Evidence for a central long-lasting antinociceptive effect of vapreotide, an analog of somatostatin, involving an opioidergic mechanism.

The antinociceptive effect of the octapeptide vapreotide, an analog of somatostatin, was studied after systemic injection in normal mice using the hot plate and abdominal stretching assays, and in normal rats using the paw pressure analgesiometric assay. Vapreotide was ineffective at 1 microgram/kg s.c. in the hot plate test in mice, but 30 min after injection it induced an antinociceptive effect at s.c. injected doses of 8, 64, 512 and 4096 micrograms/kg, with an ED50 of 213 +/- 5 micrograms/kg. For the three highest doses this effect persisted 24 hr after the injection (maximal increase: +80 +/- 23% for 512 micrograms/kg) and disappeared at 48 hr. In the phenylbenzoquinone stretching test, in mice, the ED50 was 186 +/- 6 micrograms/kg (maximal decrease: -63 +/- 5%); the effect persisted 24 hr only for the same two highest doses. Using the paw pressure test, in rats, a dose-dependent increase in paw withdrawal and vocalization thresholds was observed for 21 and 24 hr, respectively, after s.c. injections of 16, 64 and 512 micrograms/kg. Global scores obtained for vocalization thresholds were significantly increased (vs. paw withdrawal thresholds) for 64 and 512 micrograms/kg. Carrageenan-induced nociception in rats was reduced for 21 hr by 64 and 512 micrograms/kg s.c.; scores of the contralateral noninflamed paw were also increased. Vapreotide administered locally in the inflamed paw was inactive. No change in edema volume was obtained after systemic injection of vapreotide.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronotropic cardiac effects of falipamil in conscious dogs: interactions with the autonomic nervous system and various ionic conductances.

The chronotropic cardiac effects of falipamil were studied in conscious dogs with chronic atrioventricular (AV) block. Falipamil (0.5-2 mg/kg) initially increased atrial rate dose dependently. After atropine and atropine-pindolol, falipamil (2 mg/kg) decreased atrial rate, but after pindolol, it did not modify atrial rate. After atropine-pindolol-phenoxybenzamine, atropine-pindolol-yohimbine, atropine-pindolol-verapamil, and atropine-pindolol-quinidine pretreatment, falipamil produced atrial bradycardia. Falipamil dose-relatedly decreased ventricular rate. Falipamil (2 mg/kg) decreased ventricular rate after atropine, pindolol, and atropine-pindolol more than under basal conditions. After the other four pretreatments, it also produced ventricular bradycardia. Falipamil did not affect mean blood pressure (MBP) at any dose. These results (a) show that the initial atrial cardio-acceleration produced by falipamil results from its direct vagolytic action; (b) show that absence of atrial bradycardia results from buffering by the vagolytic effect and/or a relatively low basal atrial rate; (c) suggest that the falipamil ventricular bradycardia is partly buffered by the vagolytic effect, norepinephrine (NE) release, and involvement of alpha 2-adrenoceptors; (d) exclude involvement of postsynaptic muscarinic, alpha- and beta-adrenoceptors, and of the slow calcium current in the mechanism(s) by which falipamil decreases cardiac automaticity; and (e) suggest possible involvement of a quinidine-sensitive current in this (these) mechanism(s).

Cardiac electrophysiological effects of rilmenidine, a novel antihypertensive agent, in the conscious dog: comparison with clonidine.

