Atrial nitroso-redox balance and refractoriness following on-pump cardiac surgery: a randomized trial of atorvastatin.

AIMS: Systemic inflammation and increased activity of atrial NOX2-containing NADPH oxidases have been associated with the new onset of atrial fibrillation (AF) after cardiac surgery. In addition to lowering LDL-cholesterol, statins exert rapid anti-inflammatory and antioxidant effects, the clinical significance of which remains controversial. METHODS AND RESULTS: We first assessed the impact of cardiac surgery and cardiopulmonary bypass (CPB) on atrial nitroso-redox balance by measuring NO synthase (NOS) and GTP cyclohydrolase-1 (GCH-1) activity, biopterin content, and superoxide production in paired samples of the right atrial appendage obtained before (PRE) and after CPB and reperfusion (POST) in 116 patients. The effect of perioperative treatment with atorvastatin (80 mg once daily) on these parameters, blood biomarkers, and the post-operative atrial effective refractory period (AERP) was then evaluated in a randomized, double-blind, placebo-controlled study in 80 patients undergoing cardiac surgery on CPB. CPB and reperfusion led to a significant increase in atrial superoxide production (74% CI 71-76%, n = 46 paired samples, P < 0.0001) and a reduction in atrial tetrahydrobiopterin (BH4) (34% CI 33-35%, n = 36 paired samples, P < 0.01), and in GCH-1 (56% CI 55-58%, n = 26 paired samples, P < 0.001) and NOS activity (58% CI 52-67%, n = 20 paired samples, P < 0.001). Perioperative atorvastatin treatment prevented the effect of CPB and reperfusion on all parameters but had no significant effect on the postoperative right AERP, troponin release, or NT-proBNP after cardiac surgery. CONCLUSION: Perioperative statin therapy prevents post-reperfusion atrial nitroso-redox imbalance in patients undergoing on-pump cardiac surgery but has no significant impact on postoperative atrial refractoriness, perioperative myocardial injury, or markers of postoperative LV function. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01780740.

Glucagon Increases Beating Rate but Not Contractility in Rat Right Atrium. Comparison with Isoproterenol.

This study evaluated the chronotropic and inotropic responses to glucagon in spontaneously beating isolated right atria of rat heart. For comparison, we also investigated the effects resulting from stimulating ß-adrenoceptors with isoproterenol in this tissue. Isoproterenol increased both atrial frequency and contractility but glucagon only enhanced atrial rate. The transcript levels of glucagon receptors were about three times higher in sinoatrial node than in the atrial myocardium. Chronotropic responses to glucagon and isoproterenol were blunted by the funny current (If) inhibitor ZD 7288. Inhibitors of protein kinase A, H-89 and KT-5720 reduced the chronotropic response to glucagon but not to isoproterenol. Inhibition of ryanodine receptors and calcium/calmodulin dependent protein kinase II (important regulators of sarcoplasmic reticulum Ca2+ release), with ruthenium red and KN-62 respectively, failed to alter chronotropic responses of either glucagon or isoproterenol. Non selective inhibition of phosphodiesterase (PDE) with 3-isobutylmethylxantine or selective inhibition of PDE3 or PDE4 with cilostamide or rolipram respectively did not affect chronotropic effects of glucagon or isoproterenol. Our results indicate that glucagon increases beating rate but not contractility in rat right atria which could be a consequence of lower levels of glucagon receptors in atrial myocardium than in sinoatrial node. Chronotropic responses to glucagon or isoproterenol are mediated by If current but not by sarcoplasmic reticulum Ca2+ release, neither are regulated by PDE activity.

