Effects of acute and chronic alacepril treatment on exercise capacity and hemodynamics in patients with heart failure: a preliminary study.

OBJECTIVE: This study determined whether alacepril treatment improves exercise hemodynamics in patients with heart failure. METHODS: Supine bicycle ergometer exercise was performed after administration of placebo and after acute and chronic (12 weeks) alacepril treatment in 4 patients with heart failure. Oxygen uptake (VO2), arterial oxygen saturation (SaO2), and mixed venous oxygen saturation (SvO2) were measured continuously using a pulse oxymeter and a fiber optic catheter. Cardiac index was calculated with Fick's equation. RESULTS: Acute alacepril treatment did not significantly alter the VO2 or hemodynamics. After chronic alacepril treatment, peak VO2 increased (placebo vs chronic alacepril treatment: 17.7 +/- 2.8 vs 21.7 +/- 2.8 ml/min/kg, p < 0.05). Arteriovenous oxygen difference (SaO2 - SvO2) at peak exercise was not altered, however, cardiac index at peak exercise (5.07 0.67 vs 6.35 +/- 0.48 I/min/m2, p = 0.02) increased and stroke volume index at peak exercise (37.3 +/- 3.4 vs 46.5 +/- 1.1 ml/m2, p = 0.07) tended to increase. CONCLUSIONS: Chronic treatment with alacepril improved maximal exercise capacity in patients with heart failure. The increased peak VO2 was primarily due to the increased cardiac index, but not due to the widening of arteriovenous oxygen difference. Therapy-induced increase in stroke volume index may contribute to the increased cardiac index at peak exercise in our patients with heart failure.

Signaling pathway and chronotropic action of parathyroid hormone in isolated perfused rat heart.

Parathyroid hormone (PTH) activates both adenylyl cyclase and phospholipase C via the PTH-1 receptor. We previously reported that PTH increased heart rate and that this effect was mediated via the pacemaker current (I f ). However, it has been reported that PTH exerts its chronotropic effect via an interaction with adrenergic receptors or via L-type calcium channels. Thus, the objective of the study was to elucidate the exact mechanism of the chronotropic effect of PTH. We tested whether its chronotropic effects could be abolished by inhibitors of the following systems in isolated perfused rat hearts: alpha-adrenergic (prazosin); beta-adrenergic (propranolol); angiotensin II (CV11974); endothelin-1 (TAK044); calcium channel (verapamil); adenylyl cyclase (miconazole); phospholipase C (U73122) or I f (CsCl). In addition, we measured the cyclic adenosine monophosphate level of the heart after PTH administration. Whereas prazosin, propranolol, CV11974, TAK044, verapamil, and U73122 did not inhibit the chronotropic effect of PTH, CsCl or miconazole suppressed it significantly. PTH increased the cyclic adenosine monophosphate level of the atrium but not the left ventricle. These results indicate that the chronotropic actions of PTH are mediated via selective activation of adenylyl cyclase to increase the I f current.

Fragment-specific actions of parathyroid hormone in isolated perfused rat hearts.

Different regions within the parathyroid hormone (PTH) molecule are known to have different biological activities. In the heart, the physiological actions of the intact PTH molecule are known as positive chronotropy and coronary vasodilatation. However, it is unclear which region of the PTH exerts which physiological action in the heart. Therefore, to clarify this point, we examined the hemodynamic effect of intact PTH(1-84) and selected PTH analogs, namely, PTH(1-34), PTH(2-34), [Nle8, 18Tyr34]PTH(3-34), PTH(4-34), [Tyr34]PTH(7-34), and PTH(13-34) in isolated perfused rat hearts. Both PTH(1-84) and PTH(1-34) significantly increased heart rate and decreased coronary perfusion pressure. In contrast, neither PTH(2-34) nor [Nle8,18Tyr34]PTH(3-34) increased heart rate, but they did decrease coronary perfusion pressure. Peptides further truncated at the amino terminus, PTH(4-34), [Tyr34]PTH(7-34), and PTH(13-34), had no effect on hemodynamics. Furthermore, the protein kinase A inhibitor H89, but not the protein kinase C inhibitor H7, attenuated the hemodynamic effects of PTH(1-34) or PTH(2-34), while it prevented those of [Nle8,18Tyr34]PTH(3-34). These results clearly demonstrate that the first amino acid of PTH is essential for its chronotropic property whereas the first 3 amino acids of PTH are involved in its coronary vasodilatory action. Furthermore, protein kinase A, but not protein kinase C, appears to be involved in the chronotropic and coronary vasodilatory actions of PTH.

