over a CPP range of 120 to 60mmHg. Preservation of autoregulatory Gc (P = 0.069) and slope (P = 0.264) was observed during dobutamine administration ± hypoxemia. Reductions in coronary resistance in response to decreases in CPP predominantly occurred below CvPO2 values of ~ 25mmHg, irrespective of underlying vasomotor reserve. These findings support the presence of an autoregulatory threshold under which oxygen-sensing pathway(s) act to preserve sufficient myocardial oxygen delivery as CPP is reduced during increases in MVO2 and/or reductions in arterial oxygen content.

Pressão de pulso como fator de risco para eventos cardiovasculares: mito ou realidade?

Background Elevated systolic blood pressure and decreased diastolic blood pressure increase systolic load, with concurrent decrease in coronary perfusion pressure. Researches suggested a relation between elevated pulse pressure and morbidity and mortality due to cardiovascular events. This study set out to investigate whether pulse pressure is a predisposing risk factor for coronary heart disease or an aggravating risk factor in patients with coronary artery disease. Methods A total of 5,027 pressure registers were evaluated. Pulse pressure was determined invasively [...]

Troponin I, A Biomarker of Diagnosis of SIRS, Sepsis and Septic Shock

Background: Sepsis related troponin elevation (SRTE) has always been the demand and supply mismatchtheory. In the setting of sepsis, the cardiac metabolic requirements are high and in order to meet theserequirements an increase in the coronary blood flow is needed. Patients with underlying anemia andpreexisting subclinical CAD may develop a mismatch ischemia in this setting. It was always thought thatsepsis-related hypotension causes a decrease in coronary perfusion pressure thus leading to a decreasedblood flow to cardiac myocytes and thereby leading to SRTE. Objectives: To establish Troponin-I as a useful diagnostic marker for sepsis. Settings and Study Design: This prospective study was carried out in the department of Anesthesia,pain, palliative and intensive care medicine, Dhaka Medical College, Dhaka during July 2013 to June2015. Methods: This study was carried out in the department of Anesthesia, pain, palliative and intensive caremedicine, Dhaka Medical College, Dhaka during July 2013 to June 2015. According to Troponin-I valuepatients were divided into Troponin-I positive and negative for sepsis. Three cut off values of Troponin-I(0.05, 0.035, 0.015) were used for this study. By using Receiver operating characteristic (ROC) curve thebest sensitively, specificity, negative predictive value and positive predictive values of Troponin-I weredetermined. Results: The validity of troponin I (&gt;0.05 ng/dl) evaluation for blood culture positive were sensitivity45.0%, specificity 53.8%, accuracy 48.5%, positive predictive values 60.0% and negative predictive values38.9%. The validity of troponin I (&gt;0.035 ng/dl) evaluation for blood culture positive were sensitivity57.5%, specificity 23.1%, accuracy 43.9%, positive predictive values 53.5% and negative predictive values26.1%. The validity of troponin I (&gt;0.015 ng/dl) evaluation for blood culture positive were sensitivity72.5%, specificity 15.4%, accuracy 50.0%, positive predictive values 56.9% and negative predictive values26.7%. Conclusion: The cutoff values of troponin-I (&gt;0.035 ng/dl) observed more sensitivity of blood culture. JBSA 2018; 31(1): 3-11

Abstract 289: Effect of Elevated Legs on Hemodynamic Performance During Cardiopulmonary Resuscitation in a Porcine Model of Cardiac Arrest

Purpose of the study: During advanced life support (ALS) end-tidal carbon dioxide (EtCO 2 ) reflects cardiac output (CO). A recent clinical study found an association between passive leg raising (PLR) and increased EtCO 2 during ALS. This may reflect a transient increase in pulmonary blood flow and CO, but might cause a detrimental decrease in coronary perfusion pressure (CPP). We evaluated the effect of PLR during experimental ALS in a randomized, factorial design. Materials and methods: In nine anesthetized domestic pigs (30±1.8 kg) ventricular fibrillation was induced electrically. After 3 minutes of no-flow, mechanical chest compressions (5cm @ 100 min -1 ) were started. During four 5-minute segments of CPR we measured CO, EtCO 2 , perfusion pressures, carotid and cerebral cortical microcirculatory blood flow (MBF) and CPP (the average of the positive pressure difference between decompression aortic pressure (AP) and right atrial pressure (RAP)) at minute 2 and 4. Interventions were provided in a randomized sequence with PLR vs supine position, with or without epinephrine (0.5mg iv). Values are given as mean±standard deviation. Results: PLR did not increase EtCO2 compared to supine position (3.1±0.7 vs 3.0±0.8 kPa), but CO was minimally increased from 1.1±0.3 to 1.2±0.3 Lmin -1 ,(p=0.003). PLR did not significantly increase AP (57±15 vs. 48±18 mmHg, p=0.3), but RAP was higher (43±10 vs. 31±7, p=0.003). However, no difference was found in CPP due to marked variation in both groups (median(range): PLR 20 (9,43) and supine 17(9,58)). The effect of epinephrine during this experimental setup was minimal. Conclusion: We did not find a positive effect of PLR during experimental ALS, but there were no obviously detrimental effects either.