The cardiac electrophysiological effects of rilmenidine, a novel antihypertensive agent, and clonidine were studied in the conscious dog. Sinus rate, corrected sinus recovery time (CSRT) and Wenckebach point (WP) were measured in seven intact dogs. Atrial rate and atrial effective refractory period (AERP) were measured in six atrioventricular (AV)-blocked dogs with ventricular pacing. In both groups, blood pressure was also monitored. Each dog received with at least a three-day interval rilmenidine as dihydrogen phosphate and clonidine as hydrochloride in four successive intravenous injections, 30 min apart. In intact dogs, rilmenidine was administered at 50, 50, 100 and 200 micrograms/kg and clonidine at 2.5, 2.5, 5 and 10 micrograms/kg. In AV-blocked dogs, doses of rilmenidine were 25, 25, 50 and 100 micrograms/kg, those of clonidine 5, 5, 10 and 20 micrograms/kg. Rilmenidine and clonidine decreased sinus rate and atrial rate from the first dose. In this regard, rilmenidine was respectively 24 and 23 times less potent than clonidine. A lengthening of CSRT was observed at all doses with rilmenidine and at the last three doses with clonidine (ratio: 17) and a lowering of WP at all doses with rilmenidine and clonidine (ratio: 22). A shortening of AERP was also seen with rilmenidine and clonidine from the second dose (ratio: 6). All these effects may at least partly be explained by a cholinergic activation mechanism. In intact dogs both drugs produced a lowering of mean blood pressure (ratio: 17), whereas in AV-blocked dogs, in which ventricular rate was kept constant by pacing, pressure effects were more complex, being the resultant of hypotensive and hypertensive effects, the latter due to alpha vascular stimulation. Taken together, these results indicate that in the conscious dog, rilmenidine and clonidine exert qualitatively identical electrophysiological effects, but with different potency ratios.

Seven-day antinociceptive effect of a sustained release vapreotide formulation.

This work studies the antinociceptive effect of a sustained (7 day) release dosage form of vapreotide, a peptidic analogue of somatostatin, in rats submitted to a nociceptive mechanical stimulus (paw pressure). One intramuscular injection (0.6 mg/animal) induced a significant antinociceptive effect for 7 complete days with a maximal increase in vocalization thresholds of 68 +/- 5% and a plateau of activity during the first 4 days. This action was totally inhibited by naloxone (1 mg kg-1, s.c.) injected 24 h or 6 days after vapreotide, suggesting an opioidergic involvement throughout the antinociceptive effect. These findings suggest potential interest in human therapy.

Contribution of vagal blockade to the tachycardia induced by the antimuscarinic agents atropine and pirenzepine.

1. The cardiac cholinergic blockade and the chronotropic effect of the widely differing antimuscarinic drugs atropine and pirenzepine were investigated in the dog. 2. In conscious dogs, suppression of the parasympathetic system with atropine (0.2 mg kg-1 h-1) causes marked brief cardioacceleration (234 +/- 13 beats min-1) while pirenzepine (3 mg kg-1 h-1) causes moderate but persistent cardioacceleration (179 +/- 13 beats min-1). After suppression of the influence of the cardiac sympathetic system these cardioaccelerator effects are attenuated, particularly those of pirenzepine. 3. The effects of vagal stimulation are blocked completely and persistently by both agents. 4. When the cardioinhibitory action of the vagus nerve is blocked by pirenzepine the induced tachycardia can be increased by atropine, which causes an additional cardioacceleration (25 +/- 9 beats min-1). 5. These results show that the tachycardia induced by antimuscarinic agents is not only due to vagal blockade. The different mechanisms which may be involved are discussed. The results suggest that pirenzepine can suppress cholinergic influence on the heart more electively than atropine, which induced an 'excess tachycardia'. Also, intrinsic heart rate can be approached more closely when pirenzepine is used to suppress the parasympathetic system, than with atropine.

Membrane stabilizing activity and beta-adrenoceptor antagonist-induced bradycardia in conscious dogs.

The atrial effective refractory period (AERP) and atrial and ventricular chronotropic effects of the stereoisomers of propranolol, pindolol, metoprolol and penbutolol were studied in conscious atrio-ventricular blocked dogs. Atrial beta-adrenoceptor blocking activity was assessed for all the drugs against isoprenaline. All the drugs except dextro-pindolol lengthened AERP and decreased ventricular rate dose relatedly. At comparable levels of atrial beta-adrenoceptor blockade, dextro-propranolol, dextro-metoprolol and dextro-penbutolol were more potent to induce AERP lengthening than their respective levo-isomers, whereas dextro-pindolol was less potent than levo-pindolol. In addition, levo-pindolol and levo-metoprolol were more potent to produce ventricular bradycardia than the corresponding dextro-isomers, whereas the levo- and dextro-isomers of propranolol and penbutolol were equipotent. These results confirm that the ventricular bradycardia induced by the different beta-adrenoceptor antagonists is partly due to ventricular beta-adrenoceptor blockade and to the membrane stabilizing activity of these drugs, and partly to another as yet unknown factor seen especially with the levo-isomers and particularly marked with metoprolol.

