Chantal Lambert

Modulation of the anti-nociceptive effects of 2-arachidonoyl glycerol by peripherally administered FAAH and MGL inhibitors in a neuropathic pain model

There are limited options for the treatment of neuropathic pain. Endocannabinoids, such as anandamide and 2‐arachidonoyl glycerol (2‐AG), are promising pain modulators and there is recent evidence of interactions between anandamide and 2‐AG biosynthesis and metabolism. It has been clearly demonstrated that 2‐AG degradation is mainly catalysed not only by monoacylglycerol lipase (MGL) but also by a fatty acid amide hydrolase (FAAH). Inhibitors specifically targeting these two enzymes have also been described: URB602 and URB597, respectively. However, the anti‐nociceptive effects of the combination of peripherally injected 2‐AG, URB602 and URB597 in a neuropathic pain model have not yet been determined. This was performed in the presence or absence of cannabinoid CB1 (AM251) and CB2 (AM630) receptor antagonists.

Peptidic regulation of heart rate and interactions with the autonomic nervous system

Autonomic influences on the heart rate have been the subject of intense research for many decades and are classically devoted to the sympathetic and parasympathetic systems. However, developments over the past few years in our knowledge of the organization of the autonomic nervous system have led to the conclusion that in addition to the classical transmitters, peptidic transmitters are clearly present and have direct or indirect actions on cardiac conduction. Neuropeptides have been found to collocate with each other or with classical transmitters, thereby increasing the variety of chemical signals that a neuron can utilize to communicate with other cells. Neuropeptides can act as neurotransmitters, neuromodulators or neurohormones. Some are produced in endocrine glands and circulate as hormones, while others are contained in cardiac myocytes, neurons, or endothelial cells in proximity to the sinoatrial node and can therefore act in a paracrine or autocrine way on the pacemaker cells to modulate heart frequency. There is evidence supporting such a role, especially for locally situated neuropeptide Y, vasoactive intestinal peptide, calcitonin gene-related peptide, substance P, angiotensin II, natriuretic peptides, endothelins and possibly many others. The role of the peptidic neurotransmitters in the conduction system should not be exaggerated. Nevertheless, neuropeptides certainly represent a new category of neurotransmitters forming a third component of the autonomic nervous system and may have complex actions with potential therapeutic implications in man.

Upregulation of Cardiac Angiotensin II AT1 Receptors in Congenital Cardiomyopathic Hamsters

Angiotensin II (Ang II) is a growth factor that stimulates protein synthesis and induces cellular hypertrophy in cardiac myocytes. To gain insight into the role of Ang II in cardiac hypertrophy, we examined the expression and subtype distribution of Ang II receptors in the ventricles of embryonic and of 25- to 350-day-old inbred control and cardiomyopathic (CHF 146) hamsters. Studies were also performed with heterozygous (cardiomyopathic x control) animals. Compared with the control hamsters, cardiomyopathic hamsters presented decreased body weights and increased ratios of ventricular weight to body weight in every adult group studied. Typical histological lesions appeared in the left ventricle of cardiomyopathic animals around 70 to 75 days, and their severity increased with time. Radioligand binding studies with cardiac ventricular membranes indicated that iodinated [Sar1,Ile8]Ang II (sarile) binds to a homogeneous population of sites in membranes derived from adult normal and cardiomyopathic animals. Competition curves using specific receptor subtype antagonists revealed that 125I-sarile binding sites were exclusively of the AT1 subtype in both groups of animals. Importantly, the density of AT1 receptors was found to be significantly increased (90% augmentation at 70 to 75 days) in the ventricles of cardiomyopathic hamsters. This augmented expression was observed in all adult groups and was already present at 25 days, when no histological lesions were visible. The affinity of the receptor for losartan did not vary significantly between adult normal and cardiomyopathic animals (mean Kd, 19.6 and 16.7 nmol/L, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Positive chronotropic and inotropic effects of C-type natriuretic peptide in dogs

