The nature of the sheep chorionic oxytocic substance.

The effects of infusions of fresh sheep placenta in normal saline and the filtrate obtained therefrom after boiling for 15 min were investigated on guinea-pig and rat uteri, other mammalian non-vascular smooth muscles and the cardiovascular system, noting their responses to the infusion/filtrate in the presence or absence of various inhibitors or agonists. Solvent partition, acute toxicity and thin layer chromatography (TLC) studies were also performed. It was found that the infusion/filtrate had oxytocic activity independent of histamine and muscarinic receptors. It had H(1) receptor activity agonist action on the guinea-pig ileum, antagonized adrenaline-induced contractions in the vas but unlike bradykinin did not relax rat duodenum. It induced vasoconstriction in the rat hindquarters, depressed cat blood pressure but had positive inotropic effect on the guinea-pig Langendorff heart. Only the eluent from the least mobile of the five TLC bands on silica gel had oxytocic activity. It was concluded that the sheep chorionic oxytocic substance is not acetylcholine, histamine, 5-hydroxytryptamine, noradrenaline, adrenaline, prostaglandins F or E but is a peptide, which is not bradykinin, vasopressin or oxytocin.

Pharmacological basis for the use of the antivenene water soluble extract of Diodia scandens as a laxative, oxytocic agent and a possible aphrodisiac in traditional medicine practice in eastern Nigeria.

The effects of the antivenene fraction of an ethanol extract of Diodia scandens on some mammalian smooth muscles were investigated. On the guinea-pig ileum, the extract was shown to be a partial agonist acting via muscarinic receptors. Acetylcholine (ACh) was 2.5 x 10(5) times more potent. On the pregnant guinea-pig uterus, the extract induced concentration-dependent increases in the force of contraction and tonus. Oxytocin and ergometrine were respectively 10(6) and 10(3) times more potent. The extract, at subliminal concentrations, potentiated ACh and adrenaline-induced contractions in the guinea-pig was deferens. It also induced dose-related vasodilatation in the rat hindquarters and depressed the blood pressure in the anaesthetized cat. It was concluded that these pharmacological actions offer some scientific explanation for the use of Diodia scandens in traditional medicine as a laxative and as an oxytocic agent. It is suggested that the extract could enhance erection and ejaculatory processes in the male, thus accounting for its regular use by some elderly males.

The pharmacological basis for the use of dried sheep placenta in traditional obstetric practice in Nigeria.

Dried sheep placenta is sometimes used in traditional medicine to facilitate labour. The effects of an extract of powdered dried sheep placenta with normal saline on guinea-pig uterus, ileum, spontaneously beating atrium and Langendorff heart, rat uterus and hindquarters, and cat blood pressure were therefore examined. It was found that 1 g of dried sheep placenta had, on the guinea-pig uterus, an oxytocic activity equipotent with 0.075-0.32 i.u. of oxytocin. The oxytocic activity was unaffected at pHs between 4 and 10 or by boiling for 30 min or autoclaving for 15 min. Neither atropine nor promethazine inhibited the oxytocic action, but promethazine inhibited, to the same degree, contractions induced in the ileum by equipotent doses of the infusion and histamine. Atropine, however, had no effect on infusion-induced contractions in the ileum. The vasoconstriction induced in the rat hindquarters was antagonized by promethazine and phentolamine. Cat blood pressure was reduced, but it had positive inotropic and chronotropic effects on the spontaneously beating guinea-pig atrium and on the guinea-pig Langendorff heart. It was concluded that the dried placenta contains a chorionic oxytocic substance the action of which is independent of stimulation of H1 receptors or of muscarinic receptors.

Effect of levamisole hydrochloride on the guinea-pig atrium.

