Characterization of cardiotoxicity induced by 2,3,7, 8-tetrachlorodibenzo-p-dioxin and related chemicals during early chick embryo development

Cardiotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was studied in White Leghorn-Babcock (WLB) and Plymouth Rock-Barred (PRB) chick embryos. TCDD, injected on day 0 (D0), induced a dose-related increase in heart weight in both strains in the absence of pericardial edema on D10. PRB embryos were four to five times more sensitive to this cardiotoxicity than WLB. To determine if another aryl hydrocarbon receptor agonist produced a similar response, graded doses of TCDD; 3,3',4,4',5-pentachlorobiphenyl (PeCB 126); or 2,2',4,4',5,5'-hexachlorobiphenyl (HxCB 153) were injected into WLB eggs. TCDD and PeCB 126 induced a dose-related increase in heart weight without pericardial edema, while HxCB 153 had no effect. We then hypothesized that TCDD-induced cardiotoxicity progressed to heart failure and edema. In PRB, morphometric analysis revealed that TCDD (0.06-0.45 pmol/g) induced a dose-related increase in left and right ventricle cavity area without wall hypertrophy on D10, consistent with dilated cardiomyopathy. A time course showed that 0.24 pmol/g did not alter heart morphology on D8 but induced cardiac dilation on D10 and D12. The 0.24 pmol/g dose also induced changes associated with progression of cardiomyopathy toward heart failure, including increased cardiac atrial natriuretic factor mRNA expression and decreased cardiac responsiveness to isoproterenol-induced positive chronotropy, on D10 and D12. Finally, 0.24 pmol/g induced a significantly higher incidence of subcutaneous and peritoneal edema, indicative of overt heart failure, on D12 (75%, 15/20) compared to D10 (14%, 3/22). In conclusion, TCDD induced a phenotype of dilated cardiomyopathy and symptoms associated with the development of congestive heart failure.     

Ventricular preexcitation sensitive to flecainide in late stage chick embryo ECGs: 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs inotropic but not chronotropic or dromotropic responses to isoproterenol and confers resistance to flecainide

ECGs free of movement artefacts were obtained without anesthesia in 16- to 18-day-old chick embryos close to hatching and used to study the effect of the environmental toxin 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) on cardiac rhythm and conduction. The ECGs of normal late stage chick embryos exhibited short PR intervals, frequent nonisoelectric PR segments, delta waves, and inverted T waves. Those ECG characteristics are found in patients with the Wolff-Parkinson-White syndrome (WPW) in which they reflect ventricular preexcitation associated with the use of accessory conduction pathways and arrhythmias. Isoproterenol (30 microg/egg) did not alter the ECG preexcitation characteristics. Flecainide, a sodium channel blocker used clinically to suppress WPW accessory pathway activity, at 0.5 to 5 mg per egg diminished the preexcitation and caused atrioventricular (AV) block, supporting the use of accessory pathways together with AV-nodal conduction in normal late stage chick embryos. The findings challenge the dogma that accessory pathways are entirely replaced by AV conduction pathways in late fetal development. TCDD, at 1-2 nmol per egg for 48 h, did not affect heart rate, the increase in heart rate by isoproterenol, or the ECG characteristics, suggesting that short-term TCDD treatment did not affect sinus node function or cardiac conduction. The latter results taken together with prior findings indicate that TCDD differentially impairs the inotropic and lusitropic effects but not the chronotropic or dromotropic effects of isoproterenol. In TCDD-treated embryos, flecainide, tested at 5 mg per egg, caused much less inhibition of preexcitation or production of AV block than in the untreated or solvent-treated controls. The resistance to flecainide represents a new TCDD effect consistent with the reported increase of cardiac myocyte [Ca(2+)](i) by TCDD treatment.     