We have recently reported that C-type natriuretic peptide (CNP) has a positive chronotropic effect in dogs. We further investigated the effect of CNP on canine cardiac functions: 1) in situ, by exploring the effects of isoproterenol (10 microg), angiotensin II (ANG II, 5 microg), and CNP (40 microg) injections (n = 8) on computerized epicardial mapping of atrial activation to detect a shift in pacemaker location; 2) by examining the presence of natriuretic peptide receptor (NPR)-A and -B mRNAs in atrial and nodal tissues using semiquantitative reverse-transcription polymerase chain reaction; 3) in vitro, using spontaneously beating right atrial preparations (n = 6), by recording the transmembrane potentials of sinoatrial node (SAN) cells before and after injection of CNP (25 microg); and 4) by observing the effects of CNP (25 microg) on contractile force of paced isolated right atrial preparations (n = 6). The results indicate that 1) the site of earliest extracellular electrical activation in the SAN remains mostly unchanged in response to CNP, whereas it shifts to the superior region of the SAN after isoproterenol and ANG II injections; 2) NPR-A and -B mRNAs are present in atrial and nodal tissues; 3) CNP significantly increases the maximal rate of diastolic depolarization and decreases the action potential duration at 75 and 90% of repolarization; and 4) CNP significantly increases atrial contractile force. These results suggest that CNP modifies cardiac ionic currents to produce positive chronotropic and inotropic effects by stimulation of NPR-B receptors, located in the SAN region, and that CNP plays a role in the modulation of cardiac function.We have recently reported that C-type natriuretic peptide (CNP) has a positive chronotropic effect in dogs. We further investigated the effect of CNP on canine cardiac functions: 1) in situ, by exploring the effects of isoproterenol (10 μg), angiotensin II (ANG II, 5 μg), and CNP (40 μg) injections ( n = 8) on computerized epicardial mapping of atrial activation to detect a shift in pacemaker location; 2) by examining the presence of natriuretic peptide receptor (NPR)-A and -B mRNAs in atrial and nodal tissues using semiquantitative reverse-transcription polymerase chain reaction; 3) in vitro, using spontaneously beating right atrial preparations ( n = 6), by recording the transmembrane potentials of sinoatrial node (SAN) cells before and after injection of CNP (25 μg); and 4) by observing the effects of CNP (25 μg) on contractile force of paced isolated right atrial preparations ( n = 6). The results indicate that 1) the site of earliest extracellular electrical activation in the SAN remains mostly unchanged in response to CNP, whereas it shifts to the superior region of the SAN after isoproterenol and ANG II injections; 2) NPR-A and -B mRNAs are present in atrial and nodal tissues; 3) CNP significantly increases the maximal rate of diastolic depolarization and decreases the action potential duration at 75 and 90% of repolarization; and 4) CNP significantly increases atrial contractile force. These results suggest that CNP modifies cardiac ionic currents to produce positive chronotropic and inotropic effects by stimulation of NPR-B receptors, located in the SAN region, and that CNP plays a role in the modulation of cardiac function.

Chronic AT1 receptor blockade and angiotensin-converting enzyme (ACE) inhibition in (CHF 146) cardiomyopathic hamsters: effects on cardiac hypertrophy and survival.

OBJECTIVE We have reported that angiotensin II AT1 receptors are upregulated and that there are no AT2 receptors in the ventricles of cardiomyopathic hamsters. Since the upregulation was present even when no histological lesions were detectable, these results suggested that angiotensin II plays a role in the genesis/maintenance of this pathology. A survival study was conducted to compare the effects of an angiotensin II AT1 receptor antagonist, losartan (L), to those of a placebo (P). Since the angiotensin-converting enzyme (ACE) inhibitor quinapril (Q) has been shown to have beneficial effects in this animal model, a Q group was included. METHODS Male Syrian cardiomyopathic hamsters (CHF 146, n = 360) were orally administered P, low- (30 mg/kg/day) or high-dose (100 mg/kg/day) L, or Q (100 mg/kg/day), starting at day 50 of life. Inbred control hamsters (CHF 148, n = 180) were treated with P or L (100 mg/kg/day) as controls. Animals were sacrificed at intervals to evaluate cardiac hypertrophy. Kaplan-Meier analysis was performed to assess differences in survival. RESULTS High-dose L had no effects on the survival of control hamsters. There was an unexpected dose-dependent decrease in the survival of cardiomyopathics treated with L (low-dose, P = 0.14; high-dose, P = 0.0015) compared to an increase with Q (P = 0.0003). Cardiac hypertrophy compared to P was increased with L but significantly decreased with Q in cardiomyopathics. CONCLUSIONS In this model, losartan did not improve survival compared to placebo and quinapril and, if anything, increased mortality. Our results suggest that AT1 receptor antagonists and ACE inhibitors are not necessarily equivalent or interchangeable in terms of their effects on cardiac hypertrophy and survival in selected progressive heart failure models.

