The effect of gaboon viper (Bitis gabonica) venom on cardiac stroke work in the anaesthetized rabbit

The effect of Bitis gabonica venom administered intravenously in the rabbit at the dose of 0.125 mg/kg (approximately 10% of LD50) has been studied. Venom caused marked changes in cardiovascular parameters principally a precipitous but transient fall in total peripheral resistance and arterial blood pressure. Furthermore in the period occurring between 5 and 30 min after the injection of venom, a transient increase in stroke work was observed as a result of the ejection of an increased stroke volume against a blood pressure which had already returned to normal. Such a transient inotropic effect has also been observed in other small mammals and could 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.     

Factors that determine the hemodynamic response to inhalation anesthetics

The hemodynamic response to inhalation anesthesia is influenced by three factors: 1) the specific drug, 2) the dose, and 3) individual characteristics of the subject. To investigate the importance of these factors on the cardiovascular response, we administered five doses [0, 0.5, 1.0, 1.5, and 2.0 minimum alveolar concentration (MAC)] of enflurane, halothane, and isoflurane to each of six dogs. Twelve hemodynamic variables were measured. For all variables, a change in the dose of each drug produced a consistent effect in each dog. Increases in dose resulted in significant decreases in seven variables [left ventricular ejection fraction, cardiac index (CI), stroke volume index (SVI), mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), left ventricular stroke work index (LVSWI), and heart rate (HR)] and a significant increase in one variable [central venous pressure (CVP)]. In contrast, the response of individual dogs to different drugs was not consistent. For seven variables [MAP, MPAP, LVSWI, CVP, pulmonary capillary wedge pressure (PCWP), end-diastolic volume index (EDVI), and end-systolic volume index (ESVI)], a significant difference in the responses of a dog to two drugs was greater than zero, whereas a significant difference in the response of at least one other dog to the same two drugs was less than zero (discordant dog-drug interactions). Thus, in contrast to the consistency of the cardiovascular response to changes in dose, the hemodynamic response to different drugs was inconsistent among dogs. We also studied the effect of fluid challenge on hemodynamic response at 1.5 or 2.0 MAC of the three drugs given to each dog.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Identification of the cardiac and circulating form of atriopeptin in rabbit

Analysis of peptides purified from high and low molecular weight fractions of rabbit atrial extracts indicates that the sequence of the first 30 residues of rabbit atriopeptigen exhibits 80% homology with the rat peptide, and that the low molecular weight rabbit peptide (28 residues) is identical to rat atriopeptin 28 (AP 28). The effects of infused 1-deaminoarginine8-vasopressin (dAVP) and phenylephrine, volume expansion, and water immersion on AP release into the circulation of the rabbit was studied. Neither dAVP, nor water immersion elevated right atrial pressure (RAP) or plasma AP levels in the anesthetized rabbits. Phenylephrine induced a sustained increase in systemic blood pressure and right atrial pressure which was accompanied by elevated plasma AP immunoreactivity which appeared to be identical to rat AP-28 on HPLC. There is obviously a preferential conservation of the AP sequence, since the C-terminal peptide is exactly the same in rabbit, rat and mouse and differs from human, dog, cow and pig only by the single substitution of an isoleucine for a methionine residue.     

Effects of gastric distension on the cardiovascular system in rainbow trout (Oncorhynchus mykiss)

When animals feed, blood flow to the gastrointestinal tract increases to ensure an adequate oxygen supply to the gastrointestinal tissue and an effective absorption of nutrients. In mammals, this increase depends on the chemical properties of the food, as well as, to some extent, on the mechanical distension of the stomach wall. By using an inflatable nitrile balloon positioned in the stomach, we investigated the cardiovascular responses to mechanical stretch of the stomach wall in rainbow trout (Oncorhynchus mykiss). Distension with a volume equivalent to a meal of 2% of the body mass increased dorsal aortic blood pressure by up to 29%, and central venous blood pressure increased transiently nearly fivefold. The increase in arterial pressure was mediated by an increased vascular resistance of both the systemic and the intestinal circulation. Cardiac output, heart rate, and stroke volume (SV) did not change, and only transient changes in gut blood flow were observed. The increase in arterial pressure was abolished by the alpha-adrenergic antagonist prazosin, indicating an active adrenergic vasoconstriction, whereas the venous pressor response could be the consequence of a passive increase in intraperitoneal pressure. Our results show that mechanical distension of the stomach causes an instantaneous increase in general vascular resistance, which may facilitate a redistribution of blood to the gastrointestinal tract when chemical stimuli from a meal induce vasodilation in the gut circulation. The normal postprandial increase in gut blood flow in teleosts is, therefore, most likely partly dependent on mechanical stimuli, as well as on chemical stimuli.     

