Effect of an opiate antagonist (naloxone) and an agonist/antagonist (nalbuphine) in primate hemorrhagic shock: relationship to catecholamine release

Recent evidence has suggested a relationship between the endogenous opioid peptides and the pathophysiology of various shock states. In the present study, we investigated the relationship between the effectiveness of naloxone (an opiate antagonist) and nalbuphine (an opiate agonist/antagonist), and the changes in circulating levels of catecholamines in the nonhuman primate subjected to hemorrhagic shock. Plasma levels of catecholamines were measured using high-performance liquid chromatography (HPLC) during hemorrhagic shock in 15 female baboons. Plasma levels of both epinephrine and norepinephrine increased significantly during hemorrhagic shock (p less than 0.05), which correlated with an increase in heart rate. Bolus administration of naloxone (5 mg/kg) significantly increased both plasma epinephrine (p less than 0.01) and norepinephrine (p less than 0.05) over shock levels along with a transient but significant increase in cardiac output (p less than 0.05) and mean arterial pressure (p less than 0.05), and a significant decrease in heart rate (p less than 0.05). Improvements in hemodynamics were maintained with a constant infusion of naloxone (5 mg/kg/hr), which also caused a further significant increase in plasma epinephrine (p less than 0.01). Administration of a single bolus of the opiate agonist/antagonist nalbuphine (5 mg/kg) dramatically decreased cardiac output and mean arterial pressure and had no effect on circulating catecholamines. Our results suggest that (1) the beneficial action of high-dose naloxone in primate hemorrhagic shock may be attributable in part to a drug-induced increase in circulating endogenous catecholamines; and (2) the failure of high-dose nalbuphine to improve cardiovascular function may be related to its partial agonist (cardiodepressant) properties at higher doses.     

Pressor effect of nalbuphine in hemorrhagic shock is dependent on the sympathoadrenal system

Nalbuphine, an analgesic with opiate agonist and antagonist properties, increases heart rate, mean arterial pressure (MAP), and cardiac function following a moderate hemorrhage in the rat. The interaction between opiate receptors and the sympathoadrenal system was examined in control, beta receptor-blocked, and adrenal-demedullated animals. MAP and heart rate were measured continuously in chronically instrumented conscious animals. Hemorrhage decreased MAP in the control group by 50%, and nalbuphine (1 mg/kg) returned this to prehemorrhage values within 5 min. MAP remained significantly greater in the nalbuphine-treated animals for 120 min. Heart rate fell with hemorrhage and increased above prehemorrhage values in the nalbuphine-treated animals. The pressor response to nalbuphine was abolished in both beta-blocked and adrenal-demedullated animals. Plasma catecholamines were not significantly elevated in the nalbuphine-treated as compared to control animals, which suggests that nalbuphine effects do not result from an enhancement of central mediated sympathoadrenal discharge. The opiate receptor antagonist naloxone, in a concentration that was not by itself effective in alleviating the hypotensive effects of hemorrhage, prevented the pressor response with nalbuphine. These results suggest that nalbuphine's beneficial effects in hemorrhagic shock depend on an intact sympathoadrenal system and on an interaction with opiate receptor sites, possibly in the heart.     

Opiate receptor antagonism in right-sided congestive heart failure. Naloxone exerts salutary hemodynamic effects through its action on the central nervous system