Clonidine and ST-91 May Activate Imidazoline Binding Sites in the Heart to Release Atrial Natriuretic Peptide

It is well established that the antihypertensive drug clonidine acts through specific imidazoline receptors in the brain and kidney to increase diuresis, natriuresis, and kaliuresis. We have previously shown that the effects of clonidine are associated with elevated plasma atrial natriuretic peptide (ANP). Similar to clonidine, ST-91, a clonidine analogue that does not cross the blood-brain barrier, evokes renal responses that are also associated with elevated plasma ANP. The mechanisms of ANP increase elicited by these imidazoline drugs are unclear. Since ANP is primarily released from the cardiac atria, we investigated the direct effect of the imidazoline drugs on ANP release by incubating left and right atrial sections with 10(-6) mol/L ST-91 in the presence and absence of efaroxan, a selective imidazoline I1 receptor antagonist, for 30 minutes at 37 degrees C. ST-91 significantly stimulated ANP release, and the effect was inhibited by 10(-6) mol/L efaroxan. Further studies using heart perfusion with the imidazoline drugs with and without antagonists over 30 minutes revealed that both clonidine and ST-91 gradually stimulated ANP release. Also, perfusion with these compounds resulted in a gradual decrease in heart rate, but bradycardia was significant only with clonidine. The effects of ST-91 were inhibited by 10(-6) mol/L efaroxan and to a lesser extent by 10(-6) mol/L yohimbine, implying that the actions of ST-91 were mainly mediated by I1 receptors. On the other hand, the actions of clonidine were inhibited by 10(-5) mol/L efaroxan and by 10(-6) mol/L yohimbine, an alpha2-adrenoceptor antagonist, which may suggest that the actions of clonidine were preferentially mediated by alpha2-adrenoceptors in the heart. These results indicate that the peripheral actions of clonidine are probably mediated by alpha2 and imidazoline receptors and may involve direct stimulation of ANP release by the cardiac atria--an effect that may account for the increase in plasma ANP levels and diuresis and natriuresis observed in vivo after administration of clonidine and its analogues.

Efficacy of propafenone in preventing ventricular tachycardia: Inverse correlation with rate-related prolongation of conduction time

The efficacy of propafenone in preventing induction of ventricular tachycardia was evaluated in 25 consecutive patients (mean age 62 +/- 8 years) with remote myocardial infarction who underwent programmed electrical stimulation for ventricular arrhythmia using up to three extra-stimuli after basic drive at the right ventricular apex. In nine patients (Group A), propafenone prevented induction of sustained ventricular tachycardia (noninducible in four, nonsustained [less than 30 s] in five). In the other 16 patients (Group B), sustained ventricular tachycardia was still inducible; in 11 of the 16, the tachycardia configuration was unchanged but the cycle length was significantly longer (431 +/- 99 versus 284 +/- 44 ms, p less than 0.001). Propafenone did not significantly affect either sinus cycle length or AH and HV intervals. However, it prolonged QRS duration during sinus rhythm equally in both groups of patients. With ventricular pacing, propafenone also prolonged right ventricular effective and functional refractory periods and surface QRS duration. There was greater lengthening of the paced surface QRS duration when drug therapy was ineffective (for example, +35 +/- 12 ms in Group A versus +69 +/- 23 ms in Group B at a basic drive of 400 ms, p less than 0.01). Drug-induced prolongation of a paced QRS complex greater than 40 ms had a 94% positive predictive value for drug failure to prevent induction of ventricular tachycardia. Drug-induced percent prolongation of ventricular tachycardia cycle length in Group B did not correlate well with percent QRS prolongation.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiologic effects of intravenous propafenone in Wolff-Parkinson-White syndrome