The positive inotropic effect of the aqueous extract of Convallaria keiskei in beating rabbit atria

The positive inotropic effect of the aqueous extract of Convallaria keiskei (ACK) and the possible mechanisms responsible for this effect were investigated in beating rabbit atria. ACK significantly increased atrial stroke volume, pulse pressure, and cAMP efflux in beating rabbit atria. The effects were not altered by pre-treatment with staurosporine and diltiazem, a non-selective protein kinase inhibitor and an L-type Ca2+ channel blocker, respectively. In addition, ACK markedly increased the K+ concentration in the beating atria-derived perfusate. Convallatoxin, a well-known digitalis-like cardiac glycosidic constituent of ACK, also increased atrial stroke volume and pulse pressure but did not alter the cAMP efflux level. The increases in atrial stroke volume and pulse pressure induced by convallatoxin were not also altered by pre-treatment with diltiazem. These results suggest that the ACK-induced positive inotropic effect in beating rabbit atria may, at least in part, be due to the digitalis-like activity of convallatoxin.     

Possible involvement of red cell membrane proteins in the hemolytic action of Portuguese Man-of-War toxin.

Glycophorin and the fragments isolated from trypsinizing intact rat, dog, sheep and human red blood cells (rbc's) neutralize the hemolytic action of the Portuguese Man-of-War venom. This action can be blocked by rabbit antisheep hemolysin and phytohemagglutinin, a lectin which preferentially binds to glycophorin. Concanavalin A, which binds to band-3 protein of rbc membranes, does not block the neutralizing action of rbc tryptic fragments or glycophorin. The concentrations of rat, dog, human and sheep glycophorin which half neutralize venom induced hemolysis are inversely and linearly proportional to the hemolytic sensitivities of these rbc's to the venom. These data implicate glycophorin as a possible binding site for the hemolytic component of the Portuguese Man-of-War venom.     

Calcitonin gene-related peptide prevents blood-brain barrier injury and brain edema induced by focal cerebral ischemia reperfusion

Cerebral ischemia is one of the diseases that most compromise the human species. Therapeutic recovery of blood-brain barrier (BBB) disruption represents a novel promising approach to reduce brain injury after stroke. To determine the effects of calcitonin gene-related peptide (CGRP) on the BBB participate in stroke progression, rat cerebral ischemia reperfusion injury was induced by a 2-hour left transient middle cerebral artery occlusion (MCAO) using an intraluminal filament, followed by 46h of reperfusion. CGRP (1μg/ml) at the dose of 3μg/kg (i.p.) was administered at the beginning of reperfusion. Subsequently, 48h after MCAO, arterial blood pressure, infarct volume, water content, BBB permeability, BBB ultrastructure, levels of aquaporin-4 (AQP4) and its mRNA were evaluated. CGRP could reduce arterial blood pressure (P<0.001), infarct volume (P<0.05), cerebral edema (P<0.01), BBB permeability (P<0.05), AQP4 mRNA expression (P<0.05) and AQP4 protein expression (P<0.01). Furthermore, CGRP treatment improved ultrastructural damage of capillary endothelium cells and decreased the loss of the tight junction observed by transmission electronic microscopy (TEM) after 46h of reperfusion. Our findings show that CGRP significantly reduced postischemic increase of brain edema with a 2-hour therapeutic window in the transient model of focal cerebral ischemia. Moreover, it seems that at least part of the anti-edematous effects of CGRP is due to decrease of BBB disruption by improving ultrastructural damage of capillary endothelium cells, enhancing basal membrane, and inhibiting AQP4 and its mRNA over-expression. The data of the present study provide a new possible approach for acute stroke therapy by administration of CGRP.     

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.     

