Biomedical subjects

R Nadeau

Publications and source records attributed to R Nadeau.

At least 37 records · Page 2Linked to original sources

PubMed1998

Different effects of nifedipine and amlodipine on circulating catecholamine levels in essential hypertensive patients.

OBJECTIVE: To compare the acute and chronic effects of nifedipine retard (NPA), nifedipine gastrointestinal therapeutic system (NGITS) and amlodipine at trough and peak plasma concentrations of drug on blood pressure and heart rate, and on plasma norepinephrine and epinephrine levels in patients with mild-to-moderate hypertension (diastolic blood pressure 95-115 mmHg). DESIGN AND METHODS: After 3-4 weeks' placebo treatment, patients of both sexes were randomly allocated to be administered 10 or 20 mg NPA twice a day, 30 or 60 mg NGITS once a day, and 5 or 10 mg amlodipine once a day for 6 weeks. Initially, for the first 2 weeks, the lowest dose of each drug was used, but higher doses were administered after 2 weeks if sitting diastolic blood pressure was > 90 mmHg. Patients were evaluated after administration of the first dose and after 6 weeks' therapy in a hospital setting. Blood samples were taken for high-performance liquid chromatography measurement of catecholamine and drug levels at various intervals for a period covering trough to peak drug level ranges. RESULTS: Administration of all three drugs reduced clinic blood pressure to the same level after 6 weeks' therapy, but heart rate was increased slightly only with amlodipine (P < 0.05). Administration of NPA reduced blood pressure more abruptly whereas administrations of NGITS and amlodipine induced smoother falls after acute and chronic treatments: a significant increase in heart rate was observed with amlodipine after chronic treatment. Both acute and chronic treatments with NPA (n = 19) increased norepinephrine levels (P < 0.01) transiently (2-4 h). In contrast, administration of NGITS (n = 22) did not increase norepinephrine levels and even induced a slight but significant decrease in norepinephrine levels 5-6 h after chronic treatments. Although administration of amlodipine (n = 22) did not increase norepinephrine levels transiently either after acute or after chronic administration, it did induce a sustained rise in basal norepinephrine levels by more than 50% after chronic therapy (P < 0.01). Plasma epinephrine levels were not increased by any of the treatments and even a slight decrease was observed 4 h after administration of a dose following chronic treatments with NGITS and amlodipine (P < 0.05). CONCLUSIONS: The transient increase in norepinephrine levels observed with NPA and the sustained increases in norepinephrine levels observed after chronic treatment with amlodipine suggest that sympathetic activation occurs with those two drugs. The lack of increase in norepinephrine levels after administration of NGITS suggests that this formulation does not activate the sympathetic system. The lowering of epinephrine levels after administrations of NGITS and amlodipine suggests that inhibition of release of epinephrine by the adrenal medulla occurs with longer-acting dihydropyridine formulations.

Adult↗

PubMed1997

Interleukin-1 beta and tumor necrosis factor-alpha inhibit the release of [3H]-noradrenaline from isolated human atrial appendages.

In the present study, we have investigated the ability of human recombinant interleukin-1 beta (hIL-1 beta) and human recombinant tumor necrosis factor-alpha (hTNF-alpha) to modulate the stimulation-induced (S-I) outflow of [3H]-noradrenaline ([3H]-NA) from isolated superfused human atria. Pieces of human right atrial appendages were excised during routine cardiac surgery. Tissues were incubated with [3H]-NA (0.2 mumol/l) for 30 min at 37 degrees C, then inserted in a Brandel suprafusion system where the radioactivity was washed for 75 min with a Krebs-Henseleit solution at a rate of 0.4 ml/min. Thereafter, the effluent was collected for the remainder of the protocol during which two trains of electrical stimulation (50 mA intensity, 5 Hz frequency, 60 s duration, 2 ms pulses) were delivered at 10 min and 45 min (short protocol) or 85 min (long protocol). The effect of drugs on the S-I outflow of [3H]-NA was determined by adding drugs 20 min (short protocol) or 60 min (long protocol) before the second stimulation. Experiments were carried out in the continuous presence of desipramine (1 mumol/l) to prevent neuronal NA reuptake. The results showed that in human atrium, hIL-1 beta (3 ng/ml) and hTNF-alpha (0.5 ng/ml) significantly inhibited the S-I release of [3H]-NA. The inhibitory effect of hIL-1 beta was blocked by human recombinant IL-1 receptor antagonist (50 ng/ml), and by the cyclooxygenase inhibitor, diclofenac (1 mumol/l), suggesting that hIL-1 beta inhibited NA release through the formation of prostaglandins. The ability of hIL-1 beta and hTNF-alpha to inhibit NA release suggest that mediators of the immune system produced locally may modulate the activity of the sympathetic nervous system in human atrial appendages.