Altered purine nucleotide degradation during exercise in patients with essential hypertension.

Purine degradation occurs during strenuous muscle exercise and plasma levels of hypoxanthine (HX), purine degradation intermediate, increase. Purine nucleotide degradation has not been investigated in patients with essential hypertension (HTN). The present study determined whether purine nucleotide degradation is altered in patients with HTN. Cardiopulmonary exercise test was performed with serial measurements in blood lactate and plasma HX in 24 patients (14 men and 10 women) with essential HTN (World Health Organization [WHO] class I to II; mean age, 57.7 +/- 2.1 years) and 24 age-, sex-matched normal subjects. Exercise was terminated either by severe fatigue or excess blood pressure increase. Peak work rate (WR) (normal v HTN, 151 +/- 10 v 135 +/- 8 W, not significant [NS]) was not different, but peak oxygen uptake (peak Vo(2), 26.3 +/- 1.5 v 22.2 +/- 0.9 mL/min/kg, P <.05) and anaerobic threshold were lower in patients with HTN. Resting levels of blood lactate and plasma HX were similar, but the increment from rest to peak exercise (Delta) for lactate (Delta lactate: 4.4 +/- 0.4 v 3.4 +/- 0.4 mmol/L, P <.05) and for HX (Delta HX, 15.9 +/- 2.2 v 9.1 +/- 1.1 micromol/L, P <.05) were significantly smaller in patients with HTN. When normalized by the peak WR, Delta HX/peak WR (0.105 +/- 0.013 v 0.069 +/- 0.007 micromol/L/W, P <.05) was significantly lower in patients with HTN. Patients with HTN exhibited reduced HX response to exercise with impaired exercise capacity. The exercise-induced changes in plasma HX were smaller in patients with HT when normalized with peak WR. These results suggest that the purine nucleotide degradation is reduced in patients with HTN.

Mitochondrial DNA deletion associated with the reduction of adenine nucleotides in human atrium and atrial fibrillation.

BACKGROUND: Structural changes in the number, size, and shape of mitochondria (mt) have been observed in the atrial muscles of patients with atrial fibrillation (AF) and of animals with rapid atrial pacing, however, it is not known whether the mitochondrial function is impaired in human atrium with AF. MATERIALS AND METHODS: We determined adenine nucleotides concentrations and mtDNA deletions in 26 human right atria obtained at the time of cardiac surgery, using HPLC and PCR amplification, and studied the relationship between mtDNA deletions and clinical manifestations, the haemodynamic parameters of the patients and adenine nucleotide concentrations in their atrium. RESULTS: The age and the prevalence of AF were significantly higher in the patients with a mtDNA deletion of 7.4 kb than in those without a deletion; there were no significant differences regarding haemodynamic parameters between the two groups. The concentrations of ATP, ADP, AMP and total adenine nucleotides in the right atrium were significantly lower in the patients with mtDNA deletions than the patients without a deletion. In a gender- and diseased-matched population, the mtDNA deletion was still significantly associated with age and a decreased concentration of adenine nucleotides in the atrium. Using quantitative PCR analysis, the proportion of mtDNA deletion to normal mtDNA of the atrium, was estimated to be 0.3-2% in four cases. CONCLUSION: These results suggest that the deletion of mtDNA associated with ageing or AF can lead to a bioenergetic deficiency due to an impaired ATP synthesis in the human atrium; however, no conclusion can be made whether mtDNA deletion were the result or the cause of an impaired ATP synthesis, ageing, hemodynamic deterioration, or AF.