Calcitonin gene-related peptide protects the myocardium from ischemia induced by endothelin-1: Intravital microscopic observation and 31P-MR spectroscopic studies

AimsCalcitonin gene-related peptide (CGRP) is a potent vasodilator neuropeptide. We investigated the ameliorating effect of CGRP in myocardial ischemia induced by endothelin-1 (ET-1), with special emphasis on myocardial microvascular hemodynamics and levels of energy-related metabolites. Main methodsThe Langendorff preparations of rat isolated heart were perfused at a constant flow rate. Microvascular blood flow was also visualized in the anterior epicardium of the left ventricle by means of an intravital fluorescence microscope system. Energy-related metabolite contents in the myocardium were measured by means of 31P-magnetic resonance spectroscopy (31P-MRS). Key findingsIntracoronary bolus injections of CGRP caused dose-dependent decreases in coronary perfusion pressure (CPP) in the hearts exposed to ET-1 (30pmol). The vasodilator potency of CGRP was about 10,000-fold greater than that of nitroglycerin and 1,000-fold greater than that of isobutylmethylxanthine. Vasodilation of the small-sized arterioles (10–40μm in diameter) in response to CGRP (100pmol) was confirmed by direct microscopic observation. After ET-1 (30pmol) plus vehicle administration, high energy phosphates (phosphocreatine (PCr), ATP) were markedly reduced (p<0.05). CGRP administration significantly (p<0.05) attenuated the anaerobic changes in the myocardium (decrease in PCr) and macrohemodynamic alterations (increase in CPP, decrease in dP/dt etc.) induced by ET-1. SignificanceWe conclude that CGRP effectively confers hemodynamic and metabolic protections to isolated beating hearts against ET-1-induced myocardial ischemia.

Elastin Arteriopathy and William Syndrome: Do You Feel Lucky?

To the Editor: Over the past 2 yr, we have anesthetized 10 patients with Williams syndrome and concur with the recommendations by Burch et al.1 in their recent article. In addition, we have additional suggestions based on the successful resuscitation of two infants who suffered a cardiac arrest under anesthesia. In both infants, induction of anesthesia was with incremental doses of sevoflurane (2% and 3%), a remifentanil infusion and rocuronium. Cardiac arrest occurred within 5 min of induction and before intubation. The electrocardiograms demonstrated marked ST segment depression that was followed soon after by bradycardia. Neither patient had discernible systemic output (no palpable or Doppler evidence of pulses). Resuscitation with phenylephrine, epinephrine, and small fluid boluses occurred during the institution of cardiopulmonary resuscitation. Within 5 min from the start of resuscitation, the transthoracic echocardiography (TTE) demonstrated biventricular akinesis in the first and severe biventricular hypokinesis in the second patient. We used TTE to guide our therapy, allowing us to monitor wall motion abnormalities, guide fluid administration, and carefully titrate vasopressors without worsening tachycardia or the dynamic component of subarterial outflow tract obstruction. In addition, we avoided administration of epinephrine once the rhythm returned, but pulses were still absent (pulseless electrical activity) because the TTE demonstrated severely hypertrophied, underfilled ventricles. In this population, the inappropriate administration of epinephrine as per the pediatric advanced life support protocol for pulseless electrical activity could have compromised recovery. The second patient required urgent extracorporeal membrane oxygenation cannulation after sustaining another cardiac arrest several hours after arrival in the pediatric intensive care unit within 3 min after receiving a 1 μg/kg dose of fentanyl. Both the patients underwent successful surgical repair. These patients had severe bilateral outflow track obstruction with what Stamm et al.2 have termed “macaroni pulmonary arteries” (Fig. 1). It is noteworthy that the presence of an intracardiac shunt (patent foramen ovale and small restrictive ventricular septal defect) did not decrease the risk of arrest.Figure 1.: The PA hypoplasia.Despite an induction technique designed to minimize changes in coronary perfusion, our experience demonstrates that these patients continue to have a very high-anesthetic risk of cardiac arrest. We postulate that, during induction, a decrease in coronary perfusion pressure occurred secondary to vasodilation and in combination with relative hypovolemia, and severe biventricular hypertrophy precipitated ischemia leading to cardiac arrest. In the second patient, a cardiac arrest occurred within minutes after a small dose of fentanyl, highlighting the precarious hemodynamic balance of these children. We recommend preinduction hydration, ideally with an IV, but at minimum liberal PO fluids until 2 h preinduction and the early use of TTE to help treat hemodynamic abnormalities and guide therapy. Denise C. Joffe, MD Michael Richards, BM Michael Eisses, MD Brian Emerson, MD Jeremy Geiduschek, MD Department of Pediatric Anesthesiology University of Washington Seattle, Washington [email protected]