2,3,7,8-Tetrachlorodibenzo-p-dioxin induces apoptotic cell death and cytochrome P4501A expression in developing Fundulus heteroclitus embryos

Fundulus heteroclitus embryos were exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early development using nanoinjection or water bath exposure. TCDD caused developmental abnormalities that included hemorrhaging, loss of vascular integrity, edema, stunted development and death. The LC(50) and LD(50) of TCDD for Fundulus embryos were approximately 19.7+/-9.5 pg TCDD/microl (water bath) and 0.25+/-0.09 ng TCDD/g embryo (nanoinjection). To identify a possible cause for these developmental abnormalities we analyzed the effects of TCDD on apoptotic cell death and cytochrome P4501A (CYP1A) expression in the embryos. TCDD exposure increased apoptotic cell death in several tissues including brain, eye, gill, kidney, tail, intestine, heart, and vascular tissue. CYP1A expression was also increased in the TCDD-exposed embryos predominantly in liver, kidney, gill, heart, intestine, and in vascular tissues throughout the embryo. There was co-occurrence of TCDD-induced apoptosis and CYP1A expression in some, but not all, cell types. In addition the dose response relationships for apoptosis and mortality were similar, while CYP1A expression appeared more sensitive to TCDD induction.     

A mechanistic study to assess whether isoproterenol can reverse the negative chronotropic effect of fingolimod

The sphingosine-1-phosphate receptor modulator fingolimod (FTY720) elicits a negative chronotropic effect at treatment initiation that attenuates thereafter. The authors determined whether isoproterenol can counteract this effect. In this randomized, crossover study, 14 healthy subjects received 5 infusions of isoproterenol (titrated to increase heart rate to 100-120 bpm) or intravenous placebo. The first infusion was 2 hours before and the other 4 infusions were between 3 and 6 hours after a 5-mg oral dose of fingolimod. Telemetry and pharmacokinetic data were collected for 24 hours. During isoproterenol infusion 1 (before fingolimod administration), heart rate was increased 80% from preinfusion 68 +/- 9 bpm to a maximum 122 +/- 15 bpm. Administration of fingolimod decreased heart rate from 73 +/- 11 bpm predose to a nadir of 57 +/- 8 bpm. The subsequent isoproterenol infusion 2 in the presence of fingolimod increased mean heart rate by 85% to a maximum 105 +/- 21 bpm. A 41% higher total isoproterenol dose was needed to increase heart rate to the target range with fingolimod (97 +/- 6 mcg) compared with isoproterenol alone (69 +/- 27 mcg). Isoproterenol infusions 3 to 5 had similar effects on heart rate as infusion 2. Fingolimod had no significant influence on blood pressure responses to isoproterenol. Isoproterenol did not alter the pharmacokinetics of fingolimod. The pure beta-agonist isoproterenol can reverse the heart rate reduction that occurs transiently after initiating fingolimod treatment.     

NAD(P)H: quinone oxidoreductase (DT-diaphorase) in chick embryo liver. Comparison to activity in rat and guinea pig liver and differences in co-induction with 7-ethoxyresorufin deethylase by 2,3,7,8-tetrachlorodibenzo-p-dioxin