Enhanced activity of the purine nucleotide cycle of the exercising muscle in patients with hyperthyroidism.

Myopathy frequently develops in patients with hyperthyroidism, but its precise mechanism is not clearly understood. In this study we focused on the purine nucleotide cycle, which contributes to ATP balance in skeletal muscles. To investigate purine metabolism in muscles, we measured metabolites related to the purine nucleotide cycle using the semiischemic forearm test. We examined the following four groups: patients with untreated thyrotoxic Graves' disease (untreated group), patients with Graves' disease treated with methimazole (treated group), patients in remission (remission group), and healthy volunteers (control group). To trace the glycolytic process, we measured glycolytic metabolites (lactate and pyruvate) as well as purine metabolites (ammonia and hypoxanthine). In the untreated group, the levels of lactate, pyruvate, and ammonia released were remarkably higher than those in the control group. Hypoxanthine release also increased in the untreated group, but the difference among the patient groups was not statistically significant. The accelerated purine catabolism did not improve after 3 months of treatment with methimazole, but it was completely normalized in the remission group. This indicated that long-term maintenance of thyroid function was necessary for purine catabolism to recover. We presume that an unbalanced ATP supply or conversion of muscle fiber type may account for the acceleration of the purine nucleotide cycle under thyrotoxicosis. Such acceleration of the purine nucleotide cycle is thought to be in part a protective mechanism against a rapid collapse of the ATP energy balance in exercising muscles of patients with hyperthyroidism.

The release of the substrate for xanthine oxidase in hypertensive patients was suppressed by angiotensin converting enzyme inhibitors and alpha1-blockers.

OBJECTIVE: Hyperuricemia is associated with the vascular injury of hypertension, and purine oxidation may play a pivotal role in this association, but the pathophysiology is not fully understood. We tested the hypothesis that in hypertensive patients, the excess amount of the purine metabolite, hypoxanthine, derived from skeletal muscles, would be oxidized by xanthine oxidase, leading to myogenic hyperuricemia as well as to impaired vascular resistance caused by oxygen radicals. METHODS: We investigated the production of hypoxanthione, the precursor of uric acid and substrate for xanthine oxidase, in hypertensive patients and found that skeletal muscles produced hypoxanthine in excess. We used the semi-ischemic forearm test to examine the release of hypoxanthine (deltaHX), ammonium (deltaAmm) and lactate (deltaLAC) from skeletal muscles in essential hypertensive patients before (UHT: n = 88) and after treatment with antihypertensive agents (THT: n = 37) in comparison to normotensive subjects (NT: n = 14). RESULTS: deltaHX, as well as deltaAmm and deltaLAC, were significantly higher in UHT and THT (P< 0.01) than in NT. This release of deltaHX from exercising skeletal muscles correlated significantly with the elevation of lactate in NT, UHT and THT (y = 0.209 + 0.031x; R2 = 0.222, n = 139: P < 0.01). Administration of doxazosin (n = 4), bevantolol (n = 5) and alacepil (n = 8) for 1 month significantly suppressed the ratio of percentage changes in deltaHX by -38.4 +/- 55.3%, -51.3 +/- 47.3% and -76.3 +/- 52.2%, respectively (P< 0.05) but losartan (n = 3), atenolol (n = 7) and manidipine (n = 10) did not reduce the ratio of changes; on the contrary, they increased it in deltaHX by +188.2 +/- 331%, +96.2 +/- 192.2% and +42.6 +/- 137.3%, respectively. The elevation of deltaHX after exercise correlated significantly with the serum concentration of uric acid at rest in untreated hypertensive patients (y = 0.194 - 0.255x; R2 = 0.185, n = 30: P < 0.05). The prevalence of reduction of both deltaHX and serum uric acid was significantly higher in the patients treated with alacepril, bevantolol and doxazosin (67%: P < 0.02) than in the patients treated with losartan, atenolol and manidipine (12%). CONCLUSIONS: It is concluded that the skeletal muscles of hypertensive patients released deltaHX in excess by activation of muscle-type adenosine monophosphate (AMP) deaminase, depending on the degree of hypoxia. The modification of deltaHX by angiotensin-converting enzyme inhibitors and alpha1-blockers influenced the level of serum uric acid, suggesting that the skeletal muscles may be an important source of uric acid as well as of the substrate of xanthine oxidase in hypertension.