The Coronary and Myocardial Effects of Remifentanil and Sufentanil in the Erythrocyte-Perfused Isolated Rabbit Heart

Remifentanil-induced hypotension may be associated with adverse ischemic myocardial events. Although these events can be easily attributed to a decrease in coronary pressure perfusion, we tested the hypothesis that remifentanil could directly affect coronary vasomotor tone. Therefore, we assessed intrinsic coronary and myocardial in vitro effects of remifentanil on a Langendorff's rabbit model and compared these effects with those provoked by similar intracoronary concentrations of sufentanil. Under general anesthesia, hearts from New Zealand rabbits were rapidly excised and mounted on an erythrocyte-perfused and isolated heart preparation. The hearts were then exposed to increasing concentrations (10-1000 nM) of either remifentanil (n = 10) or sufentanil (n = 8). Between each concentration, hearts were allowed to return to baseline status. The maximal coronary and myocardial effects of each concentration of both drugs were noted. Baseline values of coronary blood flow and myocardial performances were comparable between groups. Neither remifentanil nor sufentanil induced significant coronary and myocardial effects. These results suggest that myocardial ischemia, which may occur during remifentanil-induced hemodynamic disturbances, especially in cardiac patients, is only related to a decrease in coronary perfusion pressure provoked by peripheral hemodynamic changes.

Oral Administration of Geranylgeranylacetone Blunts the Endothelial Dysfunction Induced by Ischemia and Reperfusion in the Rat Heart

It has been shown that geranylgeranylacetone (GGA) protects heart against ischemia/reperfusion injury via enhanced heat shock protein 72 (HSP72) expression in rats. In the present study, we investigated the protective effect of GGA on ischemia/reperfusion-induced endothelial dysfunction. Rats were given oral GGA (GGA group) or vehicle (CON group), and 24 hours later their hearts were removed and placed in the Langendorff apparatus for 30-minute low-flow ischemia followed by 30-minute reperfusion. GGA improved the postischemic functional recovery (P < 0.01), which was abolished by N-nitro-L-arginine methyl ester (L-NAME, NO synthase inhibitor). NO production during both ischemia and reperfusion were increased in the GGA group, and the acetylcholine (ACh)-induced (endothelium-dependent) vasodilation, measured as the percentage decrease in coronary perfusion pressure after ischemia/reperfusion (14.9 +/- 1.3%), was preserved as compared with that in the CON group (7.9 +/- 1.4%). LY294002, a phosphatidylinositol 3 (PI3) kinase inhibitor, abolished the protective effects of GGA on endothelial-dependent coronary vasodilation and NO production, whereas Y27632 (Rho kinase inhibitor) increased endothelium-dependent coronary vasodilation and NO production in CON group toward the level seen in GGA group. The amount of adrenomedullin in the coronary effluent at basal condition was lower in the GGA group than in the CON group (P < 0.05), and during both ischemia and reperfusion there was no difference in the amount of adrenomedullin between the GGA and CON groups. In addition, no difference was observed in the amount of endothelin-1 between the GGA and CON groups. These results indicate that GGA attenuates the ischemia/reperfusion-induced coronary endothelial dysfunction, which may contribute to its cardioprotective effect. The PI3 kinase and/or Rho kinase pathways appear to be involved in this process, whereas adrenomedullin and endothelin-1 are not necessary for the GGA-induced cardioprotection.