Opiate receptor inhibition causes adrenergic receptor-mediated increases in aortic pressure, cardiac output, and left ventricular contractile function in right heart failure. To study whether the effects of opiate receptor inhibition are mediated by means of an action on the central opiate system, we administered equimolar doses of naloxone hydrochloride and naloxone methobromide (MeBr) and normal saline to heart failure dogs. Chronic stable right heart failure was produced by progressive pulmonary artery constriction and tricuspid valve avulsion. Naloxone hydrochloride caused an increase in mean aortic pressure, cardiac output, left ventricular dP/dt and dP/dt/P, plasma catecholamines, and regional blood flows to the myocardium, quadriceps muscle, kidneys, and splanchnic beds. Plasma beta-endorphin and adrenocorticotropin also increased. In contrast, neither normal saline nor naloxone MeBr (which does not cross the blood-brain barrier) affected the systemic or regional hemodynamics or neurohormones. Naloxone hydrochloride was also administered to anesthetized heart failure dogs. Pentobarbital anesthesia removed cortical perception of nociceptive stimulation, reduced the increase in plasma epinephrine, and abolished vasodilation in skeletal muscle that occurred in conscious dogs after naloxone hydrochloride administration but had no major effects on responses of plasma norepinephrine, systemic hemodynamics, or other regional blood flows to opiate receptor inhibition. Naloxone hydrochloride had no effect in sham-operated dogs. The results indicate that the hemodynamic effects of naloxone are mediated by an action within the central nervous system. Furthermore, since pentobarbital anesthesia did not markedly alter the hemodynamic responses to naloxone hydrochloride, the acute salutary effects of opiate receptor inhibition probably are not caused by removal of the antinociceptive effect of endogenous opioids in heart failure.     

Short-term effects of naloxone hemodynamics and baroreflex function in conscious dogs with pacing-induced congestive heart failure

Objective. The purpose of this study was to determine the effects of naloxone on systemic hemodynamics and reflex function in dogs with congestive heart failure induced by rapid pacing.Background. We have shown previously that naloxone, an opiate receptor antagonist, improves cardiac output, aortic blood pressure, systolic performance and the baroreflex function in conscious dogs with chronic right-sided congestive heart failure. However, whether endogenous opioids also play a role in mediating the reduction of myocardial and baroreflex function in animals with left heart failure remains controversial.Methods. We administered naloxone (1 mg/kg body weight) and normal saline solution to 15 dogs with pacing-induced congestive heart failure (225 beats/min for 8 weeks) and 11 control dogs. In addition to systemic hemodynamic measurements, the slope of pressure-area relation obtained from echocardiography with intravenous bolus injection of phenylephrine was taken as a load-independent index of myocardial contractility. Baroreflex function was estimated by the slope of the regression line relating systolic aortic pressure and RRE interval.Results. Plasma beta-endorphin levels were elevated in dags with congestive heart failure. Naloxone administration increased heart rate, mean aortic pressure, first derivative of left ventricular pressure, cardiac output and myocardial contractility in pacing-induced congestive heart failure. These changes correlated significantly with basal plasma beta-endorphin levels and were accompanied by increases in plasma beta-endorphin and catecholamines after naloxone administration. However, unlike the hemodynamic and cardiac effects of naloxone, baroreflex function did not change after naloxone in dogs with congestive heart failure.Conclusions. The increase in basal plasma beta-endorphin suggests that the endogenous opiate system is activated in lef-tsided congestive heart failure. Because naloxone improves the systemic hemodynamics and myocardial contractile function under this condition, the endogenous opioids appear to play an important role in mediating the myocardial depression that occurs in heart failure. However, the endogenous opiate system has no apparent effect on the regulation of baroreflex control in heart failure induced by rapid pacing.     

Role of the autonomic nervous system in mediating the response to naloxone in canine hemorrhagic shock

When the opiate antagonist naloxone is administered to anesthetized dogs subjected to hemorrhagic shock, there is a transient decrease in heart rate and sustained increases in mean arterial pressure, maximum left ventricular dp/dt, and cardiac output. Surgical cardiac denervation and pharmacologic blockade of autonomic receptors were employed to investigate the mechanisms of these two responses. The transient bradycardia was prevented by beta-adrenergic receptor blockade or cardiac denervation. The sustained response was unaffected by cardiac denervation, attenuated by either alpha- or beta-adrenergic receptor blockade, and potentiated by cholinergic receptor blockade. Naloxone had no significant effect on plasma catecholamines. The sustained hemodynamic response to naloxone appears to have two components: there is an increase in parasympathetic stimulation which modestly attenuates the adrenergic component of the response. The adrenergic stimulation of the heart after naloxone administration appears to result from potentiation of existing adrenergic stimulation and not from increased sympathoadrenal discharge. These sustained sympathetic and parasympathetic responses appear to result from the action of naloxone at a myocardial site.     