Adult↗

PubMed1997

Reflex adrenal medullary secretion during coronary occlusion mediated by cardiac receptors with afferent vagal fibres in the rat.

The relative contribution of ventricular receptors and sinoaortic baroreceptors to the reflex release of adrenaline upon coronary occlusion was studied in anaesthetised rats submitted to a 30-min occlusion of the left coronary artery. Arterial adrenaline concentrations, heart rate and blood pressure were evaluated in control and sham-operated rats, and following sinoaortic denervation (SAD), bilateral vagotomy with and without SAD, ventricular application of lidocaine, neonatal treatment with capsaicin and cervical section of teh spinal cord. In all groups submitted to coronary ligation, blood pressure decreased sharply upon ligation and remained significantly reduced throughout occlusion while heart rate changes were not significant. In control rats, arterial adrenaline concentrations were significantly increased 15 and 30 minutes following coronary occlusion. The increase in adrenaline concentrations observed upon coronary ligation following SAD was not different from that of the control group. On the other hand, vagotomy with or without SAD, ventricular application of lidocaine, neonatal capsaicin treatment and spinal section all greatly reduced the increase in plasma adrenaline values. These results suggest that a large part of the reflex release of adrenaline upon coronary occlusion is mediated by ventricular receptors with unmyelinated vagal afferent fibres.

Adrenal Medulla↗

PubMed1997

Continuous ST-segment monitoring during coronary angioplasty using orthogonal ECG leads.

In order to characterize ST-segment shifts during transient coronary artery occlusion, 24 patients with single-vessel disease were continuously monitored during percutaneous transluminal coronary angioplasty by use of a computerized orthogonal lead system. Changes of ST-segment (J + 60 ms) in leads X, Y, and Z and of the ST vector magnitude were analyzed by using 20 microV as a threshold for significant ST-segment shift. The sensitivity and magnitude of this shift were compared among the left anterior descending, right coronary, and circumflex artery groups (11, 8, and 5 patients, respectively) during balloon inflation. Significant ST-segment shifts were seen in 22 patients (92%) in ST-VM, Y, and Z leads and all patients in lead X (100%). There was no significant difference in sensitivity of either the ST vector magnitude or the most sensitive lead for occlusion detection among the three groups. There was a significantly greater magnitude of ST shift during left anterior descending artery occlusion than during right coronary artery and circumflex artery occlusions in ST-VM. Analysis of the direction of ST shifts in the X, Y, and Z leads showed a characteristic pattern, which could distinguish among the three coronary groups in 21 patients (88%). The presence of collaterals was significantly associated with ST-segment depression in leads oriented toward ischemia (3 of 6 patients) as compared with ST-segment elevation in the absence of collaterals (all of 15 patients), P > .01. It is concluded that ST-segment shift in the orthogonal leads is a reliable marker for myocardial ischemia. It is equally sensitive to occlusion of each of the three major coronary arteries and can thus identify the occluded coronary. An ST-segment depression instead of an elevation was related to the presence of collaterals, which may reflect a lesser degree of ischemia.

Adult↗

PubMed1997

Spectral analysis of electrograms during ventricular tachycardia in a canine model: relation with epicardial isochronal maps.

