Cardiac performance in the rabbit as affected by the venom of bitis gabonica. (A preliminary report)

The effect of the venom of Bitis gabonica administered intravenously in the rabbit at the dose of 0.125 mg/kg has been compared with that produced by the same dose of the compound in the dog. In the rabbit the effect on total peripheral resistance, aortic blood pressure and stroke volume is less marked and shorter than in the dog. Furthermore in a period included between 5 and 30 min after the injection, in the rabbit a transient increase of stroke work is observed as a result of the ejection of an increased stroke volume against a blood pressure which has already returned to normal. Such a transient inotropic effect of the venom was also observed in other small mammalians and might be attributed to an adrenergic mechanism.     

Haemodynamic effect of the venom of Bitis Gabonica in the dog

Intravenous injection of 0.125 mg/kg of venom of Bitis Gabonica in the anaesthetized dog produces an immediate but reversible decrease in total peripheral and coronary vascular resistance. Stroke volume show a transient increase followed by an irreversible reduction. A second dose of 0.25 mg/kg produces the same effect on total peripheral and coronary vascular resistance, but furtherly reduces the stroke volume. A third dose of 0.50 mg/kg kills the animal after an extreme reduction of the stroke volume. The progressive decrease of the stroke volume might be due to a failure of the ventricle to relax, whereas its transient increase immediately after the injection depends on the abrupt fall of the total peripheral resistance.     

Contribution of inappropriate treatment for hypertension to pathogenesis of stroke in the elderly.

One hundred and seventy eight patients admitted to hospital with acute cerebral infarction or transient ischaemic attack were studied to determine if their treatment had been changed during the previous three weeks and to compare their blood pressure after the stroke with premorbid values. Blood pressure measurements taken within one year before the stroke were available for 100 patients; seven of these had had a recent change in antihypertensive or diuretic treatment. Of these, three patients who had started taking frusemide because of hypertension and one whose dosage of a reserpine combination drug had been increased experienced an appreciable decrease in blood pressure immediately after the stroke; they also showed signs of haemoconcentration. The change in treatment probably contributed to the stroke in these four patients. The other three showed a smaller decrease or even an increase in blood pressure and no signs of haemoconcentration; the relation between the change in treatment and stroke is less likely in these patients. The use of high ceiling diuretics such as frusemide in the treatment of hypertension may induce hypovolaemia and hypotension, resulting in cerebral ischaemia, and are therefore best avoided in such treatment.     

The mechanical and electrical effects of rhinoceros viper (Bitis nasicornis) venom on the isolated perfused guinea pig heart and atrial preparations

The mechanical and electrical effects of the venom of Bitis nasicornis were studied on the guinea-pig Langendorff and left atrial myocardium preparations. While Langendorff preparations were treated with individual doses of 0.1, 0.6 and 1.4 mg, isolated left atria were treated using concentrations of 2.0, 20 and 200 micrograms/ml of venom in the perfusion solution. In the Langendorff preparation, transient increases in left ventricular systolic pressure (LVSP) and heart rate (HR) were seen after 0.1 mg of venom. When 0.6 mg of venom was given, the increases were followed by decreases, while 1.4 mg doses simply induced decreases in LVSP and HR. After both 0.6 and 1.4 mg doses the decreases were accompanied by increases in left ventricular diastolic pressure. In addition to these mechanical effects, transient increases in HR with atrio-ventricular blocks, ventricular extrasystoles and tachycardia were observed after each dose. In the left atrium the 2 micrograms/ml venom concentration produced an increase, followed by a decrease, in the maximum tension developed, which was only seen to decrease with higher concentrations of 20 and 200 micrograms/ml of venom. A dose dependent significant reduction in the action potential duration was observed for the doses of 0.6 and 1.4 mg in the ventricle and for all three concentrations in the atrium.     