Augmented response in plasma brain natriuretic peptide to dynamic exercise in patients with left ventricular dysfunction and congestive heart failure.

OBJECTIVES: We have previously demonstrated that patients with symptomatic congestive heart failure (CHF), but not with asymptomatic left ventricular dysfunction (LVD), have augmented plasma atrial natriuretic peptide (ANP) response to exercise. Plasma brain natriuretic peptide (BNP) response to exercise is less extensively studied. The aim of this study was to determine whether responses of plasma BNP during exercise normalized for exercise workload are altered in patients with LVD and CHF. SUBJECTS AND METHODS: Twenty-nine patients with LVD, 32 patients with CHF (NYHA classes II-III) and 27 age-matched control subjects were studied. Ventilatory, plasma ANP and BNP responses were assessed during symptom-limited cardiopulmonary exercise testing. Plasma natriuretic peptide levels were measured at rest and immediately after peak exercise. The increment in plasma BNP was divided by the increment in oxygen uptake (VO2) from rest to peak exercise, and this ratio [BNP exercise ratio: (peak BNP - rest BNP)/(peak VO2 - rest VO2)] was compared amongst the three groups. RESULTS: Peak VO2 (Control, LVD and CHF: 28.2 +/- 1.7, 21.1 +/- 1.8, 16.2 +/- 0.6 ml, min(-1) kg(-1), respectively), anaerobic threshold and peak workload became smaller as heart failure worsened. Resting and peak plasma ANP levels were significantly higher only in CHF, whilst resting and peak plasma BNP levels displayed a significant and continuous increase from normal subjects to LVD and CHF. The ANP exercise ratio (1.25 +/- 0.36, 2.61 +/- 0.57, 7.72 +/- 1.65, ANOVA P = 0.0002) was significantly higher only in patients with CHF, whilst the BNP exercise ratio (0.35 +/- 0.10, 2.60 +/- 0.69, 4.98 +/- 0.97, ANOVA P = 0.0001) was significantly higher in patients with LVD and became progressively higher in patients with CHF. CONCLUSIONS: These data showed that the BNP exercise ratio, an exercise plasma BNP response normalized with exercise workload, was augmented in patients with LVD, and became progressively higher in CHF, suggesting that an augmented exercise BNP ratio exists early in the course of developing CHF.

Block of sodium channels by divalent mercury: role of specific cysteinyl residues in the P-loop region.