The purpose of this study was to assess the capability of magnitude-squared coherence and bicoherence to differentiate monomorphic ventricular tachycardia (MVT) and polymorphic ventricular tachycardia (PVT) in a canine model and to relate these results to the epicardial isochronal maps on a beat-to-beat basis. Unipolar electrograms were simultaneously recorded from the surface of both ventricles with a 127-lead sock electrode array in 12 open-chest anesthetized dogs. The sampling frequency was 500 Hz. Atrioventricular block was induced by formaldehyde injection into the atrioventricular node. The left anterior descending coronary artery was occluded for 60 minutes under ventricular pacing (140 beats/min). During reperfusion, 12 MVT episodes lasting more than 42 seconds were recorded. Left stellate ganglion stimulation induced five PVT episodes lasting more than 42 seconds. Each of these recordings was divided into seven segments of 3,072 points (6.144 seconds). After visual selection, 104 segments were extracted and classified as 73 MVT and 31 PVT segments. Magnitude-squared coherence was estimated as the cross-spectrum from two epicardial signals (on the right and left ventricles, respectively), normalized with the respective autopower spectrum. Bicoherence was estimated as the bispectrum normalized with the autopower spectrum. Magnitude-squared coherence correctly identified 96% of MVT and 81% of PVT segments for a total accuracy of 91%. Bicoherence estimated with the left ventricular lead correctly identified 100% of MVT and 77% of PVT segments with an accuracy of 93%. Beat-to-beat epicardial maps of MVT displayed a cluster of sites of origin close to the reperfusion area, while the sites of origin from beats during PVT were much more dispersed over both ventricles. A strong and significant correlation was found between the number of electrodes with the earliest epicardial activation and coherence (r = .76, P < .0001) and bicoherence (r = .68, P < .0001), respectively. A high and significant correlation was also found between both spectral estimators (r = .74, P < .0001). Coherence and bicoherence discriminated accurately between MVT and PVT. Coherence achieved better results compared with bicoherence. Coherence and bicoherence measurements showed a quantitative relation with the spatial dispersion of the sites of origin. Both spectral techniques seemed powerful enough to be used in the development of implantable devices.

Animals↗

PubMed1997

Free radicals generated by electrolysis reduces nitro blue tetrazolium in isolated rat heart.

Oxygen free radicals (OFR) are highly cytotoxic when produced in the myocardium under certain pathological conditions. In isolated rat hearts perfused retrogradely, OFR were generated by electrolysis of the Krebs-Henseleit buffer (two platinum electrodes, DC current, 10 mA, 1 min). In order to find evidence that OFR are produced, we used nitro blue tetrazolium (NBT) a soluble compound which yields a dark blue formazan pigment in the presence of reducing agents. Hearts were subdivided into: control, electrolysed, NBT (3.3 mg/ml) perfusion during electrolysis in the presence or absence of scavengers. The xanthine-xanthine oxidase (XXO) system known to produce superoxide radical was used as a reference. Specimens were fixed with formaldehyde and stained with eosine or Kernechtrot in preparation for light microscopical examination. Several areas of acute necrosis expressed by hyalinisation and loss of striation were observed in electrolysed hearts which present a pattern of wavy disrupted myofibers and an increase in interstitial spaces. A very faint deposition of formazan was observed in some rare areas of NBT perfused heart. Only the electrolysed group perfused with NBT and the one perfused with XXO plus NBT presented an extensive formazan deposition, mostly in the areas of fibre necrosis. Formazan was barely detectable when superoxide dismutase plus catalase were perfused in the XXO system, while it was still apparent when perfused in electrolysed hearts. These results support the hypothesis that electrolysis can be used to generate different species of OFR and to evaluate the protective action of scavenger and antioxidants against OFR-induced myocardial damage.

Animals↗

PubMed1997

Spatial resolution and role of pacemapping during ablation of accessory pathways.