Cambios agudos en la función auricular derecha post uso de iloprost inhalatorio en pacientes con hipertensión arterial pulmonar: estudio con técnicas de deformación de imagen / Acute changes in right atrial funcion after Iloprost inhalation in patients with pulmonary hypertension: a study using image deformation techniques

Introducción: El efecto de prostanoides inhalatorios sobre la función auricular derecha (AD) en hipertensión arterial idiopática (HAP) no ha sido estudiado. Objetivo: Evaluar cambios agudos en la función AD y función diastólica del ventrículo derecho en pacientes con HAP post uso de Iloprost inhalatorio. Métodos: Se incluyeron pacientes con HAP sin uso previo de prostanoides. Se realizó un ecocardiograma transtorácico basal y 30 min posterior a la inhalación de iloprost. Se midió dimensión AD, relación E/e' y strain de la AD por speckle tracking, registrando la onda negativa de contracción auricular (SaAD) y la onda positiva de la fase de reservorio (SsAD). Se midió el tiempo de inicio de la fase de reservorio AD durante el sístole ventricular. Resultados: Se estudiaron 16 pacientes (15 mujeres), con edad promedio 44 ± 7,8 años. Post Iloprost disminuyó el volumen AD (basal: 140ml, post Iloprost: 109 ml; p 0,008) y las presiones de llenado (E/e’ basal: 13, post Iloprost: 9,8; p 0,028). No se registraron diferencias en el SaAD (basal: -8,4%, post Iloprost: -8,5%; p 0,834). El SsAD fue mayor post Iloprost (basal: 8,6%, post Iloprost: 11,7%; p 0,002) iniciándose antes durante el sístole ventricular (basal: 445ms, post Iloprost: 368ms; p 0,001). Conclusión: Con Iloprost inhalatorio en pacientes con HAP se observa una reducción aguda en el tamaño de la AD y en las presiones de llenado del VD. La deformación durante la fase de reservorio de la AD aumenta y se inicia significativamente antes. Esto sugiere que el Iloprost podría mejorar en forma aguda el trabajo mecánico de la AD en paciente con HAP.

Background: The effects of inhaled prostanoids on right atrial (RA) function in patients with Pulmonary Arterial Hypertension (PAH) have not been studied. We evaluated acute changes in RA function and right ventricular diastolic function after inhaled iloprost. Methods: We included PAH patients without prior prostanoid treatment. A surface echocardiogram was performed at baseline and 30 minutes after iloprost inhalation. Measurements included RA dimensions, right E/e’ ratio and RA strain by speckle tracking, registering a RA contraction wave (RASa) and RA reservoir wave (RASs). RA time to peak of deformation during the reservoir phase was also measured. Results: We included 16 patients (15 females, aged 44±7.8 years. Post iloprost there was a reduction in RA volume (baseline: 140ml, post iloprost: 109ml; p 0.008) and right ventricular filling pressure (baseline E/e’: 13, post iloprost: 9.8; p 0.028). There was no difference in the magnitude of the RASa wave (baseline: -8.4%, post iloprost: -8.5%; p 0.834). The RASs wave was larger post iloprost (baseline: 8.6%, post iloprost: 11.7%; p 0.002), and began earlier (baseline RA time to peak of deformation during reservoir phase: 445ms, post iloprost: 368ms; p 0.001). Conclusion: Inhaled iloprost acutely reduces RA size and right ventricular filling pressure in patients with HAP It also significantly increases the magnitude of RA systolic deformation as well as making it occur earlier in RA filling phase. This suggests that iloprost might improve RA mechanical performance.

Right ventricular and right atrial function and deformation in patients with subclinical hypothyroidism: a two- and three-dimensional echocardiographic study.

BACKGROUND: We sought to investigate right ventricular (RV) function and deformation assessed by three-dimensional echocardiography (3DE) and speckle tracking in patients with subclinical hypothyroidism (SHT), and to evaluate the influence of levothyroxine (L-T4) therapy on RV remodeling. METHODS: We included 50 untreated women with SHT and 45 healthy control women matched by age. The L-T4 therapy was prescribed to all SHT patients who were followed 1 year after euthyroid status was achieved. All study participants underwent laboratory analyses which included thyroid hormone levels, and complete two-dimensional echocardiography (2DE) and 3DE examinations. RESULTS: 3DE RV end-diastolic volume and ejection fraction were significantly reduced in the SHT patients before therapy in comparison with the healthy controls and treated SHT subjects. RV longitudinal strain, systolic, and early diastolic strain rates (SRs) were significantly decreased, whereas RV late diastolic SR was increased in the SHT patients before therapy when comparing with the controls. 2DE speckle tracking imaging revealed that L-T4 substitution therapy significantly improved RV systolic mechanics, whereas RV diastolic deformation was not completely recovered. Right atrial (RA) function and deformation were significantly impacted by SHT. Replacement L-T4 treatment improved but did not completely restore RA mechanics in the SHT patients. CONCLUSION: RV and RA function and mechanics are significantly affected by SHT. L-T4 therapy and 1-year maintenance of euthyroid status improved but did not completely recover RV and RA function and deformation in the SHT patients, which implies that right heart remodeling caused by SHT is not reversible in a 1-year period.