Effects of Intravenous Levosimendan on Human Coronary Vasomotor Regulation, Left Ventricular Wall Stress, and Myocardial Oxygen Uptake

Levosimendan is a calcium-sensitizing agent and an inodilator under current investigation in the treatment of decompensated heart failure. The effects of intravenous levosimendan on the human coronary vasculature, together with myocardial wall stress and oxygen uptake, have not been adequately studied. Ten adult patients underwent right- and left-heart catheterization. Baseline coronary blood flow was determined with quantitative coronary angiography and an intracoronary Doppler-tipped guidewire. Myocardial oxygen uptake was measured with a coronary sinus catheter. Echocardiography was performed before and 30 minutes after an intravenous infusion of levosimendan (24-microg/kg bolus over 10 minutes) was begun. Pulmonary capillary wedge decreased 37% (P=0.009), cardiac output increased 9% (P=0.04), and systemic vascular resistance decreased 18% (P<0.001). Left ventricular ejection fraction increased 20% (P=0.009), and meridional systolic wall stress decreased 48% (P=0.009). Coronary artery diameter increased 10% at 15 minutes (P=0.001) and 11% at 30 minutes (P=0.01). Coronary artery velocity increased 10% over baseline (P=0.04). Coronary blood flow increased 45% (P=0.02), whereas coronary resistance decreased 36% at 30 minutes (P=0.03). Myocardial oxygen extraction decreased 9% at 30 minutes (P=0.04). Levosimendan given intravenously exerts vasodilator effects on human coronary conductance and resistance arteries. Despite a decrease in coronary perfusion pressure, coronary blood flow is increased. A reduction in coronary vascular resistance and a decrease in coronary venous oxygen content indicate primary coronary vasodilation by levosimendan. Improved left ventricular systolic function and decreased myocardial oxygen extraction suggest improved myocardial efficiency.

Enantioselective Actions of Bupivacaine and Ropivacaine on Coronary Vascular Resistance at Cardiotoxic Concentrations

The main concern with the use of the long-acting local anesthetics bupivacaine and ropivacaine is inadvertent IV injection, which exposes the heart to toxic drug concentrations. We tested the hypothesis that these chiral anesthetics exert enantioselective actions on coronary vascular tone, the regulation of which does not involve voltage-gated Na(+) channels. Coronary perfusion pressure (CPP) was continuously measured in isolated hearts perfused via the aorta at a constant flow rate. This method provides a sensitive assay of coronary vascular resistance in the intact heart. In parallel experiments, we examined the effects of bupivacaine and ropivacaine on intracellular [Ca(2+)] in coronary endothelial cells. In addition, the effect of bupivacaine on mitochondrial membrane potential was assessed using isolated ventricular myocytes. Racemic bupivacaine and R(+)-bupivacaine produced similar dose-dependent decreases in CPP. However, S(-)-bupivacaine, S(-)-ropivacaine and R(+)-ropivacaine increased CPP. In contrast to adenosine triphosphate, neither racemic bupivacaine nor S(-)-ropivacaine changed endothelial intracellular [Ca(2+)], suggesting that these clinically used drugs do not modulate endothelial nitric oxide synthase. We also showed that the putative uncoupler bupivacaine did not depolarize mitochondria in intact ventricular myocytes. In conclusion, the long-acting local anesthetics have enantioselective actions on coronary resistance vessels. Racemic bupivacaine and R(+)-bupivacaine are coronary vasodilators, whereas S(-)-bupivacaine, S(-)-ropivacaine and, to a lesser extent, R(+)-ropivacaine all induce coronary vasoconstriction.

Mechanosensitive cardiac C-fiber response to changes in left ventricular filling, coronary perfusion pressure, hemorrhage, and volume expansion in rats.

