Systemic hemodynamic effects of dopamine, (+/-)-dobutamine and the (+)-and (-)-enantiomers of dobutamine in anesthetized normotensive rats

The hemodynamic effects of dopamine, (+/-)-dobutamine (racemic mixture) and the (+)- and (-)-enantiomers of dobutamine were evaluated in anesthetized normotensive rats. Dopamine and (+/-)-dobutamine produced hemodynamic effects in anesthetized rat that were qualitatively similar to those reported for these compounds in man. The increase in cardiac output produced by dopamine and (+/-)-dobutamine was due mainly to an increase in stroke volume, with heart rate being only minimally affected. Dopamine produced a large increase in mean arterial pressure and slightly increased total peripheral vascular resistance, whereas (+/-)-dobutamine only modestly increased blood pressure and significantly reduced total peripheral resistance. The (-)-enantiomer of dobutamine, which possesses mainly alpha 1-adrenoceptor agonist activity, produced marked increases in cardiac output, stroke volume, total peripheral resistance and mean arterial pressure, but did not significantly increase heart rate. In contrast, (+)-dobutamine, which possesses predominantly beta 1-and beta 2-adrenoceptor agonist activity, elicited only a modest increase in cardiac output which was due entirely to increased heart rate since stroke volume was not increased. Total peripheral vascular resistance and mean arterial blood pressure were both reduced by (+)-dobutamine, characteristic of a beta-adrenoceptor agonist. The increase in cardiac output and blood pressure produced by (+/-)-dobutamine, but not the positive chronotropic effect, were significantly inhibited by alpha 1-adrenoceptor blockade with prazosin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Salutary effects of nitrendipine, a new calcium entry blocker, in hemorrhagic shock

Intracellular accumulation of calcium is thought to play an integral role in the progression of ischemic injury and cell death. We infused the calcium entry blocker, nitrendipine (1.5 micrograms/kg per min), into cats in order to investigate the importance of extracellular Ca2+ influx during hemorrhagic shock. Nitrendipine proved to be a potent hypotensive agent in sham shock cats when infused over a 4 h period (156 +/- 9 to 90 +/- 5 mm Hg) (P less than 0.01). However, in hemorrhaged animals, nitrendipine treatment maintained the post-reinfusion MABP at a significantly higher (P less than 0.01) value than untreated controls (79 +/- 5 vs. 51 +/- 4 mm Hg, respectively). Superior mesenteric artery flow (SMAF) for hemorrhaged animals treated with nitrendipine was significantly higher (9.8 +/- 1.4 ml/min per kg) (P less than 0.01) than that for untreated cats (4.2 +/- 0.4 ml/min per kg), at 2 h post reinfusion. There was no significant increase in SMAF during oligemia in the nitrendipine-treated animals. Nitrendipine was also found to significantly retard the appearance of cathepsin D in the plasma of hemorrhaged cats as well as reduce plasma proteolysis to values not significantly different from sham shock animals. Furthermore, myocardial depressant factor (MDF) activity in the plasma of nitrendipine-treated shock cats was not significantly different from sham shock animals, while the plasma MDF activity for shock cats receiving vehicle increased 3-fold (P less than 0.001). The beneficial effects for nitrendipine in hemorrhagic shock are likely due to both its vasodilator function and its ability to reduce intracellular Ca2+ accumulation during ischemia, thereby reducing disruption of cell membrane systems.     

Salutary effects of prostacyclin in endotoxic shock

Endotoxin shock was induced in anesthetized cats with E. coli endotoxin (5 mg/kg, i.v.) This produced a severe decline in mean arterial blood pressure and a marked decrease in superior mesenteric artery flow (SMAF) within 1 h. The plasma activity of cathepsin D, a lysosomal protease, increased 6-fold by 2 h. At 5 h, myocardial depressant factor (MDF), a toxic of 0.75 nmol.kg-1.min-1 dilated the splanchnic circulation and significantly increased SMAF. In addition, PGI2 almost completely prevented the accumulation of cathepsin D and MDF in the circulating blood of cats given endotoxin. These findings suggest that PGI2 exerts a variety of beneficial actions in endotoxin shock including vasodilation and stabilization of lysosomal membranes. In addition, PGI2 is known to prevent platelet aggregation and suppress thromboxane formation, two additional effects that may be of positive survival value in endotoxin shock.     