Long-term pulmonary hemodynamic effects of ambrisentan in pulmonary arterial hypertension.

The long-term effects of endothelin receptor antagonists on pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) are not well studied. This post hoc analysis examined changes in pulmonary hemodynamics in a cohort of patients with PAH who underwent follow-up right heart catheterization (RHC) in a long-term ambrisentan study (ARIES-E). A retrospective review was conducted of patients who underwent RHC after >3 months of ambrisentan therapy. Changes from baseline in mean PAP, mean right atrial pressure, cardiac index, and PVR were assessed and correlations between these hemodynamic changes and exercise capacity were examined. Sixty-eight patients who received ambrisentan in the ARIES studies had ≥1 follow-up RHC while receiving ambrisentan. Fifty-eight patients were on ambrisentan alone at the time of the first RHC. Median time from initiation of ambrisentan therapy to follow-up RHC was 60 weeks (range 14 to 158). Significant improvements compared to baseline were observed for mean PAP (-7.6 mm Hg, 95% confidence interval [CI] -10.0 to -5.1), PVR (-266 dyne × s/cm(5), 95% CI -350 to -180), and cardiac index (0.4 L/min/m(2), 95% CI 0.2 to 0.6 L/min/m(2)); for patients on ambrisentan alone, changes in mean PAP and PVR were inversely correlated with change from baseline 6-minute walking distance (r = -0.41 and -0.43, respectively, p <0.001 for the 2 comparisons) at time of follow-up RHC. In conclusion, ambrisentan may provide sustained improvements in pulmonary hemodynamics in patients with PAH who receive long-term treatment and these changes correlate with improvements in exercise capacity.

Role of polyamines and cAMP-dependent mechanisms on 5alpha-dihydrotestosterone-elicited functional effects in isolated right atria of rat.

Androgens produce acute vasodilation of systemic, pulmonary, and coronary arteries in several mammal preparations and increase cardiomyocyte contractility. A decrease of the spontaneous beating of sinoatrial cells has also been described. The aim of this study was to characterize the direct effect of 5alpha-dihydrotestosterone on the spontaneous chronotropism and inotropism in the same preparation as an approach to establish the effect on cardiac output and their mechanism of action. The effects were studied on isolated right atria of Wistar rats placed in an organ bath in Tyrode solution at 37 degrees C and bubbled with carbogen. In male rats, the acute administration of 5alpha-dihydrotestosterone, a nonaromatizable derivate of testosterone, elicited a positive inotropism, which was associated with a negative chronotropism. As reported in the left atria, polyamines and beta-adrenoceptors played a role in 5alpha-dihydrotestosterone-elicited positive inotropism because the effect was antagonized by alpha-difluoromethylornithine, an inhibitor of polyamine synthesis, and atenolol, a beta1-adrenoceptor blocker, but not on the negative effect on chronotropism. The androgen increased the sinoatrial node recovery time, suggesting an effect on the mechanisms of spontaneous diastolic depolarization involved in atria pacemaking. These effects of 5alpha-dihydrotestosterone are not hormonally regulated because they are similarly produced in estrogenized females and gonadectomized male and female rats. These results suggest that the androgen could acutely improve cardiac performance.

An evaluation of the cardiotoxicity of imatinib mesylate.

We studied 103 consecutive patients with chronic myeloid leukaemia on treatment with imatinib (IM) and 57 patients with chronic myeloproliferative disorders not treated with IM in order to evaluate its cardiotoxicity. There was no statistical difference regarding cardiac symptoms and signs, BNP levels and echocardiographic measurements for IM and control groups, except for peripheral oedema, more frequent in the IM group. Four patients in the IM group presented a BNP level >100pg/ml, one of them with depressed LVEF. IM was not related to systematic deterioration of cardiac function, but there is still a possibility of isolated cases of cardiotoxicity.