Divalent mercury (Hg(2+)) blocked human skeletal Na(+) channels (hSkM1) in a stable dose-dependent manner (K(d) = 0.96 microM) in the absence of reducing agent. Dithiothreitol (DTT) significantly prevented Hg(2+) block of hSkM1, and Hg(2+) block was also readily reversed by DTT. Both thimerosal and 2,2'-dithiodipyridine had little effect on hSkM1; however, pretreatment with thimerosal attenuated Hg(2+) block of hSkM1. Y401C+E758C rat skeletal muscle Na(+) channels (mu1) that form a disulfide bond spontaneously between two cysteines at the 401 and 758 positions showed a significantly lower sensitivity to Hg(2+) (K(d) = 18 microM). However, Y401C+E758C mu1 after reduction with DTT had a significantly higher sensitivity to Hg(2+) (K(d) = 0.36 microM) than wild-type hSkM1. Mutants C753Amu1 (K(d) = 8.47 microM) or C1521A mu1 (K(d) = 8.63 microM) exhibited significantly lower sensitivity to Hg(2+) than did wild-type hSkM1, suggesting that these two conserved cysteinyl residues of the P-loop region may play an important role in the Hg(2+) block of the hSkM1 isoform. The heart Na(+) channel (hH1) was significantly more sensitive to low-dose Hg(2+) (K(d) = 0.43 microM) than was hSkM1. The C373Y hH1 mutant exhibited higher resistance (K(d) = 1.12 microM) to Hg(2+) than did wild-type hH1. In summary, Hg(2+) probably inhibits the muscle Na(+) channels at more than one cysteinyl residue in the Na(+) channel P-loop region. Hg(2+) exhibits a lower K(d) value (<1. 23 microM) for inhibition by forming a sulfur-Hg-sulfur bridge, as compared to reaction at a single cysteinyl residue with a higher K(d) value (>8.47 microM) by forming sulfur-Hg(+) covalently. The heart Na(+) channel isoform with more than two cysteinyl residues in the P-loop region exhibits an extremely high sensitivity (K(d) < 0. 43 microM) to Hg(+), accounting for heart-specific high sensitivity to the divalent mercury.

Acute hemodynamic effects of insulin-sensitizing agents in isolated perfused rat hearts.

Troglitazone has direct effects on the hemodynamics of the heart. We investigated the effects of other insulin-sensitizing agents (rosiglitazone, pioglitazone and JTT-501 (4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3, 5-isoxazolidinedione)) on the hemodynamics of the heart using isolated perfused rat hearts. Rosiglitazone significantly decreased heart rate and coronary perfusion pressure, and increased peak isovolumic left ventricular pressure, peak rate of rise of left ventricular pressure and peak rate of fall of left ventricular pressure. The effects of rosiglitazone, however, were milder than those of troglitazone. Neither pioglitazone nor JTT-501 had any effect on the heart. D-alpha-tocopherol, a structural component of troglitazone, did not exert any effect on the heart. The coronary vasorelaxant effect of troglitazone and rosiglitazone was significantly suppressed by indomethacin, but not by N(omega)-nitro-L-arginine methyl ester. In conclusion, only rosiglitazone, as well as troglitazone, exerted positive inotropic, positive lusitropic, negative chronotropic, and coronary vasorelaxant effects on the heart. The coronary vasorelaxant effect of troglitazone and rosiglitazone was mediated by prostaglandin production.

Ammonia response to constant exercise: differences to the lactate response.

1. We evaluated the plasma ammonia response to constant exercise at different intensities. Ten healthy male volunteers were asked to perform constant exercise for 15 min at five different intensities: 80, 90, 100, 110 and 120% of their ventilatory threshold (VT). Blood concentrations of lactate, ammonia and hypoxanthine were measured during and after exercise. 2. The concentration of lactate increased continuously during exercise intensities equivalent to 100, 110 and 120% VT. Plasma ammonia began to increase at 6 min exercise and continued increasing during exercise at all five exercise intensities. Plasma hypoxanthine levels also increased continuously during exercise at all exercise intensities; however, they peaked at 5-10 min after exercise. The response of plasma ammonia and hypoxanthine increased with increasing intensities of exercise. 3. While the extent of the increase in lactate levels during exercise at 100, 110 and 120% VT was significantly higher than that at 80% VT, only the increase in ammonia and hypoxanthine levels at 120% VT were significantly higher than those at 80% VT. 4. In conclusion, the plasma ammonia response to constant exercise differed to the lactate and ammonia responses to short-term exhaustive exercise.