The electrophysiologic effects of intravenous propafenone were studied in 15 consecutive patients with accessory pathways. Thirteen patients had sustained orthodromic supraventricular tachycardia induced during baseline study, and two patients needed isoproterenol to render it sustained. In all except one patient, propafenone, 2 mg/kg given intravenously over a 10-minute period, was successful in converting the arrhythmia to sinus rhythm. Atrial fibrillation was inducible in 10 patients before propafenone, but was no longer inducible in seven of these patients after the drug. The HV interval (23 +/- 20 to 41 +/- 25 msec) and the anterograde (310 +/- 96 to 509 +/- 145 msec) and retrograde (256 +/- 30 to 334 +/- 105 msec) effective refractory periods of the bypass tract were all significantly prolonged after the drug. The pacing cycle length that produced conduction block over the bypass tract anterogradely (319 +/- 126 to 446 +/- 150 msec) and retrogradely (272 +/- 25 to 360 +/- 97 msec) was also increased. During orthodromic tachycardia, propafenone increased conduction time in both the anterograde and retrograde limbs of the tachycardia. Tachycardia terminated in the retrograde limb in 64% of the patients. We conclude that propafenone is very effective in terminating orthodromic tachycardia when given intravenously and that it should be considered in patients initially seen with atrial fibrillation and short refractory periods.

Direct chronotropic effects of atrial and C-type natriuretic peptides in anaesthetized dogs.

1 . The chronotropic effects of atrial natriuretic peptide (ANP) and C‐type natriuretic peptide (CNP) were investigated using injections (50 μg in 1 ml of Tyrode solution as bolus over 1 min) directly into the sinus node artery of 21 anaesthetized and vagotomized dogs which had been pretreated with a β‐adrenoceptor antagonist. The injections were also repeated following: (a) α‐adrenoceptor antagonism (prazosin) and muscarinic receptor antagonism (atropine); (b) inhibition of prostaglandin synthesis (indomethacin); (c) angiotensin II AT1 receptor antagonism (losartan); (d) histamine H1 (mepyramine) and H2 (cimetidine) receptor antagonism. 2 . The results obtained indicate that ANP had no significant effect on the basal sinus rate, whereas CNP produced a slight but significant increase of 12 ± 2 beats min−1. The effect of CNP was long‐lasting (return to pre‐injection levels after maximum effect in 17 ± 3 min) and was not influenced by the various antagonists mentioned above. 3 . During in vitro experiments on spontaneously beating right atria isolated from 6 dogs, the injection of CNP (50 μg in 1 ml of Tyrode solution) into the sinus node artery produced an increase in atrial rate of 14 ± 1 beats min−1. 4 . The results of this work indicate that CNP exerts a significant and prolonged positive chronotropic effect both in vivo and in vitro. Other studies are required to elucidate the mechanism of action of CNP on the heart conduction system, to ascertain the presence of natriuretic peptide receptor B in the region of the sinoatrial node and to determine the role of CNP in the control of heart rate.

Efficacy and safety of intravenous and oral diltiazem for Wolff-Parkinson-White syndrome

The electrophysiologic effects and safety of diltiazem administered either intravenously or orally were studied in 14 patients with Wolff-Parkinson-White syndrome during orthodromic reentrant tachycardia and atrial fibrillation (AF). Anterograde and retrograde effective refractory periods of the accessory pathway did not change significantly from baseline during either i.v. or oral administration. Administration by either route prevented induction of sustained reentrant tachycardia in 8 patients. In 6 patients, the reentrant tachycardia was either nonsustained (2 patients) or sustained at much slower rates than the baseline rates (mean +/- standard deviation, baseline, 290 +/- 41 ms; i.v., 355 +/- 40 ms [p less than 0.001]; and oral, 377 +/- 33 ms [p less than 0.001]). In these patients anterograde atrioventricular conduction was prolonged significantly from the mean baseline value of 163 +/- 36 ms to 212 +/- 35 ms with i.v. administration (p less than 0.005) and 225 +/- 33 ms with oral administration (p less than 0.005). Retrograde conduction via the accessory pathway did not change significantly after administration of diltiazem. The shortest preexcited RR intervals during AF were significantly reduced during i.v. but not during oral administration: control, 327 +/- 47 ms; i.v., 270 +/- 28 ms (p less than 0.001); and oral, 323 +/- 44 ms (difference not significant). In 5 patients AF was sustained for a mean of 20 minutes after i.v. and for 12 minutes after oral administration (p less than 0.20), compared with a baseline mean value of 0.83 minute.(ABSTRACT TRUNCATED AT 250 WORDS)