The effects of levamisole on the guinea-pig atrial preparation were determined. At 3 micrograms/ml, levamisole and lignocaine prevented electrically induced arrhythmia in 3 and 5 out of 5 preparations respectively. It was concluded that levamisole at the therapeutic anthelmintic dose would not abolish clinical atrial arrhythmia. Levamisole even at 3 micrograms/ml had definite salutary effect on the hypodynamic state induced by continuous electrical stimulation. The dose-related positive inotropic effect of levamisole 5-200 micrograms/ml was not antagonised by practolol but was absent in atria from reserpinized animals. Therefore, cAMP may not be involved in the positive inotropic effect. Levamisole antagonised verapamil-induced negative inotropic effect and no positive inotropic effect was observed when the Ca2+ content of the Ringer-Locke solution was below normal. These suggested that Ca2+ must be involved in the inotropic effect. The negative chronotropic effect due to levamisole was not antagonised by hexamethonium but was antagonised by atropine, thus indicating that stimulation of M1 or M2 receptors in the atria may be responsible.

Electrocardiographic changes induced by levamisole hydrochloride in the guinea-pig.

The effects of various i.v. doses of levamisole on the ECG of the anaesthetized guinea-pigs were determined. At 6 mg/kg there were no changes in the heart rate, P-R and Q-T intervals and no cardiotoxic effects were observed. At 10 and 20 mg/kg these parameters were affected little but cardiotoxic effects, mainly ventricular extrasystoles lasting from a few seconds to several minutes, were observed in five out of 10 animals that received either of the two doses. No animal died during the 1 h period of observation. It would appear that levamisole is much less toxic to the guinea-pig heart than to the heart of the rat.

Electrocardiographic changes induced by levamisole hydrochloride in the rat.

The acute electrocardiographic effects of levamisole hydrochloride (2, 6, 10 and 20 mg/kg) were examined in the anaesthetized rat. Levamisole caused a fall in heart rate which was greatest at 20 mg/kg. The P-R interval was increased and was longest during the first 2 min after administration of the drug. The Q-T interval, corrected for rate (QTc), was little affected but at 20 mg/kg, 2 of the 5 rats presented 58% and 94% increases over the value at equilibration. Widening of the QRS complex did not occur at 2 and 6 mg/kg, but at 10 and 20 mg/kg a marked widening occurred in 1 out of 4 and 3 out of 5 rats, respectively. Cardiac dysrhythmias occurred even at 2 mg/kg. Severe bradycardia from sino-atrial depression or from A-V block, including Mobitz Type II A-V block, as well as ventricular tachycardia and fibrillation were observed.

Some aspects of the pharmacology and physiology of the Ascaris suum muscle.

Out of 11 agonists, including such agents as bradykinin, prostaglandin E2, eledoisin, only acetylcholine (Ach) caused the isolated exposed ascaris muscle to contract during treatment for 30 sec and at 10(-7) g/ml (or lower concentrations). The possibility of using this preparation for the identification and quantification of Ach in biological tissues and fluids was highlighted. Neostigmine, but not physostigmine, augmented Ach activity. This suggests that cholinesterases present in the ascaris muscle may be structurally dissimilar to those in the mammalian gut muscle. Several chemically unrelated antagonists showed anti-Ach activity in this preparation in a descending order: d-tubocurarine (dtc) greater than mepyramine greater than atropine, decamethonium, succinylcholine greater than hexamethonium greater than piperazine. Neither adrenaline nor noradrenaline relaxed the ascaris muscle but gamma-aminobutyric acid (GABA) and, occasionally, piperazine caused immediate relaxation of the muscle. GABA was about 150 times more potent than piperazine in this regard. GABA also showed anti-Ach activity which was 0.8-3 times that of dtc. It is suggested that GABA is the inhibitory transmitter in the ascaris suum and that the anti-Ach activity of piperazine is due either to stimulation of GABA receptors and/or to nonspecific blockade of Ach receptors.

Some effects of piperazine citrate on skeletal muscle and central nervous system.

In the frog rectus abdominis and rat phrenic nerve-diaphragm preparations, piperazine citrate was shown to have some neuromuscular blocking activity. In the rat, d-tubocurarine was 500 times more potent than piperazine. This neuromuscular blocking effect of piperazine may be responsible for the hypotonia it sometimes induces in man. High doses of piperazine increased, in mice, the sleeping time due to pentobarbitone, but decreased the threshold for convulsion due to leptazol and strychnine, thus explaining piperazine-induced somnolence and worsening of epileptic attacks in man.