Adenosine can also improve the conduction between the superior vena cava and right atrium after isolation.

A 64-year-old man with atrial tachycardia (AT) 3 years after a superior vena cava (SVC) isolation for atrial fibrillation underwent electrophysiologic testing. SVC mapping with a basket catheter revealed a more frequent activation in the SVC than in either of the atria during the AT and consequently the recovered conduction between the SVC and right atrium. The conduction improved from 3 or 4-1 conduction to 2-1 conduction after adenosine was administered. Ectopic firing in the SVC persisted even after restoration of sinus rhythm by the successful SVC isolation, which was confirmed by adenosine.

Effect of the cardioselective, sarcolemmal K(ATP) channel blocker HMR 1098 on atrial electrical remodeling during pacing-induced atrial fibrillation in dogs.

PURPOSE: The progressive shortening of the atrial effective refractory period (ERP) during atrial fibrillation (AF) might be due to the activation of the KATP channels by rapid atrial rates. We tested the hypothesis that the cardioselective, sarcolemmal KATP channel blocker HMR 1098 would prevent atrial ERP shortening during AF. METHODS AND RESULTS: Nine dogs were treated with HMR 1098 (3 mg/kg bolus injection followed by a continuous intravenous (i.v.) infusion at 17 microg/kg/min rate maintained throughout the study) and 7 dogs served as controls receiving i.v. saline. Pharmacological autonomic blockade was induced by i.v. administration of atropine (0.04 mg/kg) and propranolol (0.2 mg/kg) and maintained throughout the study by continuous i.v. infusion of atropine (0.007 mg/kg/h) and propranolol (0.04 mg/kg/h). Rapid right atrial pacing at 50 msec cycle length (CL) was initiated and maintained for 6 hours. High right atrial ERP (HRA-ERP) and corrected sinus node recovery time (HRA-cSNRT), coronary sinus ERP (CS-ERP) and corrected SNRT (CS-cSNRT) at three (400, 300, 200 msec) CLs were measured before and after pacing at different time points. Baseline values were not different between control and treated dogs. In the control group the HRA-ERP progressively shortened (from 179 +/- 21 msec at baseline to 161 +/- 23 msec at 360 min at 400 msec CL) ( p = 0.002), with a gradual decrease, loss or inversion of ERP rate adaptation at shorter (300, 200 msec) CLs. HMR 1098 treatment did not prevent the shortening of HRA-ERP during the first 2 to 3 hours of rapid atrial pacing. However, beginning at 180-240 min, HMR 1098 increased the HRA-ERP ( p = 0.01) to baseline by 360 min. HMR 1098 treatment did not prevent another feature of atrial electrical remodeling, the flattening or inversion of ERP rate adaptation. In neither group did CS-ERP shortening occur. The maximum cSNRT at 360 min prolonged significantly in both groups during HRA and CS pacing as well compared with baseline. CONCLUSIONS: HMR 1098 treatment did not prevent the shortening of HRA-ERP, the salient feature of atrial electrical remodeling in the first 2 to 3 hours of rapid atrial rates, but did prevent it thereafter. Another characteristic feature of atrial electrical remodeling, the flattening or inversion of physiological ERP rate adaptation was not prevented by HMR 1098 treatment. Sinus node depression was detectable after short-term (6 hours) rapid atrial pacing and was not affected by HMR 1098.

The effects of vasoactive drugs on hepatic blood flow changes induced by CO2 laparoscopy: an animal study.

UNLABELLED: Laparoscopic surgery is associated with systemic and splanchnic hemodynamic alterations. Recent data suggest that small-dose dobutamine may attenuate the reduction in splanchnic blood flow associated with increments in intraabdominal pressure. We conducted this study to analyze the effects of dopamine and dobutamine on the hepatic circulation in this setting. Twenty-one pigs were anesthetized and mechanically ventilated. A flow-directed pulmonary artery and carotid artery catheters were inserted. Perivascular flow probes were placed around the main hepatic artery and the portal vein. CO2 was insufflated into the peritoneal cavity to reach an intraabdominal pressure of 15 mm Hg. After 60 min, animals received dopamine (5 microg x kg(-1) x min(-1); n = 8), dobutamine (5 microg x kg(-1) x min(-1); n = 8), or saline (n = 5) for 30 min. Pneumoperitoneum induced significant increases in heart rate, mean arterial pressure, and systemic vascular resistance, with decreases in cardiac output and hepatic artery and portal vein blood flows. Dobutamine infusion, in contrast to dopamine, corrected, at least in part, cardiac output, systemic vascular resistance, and hepatic artery blood flow alterations, but neither drug restored total hepatic blood flow. IMPLICATIONS: Hepatic blood flow decreases during laparoscopic surgery. A small-dose infusion of neither dobutamine nor dopamine corrects the total hepatic blood flow impairment, but the former is able to restore the hepatic arterial blood supply in an animal model mimicking this condition.