Left ventricular (LV) end-diastolic pressure (LVEDP) increase due to volume expansion (VExp) enhances mechanosensitive vagal cardiac afferent C-fiber activity (CNFA), thus decreasing renal sympathetic nerve activity (RSNA). Hypotensive hemorrhage (hHem) attenuates RSNA despite decreased LVEDP. We hypothesized that CNFA increases with any change in LVEDP. Coronary perfusion pressure (CPP), supposedly affected in both conditions, might also be a stimulus of CNFA. VExp and hHem were performed in anesthetized male Sprague-Dawley rats while blood pressure, heart rate, and RSNA were measured. Cervical vagotomy abolished RSNA response in both reflex responses. Single-unit CNFA was recorded while LVEDP was changed. Rapid changes (+/- 4, +/-6, +/-8 mmHg) were obtained by graded occlusion of the caval vein and descending aorta. Prolonged changes were obtained by VExp and hHem. Furthermore, CNFA was recorded in a modified Langendorff heart while CPP was changed (70, 100, 40 mmHg). Rapid LVEDP changes increased CNFA [caval vein occlusion: +16 +/- 3 Hz (approximately +602%); aortic occlusion: +15 +/- 3 Hz (approximately +553%); 70 units; P < 0.05]. VExp and hHem (n = 6) increased CNFA [VExp: +10 +/- 4 Hz (approximately +1,033%); hHem: +10 +/- 2 Hz (approximately +1,225%); P < 0.05]. An increase in CPP increased CNFA [+2 +/- 1 Hz (approximately +225%); P < 0.05], whereas a decrease in CPP decreased CNFA [-0.8 +/- 0.4 Hz (approximately -50%); P < 0.05]. All C fibers recorded originated from the LV. CNFA increased with any LVEDP change but changed equidirectionally with CPP. Thus neither LVEDP nor CPP fully accounts directly for afferent C-fiber and reflex sympathetic responses. The intrinsic afferent stimuli and receptive fields accounting for reflex sympathoinhibition still remain cryptic.

Death by hyperventilation: A common and life-threatening problem during cardiopulmonary resuscitation

This translational research initiative focused on the physiology of cardiopulmonary resuscitation (CPR) initiated by a clinical observation of consistent hyperventilation by professional rescuers in out-of-hospital cardiac arrest. This observation generated scientific hypotheses that could only ethically be tested in the animal laboratory. To examine the hypothesis that excessive ventilation rates during performance of CPR by overzealous but well-trained rescue personnel causes a significant decrease in coronary perfusion pressure and an increased likelihood of death. In the in vivo human aspect of the study, we set out to objectively and electronically record rate and duration of ventilation during performance of CPR by trained professional rescue personnel in a prospective clinical trial in intubated, adult patients with out-of-hospital cardiac arrest. In the in vivo animal aspect of the study, to simulate the clinically observed hyperventilation, nine pigs in cardiac arrest were ventilated in a random order with 12, 20, or 30 breaths/min, and physiologic variables were assessed. Next, three groups of seven pigs in cardiac arrest were ventilated at 12 breaths/min with 100% oxygen, 30 breaths/min with 100% oxygen, or 30 breaths/min with 5% CO2/95% oxygen, and survival was assessed. Ventilation rate and duration in humans; mean intratracheal pressure, coronary perfusion pressure, and survival rates in animals. In 13 consecutive adults (average age, 63 +/- 5.8 yrs) receiving CPR (seven men) the average ventilation rate was 30 +/- 3.2 breaths/min (range, 15 to 49 breaths/min) and the average duration of each breath was 1.0 +/- 0.07 sec. The average percentage of time in which a positive pressure was recorded in the lungs was 47.3 +/- 4.3%. No patient survived. In animals treated with 12, 20, and 30 breaths/min, the mean intratracheal pressures and coronary perfusion pressures were 7.1 +/- 0.7, 11.6 +/- 0.7, 17.5 +/- 1.0 mm Hg/min (p < .0001) and 23.4 +/- 1.0, 19.5 +/- 1.8, 16.9 +/- 1.8 mm Hg (p = .03) with each of the different ventilation rates, respectively (p = comparison of 12 breaths/min vs. 30 breaths/min for mean intratracheal pressure and coronary perfusion pressure). Survival rates were six of seven, one of seven, and one of seven with 12, 30, and 30 + CO2 breaths/min, respectively (p = .006). Despite seemingly adequate training, professional rescuers consistently hyperventilated patients during out-of-hospital CPR. Subsequent hemodynamic and survival studies in pigs demonstrated that excessive ventilation rates significantly decreased coronary perfusion pressures and survival rates, despite supplemental CO2 to prevent hypocapnia. This translational research initiative demonstrates an inversely proportional relationship between mean intratracheal pressure and coronary perfusion pressure during CPR. Additional education of CPR providers is urgently needed to reduce these newly identified and deadly consequences of hyperventilation during CPR. These findings also have significant implications for interpretation and design of resuscitation research, CPR guidelines, education, the development of biomedical devices, emergency medical services quality assurance, and clinical practice.