NAD(P)H:quinone oxidoreductase (EC 1.6.99.2; DT-diaphorase) was present in the liver of 18- and 19-day-old chick embryos as assayed both by reduction of resorufin and by the more traditional assay, reduction of 2,6-dichlorophenolindophenol (DCPIP). Both reductions had the classic characteristics of DT-diaphorase: they were equally supported by NADPH and NADH and almost entirely inhibited by dicumarol. Chick embryo liver DT-diaphorase was entirely cytosolic. It was undetectable in the microsomal and mitochondrial fractions. Chick embryo liver cytosol and mitochondrial fractions contained an enzyme oxidizer of resorufin but not of DCPIP. The Km for NADPH for resorufin reductase was an order of magnitude higher in chick embryo than in rat or guinea pig cytosol (1 mM vs 0.1 mM). Resorufin reductase activity was higher for chick embryo than for rat or guinea pig cytosols: Vmax (nmol resorufin reduced per mg cytosolic protein per min +/- SEM) 355 +/- 28 for chick embryo, 159 +/- 10 for guinea pig and 68 +/- 28 for rat. The Vmax for DCPIP reduction was also twice as high in chick embryo as rat liver cytosol. In the chick embryo, 7 days after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at 6.4 micrograms/kg egg (1 nmol/egg) mortality was increased 2.4-fold, hepatic DT-diaphorase 1.3-fold, and 7-ethoxyresorufin deethylase (7-EROD) 72-fold over control levels. At 32 micrograms/kg, mortality was increased 4.2-fold, DT-diaphorase 2.3-fold and 7-EROD 100-fold. In the guinea pig, 5 days after treatment with TCDD at 10 micrograms/kg, TCDD toxicity was also evident (loss of body weight and thymus weight); there was no change in DT-diaphorase as measured by resorufin reduction, confirming by a different assay the observation of Beatty and Neal (Biochem Pharmacol 27: 505-510, 1978) that TCDD does not induce DT-diaphorase in guinea pig liver, and 7-EROD was increased 8-fold. In contrast, in the rat, 7 days after exposure to TCDD at 10 micrograms/kg, there was no evidence of toxicity, DT-diaphorase was increased close to 7-fold and 7-EROD, 100-fold. The results demonstrate that avian liver contains DT-diaphorase and show that the extent to which DT-diaphorase is part of the pleiotypic response of the liver to an Ah (aryl hydrocarbon) receptor ligand is species dependent. They also suggest that DT-diaphorase induction and TCDD toxicity may be inversely related. The possibility that DT-diaphorase protects against TCDD toxicity and participates in species differences in sensitivity to TCDD toxicity warrants further investigation.     

Effects of Nebivolol versus Carvedilol on Left Ventricular Function in Patients with Chronic Heart Failure and Reduced Left Ventricular Systolic Function

BACKGROUND: Beta-adrenoceptor antagonist (beta-blocker) therapy results in a significant improvement in left ventricular (LV) systolic function and prognosis in patients with chronic heart failure. Both carvedilol and nebivolol produce hemodynamic and clinical benefits in chronic heart failure, but it is unknown whether their peculiar pharmacologic properties produce different effects on LV function. OBJECTIVE: To assess the effects on LV function of nebivolol compared with carvedilol in patients with chronic heart failure and reduced LV systolic function. METHODS: Seventy patients with a LV ejection fraction 相似文献   

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on murine heart development: alteration in fetal and postnatal cardiac growth, and postnatal cardiac chronotropy.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related chemicals are potent cardiovascular teratogens in developing piscine and avian species. In the present study we investigated the effects of TCDD on murine cardiovascular development. Pregnant mice (C57Bl6N) were dosed with 1.5-24 microg TCDD/kg on gestation day (GD) 14.5. At GD 17.5, fetal mice exhibited a dose-related decrease in heart-to-body weight ratio that was significantly reduced at a maternal dose as low as 3.0 microg TCDD/kg. In addition, cardiocyte proliferation was reduced in GD 17.5 fetal hearts at the 6.0-microg TCDD/kg maternal dose. To determine if this reduction in cardiac weight was transient, or if it continued after birth, dams treated with control or 6.0 microg TCDD/kg were allowed to deliver, and heart weight of offspring was determined on postnatal days (P) 7 and 21. While no difference was seen on P 7, on P 21 pups from TCDD-treated litters showed an increase in heart-to-body weight ratio and in expression of the cardiac hypertrophy marker atrial natriuretic factor. Additionally, electrocardiograms of P 21 offspring showed that the combination of in utero and lactational TCDD exposure reduced postnatal heart rate but did not alter cardiac responsiveness to isoproterenol stimulation of heart rate. These results demonstrate that the fetal murine heart is a sensitive target of TCDD-induced teratogenicity, resembling many of TCDD-induced effects observed in fish and avian embryos, including reduced cardiocyte proliferation and altered fetal heart size. Furthermore, the combination of in utero and lactational TCDD exposure can induce cardiac hypertrophy and bradycardia postnatally, which could increase the risk of cardiovascular disease development.     