Salutary consequences of blockade of platelet activating factor in hemorrhagic shock

We studied the effects of a potent, specific platelet activating factor (PAF) antagonist, CV-6209, in a murine model of hemorrhagic shock. Hemorrhaged rats treated with CV-6209 (1 mg/kg) maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving either 0.9% NaCl or a lower dose (0.2 mg/kg) of CV-6209 (final MABP 88 +/- 4 vs. 57 +/- 4, vs. 61 +/- 7 mm Hg, respectively). CV-6209 (1 mg/kg) also significantly attenuated the increase in plasma cathepsin D activity following hemorrhage compared with hemorrhaged rats receiving only its vehicle (i.e. 0.9% NaCl). CV-6209 (1 mg/kg) also significantly decreased the plasma accumulation of free amino-nitrogen compounds and the plasma activity of a myocardial depressant factor (MDF) compared to hemorrhaged rats receiving 0.9% NaCl. Rats receiving CV-6209 (1 mg/kg) exhibited a significantly increased survival rate and survival time post-reinfusion compared to rats receiving only the vehicle. These data indicate that PAF is an important mediator of hemorrhagic shock in the rat and that PAF receptor antagonists may be useful in hemorrhagic shock states.     

N-乙酰-L-半胱氨酸对失血性休克大鼠再灌注损伤的保护作用

目的　为临床应用抗氧化剂N 乙酰 L 半胱氨酸 (NAC)防治失血性休克提供实验基础。方法大鼠放血致休克 (失血量 4 9% ,血压 4～ 5 .3kPa) ,30min后 ,回输全血并再灌注 3h。回输全血的同时 ,分别给予NAC (15 0mg·kg- 1)和银杏叶提取物(Egb ,5 0mg·kg- 1) ,3h后检测血浆乳酸脱氢酶(LDH)、谷 草转氨酶 (GOT)活性和组织匀浆丙二醛(MDA)含量、髓过氧化物酶 (MPO)活性 ,并观察肾和肝组织病理变化。结果　给予NAC可明显降低缺血再灌注所致的血浆LDH、GOT活性及心、肝、肺和肾组织MPO活性和MDA含量增高 ,病理观察也显示组织损伤改善。Egb也有一定的改善作用 ,但不如NAC作用显著。结论　再灌早期给予NAC可抑制自由基的产生和脂质过氧化反应 ,对休克复苏再灌注损伤具有较好的保护作用     

Salutary effects of CG-4203, a novel, stable prostacyclin analog, in hemorrhagic shock

Prostacyclin (PGI2) is a potent vasodilator, an inhibitor of platelet aggregation, and a membrane-stabilizing agent that has been shown to exert beneficial effects in a variety of models of ischemia and circulatory shock. However, the use of PGI2 is limited by its instability and rapid biodegradation. We studied the effects of a novel, stable prostacyclin analog, CG-4203, in a murine model of hemorrhagic shock. Hemorrhaged rats treated with CG-4203 maintained postreinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving only the vehicle (final MABP 101 +/- 3 vs. 75 +/- 5 mm Hg, p less than 0.01). CG-4203 was also found to attenuate the increase in plasma cathepsin D activity (p less than 0.01), as well as the plasma accumulation of free amino-nitrogen compounds (p less than 0.05). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in CG-4203-treated hemorrhaged rats than in rats receiving the vehicle (25 +/- 2 vs. 54 +/- 7 U/ml, p less than 0.01). In addition, CG-4203 exerted an anti-proteolytic action in pancreatic homogenates and inhibited platelet aggregation in platelet-rich plasma. However, CG-4203, at concentrations expected during treatment of shock, failed to have an immediate or delayed vasodilator effect in rat aortic rings, and thus vasodilation is not an important aspect of the antishock effects of CG-4203. Our results suggest that inhibition of platelet aggregation, as well as the antiproteolytic and membrane-stabilizing actions, could mediate the beneficial effects of CG-4203 in hemorrhagic shock.     