Interactions with the cardiac cholinergic system: effects of disopyramide and its mono-N-dealkylated metabolite.

The cardiac vagolytic effects of disopyramide and its mono-N-dealkylated metabolite (MND), and their interactions with the cardiac cholinergic system, were assessed using in vivo and in vitro experiments. In chloralose anesthetized dogs, disopyramide phosphate (0.25 mg/kg/min) and MND at equimolar dose (0.173 mg/kg/min) reduced vagal bradycardia. As indicated by the ED80, MND exhibits a vagolytic activity 1.5-2 times less potent than disopyramide. Concomitantly, increases in heart rate and mean blood pressure were observed with disopyramide, whereas with MND only a rise in mean blood pressure occurred. In conscious dogs, where vagal tone is fully expressed, disopyramide and MND increased heart rate and, interestingly, prevented any atropine-induced additional tachycardia, though heart rate was relatively low. Binding studies on rat heart membranes yielded Ki values 2-2.5 times higher for MND than for disopyramide, and demonstrated that neither disopyramide nor MND binding modified the cardiac muscarinic receptor sites. Taken together, these results show that disopyramide exhibits a more potent cardiac vagolytic action than MND, very likely linked to a greater ability to bind to cardiac muscarinic receptors. They also show that disopyramide and MND are very potent in preventing atropine-induced "excess tachycardia", very likely by inhibiting the ionic pacemaker current(s) involved in its genesis.

Arrhythmogenic potencies of amrinone and milrinone in unanesthetized dogs with myocardial infarct.

1. In dogs with a 2-4 day old myocardial infarct and a predominantly sinus heart rhythm, we examine arrhythmogenic potencies of amrinone (0.5 mg/kg/min, 1 and 3 mg/kg) and milrinone (10 micrograms/kg/min, 75 and 100 micrograms/kg). 2. Amrinone and milrinone significantly reinduced ventricular ectopic beats on day 2 after coronary occlusion. 3. These effects were preceded by a cardioacceleration which intensified as the ventricular arrhythmias developed. 4. Over the following days the arrhythmogenic potencies of these inotropic drugs were modest. 5. Thus, amrinone and milrinone can impair heart rhythm chiefly in a recent myocardial infarct.

[Silent ischemic heart diseases in patients with peripheral arterial diseases. Screening and 5-year prognosis in a population of 418 patients]. / Les cardiopathies ischémiques silencieuses chez l'artéritique. Dépistage et pronostic à 5 ans dans une population de 418 patients.

Silent ischaemic heart disease was looked for by exercise stress testing in 418 patients with chronic obliterative arterial disease of the lower limbs with no clinical or electrocardiographic signs of myocardial ischaemia. In the initial work-up, 6.2% of patients had a positive exercise test and the results were suspect in 9.2% of patients. These patients were followed up for 5 years. There were 42 deaths (10%). The cause of death was cardiovascular in 53.7% of cases (myocardial infarction 40.4%) and malignant disease in 35.7%. During the 5 year follow-up, ischaemic heart disease present as angina pectoris or myocardial infarction in 115 cases (27.5%). Patients who had a positive exercise stress test initially had a particularly high death rate (23%) and developed clinical signs of coronary insufficiency in 57.5% of cases. On the other hand, the peripheral vascular complications were relatively rare in this series: cerebrovascular accidents: 1.4%; retinal vascular accident: 1.1%; carotid surgery: 1.6%; lower limb amputation: 1.9%; lower limb vascular surgery: 17.7%. Silent ischaemic heart disease is very prevalent in patients with obliterative arterial disease of the lower limbs and is a main vital prognostic factor in these patients. These results confirm the need for a complete cardiovascular check-up in all patients with peripheral arterial disease.