Changes in osmotic resistance of erythrocytes of human blood caused by Vipera berus venom

The effect of Berus viper's venom on the osmotic globular resistance of human blood, incubated for a period of 2 hours at 20 degrees C with amounts of venom in the range of 200 to 400 gamma/ml of blood, has been studied. The hemolytic effect occurs to a greater extent at NaCl concentrations higher than 0,60%.     

Early effect of Crotalus durissus terrificus venom on kidney circulation

Local blood flow was measured in renal cortex (1 mm below cortical surface) by means of the hydrogen clearance method in urethanized rats. Recording of blood pressure from femoral artery was performed. Crotalus durissus terrificus venom injection (one mg/kg i.v.) significantly decreased cortical blood flow at 10 min, without a significant arterial pressure modification. Posterior injection of mannitol 200 mg induced a significant increase in cortical blood flow, although initial values were not reached. Electron microscopy showed thromboses in the glomerular capillaries 35 minutes after venom injection. It is suggested that the precocious effect of this venom on renal cortical blood flow may be instrumental in the development of the renal acute insufficiency induced by Crotalus durissus terrificus venom.     

Feeding behavior and venom toxicity of coral snake Micrurus nigrocinctus (Serpentes: Elapidae) on its natural prey in captivity

The feeding behavior and venom toxicity of the coral snake Micrurus nigrocinctus (Serpentes: Elapidae) on its natural prey in captivity were investigated. Coral snakes searched for their prey (the colubrid snake Geophis godmani) in the cages. Once their preys were located, coral snakes stroke them with a rapid forward movement, biting predominantly in the anterior region of the body. In order to assess the role of venom in prey restraint and ingestion, a group of coral snakes was 'milked' in order to drastically reduce the venom content in their glands. Significant differences were observed between snakes with venom, i.e., 'nonmilked' snakes, and 'milked' snakes regarding their behavior after the bite. The former remained hold to the prey until paralysis was achieved, whereas the latter, in the absence of paralysis, moved their head towards the head of the prey and bit the skull to achieve prey immobilization by mechanical means. There were no significant differences in the time of ingestion between these two groups of coral snakes. Susceptibility to the lethal effect of coral snake venom greatly differed in four colubrid species; G. godmani showed the highest susceptibility, followed by Geophis brachycephalus, whereas Ninia psephota and Ninia maculata were highly resistant to this venom. In addition, the blood serum of N. maculata, but not that of G. brachycephalus, prolonged the time of death of mice injected with 2 LD(50)s of M. nigrocinctus venom, when venom and blood serum were incubated before testing. Subcutaneous injection of coral snake venom in G. godmani induced neurotoxicity and myotoxicity, without causing hemorrhage and without affecting heart and lungs. It is concluded that (a) M. nigrocinctus venom plays a role in prey immobilization, (b) venom induces neurotoxic and myotoxic effects in colubrid snakes which comprise part of their natural prey, and (c) some colubrid snakes of the genus Ninia present a conspicuous resistance to the toxic action of M. nigrocinctus venom.     

Study of Cardiotonic Effect of Venom of the Green Toad Bufo viridis

In experiments on the isolated heart of frogs, cats, and rats, cardiotonic effect of the green toad Bufo viridis Laur. venom was studied. It has been shown that both the venom and the fraction of bufodienolides isolated from it produce an increase of the strength of cardiac contractions and, to a lesser extent, of the heart rate in cold-blooded and warm-blooded animals. A high selectivity of the venom inotropic effect was seen as an increase of the rate characteristics of elevation or reduction of the pressure in the rat heart left ventricle. The venom and bufadienolides increase the frog atrial trabecula contraction without a rise of the slow incoming (calcium) current. A similarity of mechanisms of cardiotonic effects of the venom and of the plant cardiac glycosides is discussed.     