Comparative local anaesthetic and antiarrhythmic actions of levamisole hydrochloride and lignocaine hydrochloride.

Using the guinea-pig wheal preparation for determining the degree of infiltration anaesthesia, lignocaine was found to be 2 times more potent than levamisole. Lignocaine was, however, 1.27 times more toxic than levamisole in the mouse. It is suggested that levamisole could be used as a local anaesthetic agent for infiltration anaesthesia. As regards surface anaesthesia, lignocaine was 16.6 times more potent than levamisole. Levamisole would, therefore, not be of use in surface anaesthesia. Levamisole was more effective than lignocaine in protecting toads against deaths due to the minimum dose of ouabain which caused 100% mortality. The therapeutic indices for levamisole and lignocaine were 4.57 and 1.58 respectively. Unlike with lignocaine it was possible to achieve more than 50% protection with levamisole. Levamisole was, however, only marginally more effective than lignocaine in reverting to sinus rhythm, barium chloride-induced ventricular dysrhythmia in the rat. It is suggested that levamisole could have potential value as an antiarrhythmic agent.

Effects of pentazocine on the guinea-pig ileum.

The pA2 values for pentazocine-Ach, pentazocine-5HT and pentazocine-histamine antagonism on the guinea-pig ileum were found to be 8.0, 7.92 and 7.08, respectively. When the effects of a constant dose of pentazocine on equipotent doses of Ach, histamine, 5HT, and nicotine were studied, its anti-5HT and anti-Ach activities were found to be equal and about 6.3 times higher than its antihistamine activity but 0.68 times lower than its anti-nicotine activity. The antihistamine activity of pheniramine was found to be 794 times that of pentazocine while the anti-Ach activity of atropine, the anti-5HT activity of cyproheptadine and the anti-nicotine activity of hexamethonium were 20, 10 and 2.2 times, respectively, higher than that of pentazocine.

Comparative antiarrhythmic and local anaesthetic effects of piperazine citrate and lignocaine hydrochloride.

The effect of pretreatment with lignocaine hydrochloride (0.1 mg/g body weight) and piperazine citrate (1 mg/g body weight) on the number of deaths due to ouabain (0.02-0.12 mg/g body weight) was determined in the toad. Lignocaine was at least 10 times more potent than piperazine. Considering the doses that gave 50% protection from the 100% deaths due to ouabain (0.09 mg/g), lignocaine was 14.8 times more potent, but it was 56-60 times more toxic than piperazine as shown by the LD50s in the mouse and toad. Lignocaine was also about 10 times more potent than piperazine in preventing electrically-induced arrhythmia in the isolated guinea-pig atrium suspended in low potassium Ringer-Locke solution. With regard to infiltration anaesthesia, lignocaine was about 158 times more potent than piperazine. Therefore the relative potencies of the antiarrhythmic activities of piperazine and lignocaine do not correlate with the relative local anaesthetic potencies. It was concluded that, although lignocaine is 10-15 times more potent than piperazine as an antiarrhythmic agent, piperazine should be a much safer drug and could have potential utility as a substitute for lignocaine as an antiarrhythmic agent.

Electromechanical dissociation and possible uncoupling of phosphorylation following tachydysrhythmogenic dose of amrinone in the guinea-pig Langendorff heart preparation.

In the guinea-pig Langendorff heart preparation amrinone induced tachydysrhythmia and electromechanical dissociation at 1000 micrograms/ml but not at 50 and 250 micrograms/ml. At 1000 micrograms/ml, the myocardial oxygen consumption was twice the value at equilibration in spite of a very marked fall in contractile force, thus suggesting that amrinone at that toxic dose level uncoupled phosphorylation. Amrinone at 50 and 250 micrograms/ml caused a dose-related reversal of the cardiac depressant effect induced by verapamil suggesting, therefore, that the positive inotropic effect is due at least in part to influx of Ca2+ into the sarcoplasm. It is suggested that the electromechanical dissociation and the possible uncoupling of phosphorylation induced by a toxic dose of amrinone are related to a considerable influx of Ca2+ into the sarcoplasm and the mitochondria.