The in vitro effects of remifentanil, sufentanil, fentanyl, and alfentanil on isolated human right atria.

Because some clinical studies have suggested that opioids used in anesthesia may have different deleterious hemodynamic effects, we compared the direct myocardial effects of cumulative concentrations of remifentanil, sufentanil, fentanyl, and alfentanil on inotropic and lusitropic variables of isolated human myocardium in vitro. Human right atrial trabeculae, obtained from patients scheduled for coronary bypass surgery or aortic valve replacement, were suspended vertically in an oxygenated (95% oxygen/5% CO(2)) Tyrode's modified solution ([Ca(2+)](o) = 2.0 mM, 37 degrees C, pH 7.40, stimulation frequency 1 Hz). The effects of cumulative concentrations (10(-11), 10(-10), 10(-9), 10(-8), 10(-7), and 10(-6) M) of remifentanil (n = 8), sufentanil (n = 8), fentanyl (n = 8), and alfentanil (n = 8) on inotropic and lusitropic variables of isometric twitches were measured. Remifentanil, sufentanil, and fentanyl did not modify active isometric force and peak of the positive force derivative as compared with the Control group. Alfentanil induced a dose-dependent decrease in active isometric force and peak of the positive force derivative. This effect was abolished in the presence of [Ca(2+)](o) = 4.0 mM. None of these opioids altered lusitropic variables.

Potential ionic mechanism for repolarization differences between canine right and left atrium.

Experimental and clinical evidence suggests a critical role for the left atrium (LA) in atrial fibrillation (AF). In animal models, repolarization is faster in the LA than in the right atrium (RA), leading to more stable reentry circuits with a shorter intrinsic period in the LA. The ionic mechanisms underlying LA-RA repolarization differences are unknown. Therefore, we evaluated ionic currents and action potentials (APs) with the whole-cell patch clamp in isolated canine atrial myocytes. The density of the rapid delayed rectifier current (I(Kr)) was greater in the LA (eg, 1.83+/-0.10 pA/pF at +20 mV) than in the RA (1.15+/-0.07 pA/pF, P<0.01; n=16 cells per group). The slow and ultrarapid delayed rectifier, the inward rectifier, L-type Ca(2+), and transient outward K(+) currents were all comparable in the LA and RA. There were no differences in kinetic or voltage-dependent properties of currents in LA versus RA. Western blots of ether-a-go-go-related gene (ERG) protein in three RA and corresponding LA regions showed significantly greater ERG expression in LA. AP duration (APD) was shorter in the LA versus RA in both isolated cells and multicellular preparations, and the effective refractory period (ERP) was shorter in the LA compared with the RA in vivo. Dofetilide had significantly larger APD- and ERP-increasing effects in the LA compared with RA, and LA-RA repolarization differences were eliminated by exposure to dofetilide. We conclude that LA myocytes have larger I(Kr) than do RA myocytes, contributing importantly to the shorter APD and ERP in LA. The larger LA I(Kr) may participate in the ability of the LA to act as a "driver region" for AF, with potentially important implications for understanding AF mechanisms and antiarrhythmic therapy.

The effects of adenosine on isolated right atrial preparations from streptozotocin-diabetic rats.