Time course of spontaneous ventricular arrhythmias following acute coronary occlusion in the dog.

In this study, the arrhythmias occurring in dogs between 4 and 15 hr after occlusion of the left anterior descending coronary artery were continuously monitored by recording the electrocardiogram from bipolar leads. At 4.5 hr the number of dogs with less than 50% of sinus beats had increased and at 5 hr 15 min sinus beats represented on average 80% of total heart beats. In the period up to 6 hr isolated ventricular beats and ventricular salvos were seen in 95% and 63% of the dogs respectively and at 7 hr there were, on average, 50% of sinus beats and monomorphic ventricular rhythm was observed in 58% of the dogs. From 7 hr half the dogs had over 50% of ventricular ectopic beats and by 9 hr ventricular rhythm disturbances were permanently present in all the dogs. The ventricular arrhythmias reached a peak at about 11-12 hr (mean % sinus beats less than 10) when all dogs had a predominantly monomorphic (42%) and/or polymorphic (63%) ventricular heart rhythm. The characteristic time course of these cardiac disturbances suggest that it may form the basis for an experimental model that may be useful in analyzing the effects of potential antiarrhythmic drugs.

Cardiovascular profile of oxodipine, a novel dihydropyridine calcium channel blocker, in anesthetized open-chest dogs: a comparison with nitrendipine.

The cardiovascular effects of oxodipine, a new dihydropyridine calcium channel blocker, were studied after i.v. administration to chloralose-anesthetized dogs, and compared with those of nitrendipine. Nitrendipine produced more marked decreases than oxodipine in both systolic and diastolic blood pressure and in total peripheral resistance. No significant modification of heart rate was observed. Oxodipine decreased cardiac contractility, whereas nitrendipine increased it. This difference originated in reflex modifications, since both drugs, administered at doses of 30 and 60 micrograms/kg, decreased cardiac contractility during studies performed after cardiac autonomic blockade. Under these conditions, nitrendipine decreased heart rate, whereas oxodipine had no effect. The two drugs showed comparable effects on coronary and femoral vascular resistance. However, oxodipine caused a very marked persistent decrease of vertebral vascular resistance. On this local circulation, nitrendipine had a weak effect. The results from the present study indicate that oxodipine predominantly increases vertebral blood flow with a concomitant hypertension which is more moderate than after nitrendipine.

Long-lasting antinociceptive effect of RC-160, a somatostatin analog, in mice and rats.

The effect of RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2) was studied in mice by means of the hot plate test and in rats with the tail flick test. In mice, 512 micrograms/kg (s.c.) induced an antinociceptive effect maximal (+88 +/- 17%) at the 6th hour after injection but still significant at the 24th hour; 16 micrograms/kg (s.c.) was active for 3 h; 64, 256 and 1024 micrograms/kg were active 30 min, 3 and 24 h after injection. The effects of these last three doses were not different. The antinociceptive action was as high at 24 h as at 3 h (e.g. for 512 micrograms/kg, 44 +/- 9% and 51 +/- 12%, respectively); 48 h after injection the scores of the treated groups were not different from the score for saline treatment in the tail flick test, 512 micrograms/kg induced a significant antinociceptive effect for 12 h (maximal at the 3rd hour: +60%). No behavioral changes, and particularly no motor activity modifications were observed.

Influence of pentobarbital and chloralose anesthesia on quinidine-induced effects on atrial refractoriness and heart rate in the dog.