Hypertensive left ventricular hypertrophy is linked to an enhanced catecholamine response to submaximal exercise.

BACKGROUND: The serial plasma catecholamine response to exercise has not been studied fully in relation to left ventricular hypertrophy (LVH) in patients with hypertension (HT). This study determined whether plasma catecholamine responses to exercise are altered in essential HT in the presence or absence of LVH. MATERIALS AND METHODS: Plasma noradrenaline (NA) and plasma adrenaline (A) were measured at rest, during and after treadmill exercise in 59 hypertensive subjects and 22 age-matched control subjects. Patients were divided into LVH(-) (n = 20) and LVH(+) (n = 39) stratified by left ventricular mass index [LVMI: control subjects, LVH(-), LVH(+): 114 +/- 4, 105 +/- 3, 151 +/- 3 g m-2]. RESULTS: Exercise time (9.9 +/- 0.6, 7.6 +/- 0.7, 7.3 +/- 0.6 min) was shorter in patients with HT. Both systolic and diastolic blood pressures were higher in patients with HT, and no difference was observed between LVH(-) and LVH(+) patients. Resting plasma NA was not different (157 +/- 16, 173 +/- 17, 167 +/- 14 pg mL-1), but plasma NA at stage I (300 +/- 30, 342 +/- 40, 469 +/- 40 pg mL-1) was higher in LVH(+) patients than in LVH(-) patients or control subjects. Plasma A response to exercise was similar among the three groups. There was a positive correlation (r = 0.38, P < 0.001) between LVMI and Deltaplasma NA at stage I in all subjects. CONCLUSIONS: Patients with essential HT with LVH had augmented plasma NA response during submaximal exercise, whereas patients without LVH did not exhibit this augmentation. The positive correlation between LVMI and Deltaplasma NA suggested a possible association between the degree of cardiac hypertrophy and sympathetic activation during exercise.

A TSH/dibutyryl cAMP activated Cl-/I- channel in FRTL-5 cells.

An iodide (I) and chloride (Cl) channel has been identified in the continuously cultured FRTL-5 thyroid cell line using a cell attached patch clamp technique. The channel is activated by TSH and dibutyryladenosine cyclic monophosphate (Bt2-cAMP) but not by phorbol 12-myristate 13-acetate (TPA). Gluconate can not replace chloride or iodide and the channel is impermeable to Na+,K+ and tetraethylammonium ions. The current-voltage relationship demonstrates that the single channel current is a linear function of the clamp voltage. Single channel currents reversed at a pipette potential close to 0 mV. The mean single channel conductance was 60 pS for Cl- and 50 pS for I-. From the I-V relationship there was a strong outward rectification with Cl-, and a complete block with I-, in the single channel current above +40 mV. The feature of the channel is manifested in the single channel records by four distinct, equally spaced conductance levels. We suggest the channel is important for the transport of I and Cl ions across the apical membrane into the colloid space and is important for hormone synthesis and follicle formation.

Effects of amlodipine on native cardiac Na+ channels and cloned alpha-subunits of cardiac Na+ channels.

The inhibitory effects of amlodipine besilate (CAS 11470-99-6) on the native Na+ current (INa) and cloned human cardiac Na+ channel alpha subunit (hH1) were studied by whole cell patch clamp techniques. Amlodipine produced tonic block of INa in a concentration- and holding potential (HP)-dependent manner with hyperpolarization of H infinity. Amlodipine produced phasic blockade of INa, which was dependent on HP and pulse duration. Amlodipine produced tonic blockade of hH1 in a concentration-dependent manner with 1 : 1 stoichiometry, and phasic blockade of hH1 which was dependent on the pulse duration. Amlodipine blocked INa in a voltage- and frequency-dependent manner via affinity to the resting as well as inactivated conformations of the alpha subunit.

Mechanism of inhibition of the Na current by tocainide in guinea-pig isolated ventricular cells.