1. The aim of the present study was to investigate the inhibitory effects of adenosine on the contractile force and chronotropic action of isolated right atrial preparations from streptozotocin (STZ)-diabetic rats. 2. The rats were anaesthetized with diethyl ether and STZ (65 mg kg(-1)) was injected intravenously via the tail vein. 3. Adenosine produced concentration-dependent decreases in the force of contraction and a negative chronotropic action of atria both in control and diabetic groups. The inhibition responses to adenosine were significantly higher in diabetic rat atria than control. 4. Dypiridamole incubation caused a significant potentiation of the inhibitory effect of adenosine on contractile force and chronotropic action of atria in the control group, but not in the diabetic group. In the presence of dipyridamole, the inhibitory effects of adenosine on measured parameters in diabetic rats were not significantly different from those in control rats. 5. These results suggested that atria from 6 weeks STZ-diabetic rats exhibited a supersensitivity to the negative inotropic and chronotropic effects of adenosine compared with atria from control rats because of an impairment in adenosine uptake mechanism. Altered sensitivity to effects of adenosine might reflect relatively early changes in the course of diabetes.

Adenosine triphosphate-dependent potassium channel modulation and cardioplegia-induced protection of human atrial muscle in an in vitro model of myocardial stunning.

OBJECTIVES: Although adenosine triphosphate-dependent potassium channel openers have been shown to enhance cardioplegic protection in animal myocardium, there is a lack of data on human cardiac tissues. We aimed at determining, on human atrial muscle, whether adenosine triphosphate- dependent potassium channels are involved in protection caused by high-potassium cardioplegia and whether adenosine triphosphate-dependent potassium channel activation might improve cardioplegic protection in an in vitro model of myocardial stunning. METHODS: Human atrial trabeculae were obtained from adult patients undergoing cardiac operations. In an organ bath at 37 degrees C, the preparations were subjected to 60 minutes of hypoxia at a high stimulation rate either in Tyrode solution (control, n = 17) or in St Thomas' Hospital solution without additives (n = 6) or associated with 100 nmol/L bimakalim (n = 7) or 1 micromol/L glibenclamide (n = 7), followed by 60 minutes of reoxygenation and 15 minutes of positive inotropic stimulation with 1 micromol/L dobutamine. RESULTS: Atrial developed tension was reduced by hypoxia to 27% +/- 5% of baseline and incompletely recovered after reoxygenation to 38% +/- 7%, whereas dobutamine restored contractility to 74% +/- 7% of basal values. St Thomas' Hospital solution with or without bimakalim improved developed tension after reoxygenation and dobutamine (P <.0001 vs control), whereas glibenclamide inhibited these protective effects of cardioplegic arrest (P =.001 vs St Thomas' Hospital solution). After reoxygenation, the protective effect of bimakalim disappeared at a high pacing rate (400- and 300-ms cycle length) but recovered during dobutamine superfusion. CONCLUSIONS: Adenosine triphosphate-dependent potassium channels are likely involved in the cardioprotective effects of cardioplegia in human atrial trabeculae and adenosine triphosphate-dependent potassium channel activation with bimakalim used as an additive to cardioplegia enhanced protection.

Biochemical and functional characterization of 1-benzyl substituted trimetoquinol affinity analogs on rat and human beta-adrenoceptors.

The site of interaction for the 1-(3',4',5'-trimethoxybenzyl) group of trimetoquinol (TMQ) with beta-adrenoceptors (beta-ARs) is important for the rational design of highly potent and beta3-AR-selective analogs. 1-Benzyl ring-substituted TMQ analogs were evaluated for binding affinities and biochemical activities (cyclic AMP accumulations) in Chinese hamster ovary (CHO) cells expressing the rat and human beta3-AR, and for functional activities on isolated rat tissues. Binding affinities (K1 approximately 0.055 to 1.5 microM) for the rat beta3-AR and potencies for adenylyl cyclase activation (K(act) approximately 0.43 to 2;5 nM) of the 3'-monoiodo or 3',5'-diiodo derivatives with 4'-isothiocyanato-, 4'-amino, 4'-acetamido, or 4'-alpha-haloacetamido substitutions were higher than those of (-)-isoproterenol, and comparable to those of BRL 37344 [(+/-)-(R*,R*-[4-[2-[[2-(3-chlorophenyl)-2-hydroxy-ethyl]amino]propyl]ph enoxy]-acetic acid sodium]. A similar rank order of binding affinities (K(i) approximately 0.11 to 2.5 microM) and potencies (K(act) approximately 0.45 to 9.5 nM) was obtained for TMQ analogs on the human beta3-AR. The 4'-acetamido and 4'-alpha-chloroacetamido analogs of 3',5'-diiodoTMQ were more potent than (-)-isoproterenol in rat atria (beta1-AR) and rat trachea (beta2-AR) and exhibited partial agonist activities, whereas full agonist activities were observed in rat esophageal smooth muscle (EC50 approximately 2-8 nM, beta3-AR). 4'-alpha-Chloroacetamido-3',5'-diiodoTMQ-mediated chronotropic responses in atria were sustained and resistant to washout. Further, the 4'-alpha-chloroacetamido and 4'-alpha-bromoacetamido analogs of 3',5'-diiodoTMQ demonstrated significant concentration-dependent irreversible binding to the rat beta3-AR. Reversible beta-AR agonists such as (-)-isoproterenol, BRL 37344, and 4'-acetamido-3',5'-diiodoTMQ or nucleophilic 1-amino acids (lysine, glutathione, cysteine) did not protect against this irreversible binding. Thus, the lipophilic 1-benzyl ring of TMQ analogs interacts with a hydrophobic region of the beta-AR that may represent an exo-site or an allosteric binding site.