Involvement of the sympathetic nervous system in the cardiovascular effects of ACTH-(1-24) during hemorrhagic shock in rats

Summary In urethane-anesthetized rats, removal of about 50% of the total blood volume over a period of 25 – 30 min caused hypovolemic shock, with extreme hypotension (MAP = 18–25 mmHg and death of all animals within 22±5 min. The i.v. injection of ACTH-(1-24) in the dose range of 40–160 g/kg induced a sustained, dose-dependent, and, at the highest dose used, an almost complete recovery of blood pressure, and 100% survival, at least for 2 h after treatment. The effect of ACTH-(1–24) was completely prevented by reserpine (5 mg/kg) and clonidine (0.1 mg/kg), significantly reduced by prazosin (0.1 mg/kg), dibenamine (15 mg/kg) and i.v. yohimbine (1 mg/kg) and unaffected by i.c.v. yohimbine (0.2 mg/kg) and i.v. practolol (15 mg/kg). These data suggest that the effect of ACTH-(1–24) in hypovolemic shock depends on the functional integrity of the sympathetic nervous system and is mediated through an activation of peripheral alpha-adrenoceptors.Abbreviations MAP mean arterial pressure - PP pulse pressure - i.c.v. intracerebroventricular Send offprint requests to A. Bertolini at the above address     

Comparison of the cardiovascular effects of meptazinol and naloxone following haemorrhagic shock in rats and cats.

The cardiovascular effects of the opioid mixed agonist-antagonist, meptazinol, and the opioid antagonist, naloxone, have been evaluated in conscious rats, anaesthetized rats and anaesthetized cats following the induction of haemorrhagic shock. The mean arterial pressure of conscious rats decreased by 17-29 mmHg following a haemorrhage of 20% of blood volume. Meptazinol (17 mg kg-1, i.m.) administered after haemorrhage evoked a rapid and sustained increase in mean arterial pressure to pre-haemorrhage levels. Naloxone (10 mg kg-1, i.v.) also increased mean arterial pressure to a level significantly higher than post-haemorrhage values. Neither haemorrhage nor subsequent drug treatments evoked significant changes in the heart rates of conscious rats. In anaesthetized rats, 20% haemorrhage evoked decreases in mean arterial pressure, heart rate and cardiac output. Blood flow to the heart, skin, skeletal muscle, kidneys, spleen and liver (arterial) was decreased. Meptazinol and naloxone increased blood pressure and total peripheral resistance, but did not significantly alter heart rate or cardiac output. Hepatic arterial flow decreased further in both drug and vehicle treated groups. In addition meptazinol slightly reduced skeletal muscle flow. In anaesthetized cats 40% haemorrhage decreased mean arterial pressure by 46 +/- 3 mmHg. An intravenous infusion of either meptazinol or naloxone (cumulative 2 mg kg-1, i.v.) partially restored blood pressure. In experimental animal models of haemorrhagic shock, meptazinol has a similar cardiovascular profile to naloxone. The established analgesic activity of meptazinol may confer an advantage in some shock states.     

Characterization of the effects of (+/-)-meptazinol, its individual enantiomers and N-methyl meptazinol on food consumption in the rat.

Both (+/-)-meptazinol (2 mg kg-1) and levorphanol (1 mg kg-1) produced hyperphagia over a 4 h period after intraperitoneal injection in free feeding rats during the daylight phase. The individual (+)- and (-)-enantiomers of meptazinol (2 mg kg-1 i.p.) induced comparable increases in cumulative food intake. N-methyl meptazinol (2-10 mg kg-1 i.p.), the quaternary analogue of meptazinol, produced no modification of food intake though it increased food consumption when injected intracerebroventricularly (10-100 micrograms per animal). Meptazinol and levorphanol hyperphagia was abolished by 1 mg kg-1 doses (i.p.) of the opioid antagonists naltrexone, naloxonazine and (-)-Mr 1452 but not by its (+)-enantiomer Mr 1453 which is not effective as an opioid antagonist. Intracerebroventricular administration of the delta-opioid antagonist ICI 154,129 (10 micrograms per animal) suppressed meptazinol but not levorphanol hyperphagia. It was concluded that meptazinol produces centrally mediated stereospecifically reversible hyperphagia through a mu-opioid receptor mechanism common to levorphanol, and also through delta-opioid receptor mechanism(s).     