Morphine depression of myocardial function

A modified Langendorff rat heart preparation with an isolated working rat heart was used to establish the presence of opiate receptors in the myocardium and to demonstrate the effects of an opiate agonist on myocardial function in the absence of neuronal and humoral factors. Twenty-five Sprague-Dawley rats weighing 400-500 gm were anesthetized and had their hearts excised and attached to the Langendorff perfusion apparatus. After a 30 min control period, the Krebs-Henseleit Buffer (KHB) perfusion solution was altered by the addition of 0.9% NaCl (S) or morphine sulfate (MS), which resulted in a final concentration of 2 X 10(-4) M or 3 X 10(-4) M MS in the KHB. Temperature, preload, and afterload were kept constant while heart rate (HR), cardiac output (CO), and aortic dP/dtmax were measured. Significant dose-related depression of HR, CO, and less significantly, aortic dP/dtmax were demonstrated. The data suggest that opiate receptors are present in the myocardium and that morphine sulfate directly effects the myocardium causing a significant decrease in HR, CO, and aortic dP/dtmax. These changes are a result of opiate receptor agonism, which seems to be primarily a negative chronotropic effect and might explain the mechanism for the role of endogenous opiates during shock.     

Acute hemodynamic effects of ethanol in conscious spontaneously hypertensive and normotensive rats

This study investigated the differential hemodynamic effects of small to high doses of ethanol in conscious age-matched spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (WKYs). Changes evoked by ethanol (0.25, 0.5, or 1 g/kg, i.v.) or equal volume of saline in mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), and total peripheral resistance (TPR) were followed for 90 min in the two rat strains. The baseline MAP (163 +/- 4 vs. 113 +/- 2 mm Hg) of SHRs was significantly (p < 0.05) higher, compared with WKYs due mainly to the presence of an elevated TPR 13.82 +/- 0.12 vs. 2.51 +/- 0.09 mm Hg/ml/min/100 g, p < 0.05) in SHRs. In both rat strains, all doses of ethanol produced immediate increases in MAP at 1 min, after which the MAP responses varied and depended on the rat strain and dose of ethanol used. In WKYs, 0.25 g/kg ethanol had no effect on MAP, but caused significant decreases in CO and SV and increased HR. Ethanol (0.5 and 1 g/kg) produced a short-lived (10 min) and dose-related increase in MAP. The higher dose (1 g/kg) of ethanol elicited significant (p < 0.05) increases in TPR that were counterbalanced by concomitant decreases in CO and SV. In SHRs, the two higher doses (0.5 and 1 g/kg) of ethanol elicited significant (p < 0.05) decreases and increases in MAP, respectively, compared with control (saline-treated) values. The pressor response to the 1 g/kg dose of ethanol was associated with an increase in TPR that achieved a statistical significance (p < 0.05) at 50 and 80 min after ethanol administration. HR was significantly (p < 0.05) reduced by the two higher doses of ethanol, whereas SV and CO were not changed. Blood ethanol concentrations measured 10, 30, and 60 min after ethanol administration were similar in SHRs and WKYs. These findings suggest that acute administration of ethanol to conscious rats elicits hemodynamic responses that are strain- and dose-dependent. In contrast to a short-lived and dose-related pressor response in WKYs, ethanol (0.5 and 1 g/kg) elicited opposite and longer lasting effects on MAP (decreases and increases, respectively) in SHRs. In both rat strains, the pressor response to the higher dose of ethanol was associated with an increase in TPR; an effect that was compromised by a concomitant decrease in CO in WKYs but not SHRs.     