Functional studies in atrium overexpressing A1-adenosine receptors.

1. Adenosine and the A1-adenosine receptor agonist R-PIA, exerted a negative inotropic effect in isolated, electrically driven left atria of wild-type mice. 2. In left atria of mice overexpressing the A1-adenosine receptor, adenosine and R-PIA exerted a positive inotropic effect. 3. The positive inotropic effect of adenosine and R-PIA in transgenic atria could be blocked by the A1-adenosine receptor antagonist DPCPX. 4. In the presence of isoprenaline, adenosine exerted a negative inotropic effect in wild-type atria but a positive inotropic effect in atria from A1-adenosine receptor overexpressing mice. 5. The rate of beating in right atria was lower in mice overexpressing A1-adenosine receptors compared with wild-type. 6. Adenosine exerted comparable negative chronotropic effects in right atria from both A1-adenosine receptor overexpressing and wild-type mice. 7. A1-adenosine receptor overexpression in the mouse heart can reverse the inotropic but not the chronotropic effects of adenosine, implying different receptor-effector coupling mechanisms.

Hemodynamic, hormonal, and renal effects of adrenomedullin in conscious sheep.

Adrenomedullin is a recently discovered peptide that has been shown to reduce arterial pressure and induce natriuresis. However, few studies have examined the biological actions of adrenomedullin in conscious animals in an integrative manner. Accordingly, we have examined the hemodynamic, renal, and endocrine actions of adrenomedullin infused intravenously at 10 and 100 ng.kg-1.min-1 (each 90 min) in a vehicle-controlled study in eight normal conscious sheep. Adrenomedullin reduced right atrial pressure (P < 0.05) and diastolic (15 mmHg, P < 0.01) and mean arterial pressure (10 mmHg, P < 0.05) and increased cardiac output (3 l/min, P < 0.001). Total peripheral resistance was reduced 40% (P < 0.001). Urinary sodium was reduced to 35% of control during the 90-min clearance period immediately postinfusion (P < 0.05). Adrenomedullin increased plasma adenosine 3',5'-cyclic monophosphate levels (P < 0.001). Plasma renin activity was elevated during adrenomedullin (P < 0.001) coincident with the peak hypotensive effect, whereas plasma aldosterone was not affected and plasma norepinephrine levels fell (P < 0.05). In conclusion, adrenomedullin had clear blood pressure-lowering effects with increased cardiac output and stimulation of renin but suppressed sympathetic activation in conscious sheep. The physiological implications of these findings require further study.

Effects of tolbutamide on ATP-sensitive K+ channels from human right atrial cardiac myocytes.