The objectives of this study were: (1) to evaluate quantitatively the spatial resolution of pacemapping; and (2) to assess the predictive value and role of pacemapping for the catheter ablation of overt APs. Sixty-three unipolar leads were used instead of the standard 12-lead ECG to acquire more information and assess the intrinsic accuracy of pacemapping. Spatial resolution was evaluated in 19 patients for whom data were recorded during bipolar ventricular pacing near the AV ring using the three electrode pairs of a quadripolar ablation catheter with a 5-mm interelectrode spacing. The predictive value was assessed in 27 patients with overt APs who underwent RF ablation; their data were recorded during pacing at the site of successful ablation and at one or two sites where RF energy delivery was ineffective. Data from different beats were compared visually by using body surface potential maps and quantitatively by computing average correlation coefficients (r). Reproducibility was high for paced beats (r = 0.98 +/- 0.02). Displacements of 5 mm of the pacing site could be detected with a sensitivity of 90% and a specificity of 87%. Correlation between pacing at successful ablation sites and preexcited sinus rhythm was low (r = 0.79 +/- 0.11) and the ablation outcome could be predicted with a negative prediction accuracy of 87% and a positive prediction accuracy of 49%. Despite an excellent spatial resolution, pacemapping is of limited value for the identification of successful AP ablation sites, probably because APs can be interrupted at some distance from their ventricular insertion point.

Adult↗

PubMed1997

Transient ischemia inhibits nonexocytotic release of norepinephrine following sustained ischemia in rat heart: is bradykinin involved?

Previous studies have demonstrated that transient ischemia inhibits the release of norepinephrine (NE) following a sustained ischemia. However, the mechanism underlying this inhibition is unknown. Therefore, this study was designed to investigate whether bradykinin (BK) may be involved in the inhibition of NE release following ischemic preconditioning. The effects of transient ischemia, exogenous BK, and kinin receptor blockers on NE release after a prolonged ischemia were tested in the isolated rat heart preparation. Three cycles of 5-min ischemia and reperfusion resulted in the reduction of NE release from 115.3 +/- 14.5 to 51.6 +/- 9.3 pmol.g-1 (p < 0.05) after 30 min of subtotal global ischemia. This effect was not prevented by the administration of either Lys-[Leu8]-des-Arg9-BK (1 mumol.L-1), a B1 antagonist, or HOE-140 (1 mumol.L-1), a B2 antagonist. Three cycles of 5-min BK or des-Arg9-BK infusion also resulted in a dose-dependent inhibition of NE release after 30 min of ischemia. The inhibitory effects of BK (1 mumol.L-1) or des-Arg9-BK (0.5 mumol.L-1) were blocked by Lys-[Leu8]-des-Arg9-BK (1 mumol.L-1), but not by HOE-140 (1 mumol.L-1). The results show that transient ischemia and BK protect sympathetic nerve endings in the isolated rat heart. The inhibition of NE release by pretreatment with BK is mediated by the activation of B1 receptors, whereas preconditioning provided by transient ischemia may be mediated by a different, yet unknown, mechanism in the rat heart.

Animals↗

PubMed1997

Modulation of noradrenaline release by B1 and B2 kinin receptors during metabolic anoxia in the rat isolated atria.

A model of metabolic anoxia was used to investigate the modulatory effect of bradykinin (BK) on the release of noradrenaline (NA) in isolated rat atria. Atria were isolated from Wistar rats and inserted into a perfusion system. After an equilibration period of 20 min, the perfusate was collected every 5 min for a period of 85 min, during which the atria were field stimulated (5 Hz, 2 ms, 50 mA, 60 s) at 10 (S1) and 75 (S2) min. The metabolic anoxia was started 40 min before S2 by replacing O2 with N2 and by removing glucose. The drugs were added 20 min before S2, and their effects on NA release were assessed by the ratio S2/S1. The spontaneous and electrically stimulated induced (S-I) releases of NA were significantly increased by the anoxic procedure. BK (30 nM) significantly increased the S-I release of NA under normoxic conditions. However, under anoxia, BK had no effect on the S-I release of NA but inhibited its spontaneous release. BK coadministered with HOE-140 (100 nM), a B2 receptor antagonist, significantly increased the S-I release of NA during anoxia, whereas the coadministration of BK with Leu3-des-Arg9-BK (100 nM), a B1 receptor antagonist, significantly inhibited that release. Administration of des-Arg9-BK (100 nM) had no effect on the S-I outflow of NA following anoxia, although its coadministration with a B1 antagonist resulted in a significant inhibition of the S-I outflow of NA. The present results suggest that BK inhibits NA release through the activation of a B2 receptor following a 40-min period of metabolic anoxia. Because this inhibition can be observed only in the presence of a B1 receptor antagonist, this could imply that B1 receptor activation, revealed by the anoxia, is involved in the facilitation of NA release.