Atriopeptin III does not alter cardiac performance in rats

The effects of atriopeptin III (APIII) on systemic haemodynamics were examined in 12 anaesthetized rats. Five minutes following intravenous injection (i.v.) of 10 micrograms/kg APIII, cardiac output CO, measured by electromagnetic flowmetry, stroke volume and mean arterial pressure (MAP) decreased by 14, 13 and 8% (P less than 0.05), respectively, and total peripheral resistance (TPR) increased by 10% (P less than 0.05). Heart rate (HR) and left ventricular end-diastolic pressure (LVEDP) did not change. In order to examine cardiac performance, whole blood was infused into three groups of 12 rats each receiving either no injection, APIII (10 micrograms/kg i.v.) or APIII (10 micrograms/kg i.v.) plus a continuous infusion of phenylephrine to increase MAP to pre-injection levels. Cardiac performance curves did not differ among the three groups. These data indicate that the immediate decreases in MAP and CO produced in rats by a maximum natriuretic bolus dose of APIII were not mediated by a negative myocardial inotropic effect.     

Sinoaortic denervation does not increase cardiovascular/endocrine responses to stress.

Sinoaortic baroreceptor denervation is reported to produce exaggerated centrally derived cardiovascular and endocrine responses. We examined the effect of sinoaortic denervation (SAD) on the cardiovascular and endocrine responses to two acute stressors, footshock and immobilization, in male Sprague-Dawley rats. Parameters measured were mean arterial pressure (MAP), heart rate (HR) and plasma levels of oxytocin (OT) and vasopressin (VP). Baseline MAP was elevated in the SAD group (approximately 25 mm Hg) and footshock stress increased arterial pressure equivalently in both groups. This stress caused tachycardia and increased plasma OT, with a tendency for the SAD group to show blunted responses. Immobilization increased HR but caused no change in MAP and no significant difference between the groups. This form of stress also increased plasma OT, and again the SAD group showed a diminished response. Plasma VP was not significantly altered by either stressor. The results of these studies indicate that SAD does not uniformly increase the cardiovascular and endocrine responses to all stressors or centrally derived stimuli. These results also suggest that the lack of an increase in plasma VP is not related to baroreceptor-mediated inhibition of secretion under stressful conditions.     

Alterations in systemic haemodynamics induced by atriopeptin III

The mechanism of the hypotensive response to the intravenous administration of atriopeptin III was investigated in rats of the Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) Okamoto strains. Cardiac performance and the systemic haemodynamic response to acute volume loading were evaluated before and during atriopeptin infusion. Cardiac output was measured by a thermo-dilution technique in conscious rats, and left ventricular pressures with differential (dP/dt) calculations were obtained in anaesthetized animals. Bolus injections followed by a 1-h continuous infusion of atriopeptin caused a progressive decrease in mean arterial pressure (MAP) and cardiac output with no significant change in heart rate. In addition there was a transient decrease, maximal at 5 min, and a subsequent increase in peripheral resistance. Atriopeptin did not alter the maximal cardiac output achieved following acute volume expansion. In the anaesthetized animals, bolus injection with a subsequent 15-min continuous infusion of atriopeptin III significantly reduced left ventricular pressures, dP/dt and mean arterial pressure. Volume expansion fully restored intraventricular pressures and dP/dt while increasing mean arterial pressure toward baseline. We conclude that the steady decrease in mean arterial pressure produced by atriopeptin III is due to a decrease in cardiac output secondary to a fall in stroke volume caused by a lowered filling pressure.     