In vivo actions of atraxin, a protein neurotoxin from the venom glands of the funnel-web spider (Atrax robustus)

The effects of atraxin, a neurotoxic protein from the venom glands of the funnel-web spider (Atrax robustus), have been studied in anaesthetized monkeys. At doses of 70 and 80 micrograms kg-1 i.v., atraxin caused respiratory disturbances (dyspnoea and apnoea), and profound alterations in heart rate and blood pressure. These doses also caused salivation, lachrymation, skeletal muscle fasciculation and an elevation in body temperature. Concurrent increases in firing were recorded from the phrenic nerve and from respiratory and other skeletal muscles. It is concluded that atraxin produces the same syndrome in primates as that observed with whole milked male funnel-web venom.     

Ten year cerebrovascular morbidity and mortality in 68 year old men with asymptomatic carotid stenosis.

OBJECTIVE--To study the natural course of carotid artery stenosis detected by ultrasonography. DESIGN--Prospective cohort study. Baseline examination in 1982-3 included ultrasound examination of carotid arteries, measurement of ankle-brachial blood pressure index, and detection of atrial fibrillation by 24 hour ambulatory electrocardiography. SETTING--Malmö, a city in southern Sweden with 230,000 inhabitants. SUBJECTS--470 men aged 68 years randomly selected from the population. MAIN OUTCOME MEASURES--Incidence of stroke and transient ischaemic attack and all cause mortality during 10 years of follow up in relation to carotid stenosis, leg artery disease (ankle-brachial blood pressure index below 0.9), and atrial fibrillation. RESULTS--Fifty men had a stroke; six of these were haemorrhagic. Another 11 had a transient ischaemic attack. Eighteen of the men with carotid stenosis (21.6 events/1000 person years) and 43 of the men with normal carotid arteries (14.8 events/1000 person years) had a stroke or transient ischaemic attack (P = 0.188). Men with atrial fibrillation had an increased rate of cerebrovascular events (36.7/1000 person years (P = 0.048). The highest rate was found in men with asymptomatic disease of the leg arteries (38.6/1000 person years) (P < 0.001). The increased risk of stroke or transient ischaemic attack in this group remained after multivariate analysis (relative risk 2.0; 95% confidence interval 1.1 to 3.7). CONCLUSIONS--In this cohort carotid stenosis was not associated with an increased risk of stroke. Part of this lack of association was explained by the high mortality from ischaemic heart disease in men with severe stenosis. Twenty seven of the 61 cerebrovascular events, however, occurred in men who had normal carotid arteries, normal ankle pressure, and no atrial fibrillation.     

Wasp venom blocks central cholinergic synapses to induce transient paralysis in cockroach prey

The parasitoid wasp Ampulex compressa induces a set of unique behavioral effects upon stinging its prey, the cockroach. It stings into the first thoracic segment inducing 2 to 3 min of transient flaccid paralysis of the front legs. This facilitates a second sting in the cockroach's head that induces 30 min of excessive grooming followed by a 2 to 5-week long lethargic state. In the present study, we examine the immediate effect of the first sting, which is a transient paralysis of the front legs. Using radiolabeled wasps, we demonstrate that the wasp injects its venom directly into the cockroach's first thoracic ganglion. The artificial injection of milked venom into a thoracic ganglion abolishes spontaneous and evoked responses of the motoneurons associated with leg movements. To investigate the physiological mechanism of action of the venom, we injected venom into the last abdominal ganglion of the cockroach, which houses a well-characterized cholinergic synapse. Injected venom abolishes both sensory-evoked and agonist-evoked postsynaptic potentials recorded in the postsynaptic neuron for 2 to 3 min without affecting action potential propagation. Thus, the venom blocking effect has a postsynaptic component that follows the same time course as the transient paralysis induced by the thoracic sting. Finally, injection of a nicotinic antagonist in the front thoracic ganglion induces paralysis of the front legs. We conclude that the transient paralytic effect of the thoracic sting can be mainly accounted for by the presence of a venom active component that induces a postsynaptic block of central cholinergic synaptic transmission.     