The effects of pentobarbital and chloralose on the atrial effective refractory period (AERP), atrial and ventricular rates, and mean blood pressure and also on the effects of quinidine on the same parameters were investigated in dogs with chronic atrioventricular block and implanted atrial pacing electrodes. Pentobarbital (30 mg/kg) increased the AERP by up to 12%, atrial and ventricular rates by 39 and 40%, respectively, and after initial lowering (48%) it increased the mean blood pressure (46%). Chloralose (100 mg/kg) increased the AERP (less than 30 min) by up to 7%, the atrial rate by 49%, the ventricular rate (less than 5 min) by 18%, and the mean blood pressure by 47%. In conscious dogs, quinidine at cumulative doses of 2, 4, and 8 mg/kg, i.e., at plasma levels between 2.7 +/- 0.6 and 6.3 +/- 1.3 micrograms/ml, increased the AERP by up to 21, 28, and 46%, the atrial rate by 49, 65, and 72%, and the ventricular rate (less than or equal to 5 min) by 17, 14, and 14%, and lowered the mean blood pressure by 19, 33, and 43%, respectively. Pentobarbital increased the quinidine-induced lengthening of the AERP by up to 10, 21, and 25 ms, respectively, and reduced the corresponding atrial (38, 53, and 67 beats/min) and ventricular (4, 4, and 5 beats/min) chronotropic effects. In contrast, chloralose reduced the quinidine-induced lengthening of the AERP (5, 12, and 22 ms, respectively), but did not modify the corresponding atrial and ventricular chronotropic effects. Neither pentobarbital nor chloralose altered quinidine plasma levels or the hypotensive effects of this drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of bepridil, diltiazem and verapamil on atrial refractoriness and heart rate in the conscious dog: comparison with quinidine.

1. Bepridil at cumulative doses between 1.25 and 8.75 mg/kg and quinidine between 2.5 and 17.5 mg/kg given in conscious dogs with chronic atrioventricular block and implanted atrial pacing electrodes, dose-relatedly lengthened atrial effective refractory period (AERP), as reflected by the decrease in maximal atrial frequency determined by pacing. 2. Diltiazem shortened AERP at 0.25 mg/kg and lengthened it at 1.75 mg/kg, but both effects were very slight. 3. Verapamil between 0.06 and 0.435 mg/kg did not alter AERP at all. 4. Except for diltiazem at 0.75 and 1.75 mg/kg and bepridil at 8.75 mg/kg, each dose of each drug increased atrial rate. Each drug produced an increase in ventricular rate and a short-lasting lowering in mean blood pressure. 5. Thus, these results indicate that bepridil exhibits more marked antiarrhythmic potentialities than quinidine and that the atrial and ventricular tachycardic effects observed are mainly baroreceptor reflex effects.

Comparison of standard one-minute treadmill exercise and strandness test (absolute walking distance) in relation to site of lesion, walking distance, and diastolic blood flow velocity (Doppler curves).

In 215 outpatients suffering from occlusive arterial disease of the lower limbs the authors compared the decrease in the ratio of ankle systolic pressure to brachial systolic pressure according to whether the treadmill exercise was limited to one minute or extended until pain forced the patient to stop. After a one-minute walk the pressure index always decreased significantly, especially when walking was restricted. The decrease in the pressure index was generally greater when the exercise was continued until the absolute walking distance, and the recovery time was usually twice as long. The fall in the pressure index was significantly greater for patients with single and multiple iliac stenoses than for those with stenoses at lower levels. In patients having a diastolic blood flow velocity on Doppler curves at rest, not modified by walking, a maximum drop in peripheral pressure was recorded after walking for one minute. In this instance there was no intensification of the decrease in peripheral pressure, unlike in patients without a diastolic blood flow velocity at rest. This one-minute test is not a maximal hemodynamic response, but it is sufficient for the appreciation of ischemia during exercise, according to the different parameters measured.

Comparison of anticholinergic effects of cibenzoline, disopyramide, and atropine.