Effects of piperazine citrate and of the anti-Ascaris fraction of the ethanolic extract of the bark of Polyadoa umbellata (erin) on mammalian non-vascular smooth muscle.

At 500 micrograms-4 mg/ml piperazine and the anti-Ascaris fraction of the ethanolic extract of the bark of the erin tree (Polyadoa umbelleta) have equipotent inhibitory effects on submaximal contractions induced by equipotent doses of acetylcholine, nicotine and 5-hydroxytryptamine on the guinea-pig ileum and the rabbit duodenum. Similar inhibitory effects were noted on: acetylcholine, adrenaline, histamine, and barium chloride-induced contractions in the guinea-pig vas deferens, oxytocin and acetylcholine-induced contractions in the non-pregnant rat uterus. These actions indicate that piperazine and erin possess definite non-specific smooth muscle depressant properties. The need for the elucidation of the chemical nature of the active constituent in "erin" and for in-vivo anti-Ascaris activity studies in man is stressed.

Electrocardiographic changes induced by amrinone in the isolated perfused guinea-pig Langendorff heart preparation.

ECG changes induced by three different concentrations of amrinone were determined in the spontaneously beating guinea-pig Langendorff heart preparation. At a concentration of 50 micrograms/ml, there were no ECG changes except for a sinus tachycardia having a mean increase of 15.64 +/- 4.0, (P less than 0.01). At a concentration of 250 micrograms/ml, sinus tachycardia was more evident (+ 20.86% +/- 1.22; P less than 0.001). There was also a statistically significant shortening of the Q-T interval (P less than 0.001). With 1000 micrograms/ml, amrinone further increased heart rate (+ 45.10% +/- 13.26; P less than 0.001). There was a greater shortening of the Q-T interval, and occasionally sagging of the S-T segment. Dysrhythmic phenomena including coupled beats, at times with R waves appearing during the vulnerable period of the T wave; ventricular premature beats and alternating polymorphic ECG patterns, were evident. Second and third degree atrioventricular block preceded by marked prolongation of the P-R interval less commonly developed at this concentration. On the basis of these observations and others, it appears that as regards the development of cardiotoxocity, amrinone possesses a relatively wide margin of safety not less than 5 and may even approach 20.

Cardiac effects of amrinone on rabbit papillary muscle and guinea pig Langendorff heart preparations.

Amrinone (50-1,000 microgram/ml) produces a dose-dependent inotropic action on rabbit papillary muscle. The hypodynamic state following prolonged stimulation is prevented or abolished by amrinone, and contractile force remains significantly elevated over drug-free controls throughout the ensuing 3-h duration of exposure. In a concentration of 1 mg/ml, dysrhythmic phenomena occasionally appeared, e.g., bigeminy, automaticity, and elevated threshold to electrical stimulation. Bigeminy could be abolished either by increasing the external K+ concentration in the bathing media, or by raising the stimulating voltage. However, amrinone failed to alter the refractory period following 60 min of exposure. In isolated perfused guinea pig Langendorff heart preparations, amrinone (50 microgram/ml) significantly increased coronary flow, myocardial oxygen consumption (MVO2), cardiac work, and, during the period of peak activity, dP/dt. However, it had no significant effect on cardiac efficiency. And, as in the papillary muscle preparation, the effect of amrinone was easily reversed by perfusing the preparation with fresh (no-drug) media. Preliminary evidence shows that amrinone fails to reverse the negative inotropic action of verapamil as well as calcium-free media, although the effects on heart rate, coronary flow, and MVO2 were reversed. However, the higher the external calcium concentration, the greater was the level of contractile response achieved by amrinone. Thus, the mechanism of amrinone-induced augmentation appears to be dependent upon the availability of calcium.

Pharmacological and biochemical studies of puff adder venom.

Bitis arietans venom made up of six protein fractions was found to be proteolytic, anticoagulant, plasmalytic and cardiotoxic. There were no spasmodic or hemolytic fractions. Protamine sulphate in vitro antagonized anticoagulant properties but did not protect mice from toxic envenomation; because venom was also neurotoxic and showed a curare like effect at the neuromuscular junction. Results were discussed in terms of pharmacology and biochemistry of African snake venoms.