Melatonin and the cardiovascular system

Melatonin concentrations in serum, as well as urinary levels of its main metabolite, 6-sulphatoxymelatonin, decrease with age. In the course of aging, the frequency of heart diseases, both acute and chronic, systematically increases. The evidence from the last 10 years suggests that melatonin influences the cardiovascular system. The presence of vascular melatoninergic receptors/binding sites has been demonstrated; these receptors are functionally linked with vasoconstrictor or vasodilatory effects of melatonin. Melatonin can contribute in cardioprotection of the rat heart, following myocardial ischemia. It has been shown that patients with coronary heart disease have a low melatonin production rate, especially those with higher risk of cardiac infarction and/or sudden death. There are clinical data reporting some alterations of melatonin in human stroke and coronary heart disease. The suprachiasmatic nucleus and, possibly, the melatoninergic system may also modulate cardiovascular rhythmicity. Hypercholesterolemia and hypertension are the other age-related symptoms. People with high levels of LDL-cholesterol have low levels of melatonin. It has been shown that melatonin suppresses the formation of cholesterol by 38% and reduces LDL accumulation by 42%. A 10-20% reduction of cholesterol concentration in women using the B-oval pill has been observed. It is a very important because, even a 10-15% reduction in blood cholesterol concentration has bee shown to result in a 20 to 30% decrease in the risk of coronary heart disease. People with hypertension have lower melatonin levels than those with normal blood pressure. The administration of the hormone in question declines blood pressure to normal range. It has been observed that melatonin, even in a dose 1 mg, reduced blood pressure and decreased catecholamine level after 90 min in human subjects. Melatonin may reduce blood pressure via the following mechanisms: 1) by a direct effect on the hypothalamus; 2) as an antioxidant which lowers blood pressure; 3) by decreasing the level of catecholamines, or 4) by relaxing the smooth muscle in the aorta wall.     

Lowering of blood pressure in chronic aortic coarctate hypertensive rats with anti-digoxin antiserum

A marked lowering of arterial blood pressure was observed in chronic aortic coarctate (CAC) hypertensive rats after intravenous administration of anti-digoxin antiserum. The hypotensive effect lasted for about 30 min after dosing. In contrast to the pronounced changes observed following treatment with anti-digoxin antiserum in CAC rats, only a transient pressor effect was observed in both water-and saline-drinking CAC rats following injection of normal goat serum. In addition, a transient depressor effect was observed in normotensive rats after injection of anti-digoxin antiserum. The results of this study provide additional evidence indicating that an endogenous digoxin-like substance may play an important role in the maintenance of chronic low-renin hypertension induced by aortic coarctation.     

Bee Venom and Its Component Apamin as Neuroprotective Agents in a Parkinson Disease Mouse Model

Bee venom has recently been suggested to possess beneficial effects in the treatment of Parkinson disease (PD). For instance, it has been observed that bilateral acupoint stimulation of lower hind limbs with bee venom was protective in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In particular, a specific component of bee venom, apamin, has previously been shown to have protective effects on dopaminergic neurons in vitro. However, no information regarding a potential protective action of apamin in animal models of PD is available to date. The specific goals of the present study were to (i) establish that the protective effect of bee venom for dopaminergic neurons is not restricted to acupoint stimulation, but can also be observed using a more conventional mode of administration and to (ii) demonstrate that apamin can mimic the protective effects of a bee venom treatment on dopaminergic neurons. Using the chronic mouse model of MPTP/probenecid, we show that bee venom provides sustained protection in an animal model that mimics the chronic degenerative process of PD. Apamin, however, reproduced these protective effects only partially, suggesting that other components of bee venom enhance the protective action of the peptide.     

Variations in the effect of clonidine on arterial pressure in rats in the presence of various anesthetics]

The central hypotensive agent, clonidine (30 microgram/kg i.v.) has been injected in normotensive rats anesthetized with various agents. This dose of clonidine elicits usually a biphasic blood pressure response, i.e. a transient increase due to peripheral vasoconstriction, followed by a long lasting decrease. This has been observed in the animals anesthetized with pentobarbitone as well as with urethane. The hypotensive effect is abolished during chloralose, ketamine or Alfatésine anesthesia. These data emphasize that some anesthetics mays particularly modify the effects of centrally acting cardiovascular drugs.     