Natriuretic peptide receptor-C regulates coronary blood flow and prevents myocardial ischemia/reperfusion injury: novel cardioprotective role for endothelium-derived C-type natriuretic peptide.

Ischemia/reperfusion (I/R) injury complicates myocardial infarction and stroke by exacerbating tissue damage and increasing risk of mortality. We have recently identified C-type natriuretic peptide (CNP) as an endothelium-derived hyperpolarizing factor in the mesenteric resistance vasculature and described a novel signaling pathway involving activation of natriuretic peptide receptor C (NPR-C), which plays a pivotal role in the regulation of local blood flow. We tested the hypothesis that CNP/NPR-C signaling is a novel regulatory pathway governing coronary blood flow and protecting against I/R injury. CNP and (Cys18)-atrial natriuretic factor (4-23) amide (cANF(4-23)) elicited dose-dependent decreases in coronary perfusion pressure (CPP) that were blocked by Ba(2+) and ouabain in the isolated Langendorff rat heart. The endothelium-dependent vasodilator acetylcholine elicited the release of CNP from the coronary endothelium. CNP and cANF(4-23) reduced infarct size after 25 minutes of global ischemia and 120 minutes of reperfusion, maintaining CPP and left ventricular pressure at preischemic values. The vasorelaxant and protective activity of CNP and cANF(4-23) were enhanced in the absence of endothelium-derived nitric oxide. Endothelium-derived CNP is involved in the regulation of the coronary circulation, and NPR-C activation underlies the vasorelaxant activity of this peptide. Moreover, this newly defined pathway represents a protective mechanism against I/R injury and a novel target for therapeutic intervention in ischemic cardiovascular disorders.

Involvement of nitric oxide in amiodarone- and dronedarone-induced coronary vasodilation in guinea pig heart

Amiodarone, a powerful antiarrhythmic compound, possesses coronary and peripheral vasodilator properties. The mechanisms responsible for these effects remain incompletely understood. In the present study, the coronary effects of amiodarone and dronedarone, a non-iodinated amiodarone-like compound, were investigated in isolated guinea pig hearts perfused at constant flow with high K + solution (40 mM). Amiodarone (0.01–10 μM), dronedarone (0.01–1 μM) and verapamil (0.01–10 μM) induced concentration-dependent decreases in coronary perfusion pressure. Amiodarone- and dronedarone-mediated reductions in coronary perfusion pressure were not modified by a cyclooxygenase inhibitor, indomethacin (3 μM). l-Nitro- l-arginine ( l-NOARG; 3–100 μM) caused a rightward shift of concentration–response curves to amiodarone and dronedarone in a dose-dependent way; l-arginine, a nitric oxide (NO) precursor, reversed this effect. Furthermore, when guinea pigs were treated with N G-nitro- l-arginine methyl ester ( l-NAME; 20 mg/kg), amiodarone could not reduce coronary perfusion pressure. NO synthase inhibition did not affect the coronary perfusion pressure response to verapamil. 1 H-[1,2,4]Oxadiazole (4,3- a) quinoxalin-1-one (ODQ), a specific inhibitor of the guanylyl cyclase, inhibited the effects of amiodarone but not those of verapamil. In the presence of l-NOARG and ODQ, and in hearts from animals treated with l-NAME, a decrease in coronary perfusion pressure was still observed at the highest concentration of dronedarone. These results show that, in guinea pig hearts, the coronary vasodilation induced by amiodarone highly depends on nitric oxide. Dronedarone differs from amiodarone by a remaining relaxant effect, refractory to inhibition of NO synthase pathway, probably due to its Ca + antagonist properties.