The Impact of Baseline HR and BP on the Tolerability of Carvedilol in the Elderly

BACKGROUND: The COLA (Carvedilol Open Label Assessment) II Study prospectively evaluated the tolerability of carvedilol in 1030 patients >70 years of age with chronic heart failure (CHF). Tolerability, defined as patients receiving > or =3 months of carvedilol and achieving a maintenance dosage > or =12.5 mg/day, was 80%. In a multivariate analysis, advanced age, low DBP, left ventricular ejection fraction, obstructive airways disease, and a presence of diabetes mellitus were predictors of tolerability. The aim of this analysis was to evaluate further the relationship between baseline HR, SBP, DBP and tolerability in COLA II. METHODS: Baseline HR, SBP and DBP data were available in 1009 patients (98%). These data were analyzed as both continuous and categorical variables. For the latter analysis, the following categories were created: HR <70, 70 < or = HR <90, HR > or =90 bpm; SBP <120, 120 < or = SBP <160, SBP > or =160 mm Hg; DBP <70, 70 < or = DBP <90, DBP > or =90 mm Hg. RESULTS: Baseline HR did not differ between patients who tolerated carvedilol (T) and those who did not (non-T) [81 +/- 16 vs 79 +/- 16 bpm]. However, SBP and DBP were significantly lower in the non-T versus the T group (131 +/- 20 vs 139 +/- 22 mm Hg for SBP [p < 0.001] and 77 +/- 11 vs 81 +/- 12 mm Hg for DBP [p < 0.001]). Seventy-four percent of patients in the lowest category for baseline HR (<70 bpm tolerated carvedilol versus 82% and 79% of those in the higher categories (p = not significant). Seventy percent of patients in the lowest category of baseline SBP (<120 mm Hg) tolerated carvedilol versus 80% and 89% of those in the upper categories (p < 0.001). Similarly, 73% of patients in the lowest category for DBP (<70 mm Hg) tolerated carvedilol versus 78% and 87% of those in the upper categories (p < 0.005). CONCLUSIONS: Carvedilol is generally well tolerated by elderly patients with CHF, even in those with low baseline BP or HR. However, a low baseline SBP or DBP does identify patients who are less likely to tolerate the drug. Baseline HR does not appear to significantly affect tolerability in this population.     

Cardiovascular effects and risk of syncope related to donepezil in patients with Alzheimer's disease

BACKGROUND: When otherwise unexplained, syncope in patients with Alzheimer's disease may be attributed to bradycardia caused by cholinesterase inhibitors. We studied prospectively the clinical events and cardiovascular changes occurring during treatment with donepezil in patients with Alzheimer's disease. METHODS: Consecutive patients presenting with mild-to-moderate Alzheimer's disease were included in the study. Their clinical characteristics, blood pressure, heart rate and electrocardiogram were recorded before (baseline) and during treatment with donepezil. The drug was administered at a dosage of 5 mg/day for 1 month and 10 mg/day for the following 7 months, as tolerated. We compared the baseline observations with those made at 1, 2 and 8 months of donepezil treatment. We also examined the effects of negatively chronotropic or dromotropic drugs concomitantly administered with donepezil. RESULTS: Thirty patients were included in the study, of whom 43% were taking negatively chronotropic or dromotropic drugs. The first month of therapy (donepezil 5 mg/day) was completed by 26 patients. During the 7-month high-dosage phase (10 mg/day), four patients dropped out of the study; thus, 22 patients completed the full 8 months of the study.The mean heart rate was 66 +/- 8 beats/min at baseline in the overall study population. This decreased significantly to 62 +/- 9, 61 +/- 7 and 62 +/- 8 beats/min at the 1, 2 and 8 month timepoints, respectively (all p = 0.002 vs baseline). Among patients not receiving negatively chronotropic or dromotropic drugs, heart rate decreased significantly over the course of the study (from 67 +/- 8 beats/min at baseline to 62 +/- 8 beats/min at 1 month, 62 +/- 7 beats/min at 2 months and 62 +/- 8 beats/min at 8 months [all p = 0.005 vs baseline]). There was no significant change in heart rate in patients who were receiving negatively chronotropic or dromotropic drugs.The PR interval increased over the course of the study in all patient groups, but these changes were only statistically significant in the group of patients who were not taking negatively chronotropic or dromotropic drugs (155 +/- 23ms at baseline vs 158 +/- 21, 160 +/- 22 and 163 +/- 24ms at the 1, 2 and 8 month timepoints; all p = 0.02 vs baseline).One patient developed syncope due to orthostatic hypotension; there were no cases of bradycardia-induced syncope. Gastrointestinal manifestations were reported in ten of the study patients. Abdominal pain and vomiting were the reasons for study termination in five of the eight patients who did not complete the trial. CONCLUSION: A donepezil-induced decrease in heart rate and increase in PR interval were observed only in patients with Alzheimer's disease who were not treated with negatively chronotropic or dromotropic drugs. These changes were not associated with bradycardia-induced syncope.     