Effects of alpha-1 adrenergic receptor antagonist, terazosin, on cardiovascular functions in anaesthetised dogs

Initially a dose-response curve of phenylephrine was constructed at dose strengths of 1-16 microg/kg in a cumulative manner. Phenylephrine caused a significant rise in the mean arterial pressure, left ventricular systolic pressure, left ventricular contractility, stroke volume and a significant decline in the heart rate. Terazosin was administered in three selected doses of 10, 100 and 300 microg/kg. Following each dose of terazosin, dose-response curve of phenylephrine was constructed. Terazosin, per se, decreased the basal mean arterial pressure, left ventricular systolic pressure, left ventricular contractility and stroke volume significantly in a dose dependent manner with an increase in the heart rate with no significant change in the cardiac output. The baroreflex sensitivity at all the three doses remained unchanged. In conclusion, the present findings support the view that terazosin reduces the blood pressure in a physiologically more favorable manner by maintaining the neural integrity of the cardiovascular system.     

Potential usefulness of renal vasodilators in hypertension and renal disease: SK&F 82526

SK&F 82526 and its enantiomers have been shown to increase renal blood flow and decrease renal vascular resistance in the anesthetized dog. The effect of the racemate on lowering systemic blood pressure in the anesthetized dog and the spontaneously hypertensive rat has been shown to be caused by the R-enantiomer with the S-enantiomer being devoid of significant activity on blood pressure. The mechanism by which the R-enantiomer decreases blood pressure is not systemic vasodilatation or prejunctional inhibition of norepinephrine release but appears to result from a unique stimulation of the postjunctional dopamine receptor. Racemic SK&F 82526 also has been shown to increase renal blood flow in an ischemic model of acute renal failure.     

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.     

Pulmonary vascular changes following air embolism in the dog.

The effect of an intravenous injection of air in a dose of 1 ml/kg body weight was determined in 15 healthy mongrel dogs. In 4 control dogs the mean pulmonary artery pressure rose to 2-3 times the resting values at 30 seconds, and carbon monoxide diffusing capacity and pulmonary capillary blood volume decreased by half. In the animals pretreated either with heparin or with methysergide (antiserotonin group) the results were the same as in the control animals. In the vagotomized dogs, the rise in pulmonary artery pressure was not significant, and the decrease in pulmonary capillary blood volume was of lesser magnitude and shorter duration than in the control and the antiserotonin dogs. It is concluded that the intravenous injection of air in supine dogs causes a transient obstruction of small pulmonary arteries. Evidence is presented to implicate a vagal mechanism in both main aspects of the response, namely the pulmonary artery pressure rise, and the partial obstruction of the pulmonary capillary bed. These studies offer additional explanation of the symptoms of respiratory distress observed in rapid decompression.     

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-1-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 ~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 (~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 ~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.     

Arterial hemodynamics during head-up tilt in conscious dogs

The purpose of this study was to measure the major arterial hemodynamic responses to head-up tilt in the conscious dog. After recovery from surgery for instrumentation, and after habituation to tilt, the dogs were tilted from horizontal to 75 degrees for 5 min. The arterial hemodynamic response after the initial cardiovascular adjustments to the tilt consisted of no change in heart rate and significantly increased arterial blood pressure, with significantly reduced stroke volume and cardiac output. Both renal blood flow and terminal aorta blood flow declined significantly, even more than cardiac output. Muscular exertion was not part of the tilt response because upright standing on the hindlimbs elicited a sustained increase in heart rate and a significantly smaller increase in estimated total peripheral resistance. When compared with the orthostatic response in humans, the increase in arterial pressure was exaggerated in the dogs.     

Effects of enhanced ventricular filling on cardiac pump performance in exercising dogs

The extent to which the normal increase in stroke volume during exercise can be augmented by increasing preload by dextran infusion was studied in seven dogs. Each dog ran 3 min on a level treadmill at mild (3-4 mph), moderate (6-8 mph), and severe (9-13 mph) loads during the control study and immediately after 10% dextran 14 ml/kg iv. During severe exercise dextran-augmented stroke volume (+5.4 ml or 19% vs. exercise without dextran, P less than 0.01) and left ventricular end-diastolic diameter and pressure did not change heart rate, aortic pressure, or maximum derivative of left ventricular pressure but decreased systemic vascular resistance by 16%. Similar increases in stroke volume and preload after dextran occurred during mild and moderate exercise when arterial pressure and heart rate were unchanged or increased and systemic vascular resistance was decreased. Thus altering preload above those levels normally encountered during exercise is a potential mechanism to increase stroke volume and cardiac output.     