Tocainide blocked the Na current (I(Na)) in ventricular myocytes in either a tonic or a phasic block manner, having a higher affinity for the inactivated state (K(di) = 18 microM) than for the rested state (Kd(rest) = 606 microM). The degree of phasic block was enhanced and the onset of phasic block was faster with an increase in pulse duration as well as at less-negative holding potential (HP). The recovery-time constant from the phasic block of I(Na) induced by tocainide was independent of either the HP or the removal of fast inactivation. After removal of fast inactivation, tocainide showed the pulse-duration dependency of phasic block but not the voltage dependency. These results suggest that tocainide could bind to the inactivated-state receptor through the hydrophilic pathway and leave the receptor through the hydrophobic pathway, producing the tonic and phasic block of I(Na).

QRST integral analysis of body surface electrocardiographic mapping for assessing exercise-induced changes in the spatial distribution of local repolarization properties in patients with coronary artery disease and in patients with previous anterior infarction.

We studied resting, postexercise, difference (postexercise - rest) QRST isointegral maps, and the correlation coefficient between resting and postexercise maps. Study I Fifteen controls and 48 patients without previous myocardial infarction were studied. In coronary syndrome X group (n = 14), no patients showed an abnormally negative area on the postexercise map. In coronary ST depression group (n = 26), 12 patients (46%) showed an abnormally negative area on the postexercise map, and the correlation coefficient was low. Although all control, syndrome X, and coronary ST depression patients showed the global-downward type of difference map, coronary ST elevation patients (n = 8) showed the right-downward and left-upward type, right-upward and left-downward type, or reversed saddle type. Coronary ST depression is related to a globally marked decrease in local repolarization forces. Coronary ST elevation is associated with multidirectional changes in local repolarization forces. Study II Fifty-one patients with previous anterior infarction (29 with residual ischemia and 22 without) were studied. The incidence of the global-positive type of maps was increased and that of the saddle-type map was decreased from rest to postexercise in both groups. The global-upward type or right-downward and left-upward type of difference map was observed in both groups, but the reversed saddle type, right-upward and left-downward type, or global-downward type was observed in the residual ischemia group (34%, 24%, and 14%, respectively). Residual ischemia causes multidirectional changes or a global decrease in local repolarization forces. In both studies, multidirectional changes in local repolarization forces may be related to the vulnerability to ventricular arrhythmias.

Enhancing effects of salicylate on tonic and phasic block of Na+ channels by class 1 antiarrhythmic agents in the ventricular myocytes and the guinea pig papillary muscle.

OBJECTIVE: To study the interaction between salicylate and class 1 antiarrhythmic agents. METHODS: The effects of salicylate on class 1 antiarrhythmic agent-induced tonic and phasic block of the Na+ current (INa) of ventricular myocytes and the upstroke velocity of the action potential (Vmax) of papillary muscles were examined by both the patch clamp technique and conventional microelectrode techniques. RESULTS: Salicylate enhanced quinidine-induced tonic and phasic block of INa at a holding potential of -100 mV but not at a holding potential of -140 mV; this enhancement was accompanied by a shift of the hinfinity curve in the presence of quinidine in a further hyperpolarized direction, although salicylate alone did not affect INa. Salicylate enhanced the tonic and phasic block of Vmax induced by quinidine, aprindine and disopyramide but had little effect on that induced by procainamide or mexiletine; the enhancing effects were related to the liposolubility of the drugs. CONCLUSIONS: Salicylate enhanced tonic and phasic block of Na+ channels induced by class 1 highly liposoluble antiarrhythmic agents. Based on the modulated receptor hypothesis, it is probable that this enhancement was mediated by an increase in the affinity of Na+ channel blockers with high lipid solubility to the inactivated state channels.

Effects of hypoxic exercise conditioning on work capacity, lactate, hypoxanthine and hormonal factors in men.