Variation in heart rate regulation and the effects of particle exposure in inbred mice

Altered autonomic control of heart rate (HR) rhythm during exposure to particulate matter (PM) has been suggested in human and animal studies. Our lab has shown strain variation in HR regulation between quiescent C3H/HeJ (C3) and C57BL/6J (B6) mice: that is, C3 mice show a consistently higher HR by approximately 80 bpm compared with B6 mice during a normal 24-h circadian cycle. In the current study, we hypothesize that the balance between sympathetic and parasympathetic control of HR during PM exposure varies between C3 and B6 mice. Radiotelemeters were implanted in C3 and B6 mice to measure HR responses and HR variability (HRV) parameters during successive 3-h exposures to filtered air (FA) or carbon black (CB, < 300 mug/m3). Exposures were repeated following administration of saline or parasympathetic (PS; atropine, 0.5 mg/kg i.p.) and sympathetic (S; propranolol, 1 mg/kg i.p.) blockade to study the autonomic regulation of HR during CB exposure. During FA exposure with saline, a significantly (p < .05) greater 3-h average HR response (bpm +/- SEM) occurred in C3 compared with B6 mice (496 +/- 22 vs. 427 +/- 3). With PS blockade, the strain difference between C3 and B6 mice was not evident (485 +/- 23 vs. 503 +/- 61). With S blockade, the 3-h average HR responses for C3 mice were significantly (p < .05) reduced compared with saline (413 +/- 18 vs. 392 +/- 15 for B6). During CB exposure with saline, HR responses were again significantly (p < 0.05) elevated in C3 compared with B6 mice, but these HR responses were not different relative to FA exposure. With S blockade, HR was significantly (p < .05) elevated in B6 mice during CB relative to FA, but was unchanged in C3 mice. Collectively, these results suggest that strain variation in HR regulation is due to a robust PS tone evident in B6 mice and a predominant S tone in C3 mice. Furthermore, CB exposure alters HR regulation in B6 mice by modulating a withdrawal of PS tone. Finally, strain variation in HR between B6 and C3 mice in responding to acute PM exposure implies that robust genetic determinants modulate altered autonomic regulation in susceptible individuals.     

Hemodynamic effects of a new inotropic compound,PST-2744, in dogs with chronic ischemic heart failure

Inotropic agents for acute decompensated heart failure are associated with a lack of efficacy or increased mortality. New compounds are needed to support patients with acute exacerbations of heart failure. This study examined the hemodynamic effects of a new inotropic agent (PST-2744) in dogs with chronic ischemic heart failure. Eight mongrel dogs at low risk for postmyocardial infarction (MI) sudden death entered the protocol. Dogs were studied after ischemic left ventricular dysfunction was induced by repeated injections of latex microspheres into the circumflex artery until the ejection fraction reached 35%. Hemodynamic parameters were measured at baseline and peak drug effect (PST-2744 5 microg.kg-1.min-1). In 5 animals, PST-2744 effects were compared with dobutamine. Heart rates, PR intervals and QT intervals were unchanged following PST-2744 administration. PST-2744 increased contractility (+dP/dt) by 56% from 1881 +/- 282 mm Hg/s to 2939 +/- 734 mm Hg/s (P < 0.01). The inotropic effect of PST-2744 was equal to that produced by 5-microg.kg-1.min-1 dobutamine (56% increase in +dP/dt), but peak heart rates were significantly higher with dobutamine (129 +/- 24 bpm PST-2744 versus 160 +/- 6 bpm 5-microg.kg-1.min-1 dobutamine, P < 0.002). No arrhythmias or conduction delays were seen with either compound. PST-2744 is an effective inotropic agent without positive chronotropic effect in subjects with stable moderate left ventricular dysfunction.     