In order to gain further insight into possible deleterious effects on ischaemia-induced myocardial damage induced by sulfonylureas when administered to humans, the effects of tolbutamide on ATP-sensitive K+ (KATP) channels from human right atrial myocytes were studied. Single myocytes were enzymatically isolated from human right atrium. The cell-attached and inside-out configuration of the patch-clamp technique were employed at room temperature (both the pipette and the bath solution contained high [K+]). KATP channels in inside-out patches showed slight inward rectification, had a slope conductance of 75.1 +/- 2.4 pS (mean +/- S.E.M.; n = 5) at negative membrane potentials and these channels were blocked by ATP (half-maximal block (EC50) at 39 microM; Hill coefficient = 1.65). In cell-attached recordings, cromakalim (300 microM) opened KATP channels (with a slope conductance of 73.3 +/- 1.8 pS (n = 16) at negative membrane potentials) in previously silent patches. Cromakalim-induced openings of KATP channels were not markedly affected by 100 or 300 microM tolbutamide but were blocked by tolbutamide at millimolar concentrations (1-3 mM). The concentration-response relationship for tolbutamide-induced block of KATP channels in the presence of 300 microM cromakalim in cell-attached patches was calculated to values for the EC50 of 1.325 mM and for the Hill coefficient of 1.0, respectively. 1 mM tolbutamide-induced block of cromakalim-induced KATP channel openings was not different at room temperature when compared to 37 degrees. It is concluded that KATP channels from human right atrial myocytes have a low sensitivity towards tolbutamide-induced block.

Comparison of isoflurane, halothane and fentanyl in patients with decreased ejection fraction undergoing coronary surgery.

The aim of the study was to compare three anaesthetic agents in patients with ejection fraction below 0.40 subjected to coronary revascularization surgery. Twenty five elective coronary surgical patients with ejection fraction below 0.40 were prospectively studied. Premedication was pethidine 1 mg/kg and induction was fentanyl 0.03 mg/kg and pancuronium 0.1 mg/kg. The patients were randomized to one of three maintenance techniques (fentanyl, isoflurane or halothane). Radial arterial pressure, heart rate, right atrial pressure, pulmonary arterial and occluded pressures, and thermodilution cardiac output were measured, and cardiac index and resistance calculated, at the following times: before induction; 5 min after intubation; 2 min after sternotomy; immediately after discontinuation of bypass; 15 min afterwards; immediately after sternal closure; during suture of the skin; 5 min after arrival in the postoperative care unit; and 60 min postoperatively. Mean arterial pressure decreased significantly in the isoflurane group and nonsignificantly in the halothane group after induction. Cardiac index decreased significantly in the isoflurane group and nonsignificantly in the halothane group after induction and after sternotomy. Neither pressure nor flow decreased in patients receiving fentanyl. Following weaning from cardiopulmonary bypass, systemic vascular resistance decreased significantly in all groups. Cardiac index, however, did not increase above control values and arterial pressure consequently decreased; there was no significant difference between groups.

Age-related characterization of atrial adenosine A1 receptor activation: direct effects on chronotropic and inotropic function in the Fischer 344 rat.

Adenosine, an endogenously produced nucleoside, has direct negative chronotropic and inotropic effects on right and left atrial tissues, respectively. Age-related differences in the effects of A1 adenosine receptor activation on atrial rhythmic and contractile function were investigated in adult (6-8 months) and senescent (23-24 months) Fischer 344 (F344) rats. Senescent right atria (RA) were more sensitive to the negative chronotropic effects of R-phenylisopropyladenosine (R-PIA), a selective A1 receptor agonist, than adult RA (EC50: 4.8 +/- 0.7 vs 10.8 +/- 1.5 nM). However, senescent left atria (LA) were 15.4% less responsive to the maximal negative inotropic effects of R-PIA than adult LA. R-PIA did not significantly change resting force from basal values in either age group, but 90% relaxation time was prolonged threefold in senescent LA compared with adults. Radioligand binding experiments with 1,3-[3H]dipropyl-8-cyclopentylxanthine, a selective adenosine A1 receptor antagonist, showed a 56% greater density (Bmax) of adenosine A1 receptor in senescent than adult without differences in affinities (Kd). The increased sensitivity of senescent RA to the negative chronotropic effects of adenosine A1 receptor stimulation suggests a role for adenosine in abnormal sinus node function that occurs more frequently with age. Adenosine A1 receptor stimulation has more effect on relaxation than contraction in senescent LA compared with LA from adult F344 rats. However, the increase in density of adenosine A1 receptors suggests a functional dissociation between the availability of binding sites and receptor activation.