丹参提取物对心力衰竭模型大鼠心功能及心肌细胞凋亡的影响

目的观察丹参提取物对心力衰竭模型大鼠心功能及心肌细胞凋亡的影响。方法选取Wistar雄性大鼠50只,建立心力衰竭模型,其中假手术组10只,模型组、低剂量组(0.1 mL/kg)、中剂量组(0.3 mL/kg)、高剂量组(0.5 mL/kg)各10只,比较各组动脉收缩压(SAP)、平均动脉压(MAP)、心率(HR)、左心室收缩压(LVSP)。心肌病理组织染色观察心肌细胞凋亡情况,检测ColⅠ、ColⅢ、p53、磷酸化细胞外调节蛋白激酶(p-ERK)、磷酸化c-Jun氨基末端激酶(p-JNK)蛋白表达情况。结果与模型组相比,假手术组、低剂量组、中剂量组、高剂量组HR、LVSP、SAP、MAP均升高,ColⅠ、ColⅢ、心肌细胞凋亡率、p-ERK、p-JNK均降低,假手术组、中剂量组p53水平均降低,差异均有统计学意义(P<0.05)。与假手术组相比,低剂量组、高剂量组HR、LVSP、SAP、MAP降低,ColⅠ、ColⅢ、心肌细胞凋亡率、p53、p-ERK、p-JNK升高(P<0.05)。假手术组与中剂量组HR、LVSP、SAP、MAP、ColⅠ、ColⅢ、心肌细胞凋亡率、p53、p-ERK、p-JNK比较,差异无统计学意义(P>0.05)。高剂量组、低剂量组HR、LVSP、SAP、MAP低于中剂量组(P<0.05),ColⅠ、ColⅢ、心肌细胞凋亡率、p53、p-ERK、p-JNK高于中剂量组(P<0.05)。结论丹参提取物能改善大鼠心功能,通过调控p53、p-ERK、p-JNK蛋白表达,抑制心肌细胞凋亡,为临床应用提供理论依据。     

静脉注射艾司洛尔对冠状动脉分流术后心脏功能的影响

目的 观察静脉注射艾司洛尔对心脏功能的影响。方法 通过飘浮导管动态监测25例冠状动脉旁路移植术后发生快速性室上性心律失常患者,记录返监护室时(简称T1)、应用艾司洛尔前(简称T2)、应用艾司洛尔后2、10、60 min(简称T3、T4、T5)的心率、平均动脉压、心排量、每搏输出量、肺毛嵌压等指标的变化。结果 静脉注射艾司洛尔后心率显著下降,肺毛嵌压明显升高;平均动脉压T3、T4、T5较T2显著下降,与T1相比无明显变化;心排量T4、T5较T2显著下降,与T1相比亦无明显变化;每搏输出量T3、T4、T5较T2明显升高;观察过程中患者无低灌注情况发生,循环状况维持稳定。结论 静脉注射艾司洛尔治疗冠状动脉旁路移植术后快速性室上性心律失常是安全有效的。     

Autonomic control of the diurnal variation in arterial blood pressure and heart rate in spontaneously hypertensive and Wistar-Kyoto rats

The relative influences of sympathetic and parasympathetic neural modulation on mean arterial pressure (MAP) and heart rate (HR), and their respective variabilities, were studied in young spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). An on-line computerized system was used for continuous intra-arterial measurements of MAP and HR in unrestrained rats. In addition, the autonomic nervous control of MAP and HR was studied in ageing SHR and WKY. Both WKY and SHR showed diurnal rhythms with regard to MAP and HR. The MAP variability was higher in SHR than in WKY during both daytime (inactive) and night-time (active), and did not change in response to either beta 1-adrenoceptor- or cholinergic blockade. Structural vascular changes, with a resultant increase in reactivity, may explain the elevated MAP variability in SHR. HR variability was clearly reduced in SHR; this was not influenced by vagal blockade, whereas HR variability was significantly reduced in WKY. This pattern is suggested to be due to a reduced tonic vagal discharge in SHR, as part of a persistent, mild defence reaction. The initial reduction in vagal activity will in turn eliminate vagally mediated tachycardias. Furthermore, administration beta 1-blockade to SHR of different ages caused a greater fall in MAP and HR than in WKY, indicating an increased dependence upon the sympathetic nervous system in SHR with age.     

The effect of docarpamine, a dopamine pro-drug, on blood pressure and catecholamine levels in spontaneously hypertensive rats

We studied the effects of bolus intravenous injection of the dopamine prodrug, docarpamine (200 microg/kg), on mean arterial pressure (MAP) and heart rate (HR) in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs). In WKY rats (n=18), MAP and HR increased 5 min after docarpamine and then returned to baseline levels within 15 min. In contrast, in SHRs (n=15), MAP and HR gradually decreased, reaching a nadir 20 min after injection. Five min after docarpamine, plasma dopamine and 3,4-dihydroxy phenyl acetic (DOPAC) levels increased in both WKY rats (n=5) and SHRs (n=5). The docarpamine-induced changes in MAP and HR in both rat strains (n=5/strain) were blocked by the D1-like antagonist, SCH23390. alpha-Adrenergic (n=4) and vasopressin V1 (n=3) receptor blockade also abrogated the effects of docarpamine in WKY rats. We conclude that docarpamine differentially affects MAP and HR in WKY and SHRs. In SHRs, the depressor and bradycardiac effects of docarpamine are mediated by D1-like receptors. In WKY rats, the pressor and tachycardiac responses are caused by an interaction among D1-like, alpha-adrenergic, and V1 receptors.     