Effects of atropine on human cardiac beta 1- and/or beta 2-adrenoceptor stimulation

The aim of this study was to find out whether, in humans, the increase in vagal tone accompanying cardiac beta-adrenoceptor (beta-AR) stimulation might be different dependent on beta1- or beta2-AR stimulation. For this purpose we studied, in six male healthy volunteers (aged 28+/-1 years), the effects of atropine infusion (0.15 microg/kg/min continuously) on increase in heart rate (HR) and contractility (determined as shortening of HR-corrected duration of electromechanical systole-QS2c) evoked by infusion of isoprenaline (3.5-35 ng/kg/min, increasing HR and QS2c via beta1-and beta2-AR), terbutaline (25-150 ng/kg/min, increasing HR and QS2c via beta2-AR), adrenaline (20-160 ng/kg/min, increasing HR via beta2-and QS2c via beta1-AR) and bicycle exercise in supine position (increasing HR and QS2c via beta1-AR). The three beta-AR agonists and exercise increased HR and shortened QS2c in a dose- or work-load-dependent manner, respectively. Atropine enhanced HR-increasing effects of all three beta-AR agonists and exercise; increases were larger for beta2-AR (terbutaline, adrenaline) mediated effects than for beta1-AR (exercise) mediated effects. Moreover, atropine enhanced beta-AR agonists-induced QS2c shortening; however, atropine effects on QS2c were markedly less pronounced than on HR. From the results we conclude that, in humans, beta1-and beta2-AR mediated stimulation evoked HR-increases are composed of two components: increases via direct beta-AR stimulation and simultaneously decreases via increase in vagal tone. In addition, beta-AR mediated increases in contractility are also dampened by simultaneous activation of vagal tone but to a lesser extent possibly because human ventricular myocardium is only sparsely parasympathetically innervated.     

Modulation of pressor response to muscle contraction via monoamines following AMPA-receptor blockade in the ventrolateral medulla

We hypothesized that cardiovascular responses to static muscle contraction are mediated via changes in extracellular concentrations of monoamines (norepinephrine, dopamine and serotonin) following the administration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, an AMPA-receptor antagonist) into the rostral (RVLM) or caudal (CVLM) ventrolateral medulla. For the RVLM experiments (n= 8), a 2-min static muscle contraction increased the mean arterial pressure (MAP) and heart rate (HR) by 23 +/- 2 mmHg and 28 +/- 8 bpm, respectively. During this contraction, the concentrations of norepinephrine, dopamine, and serotonin within the RVLM increased by 278 +/- 52%, 213 +/- 23%, and 232 +/- 24%, respectively. Microdialysis of CNQX (1.0 microM) for 30 min into the RVLM attenuated the increases in MAP and HR ( 11 +/- 2 mmHg and 14 +/- 5 bpm) without a change in developed muscle tension. The levels of norepinephrine, dopamine, and serotonin within the RVLM were also attenuated. In contrast, microdialysis of CNQX into the CVLM (n= 8) potentiated the contraction-evoked responses in MAP ( 21 +/- 2 vs 33 +/- 5 mmHg) and HR ( 25 +/- 5 vs 46 +/- 8 bpm) without any effect on the monoamine levels within the CVLM region. These results suggest that AMPA-receptor blockade within the RVLM and CVLM has opposing effects on cardiovascular responses during static muscle contraction. In addition, such receptor blockade modulates extracellular concentrations of monoamines within the RVLM but not in the CVLM. These results provide evidence that AMPA receptors within the ventrolateral medulla play a role in exercise pressor reflex.     