Animals↗

PubMed1997

Paradoxical action of desipramine on the modulatory effect of bradykinin on noradrenaline release in a model of metabolic anoxia in rat isolated atria.

We have previously shown that bradykinin (BK) can modulate the release of noradrenaline (NA) in a model of metabolic anoxia in the rat isolated atria. In this study, we tested the effect of an inhibitor of NA reuptake, desipramine, on the modulatory action of BK on NA release in this experimental model. Atria were isolated from Wistar rats and inserted into a perfusion system. After an equilibration period of 20 min, the perfusate was collected every 5 min for a period of 85 min, during which the atria were field stimulated (5 Hz, 2 ms, 50 mA, 60 s) at 10 (S1) and 75 (S2) min. Desipramine (1 microM) was present throughout the experimental procedures. The metabolic anoxia was started 40 min before S2 by replacing O2 with N2 and by removing glucose. The drugs were added 20 min before S2, and their effects were assessed by the ratio S2/S1. The spontaneous release of NA was not changed by the anoxic procedure, which significantly increased the electrically stimulated induced (S-I) release of NA. BK (30 nM) significantly increased the S-I release of norepinephrine under normoxic conditions. However, following anoxia, both BK and the B1 receptor agonist des-Arg9-BK (100 nM) significantly inhibited the S-I release of NA. The inhibition induced by BK was prevented by selective antagonists for B1 and B2 receptors. These observations contrast with the results obtained without desipramine, where BK, but not des-Arg(9)-BK, inhibited the S-I release of NA during anoxia. Therefore, blockade of NA reuptake during metabolic anoxia appears to alter the modulatory effect of kinins on NA release via the B1 receptor in the rat isolated atria.

Adrenergic Uptake Inhibitors↗

PubMed1997

Altered hypoxia-induced coronary vasodilatation in diabetic rabbit heart.

The effect of type 1 diabetes mellitus on hypoxia-induced coronary vasodilation was studied in isolated perfused rabbit hearts. Four groups of hearts were compared: control hearts from normal rabbits perfused with physiological buffer (5 mM glucose and 2 mM pyruvate added), hearts from alloxan-induced diabetic rabbits (same perfusion as control), hyperglycemic hearts from normal rabbits perfused with 22 mM glucose and 2 mM pyruvate, and hyperosmotic hearts from normal rabbits perfused with 5 mM glucose, 2 mM pyruvate, and 8.5 mM choline chloride. Hypoxia was produced by perfusion with a mixture of N2- and O2- saturated solutions. Endothelium-dependent and -independent dilators were also tested. Papaverine-induced coronary vasodilatation was unaltered, whereas that of serotonin and adenosine was significantly reduced in hyperglycemic and hyperosmotic hearts but not in diabetic hearts perfused with normoglycemic buffer. Hypoxia (PO2 from 515 +/- 86 to 131 +/- 24 mmHg; 1 mmHg = 133.3 Pa) caused a significant coronary vasodilatation in normal hearts (-66 +/- 3%). This vasodilatation was reduced slightly in diabetic (-45 +/- 7%, p < 0.05) and severely in hyperglycemic (-21 +/- 5%, p < 0.05) and hyperosmotic (-24 +/- 5%, p < 0.05) hearts. The adenosine-receptor antagonist 8-phenyltheophylline (10 microM) reduced hypoxia-induced vasodilatation in normal and diabetic hearts. However, inhibition of prostaglandin synthesis with diclofenac (1 microM), which reduces hypoxia-induced vasodilatation in normal hearts, had no effect in diabetic hearts. In conclusion, alloxan-induced type 1 diabetes mellitus in rabbits is accompanied by a reduced coronary vasodilator response to hypoxia. The contribution of adenosine in this response is unaffected. However, the abated contribution of cyclooxygenase products may account for the reduced vasodilatation during hypoxia in this particular model.

Adenosine↗

PubMed1996

Modulation of noradrenaline release from isolated human atrial appendages.