The anticholinergic effects of cibenzoline, disopyramide, and atropine were compared on experimental models. Using inhibition of specific binding of 3H-quinuclidinyl benzylate (3H-QNB) in rat heart and cerebral cortex, Ki values were 15.8 +/- 1.6, 12 +/- 3.5, and 0.013 +/- 0.001 microM, respectively, for heart membranes and 31.6 +/- 1.5, 7.8 +/- 1.3, and 0.006 +/- 0.001 microM, respectively, for cerebral cortex membranes. In isolated guinea pig ileum, disopyramide was about 15 times more anticholinergic than cibenzoline but about 900 times less so than atropine. In anesthetized dogs, the three drugs administered by intravenous bolus reduced bradycardia caused by vagal stimulation. The effect of cibenzoline at 7 mg/kg i.v. (double the antiarrhythmic dose) was approximately the same as that of disopyramide at 2.5 mg/kg (half the antiarrhythmic dose). The drugs were infused for 1 h at 0.17 mg/kg/h for atropine, 11.6 mg/kg/h for disopyramide, and 5.5 mg/kg/h for cibenzoline. The maximal inhibition of the vagal stimulation was 98, 95, and 52%, respectively, for the three drugs. In nonanesthetized dogs, inhibition of the vagal-tone-induced tachycardia reached 33 +/- 4, 134 +/- 20, and 206 +/- 19% for cibenzoline, disopyramide and atropine, respectively. These results show cibenzoline to exert less potent anticholinergic effects than disopyramide.

Evidence for postsynaptic alpha 1- and alpha 2-adrenoceptors mediating catecholamine-induced negative chronotropic ventricular responses in the conscious dog.

1. Adrenaline (0.25-1 microgram/kg), noradrenaline (0.125-0.5 microgram/kg) and dopamine (25-100 micrograms/kg) given in the conscious dog with chronic atrio-ventricular block after beta-adrenoceptor blockade, increased ventricular cycle length (VCL) and mean blood pressure (MBP). 2. Atropine (muscarinic receptor blocker) reduced the catecholamine-induced effects on VCL without modifying their hypertensive effects. 3. Phenoxybenzamine or phentolamine (alpha-adrenoceptor blockers) only decreased the effects of adrenaline on VCL but suppressed those of noradrenaline and dopamine. They only reduced the effects of adrenaline and noradrenaline on MBP, but reversed that of dopamine. 4. Yohimbine (alpha-adrenoceptor blocker) suppressed the catecholamine-induced effects on VCL, and reduced strongly the hypertensive effects of adrenaline and noradrenaline and reversed that of dopamine. 5. Thus, these results show the existence of negative chronotropic postsynaptic alpha-adrenoceptors in the ventricles.

[Pharmacokinetic study of a new benzyl-1 isoquinoline derivative (458 L) after oral administration in men]. / Etude pharmacocinétique d'un nouveau dérivé de la benzyl-1 isoquinoléine (458 L) après administration orale chez l'homme.

Pharmacokinetic study of 458 L. via oral route, was performed in twelve normal volunteers, in a randomized crossover design of three galenic forms. Plasma concentrations were determined, after extraction, by HPLC, with spectrofluorimetric detection. Plasmatic kinetics were fitted to a bi-exponential function with a distribution half-life of 1h and an elimination half-life of 11.5 to 14.7 h according to the form. Pharmacokinetic parameters evaluated as area under the curve (AUC), maximum plasma concentrations (Cmax), relative bioavailability (F'), have shown strong interindividual differences, specially in women group, and this with tobacco smoking.

[Therapeutics using plants: medications based on plants]. / Thérapeutique par les plantes: les médicaments à base de plantes.

There has been renewed interest in the age-old practice of using plants to treat disease. The general public prefers to emphasize the side effects of modern drugs rather than consider the efficacy of the revolutionary changes in therapeutics over the past forty years. So the need to implement protective measures to prevent the uncontrolled use of herbal remedies is being discussed throughout Europe. It is impossible to confirm whether the suggested plants are just placebos but even if they were, the need for the doctor to resort to this form of therapy must be stressed because of its unquestionable success rate. However, it is vital that the doctor's and perhaps public education allow the precise recognition of cases in which this form of treatment should be formally prohibited.