Effects of dinucleoside polyphosphates on regulation of coronary vascular tone

The aim of the present study was to investigate the effects of Xp 5X and Xp 6X (X=guanosine (G) or adenosine (A); n=5 and 6), which have been identified in human platelets, on coronary vascular tone. The activation of purinoceptors in rat coronary vasculature by Xp 5X and Xp 6X was evaluated by measuring their effects on perfusion pressure in the Langendorff perfused rat. Ap 5X and Ap 6X induced dose-dependent vasodilation that was due to P2Y 1 receptor activation, as evidenced by use of the selective P2Y 1 receptor antagonist 2′-deoxy- N 6-methyl-adenosine 3′,5′-diphosphate diammonium (MRS2179). Vasodilation was induced by NO release, as evidenced by inhibition of nitric oxide synthases (NO synthases) by N G-nitro- l-arginine methyl ester ( l-NAME). The dose-dependent decrease in coronary perfusion pressure induced by Ap 5X and Ap 6X was converted to a dose-dependent increase in perfusion pressure after inhibition of NO synthases by l-NAME. After endothelium removal, the vasodilation elicited by Ap 5X and Ap 6X was converted to a vasoconstriction which could be inhibited by P2X receptor blockade. Ap 5A, Ap 5G, Ap 6A and Ap 6G are vasodilating or vasoconstricting nucleotides that activate P2Y 1 or P2X receptors depending on the status of the coronary vascular endothelium.

Effects of cocaine on the coronary arteries

Background A number of studies have documented myocardial ischemia and infarction associated with cocaine use. Mismatch between myocardial oxygen supply and demand from cocaine-induced vasoconstriction and increased myocardial workload are often invoked as the major postulated mechanism by which cocaine induces myocardial ischemia. This article reviews the literature studying the effects produced by cocaine on the coronary arteries to provide insight into the various pathophysiologic mechanisms by which cocaine triggers acute cardiac ischemia or infarction. Methods We reviewed the published literature describing the effects of cocaine on the coronary arteries. A MEDLINE search of English language articles published between 1985 and 2000 was performed. Key words included coronary arteries, coronary vasoconstriction, vasospasm, coronary vasodilation, cardiac vasculature, myocardial ischemia, platelets, thrombosis, and cocaine. Both animal and human studies were included. The bibliographies of identified articles were also explored for additional sources of information. Results A recreational dose of cocaine increases the heart rate by approximately 30 beats/min. It also increases the blood pressure by 20/10 mm Hg. These increases are modest, are equivalent to mild exercise, and are not believed to be sufficient to result in myocardial ischemia in the majority of cases. Animal and human studies have documented cocaine-induced early coronary artery vasodilation as shown by a decrease in coronary perfusion pressure ranging from 13% to 68%. This was followed by a more sustained vasoconstriction demonstrated by a decrease in epicardial coronary artery diameter ranging from 5% to 30% with various doses of cocaine by various methods of administration. These changes alone are also an unlikely explanation for cocaine-induced myocardial ischemia. Therefore neither increases in myocardial workload nor hemodynamic changes are sufficient to explain cocaine-induced myocardial ischemia. However, evidence also exists that cocaine activates platelets and promotes thrombosis, resulting in intracoronary thrombus formation. Cocaine may also promote premature and more severe coronary atherosclerosis. Conclusion The etiology of cocaine-induced myocardial ischemia is complex and is likely to be multifactorial. It appears to be the result of coronary artery vasoconstriction, intracoronary thrombosis, and accelerated atherosclerosis. (Am Heart J 2001;142:402-10.)

Safety Profile and Hemodynamic Responses to β-Adrenergic Stimulation by Dobutamine in Heart Transplant Patients

Dobutamine stress echocardiography (DSE) has been used as a screening tool for coronary artery disease after heart transplantation and in the identification of patients at risk for development of cardiac events. However, the safety profile of high-dose dobutamine in heart transplant patients has not been systematically examined. Accordingly, we studied the safety profile and hemodynamic responses to escalating doses of dobutamine to determine the influence of denervation. We assessed the hemodynamic responses, heart rate (HR), and arterial BP indexes (mean arterial pressure, systolic BP [SBP], diastolic BP [DBP], and pulse pressure) to dobutamine in 87 heart transplant patients ([mean +/- SD] age, 51 +/- 1 years) and compared the results with 97 nontransplant patients (age, 63.0 +/- 1 years) who served as innervated control subjects. The baseline HR (84 +/- 2 vs 69 +/- 1 beats/minute, respectively; p < 0.001) and peak HR response (144 +/- 2 vs 117 +/- 2 beats/minute, respectively; p < 0.001) were significantly higher in heart transplant patients than in the nontransplant patients. SBP was lower in heart transplant patients than in nontransplant patients at baseline (131 +/- 2 vs 138 +/- 2 mm Hg, respectively; p < 0.02) and at peak (150 +/- 3 vs 158 +/- 3 mm Hg, respectively; p < 0.03). However, baseline DBP was higher in transplant patients than in nontransplant patients (86 +/- 1 vs 77 +/- 1 mm Hg, respectively; p < 0.001). The decrease in DBP was similar in both groups (15 mm Hg). The dose-response curve for HR was shifted leftward in heart transplant patients. Heart transplant patients attained a higher absolute HR at each infusion stage and higher rates of increase, but the decrease in DBP was not significantly different in the two groups. These results show that there is augmented chronotropic response and expected decline in DBP in response to dobutamine infusion in heart transplant patients. This increase in myocardial oxygen demand and a decrease in coronary perfusion pressure may be important mechanisms in the development of ischemic abnormalities that are detectable as regional dysynergy on echocardiography.