Sexually dimorphic hemodynamic effects of intragastric ethanol in conscious rats

This study investigated the gender-related differences in hemodynamic effects of small to moderate doses of intragastrically (i.g.) administered ethanol in conscious rats. Changes evoked by ethanol (0.25, 0.5 or 1 g/kg) in mean arterial pressure (MAP), heart rate, cardiac index (CI), stroke volume (SV), and total peripheral resistance (TPR) were followed for 90 min in age-matched male and female Sprague-Dawley rats. Baseline values of MAP (121+/-2 vs. 124+/-2 mm Hg) were similar whereas CI (55+/-2 vs. 43+/-2 ml/min/100 g) and TPR (2.2+/-0.1 vs. 3.0+/-0.1 mm Hg/ml/min/100 g) were significantly (P<0.05) higher and lower, respectively, in female compared with male rats. In male rats, the middle dose (0.5 g/kg) of ethanol caused a slight increase in MAP due to significant (P<0.05) increases in CO whereas the other two doses (0.25 and 1 g/kg) had no effect on MAP. In female rats, MAP was not affected by ethanol (0.25 and 0.5 g/kg) and showed a significant reduction by the higher dose (1 g/kg) that was associated with decreases in CO and SV while TPR did not change. The hypotensive effect of ethanol (1 g/kg) in female rats started after 50 min, was maximal (13+/-1.7 mm Hg) at 70 min and remained so for the remaining 20 min of the study. Blood ethanol concentrations were similar in male and female rats. These findings suggest that the hemodynamic responses to i.g. ethanol are gender-related and that ethanol-evoked hypotension in female rats appears to involve a reduction in cardiac output.     

Central nervous system is involved in the cardiovascular responses to naloxone in canine endotoxic but not hemorrhagic shock

We used naloxone to investigate the role of central nervous system opiate receptors in the cardiovascular depression of canine hemorrhagic and endotoxic shock. Shock was induced by bleeding dogs into a reservoir to achieve and maintain a mean arterial pressure (MAP) of 45 mmHg for 30 min; at 30 min the reservoir was clamped and the animals were treated with intracerebroventricular (ICV) perfusion of naloxone 0.1 mg/kg (n = 5) or artificial CSF (n = 5) for 30 min. Endotoxemic shock was induced by the iv injection of E. coli endotoxin 1 mg/kg; 15 min later the animals were given naloxone 0.1 mg/kg (n = 5) or artificial CSF (n = 5) ICV for 30 min. ICV naloxone significantly increased MAP, cardiac output (CO), and left ventricular performance (LV dP/dt max) compared to artificial CSF in canine endotoxic shock but not hemorrhagic shock. Naloxone 0.1 mg/kg (n = 5) given into the cisterna magna failed to significantly improve MAP, CO, or LV dP/dt max in dogs subjected to reservoir hemorrhagic shock for 60 min compared to artificial CSF (n = 5). These results are compatible with opiate-receptor-mediated central cardiovascular depression in endotoxic shock and peripheral cardiovascular depression in hemorrhagic shock. Accordingly, the sites of action of naloxone are mainly central in endotoxic shock and peripheral in hemorrhagic shock.     