Transient analysis of cardiopulmonary interactions. II. Systolic events

The etiology of the fall in left ventricular stroke volume (LVSV) and arterial pressure with a negative intrathoracic pressure (NITP) during inspiration is controversial. An increase in LV afterload produced by NITP has been proposed as one explanation but is difficult to evaluate if preload is also altered. To test the hypothesis that a systolic event alone, i.e., a change in LV afterload or contractility, can reduce LVSV during inspiration independent of changes in LV preload, a rapid transient NITP confined to systole was produced by electrocardiogram-triggered phrenic nerve stimulation in eight anesthetized dogs. Intrathoracic descending aortic diameters were measured by sonomicrometry to transduce qualitative changes in aortic transmural pressure. With the airway completely obstructed systolic NITP resulted in a decrease in LVSV (-8.1%, P less than 0.001) but an increase in the systolic anteroposterior (0.54 mm, P less than 0.01) and right-to-left (0.45 mm, P less than 0.01) aortic diameters compared with preceding beat. Similar significant changes were observed with the airway unobstructed. These observations are consistent with an increased afterload imposed on the LV reducing LVSV and egress of blood out of the thorax. Prolonging NITP to include both systole and diastole, a profound fall in LVSV is observed, consistent with the independent influences of systolic and diastolic events combining to diminish LVSV.(ABSTRACT TRUNCATED AT 250 WORDS)     

Initial blood pressure fall on stand up and exercise explained by changes in total peripheral resistance

To elucidate the underlying mechanisms of the initial fall in blood pressure on standing upright from the supine position, we measured the beat-to-beat changes in intra-arterial pressure in eight healthy male subjects in response to standing. Changes in stroke volume, cardiac output, and total peripheral resistance were computed from the pressure waveform using a pulse contour method. To determine possible mechanisms for the changes observed on standing, similar measures were made on passive tilting and a brief (3-s) bout of cycle exercise. Standing elicited a transient 25% (23-mmHg) fall in mean blood pressure as a result of a 36% fall in total peripheral resistance. Head-up tilt elicited a gradual change in haemodynamic parameters, which reached plateau levels in 20-30 s. Cycling elicited a transient 17% (18-mmHg) fall in blood pressure and a 41% fall in total peripheral resistance. In addition, we measured right atrial and esophageal pressures in two subjects on standing and cycling and found a 10- to 15-mmHg rise in right atrial pressure without a corresponding change in esophageal pressure. This points to the cardiopulmonary reflex as the primary effector of peripheral vasodilation, but we cannot exclude the possibility that 1) local metabolic vasodilation and 2) central command-mediated cholinergic vasodilation contributed to the fall in vascular resistance.     

Venom peptide analysis of Vipera ammodytes meridionalis (Viperinae) and Bothrops jararacussu (Crotalinae) demonstrates subfamily-specificity of the peptidome in the family Viperidae

Snake venom peptidomes are valuable sources of pharmacologically active compounds. We analyzed the peptidic fractions (peptides with molecular masses < 10,000 Da) of venoms of Vipera ammodytes meridionalis (Viperinae), the most toxic snake in Europe, and Bothrops jararacussu (Crotalinae), an extremely poisonous snake of South America. Liquid chromatography/mass spectrometry (LC/MS), direct infusion electrospray mass spectrometry (ESI-MS) and matrix-assisted desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) were applied to characterize the peptides of both snake venoms. 32 bradykinin-potentiating peptides (BPPs) were identified in the Crotalinae venom and their sequences determined. 3 metalloproteinase inhibitors, 10 BPPs and a Kunitz-type inhibitor were observed in the Viperinae venom peptidome. Variability in the C-terminus of homologous BPPs was observed, which can influence the pharmacological effects. The data obtained so far show a subfamily specificity of the venom peptidome in the Viperidae family: BPPs are the major peptide component of the Crotalinae venom peptidome lacking Kunitz-type inhibitors (with one exception) while the Viperinae venom, in addition to BPPs, can contain peptides of the bovine pancreatic trypsin inhibitor family. We found indications for a post-translational phosphorylation of serine residues in Bothrops jararacussu venom BPP (S[combining low line]QGLPPGPPIP), which could be a regulatory mechanism in their interactions with ACE, and might influence the hypotensive effect. Homology between venom BPPs from Viperidae snakes and venom natriuretic peptide precursors from Elapidae snakes suggests a structural similarity between the respective peptides from the peptidomes of both snake families. The results demonstrate that the venoms of both snakes are rich sources of peptides influencing important physiological systems such as blood pressure regulation and hemostasis. The data can be used for pharmacological and medical applications.     