Prejunctional modulation of noradrenaline release has been studied extensively in various experimental preparations. However, the presence and importance of prejunctional noradrenaline release modulation in human cardiac tissue is still unclear. In this study, we have used superfused human right atrial appendages excised from patients undergoing open heart surgery. The tissues were cut into six pieces and incubated with [3H]noradrenaline (4 microCi/ml. 0.2 microM) for 30 min at 37 degrees C. The tissues were then inserted into a suprafusion system and washed for 75 min with a Krebs-Henseleit solution at a rate of 0.4 ml/min. The experimental protocol consisted of a 60-min perfusion period during which a field stimulation (2 ms pulses, 60 s. 50 mA, 5 Hz) was delivered at 10 and 45 min. The effect of the drugs on the stimulation-induced outflow of radioactivity was determined by adding them 20 min before the second stimulation. Each experiment was carried out with or without desipramine (1 microM) to study the influence of the reuptake blockade. Fenoterol (1-1000 nM), a beta 2-adrenoceptor agonist, and angiotensin II (1-1000 nM) significantly increased noradrenaline release in a concentration-dependent manner. The administration of arecaidine propargyl ester (0.03-3 microM), a non-specific muscarinic receptor agonist, and propylnorapomorphine (0.1 nM-1 microM), a DA2-dopaminergic agonist, produced a concentration-dependent inhibition of the stimulation-induced outflow of radioactivity. The alpha 2-adrenoceptor agonist, oxymetazoline (1 microM) inhibited noradrenaline release at a stimulation frequency of 2 Hz, but not at 5 and 10 Hz. The alpha 2-adrenoceptor antagonist, idazoxan (1 microM), significantly increased the release of noradrenaline at 2 and 5 Hz but not at 10 Hz. The results obtained in the present study demonstrated the presence of the facilitatory beta 2-adrenoceptor and angiotensin II receptor as well as the presence of inhibitory alpha 2-adrenoceptor, muscarinic and DA2-dopamine receptors in the human atrial appendage.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1996

Use of an indirect pharmacodynamic stimulation model of MX protein induction to compare in vivo activity of interferon alfa-2a and a polyethylene glycol-modified derivative in healthy subjects.

Interferon alfa-2a was chemically modified by the covalent attachment of a polyethylene glycol (PEG) moiety to enhance its circulating half-life and to reduce its immunogenicity. A comparative evaluation of the pharmacokinetics of the PEG-modified interferon alfa-2a showed a greater than twofold increase in the circulating half-life as a result of this chemical modification. An indirect physiologic response model was developed to characterize the time course of the MX protein response after subcutaneous administration of single ascending doses of either interferon alfa-2a or PEG-interferon alfa-2a in healthy volunteers. Analysis of the pharmacokinetic-pharmacodynamic relationship suggested that the PEG-modified interferon alfa-2a could not be administered less than twice weekly and therefore offered little therapeutic advantage over its unmodified counterpart, which is administered three times weekly. These results were consistent with findings in phase II trials. This study substantiates the usefulness of pharmacodynamic modeling as a tool for the development of dose recommendations and for the early selection of drug candidates in the drug development process.

Adult↗

PubMed1996

Mapping of septal ventricular tachycardia: clinical and experimental correlations.