In Situ Microparticles Loaded with S-Nitrosoglutathione Protect from Stroke

Treatment of stroke, especially during the first hours or days, is still lacking. S-nitrosoglutathione (GSNO), a cerebroprotective agent with short life time, may help if administered early with a sustain delivery while avoiding intensive reduction in blood pressure. We developed in situ forming implants (biocompatible biodegradable copolymer) and microparticles (same polymer and solvent emulsified with an external oily phase) of GSNO to lengthen its effects and allow cerebroprotection after a single subcutaneous administration to Wistar rats. Arterial pressure was recorded for 3 days (telemetry, n = 14), whole-blood platelet aggregation up to 13 days (aggregometry, n = 58), and neurological score, cerebral infarct size and edema volume for 2 days after obstruction of the middle cerebral artery by autologous blood clots (n = 30). GSNO-loaded formulations (30 mg/kg) induced a slighter and longer hypotension (-10 vs. -56 ± 6 mmHg mean arterial pressure, 18 h vs. 40 min) than free GSNO at the same dose. The change in pulse pressure (-50%) lasted even up to 42 h for microparticles. GSNO-loaded formulations (30 mg/kg) prevented the transient 24 h hyper-aggregability observed with free GSNO and 7.5 mg/kg-loaded formulations. When injected 2 h after stroke, GSNO-loaded microparticles (30 mg/kg) reduced neurological score at 24 (-62%) and 48 h (-75%) vs. empty microparticles and free GSNO 7.5 mg/kg and, compared to free GSNO, divided infarct size by 10 and edema volume by 8 at 48 h. Corresponding implants reduced infarct size and edema volume by 2.5 to 3 times. The longer (at least 2 days) but slight effects on arterial pressures show sustained delivery of GSNO-loaded formulations (30 mg/kg), which prevent transient platelet hyper-responsiveness and afford cerebroprotection against the consequences of stroke. In conclusion, in situ GSNO-loaded formulations are promising candidates for the treatment of stroke.     

Systemic and renal hemodynamic responses to vascular blockade of vasopressin in conscious dogs with ascites

A role for arginine vasopressin has been implicated in the compensatory control of arterial blood pressure in several animal models with reported increases in plasma levels of arginine vasopressin. A threefold elevation in plasma vasopressin has been reported in conscious dogs following constriction of the inferior vena cava. In the present study, infusion of the arginine vasopressin antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-O-methyltyrosine] Arg8-vasopressin into conscious dogs with chronic caval constriction did not decrease mean arterial blood pressure. However, the dose of infused antagonist completely blocked the pressor response to 2 micrograms of exogenous vasopressin. Also the antagonist produced no effect on heart rate, plasma renin activity, or urinary volume and electrolyte excretions. A slight, transient increase (P less than or equal to 0.05) was observed in creatinine clearance and in PAH clearance following antagonist infusion, suggesting a possible decrease in renal vascular resistance. These data suggest that the direct vasoconstrictor actions of vasopressin contribute minimally, if at all, to blood pressure maintenance following chronic caval constriction. Alternatively, blockade of endogenous vasopressin receptors at the level of peripheral arterioles may have resulted in no depressor response due to a masking of this response by other compensatory hormonal and neural pressor systems.     

Acid-base, plasma lactate and glucose changes in the rabbit following administration of Gaboon viper (Bitis gabonica) venom

The acid-base and metabolic effects of Bitis gabonica venom administered intravenously to the anaesthetised rabbit were studied. Doubling doses of venom from 0.125 mg/kg to 1.0 mg/kg were used. Venom caused progressive and significant increases in plasma glucose and plasma lactate levels although oxygen consumption only became significantly lower after the fourth dose. Standard base excess (SBE) became significantly more negative after the third dose of venom and the fall in pH became significant at the same point. The results indicate that venom induces a metabolic acidosis in the rabbit and because the acidosis occurs in the absence of any fall in arterial PO2, it cannot be considered a consequence of impaired pulmonary ventilation. The reduction in oxygen uptake is likely to occur at a cellular level with a shift from aerobic to anaerobic metabolism hence the increase in plasma lactate levels. However, the magnitude of the acidosis is unlikely to be the principal cause of death under experimental conditions.