Differential effects of the (+)- and (–)-gossypol enantiomers upon Entamoeba histolytica axenic cultures

Abstract— The in-vitro anti-amoebic effects of (±)-, (+)-, (–)-gossypol and emetine were tested against axenic trophozoites from five Entamoeba histolytica strains. The (–)-isomer was more active than the racemate and the (+)-isomer. These results indicate that the gossypol anti-amoebic activity is mainly due to its content of (–)-gossypol in all strains tested.     

Rapid and brief tolerance to (+)- and (-)-nicotine in unanesthetized rats

When given intravenously to unanesthetized rats as a bolus dose, (-)-nicotine produced a dose-related rise in blood pressure and fall in heart rate in the dose range of 5-40 micrograms/kg. Tolerance did not develop when doses were given at 30 min intervals. At the highest dose, the effects on heart rate persisted. In addition, severe arrhythmias and apnea were observed. (+)-Nicotine at 100 micrograms/kg produced effects similar to 10 micrograms/kg of (-)-nicotine. When given at 1 min intervals, tolerance quickly developed after only 6 injections at 5 micrograms/kg and after 4 injections at 10 micrograms/kg. Tolerance to (+)-nicotine also developed rapidly and was no longer evident at 5 min. The results suggest the tolerance is related to frequency of administration and dose. The implication of these results are discussed with regard to cardiovascular disease and dependence. In addition, we postulate that the relatively low degree of biological stereoselectivity of the optical isomers of nicotine, compared with that of the enantiomers of morphine, is due to the simplicity and flexibility of the nicotine molecule. It can be shown using Dreiding models that the nitrogen atoms in the enantiomers are nearly superimposable.     

Chiral selective effects of doxazosin enantiomers on blood pressure and urinary bladder pressure in anesthetized rats

AIM: To study chiral selective effects of doxazosin enantiomers on blood pressure and urinary bladder pressure in anesthetized rats. METHODS: In anesthetized rats, the carotid blood pressure, left ventricular pressure of the heart and the urinary bladder pressure were recorded. RESULTS: Administration of S-doxazosin at 0.25, 2.5, 25, and 250 nmol/kg iv produced a dose-dependent decrease in blood pressure, but its depressor effect was significantly weaker than that induced by R-doxazosin and racemic-doxazosin (rac-doxazosin), and the ED(30) values (producing a 30% decrease in mean arterial pressure) of R-doxazosin, rac-doxazosin and S-doxazosin were 15.64, 45.93, and 128.81, respectively. Rac-doxazosin and its enantiomers administered cumulatively in anesthetized rats induced a dose-dependent decrease in the left ventricular systolic pressure and +/-dp/dt(max), and the potency order of the 3 agents was R-doxazosin > rac-doxazosin > S-doxazosin. Rac-doxazosin and its enantiomers decreased the vesical micturition pressure dose-dependently at 2.5, 25, and 250 nmol/kg, and the inhibitory potency among the 3 agents was not significantly different. CONCLUSION: S-doxazosin decreases the carotid blood pressure and left ventricular pressure of the heart less than R-doxazosin and rac-doxazosin, but its effect on the vesical micturition pressure is similar to R-doxazosin and rac-doxazosin, indicating that S-doxazosin has chiral selectivity between cardiovascular system and urinary system in anesthetized rats.     