In patients with chronic myocardial infarction, ventricular tachycardia originating in the interventricular septum may account for a significant number of arrhythmia recurrences after direct ablative operations. We used total computer-assisted cardiac mapping (epicardial sock, left and right ventricular endocardial balloon electrode arrays) to assess whether tachycardia originating in deep or right-sided layers of the interventricular septum is associated with a specific pattern of epicardial activation sequence. We performed these studies during operations in 18 patients and during experiments in 12 dogs in which a septal myocardial infarction was produced by ligating the anterior septal coronary artery. Intraseptal needle electrodes were plunged into the septum of all animal preparations to generate pace-mapping data and to obtain intraseptal recordings (six preparations) during reentrant ventricular tachycardia induced by programmed stimulation. In addition, pace-mapping data of infarcted canine heart preparations were compared with those of nine healthy heart preparations. In the clinical study, 31 ventricular tachycardias with a septal site of origin were analyzed. Twenty tachycardias displayed an epicardial breakthrough in the area of the interventricular groove, whereas 11 had an epicardial breakthrough in the right ventricular free wall. Biventricular endocardial mapping revealed that left septal endocardial activation preceded right septal activation in the former and that right septal activation occurred earlier in the latter. In the experimental study, 14 ventricular tachycardias (cycle length 146 +/- 34 msec) were induced by programmed stimulation in 11 infarcted heart preparations. Eight tachycardias displaying an epicardial breakthrough on the right ventricle were found to originate in the right ventricular septal subendocardial layers, whereas six tachycardias in which the epicardial breakthrough occurred on the anterior interventricular groove originated in the left ventricular septal subendocardial layers. The epicardial breakthrough preceded the left ventricular endocardial breakthrough in six tachycardias (85.7%) originating in intermediate or right ventricular septal layers, but in only one of five tachycardias originating in the left ventricular septal layers. In the pace-mapping study, the epicardial breakthrough shifted progressively from the right ventricular free wall toward the interventricular groove area in response to pacing from the right, intermediate, and left ventricular thirds of the basal septum. This relationship was similar for infarcted and noninfarcted hearts, although transseptal conduction time was prolonged in infarcted hearts (45 +/- 10 msec vs 33 +/- 7 msec, p < 0.01). Therefore the information integrated from the localization of the epicardial breakthrough and the relative timing between the epicardial and the left ventricular endocardial breakthroughs can be used to estimate the depth of the site of origin of septal ventricular tachycardias. This study confirms that a three-dimensional view of the substratum of ventricular tachycardia can be derived from simultaneous epicardial and left ventricular endocardial mapping and can provide a superior basis for therapeutic interventions.

Animals↗

PubMed1996

Kinin-induced prolongation of action-potential duration in right ventricular muscle from rat: involvement of B1 and B2 receptors.

Previous work has shown that, in rat ventricular muscle, bradykinin (BK) causes a dose-dependent increase in action potential duration (APD), an action that may be responsible for APD prolongation by captopril (kininase II). To determine which kinin receptor might be involved in APD prolongation, we studied the effects of B1- and B2-receptor agonists, as well as those of antagonists and mergepta (a kininase I inhibitor) added during BK superfusion. Action potentials were recorded by using the standard glass microelectrode technique in rat ventricular muscle preparations. Action-potential characteristics were compared between preparations superfused with peptide/drug-free Tyrode's solution (control group) and preparations superfused with peptide/drug-containing solution. APD was significantly longer in preparations superfused with BK (10(-8) M) than in the control group. The APD prolongation induced by BK, a known B2-receptor agonist, was significantly reduced by Hoe 140 (a B2 antagonist) and also by Lys[Leu8]des-Arg9-BK (a B1 antagonist), an action presumably related to inhibition of B1 receptor stimulation by the BK metabolite des-Arg9-BK. When mergepta was added in the presence of BK, APD prolongation by BK was significantly reduced, an effect that could have been related to reduced B1-receptor stimulation after inhibition of the endogenous generation of des-Arg9-BK by kininase I. Sar4-[d-Phe8]des-Arg9-BK, a B1-receptor agonist that is not degraded by kininase II, also prolonged APD. We conclude that both B1 and B2 receptors may be involved in APD prolongation induced in rat ventricular muscle preparations.

3-Mercaptopropionic Acid↗

PubMed1996

Mechanisms of kinin B1-receptor-induced hypotension in the anesthetized dog.