The effects of endothelin-1 on the cardiorespiratory physiology of the freshwater trout (Oncorhynchus mykiss) and the marine dogfish (Squalus acanthias).

The aim of the present study was to evaluate the effects of endothelin-l-elicited cardiovascular events on respiratory gas transfer in the freshwater rainbow trout (Oncorhynchus mykiss) and the marine dogfish (Squalus acanthias). In both species, endothelin-1 (666 pmol kg(-1)) caused a rapid (within 4 min) reduction (ca. 30-50 mmHg) in arterial blood partial pressure of O2. The effects of endothelin-1 on arterial blood partial pressure of CO2 were not synchronised with the changes in O2 partial pressure and the responses were markedly different in trout and dogfish. In trout, arterial CO2 partial pressure was increased transiently by approximately 1.0 mmHg but the onset of the response was delayed and occurred 12 min after endothelin-1 injection. In contrast, CO2 partial pressure remained more-or-less constant in dogfish after injection of endothelin-1 and was increased only slightly (approximately 0.1 mmHg) after 60 min. Pre-treatment of trout with bovine carbonic anhydrase (5 mg ml(-1)) eliminated the increase in CO2 partial pressure that was normally observed after endothelin-1 injection. In both species, endothelin-1 injection caused a decrease in arterial blood pH that mirrored the changes in CO2 partial pressure. Endothelin-1 injection was associated with transient (trout) or persistent (dogfish) hyperventilation as indicated by pronounced increases in breathing frequency and amplitude. In trout, arterial blood pressure remained constant or was decreased slightly and was accompanied by a transient increase in systemic resistance, and a temporary reduction in cardiac output. The decrease in cardiac output was caused solely by a reduction in cardiac frequency; cardiac stroke volume was unaffected. In dogfish, arterial blood pressure was lowered by approximately 10 mmHg at 6-10 min after endothelin-1 injection but then was rapidly restored to pre-injection levels. The decrease in arterial blood pressure reflected an increase in branchial vascular resistance (as determined using in situ perfused gill preparations) that was accompanied by simultaneous decreases in systemic resistance and cardiac output. Cardiac frequency and stroke volume were reduced by endothelin-1 injection and thus both variables contributed to the changes in cardiac output. We conclude that the net consequences of endothelin-1 on arterial blood gases result from the opposing effects of reduced gill functional surface area (caused by vasoconstriction) and an increase in blood residence time within the gill (caused by decreased cardiac output.     

Effect of heparin on fibrinogen formation during experimental toxic syndrome of disseminated intravascular coagulation

The formation of circulation components of fibrinogen pool in toxigenic syndrome of disseminated intravascular blood coagulation (DBC-syndrome) caused by the Vipera lebetina turanica venom has been examined by the gel-filtration method. Simultaneously it has been studied what components of fibrinogen pool are removed in paracoagulation tests and with addition of the coagulating enzymes (thrombin, reptilase and the Echis multisguamatus venom) to the plasma. The preliminary heparinization of animals poisoned by Vipera lebetina turanica venom was found to prevent the fibrinogen formation mainly at the fibrin-monomer formation stage. Besides, the effect of polymerization inhibition was revealed in the plasma of such animals.