Interaction of adenosine and prostacyclin in coronary flow regulation after myocardial ischemia

The role of adenosine and prostacyclin in post-ischemic vasodilation was investigated using a model of sequential perfusion of two isolated hearts. Two guinea pig hearts were sequentially perfused (10 ml/min) without (control, n=4) or with preceding 10-min ischemia ( n=6) of Heart I. Under control conditions no hemodynamic changes were observed in Heart II during sequential perfusion. After 10 min of ischemia of Heart I coronary perfusion pressure decreased by 23% in Heart II at the onset of sequential perfusion. Adenosine A 1 and A 2 receptor antagonists 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (2 μM) and 3,7-dimethyl-1-propargylxanthine (DMPX) (20 μM) infused simultaneously inhibited this decrease in coronary perfusion pressure by 74%, whereas indomethacin (5 μM) had no effect. DPCPX, DMPX and indomethacin in combination induced a significant increase in coronary perfusion pressure. Adenosine release (HPLC) into the coronary effluent after ischemia was significantly enhanced in the presence of indomethacin. These results suggest that after myocardial ischemia prostacyclin has an inhibitory effect on adenosine release.

Acidosis-induced coronary constriction in the rat heart: evidence for the activation of L-type calcium channels.

Perfused rat hearts were used to study the effects of acidosis on coronary tone. When pH was decreased, over the range pH 7.4 to pH 6.2, by reducing perfusate bicarbonate levels, under constant flow conditions, there was a transient decrease in coronary perfusion pressure (CPP), followed by a sustained acidosis-dependent increase in CPP, which reversed when pH was returned to pH 7.4. This increase in CPP was seen at perfusion rates of 5, 10, and 20 ml/min(-1). When using constant pressure perfusion acidosis reduced coronary flow. In a HEPES-buffered bicarbonate-free solution, acidosis did not cause a transient fall in CPP but it did produce a sustained increase in CPP. Addition of ammonium chloride (10 mM) reduced CPP, while washout of ammonium chloride increased CPP. The acidosis-induced increase in CPP was not affected by indomethacin, nitro-L-arginine, the nonselective adenosine receptor antagonist, 8-phenyl theophylline, or the thromboxane receptor antagonist, ZD 1542. The acidosis-induced increase in CPP was independent of the myocardial depressant effects of acidosis, but was attenuated by three different L-type calcium channel blockers. These results demonstrate that the coronary circulation of the rat constricts in response to acidosis. Experiments performed with L-type calcium channel blockers, and the calcium channel activator BAY K8644, suggest that constriction occurs via activation of L-type calcium channels. This would not be expected on the basis of electrophysiological studies, which have shown an inhibition of L-type calcium channels by acidosis.

Direct effects of thyroid hormones on rat coronary artery: nongenomic effects of triiodothyronine and thyroxine.

To determine whether thyroid hormones, triiodothyronine (T3) and thyroxine (T4), have any direct, nongenomic effects on vascular smooth muscle cells, we evaluated the effects of these hormones on rat coronary arteries. Bolus injection of T3 or T4 elicited a transient, dose-dependent decrease in coronary perfusion pressure (CPP), as well as an increase in arterial vasodilation. Vasodilation occurred immediately after injection, peaked at 15 seconds, and lasted 80 seconds. Reverse T3 had no effect on CPP or vasodilation. The rapidity of these effects suggests that they are not mediated by the T3-nuclear receptor, but are direct, nongenomic effects of thyroid hormones. Our results also suggest that thyroid hormones may play a role in preventing myocardial ischemia by inducing coronary artery vasodilation.