Naloxone does not alter haemodynamics in cirrhosis. Studies in humans and rats

In order to test the hypothesis that endogenous opioids may mediate some of the circulatory derangements in cirrhosis, we studied the haemodynamic effects of naloxone, an opioid antagonist, in patients and in a rat model of biliary cirrhosis. In 9 patients with alcoholic cirrhosis and 5 control patients without significant liver disease, cardiac output, systemic vascular resistance, mean arterial pressure, heart rate, hepatic venous pressures and O2 content, hepatic and azygos blood flows and serum catecholamines were measured before and 30 min after naloxone 3.2 mg i.v. bolus. No significant changes were observed in either group of patients. Similarly in 16 conscious rats, 8 sham-operated and 8 with cirrhosis due to bile duct ligation, cardiac output, systemic vascular resistance, mean arterial pressure, heart rate, and splanchnic organ blood flows were measured by radioactive microspheres, before and 20 min after naloxone 1 mg/kg i.v. bolus. No significant changes were observed in either group. We failed to detect any evidence that endorphins are involved in tonic haemodynamic control in cirrhosis.     

Effects of calcium channel blockade on the hemodynamic responses to endothelin infusion in conscious sheep

The hemodynamic responses to bolus injection of endothelin I (ET) at 5, 15, and 50 micrograms were examined in conscious sheep (n = 5) before and after infusion of nisoldipine at 25 micrograms/kg/h. Endothelin produced dose-dependent increases in mean arterial pressure (MAP + 87 +/- 6 mm Hg at 50 micrograms) and calculated total peripheral resistance (CTPR + 54 +/- 15 mm Hg/L/min at 50 micrograms) and decreases in heart rate (HR - 34 +/- 6 beats/min at 50 micrograms) and cardiac output (CO - 2.6 +/- 0.3 L/min at 50 micrograms) but no change in stroke volume (SV). Nisoldipine attenuated (P less than .05) the endothelin-induced changes in MAP (+26 +/- 3 mm Hg at 5 micrograms) and CTPR (+13.0 +/- 2.1 mm Hg/L/min at 50 micrograms), but not the fall in heart rate or cardiac output. These data are compatible with the hypothesis that vasoconstrictor effects of ET in sheep are in part dependent on influx of calcium through L-type channels.     

Cardiovascular profile after intravenous injection of Africanized bee venom in awake rats

The manifestations caused by Africanized bee stings depend on the sensitivity of the victim and the toxicity of the venom. Previous studies in our laboratory have demonstrated cardiac changes and acute tubular necrosis (ATN) in the kidney of rats inoculated with Africanized bee venom (ABV). The aim of the present study was to evaluate the changes in mean arterial pressure (MAP) and heart rate (HR) over a period of 24 h after intravenous injection of ABV in awake rats. A significant reduction in basal HR as well as in basal MAP occurred immediately after ABV injection in the experimental animals. HR was back to basal level 2 min after ABV injection and remained normal during the time course of the experiment, while MAP returned to basal level 10 min later and remained at this level for the next 5 h. However, MAP presented again a significant reduction by the 7th and 8th h and returned to the basal level by the 24th h. The fall in MAP may contribute to the pathogenesis of ATN observed. The fall in MAP probably is due to several factors, in addition to the cardiac changes already demonstrated, it is possible that the components of the venom themselves or even substances released in the organism play some role in vascular beds.     

Consequences of opiate agonist and antagonist in myocardial ischaemia suggest a role of endogenous opioid peptides in ischaemic heart disease.

OBJECTIVE: The aim was to evaluate the effects of an opiate agonist (U50,488H) and an opiate antagonist (naloxone) in myocardial ischaemia. METHODS: A left thoracotomy was performed and the left coronary artery was ligated in adult Sprague-Dawley rats of either sex (350-400 g). Blood pressure, heart rate and electrocardiogram were measured before and after injections of U50,488H or naloxone and throughout the 30 min postligation period. RESULTS: Following coronary artery occlusion, all rats in the control group developed arrhythmias, bradycardia, and hypotension. U50,488H potentiated and naloxone attenuated the ischaemia induced arrhythmias, bradycardia, and hypotension. CONCLUSIONS: The potentiating and blocking effects of U50,488H and naloxone, respectively, suggest that endogenous opioid peptides are involved in the pathophysiology of myocardial ischaemia and play an important role in ischaemic heart disease.