1. Hypoxanthine is a purine degradation product and exercise plasma hypoxanthine can be an index of ATP supply-demand imbalance during exercise. The present study determined the effects of hypoxic exercise conditioning on work capacity, blood lactate, plasma hypoxanthine and various neurohormonal factors. 2. Blood lactate, plasma hypoxanthine and neurohormonal factors (catecholamines, renin-angiotensin system activity and natriuretic peptides) were measured at rest and after maximal cardiopulmonary exercise testing (at sea level) both at pre- and post-hypoxic exercise conditioning in six males (40 +/- 2 years). The training protocol consisted of ergometer exercise twice weekly for 40 min in a hypobaric chamber (61.7-47.2 kPa) for 3 weeks. 3. Pulmonary function and haematological and echocardiographic parameters were not altered after hypoxic exercise conditioning. Work rate at peak exercise (264 +/- 10 vs 321 +/- 31 W; P = 0.10) tended to be increased and peak O2 pulse (15.0 +/- 1.0 vs 18.4 +/- 1.4 mL/beat; P < 0.05) increased after exercise conditioning. The double product during submaximal exercise decreased and systolic blood pressure at peak exercise increased after exercise conditioning. Resting and exercise neurohormonal factors were unchanged, except for reduced resting plasma adrenaline levels. Blood lactate at peak exercise (7.4 +/- 0.7 vs 4.8 +/- 0.5 mmol/L; P < 0.05) became lower and peak plasma hypoxanthine (43.2 +/- 5.7 vs 26.4 +/- 5.0 mumol/L; P < 0.1) tended to be decreased after exercise conditioning. 4. Hypoxic exercise conditioning tended to increase maximal power output with a decrease in exercise blood lactate and a trend towards a decrease in exercise plasma hypoxanthine. These data suggest that exercise conditioning under simulated altitude may improve ATP supply-demand imbalance during exercise with less anaerobiosis, which could contribute to enhanced endurance performance.

Altered purine and glycogen metabolism in skeletal muscle during exercise in patients with heart failure.

Plasma levels of ammonia and hypoxanthine (HX) can be indices of purine nucleotide degradation. The present study determined if patients with heart failure (HF) have altered exercise plasma ammonia and HX levels relative to the peak work rate performed. Blood lactate, plasma ammonia, and plasma HX levels were measured in 59 patients with HF (New York Heart Association [NYHA] classes I:20, II:21, and III:18) and 21 controls at rest and after a maximal cardiopulmonary exercise test. The peak work rate (normal and NYHA I, II, and III, 163+/-11, 152+/-9, 94+/-5, and 69+/-5 W) and peak oxygen uptake ([VO2] 32.3+/-1.7, 25.1+/-0.9, 18.6+/-0.5, and 14.1+/-0.6 mL/min/kg) decreased as the NYHA functional class increased. The increment from rest to peak exercise (delta) for lactate ([(delta)lactate] 6.1+/-0.3, 4.8+/-0.4, 4.6+/-0.3, and 2.9+/-0.3 mmol/L), (delta)ammonia (132+/-14, 119+/-20, 94+/-13, and 32+/-6 microg/dL), and (delta)HX (33.5+/-3.4, 24.9+/-4.7, 20.6+/-3.0, and 9.9+/-1.2 micromol/L) was progressively smaller as HF worsened. The ratio for (delta)lactate to peak work rate (0.037+/-0.003, 0.032+/-0.004, 0.049+/-0.003, and 0.042+/-0.005) was higher in classes II to III HF, while the ratio for (delta)ammonia to peak work rate (0.81+/-0.14, 0.78+/-0.16, 0.99+/-0.11, and 0.47+/-0.11) was significantly lower in class III HF. In summary, patients with HF exhibited a smaller ammonia response with a higher lactate response to exercise when normalized with the peak work rate. These results suggest there may be an altered purine and glycogen metabolism during exercise in skeletal muscle in patients with HF.