Our study was performed to investigate the mechanism underlying the phypotensive effect of kinin B1-receptor activation with des-Arg9-bradykinin (des-Arg9-BK), in comparison with B2-receptor activation with bradykinin (BK), in anesthetized dogs. Bolus intravenous and intraarterial injections of both kinins were compared. BK (0.6 microgram/kg) produced a transient hypotension of the same magnitude, regardless of the route of administration (from 110 +/- 6 mm Hg to 66 +/- 6 mm Hg, or -41 +/- 5%). In contrast, intraarterial injection of des-Arg9-BK (0.6 microgram/kg) induced a weaker hypotension compared with its intravenous injection (-27 +/- 2% vs. -39 +/- 3%, p < 0.05). The hypotension induced by both kinins was accompanied by increases in heart rate, maximum left ventricular dP/dt, and aortic blood flow, suggesting a reduction in peripheral resistance. The positive inotropic and chronotropic effects of BK and des-Arg9-BK were found to be mediated by the sympathetic nervous system, because they were abolished by propranolol. The hypotension induced by intravenous and intraarterial injections of BK and intravenous injections of des-Arg9-BK was only slightly reduced after nitric oxide (NO) synthase inhibition with NG-nitro-L-arginine (L-NNA). In contrast, the hypotensive effect of intraarterial injection of des-Arg9-BK was reduced by half after treatment with L-NNA (p < 0.05). Neither bilateral vagotomy nor ganglionic blockade with pentolinium reduced the hypotension induced by both kinins. In conclusion, the hypotensive effect of des-Arg9-BK and BK results from a peripheral vasodilation. The contribution of NO in this vasodilation is substantial for des-Arg9-BK when administered intraarterial but limited for BK and intravenous des-Arg9-BK.

Animals↗

PubMed1996

Comparative antioxidant and cardioprotective effects of ceruloplasmin, superoxide dismutase and albumin.

The antioxidant effects of ceruloplasmin (CAS 9031-37-2) against oxygen free radicals (.O2-, .OH, 1O2) and their by-products (H2O2, HOCl), generated by electrolysis of Krebs-Henseleit buffer, were determined in vitro by the DPD (N,N-diethyl-p-phenylenediamine) colorimetric method and ex vivo by quantifying cardiodynamic variables of the isolated perfused rat heart. Purified ceruloplasmin (1 mumol/l) displayed a high antioxidant capacity in vitro (89.2%), while the scavenging capacity of superoxide dismutase (SOD) in equimolar concentrations was 38.1%. A relatively high scavenging activity (72.1%) was observed with bovine serum albumin (BSA). A control group of Langendorff isolated rat hearts (n = 8) was submitted to electrolysis (10 mA, for 1 min) without treatment, whereas the treated groups were perfused with ceruloplasmin, SOD or BSA (1 mumol/l) in the inflow cannula for 5 min before, during, and 5 min after electrolysis. The cardioprotective effect afforded by ceruloplasmin (83-89%) was higher than that observed with the same optimal dose of 1 mumol/l SOD (20-45%). With BSA, no protection was observed ex vivo. Particularities in scavenging specificities and mechanisms seem to explain the important differences between in vitro and ex vivo antioxidant capacities for these proteins.

Animals↗

PubMed1996

Class III antiarrhythmic effects of ceruloplasmin on rat heart.

Recently it has been shown that ceruloplasmin presents a protective action against reperfusion-induced arrhythmias in the isolated perfused rat heart, an effect that is lost when the protein is denaturated by heat. The present study was carried out to see whether ceruloplasmin can alter electrophysiological properties such as ventricular effective refractory periods, conduction time, and action potential duration calculated at 50, 75, and 90% levels of repolarization (APD50, APD75, APD90). To check the specificity of the electrophysiological effects of ceruloplasmin, we have also compared them with those of heat-denatured ceruloplasmin, superoxide dismutase, catalase, deferoxamine, and albumin. In isolated rat hearts, ceruloplasmin (0.25-3 microM) (n = 8 for each concentration) was shown to increase the effective refractory period in a concentration-dependent manner by 26 to 89%. Conduction time was not significantly altered. Heat-denatured ceruloplasmin (0.50-3 microM) (n = 8 for each concentration) increased the effective refractory period by 33 to 70% and did not affect the conduction time. In contrast, superoxide dismutase (1-4 microM), catalase (1-2 microM), deferoxamine (500 microM-1 mM), and albumin (1-4 microM) (n = 8 for each substance and for each concentration) had no significant effect on effective refractory period and conduction time at any dose, suggesting that the ceruloplasmin effect might be specific. In rat ventricular preparations, ceruloplasmin (1 microM) also induced a constant prolongation of APD50 (52%), APD75 (64%), and APD90 (41%) after 15 min of infusion (n = 6). The prolongation of effective refractory period and of action potential duration, by native and heat-denatured ceruloplasmin, suggests that this substance has specific class III effects, although this cannot entirely account for its antifibrillatory action at reperfusion in isolated rat hearts.

Action Potentials↗