The effect of amiloride on the cardiac chronotropic responses to isoproterenol in myocardial aggregate cells in culture

The purpose of this study was to test the hypothesis that amiloride alters the response of cardiac myocytes to isoproterenol. Myocardial cell aggregates were prepared from 7 day-old chick embryos maintained in culture for 72 hrs before study. Isoproterenol, 10-8 M to 10-5 M, significantly (P less than 0.05) increased contractile frequency of myocardial aggregates. The effects of isoproterenol were maximum within 5 min. of exposure and declined thereafter. In the absence of isoproterenol, amiloride, at 10-6 M and 10-7 M produced a transient decrease in contractile frequency while amiloride at 10-5 M produced a significant (P less than 0.05) decrease in contractile frequency. Amiloride significantly (P less than 0.05) increased the effect of isoproterenol on cardiac contractile frequency. There was a greater and more sustained response to isoproterenol in the presence of amiloride. Furthermore, the magnitude of these effects were greater with higher concentrations of amiloride. These data indicate that amiloride accentuates the cardiac chronotropic response to isoproterenol and suggest that, because amiloride inhibits sodium entry in these cells, change in intracellular sodium may be one of the mechanisms mediating the chronotropic action of isoproterenol on the heart.     

Simvastatin improves the attenuated heart rate recovery of type 2 diabetics

Heart rate recovery at 1min (HRR1) is a strong predictor of all-cause mortality. The effects of statins on the autonomic nervous system may account for their beneficial effects in survival. Our aim was to determine if statin therapy improves heart rate recovery in hypercholesterolemic patients with type 2 diabetes mellitus. Thirty type 2 diabetic patients without known coronary artery disease and low density lipoprotein cholesterol>100mg/dl and 30 age and sex matched non-diabetic controls were included in a prospective study. Patients with diabetes were treated with simvastatin 40mg/day for 1 year. No lipid-lowering therapy was administered to the control group. Exercise testing with 2min cool-down period was performed at baseline, 6, 12 weeks and at 1 year. The diabetics had significantly lower HRR1 compared with non-diabetics at baseline (19.2+/-5.4bpm versus 24.2+/-4bpm, p<0.0001). Simvastatin therapy significantly improved HRR1 after 12 weeks compared to baseline (19.2+/-5.4bpm versus 24+/-5bpm, p<0.0001) and this improvement remained significant at 1 year (26+/-4.4bpm, p<0.0001 compared to baseline). HRR1 did not change in the control group (p=0.39 by ANOVA). This study demonstrates that treatment with simvastatin might improve the attenuated heart rate recovery of diabetic subjects. In patients with diabetes, the mortality benefit provided by statins might involve their effects on the autonomic nervous system.     

Ethanol and cocaine interactions in humans: cardiovascular consequences

Intranasal cocaine (COC) and oral ethanol (ETOH) were administered to nine research volunteers during daily experimental sessions. Following the determination of baseline cardiovascular indexes, an ETOH cocktail (0, 19.4, 38.7, or 58.1 g of ETOH in lemonade) was consumed over a ten-minute period. Cocaine hydrochloride (4, 48, 96 mg) was inhaled 25 minutes after the start of ETOH drinking. Breath samples were collected 50 minutes after the start of ETOH drinking to estimate blood alcohol level (BAL). The effect of these doses, alone and in combination, on heart rate (HR) and blood pressure (BP), while resting and while performing a serial acquisition task, were determined. COC and ETOH alone significantly increased HR up to 6 bpm without affecting BP. Combining the two highest doses of COC with the highest BAL increased HR by 20 bpm. During task performance, in the absence of drug, HR was increased up to 5 bpm, and BP was unchanged. Combining the highest COC dose and BAL with task performance increased HR by 40 bpm. Small increases in BP were also observed under these conditions. These results indicate that combinations of ETOH, COC and task performance produce greater increases in HR than BP, and, in addition, this increase in HR is greater than that observed following COC, ETOH, or task performance alone.