Na(+)-H(+) exchange blockade, using amiloride, decreases the inflammatory response following hemorrhagic shock and resuscitation in rats

Na⁺–H⁺ exchanger activation on resuscitation following hemorrhagic shock has been shown to result in myocardial injury and dysfunction. Amiloride, an inhibitor of the Na⁺–H⁺ exchanger has been shown to protect the myocardium against reperfusion injury in the ischemic hearts. However, the mechanism of protection remains unclear. Na⁺–H⁺ exchanger blockers have been implicated in the regulation of inflammatory responses and chemokine production. The present study investigated the therapeutic anti-inflammatory value of amiloride on myocardial contractile function in post-resuscitation following hemorrhagic shock in rats. Male Sprague–Dawley rats were assigned into 3 groups: 1) hemorrhage, 2) hemorrhage treated with amiloride, and 3) sham hemorrhage (n = 6 per group). Rats were hemorrhaged over 60 min to reach a mean arterial blood pressure of 40 mm Hg. After 60 min of hemorrhagic shock, rats were treated or not by injection of 1 ml of 100 μM amiloride (0.027 mg/ml) intra-arterially. Resuscitation was made in vivo by reinfusion of the shed blood to restore norm tension for 30 min. Left ventricular contractile function was measured in the isolated hearts following hemorrhage and in vivo resuscitation using the Langendorff apparatus. Arterial blood samples were collected from all groups at the end of the experimental period (90 min) for cytokine measurements (TNF-α). Amiloride decreased the inflammatory response to hemorrhagic shock and resuscitation by lowering the levels of TNF. These results indicate that amiloride protects the myocardium by down regulating the inflammatory response to hemorrhagic shock and resuscitation.     

Diuretic effects of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) in anesthetized rats

A synthetic amino acid, L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), can be converted to (-)-norepinephrine (NE) by aromatic L-amino acid decarboxylase (AADC) in various mammalian tissues. Recent studies have indicated the pressor and diuretic effects of L-threo-DOPS. In this study, we examined the effects of L-threo-DOPS on renal hemodynamics and function in anesthetized rats, and evaluated possible mechanisms of the diuresis. Intravenous infusion of L-threo-DOPS at 120 micrograms/kg/min exerted a significant increase in mean arterial pressure (MAP). There was a slight but nonsignificant decrease in renal blood flow (RBF). Although the glomerular filtration rate (GFR) remained at a constant level, urine flow (UF) and urinary sodium excretion (UNaV) increased significantly during the drug infusion. Pretreatment with AADC inhibitor, benserazide, completely blocked both the pressor and diuretic effects of L-threo-DOPS. When the renal perfusion pressure was protected from the pressor effect of the drug by using a Blalock clamp, the drug-induced diuresis was abolished. The diuretic effect of L-threo-DOPS was markedly attenuated by the administration of phentolamine. There was a positive correlation between plasma NE concentration and UF during the infusion of L-threo-DOPS. Intrarenal arterial infusion of L-threo-DOPS at 20 micrograms/kg/min was without effect on renal function. These results indicate that diuresis and natriuresis induced by L-threo-DOPS are dependent on the pressor effect of NE via peripheral alpha-adrenoceptor activation.     

Antinociceptive effects of (+/-)-, (+)- and (-)-nefopam in mice

The antinociceptive activity of (+/-)-, (+)- and (-)-nefopam in mice has been examined using the hot-plate, formalin and tail-flick tests. Nefopam was administered by the intraperitoneal, intracerebroventricular (i.c.v.) and intrathecal (i.th.) routes. Intraperitoneal injection of (+/-)-nefopam (10-20 mg kg-1) had powerful analgesic effects in the hot-plate and formalin tests. In the tail-flick test it produced a weak, but significant elevation of the response latencies. In spinalized animals, however, the effect was abolished, indicating that nefopam prolonged the tail-flick latencies by activation of descending pain-modulating pathways. (+/-)-Nefopam (5-20 micrograms) elicited analgesia in the hot-plate test after i.c.v. or i.th. injection. These findings suggest that nefopam has both a spinal and a supraspinal site of action. (+)-Nefopam was significantly more potent than (-)-nefopam after both systemic and central administration.     

An in vitro profile of activity for the (+) and (-) enantiomers of spiradoline and PD117302

Kappa- and mu-opioid binding site affinities of the kappa-selective ligand U62066 and its optical isomers, (+)-U63639 and (-)-U63640 were compared with those of the structurally related ligand PD117302 and its respective isomers, (+)-PD123497 and (-)-PD123475. The relative efficacies of each compound were also established using the guinea-pig ileum, rat and rabbit vas deferens smooth muscle bioassays. The specific opioid receptor mediating the agonist behaviour was determined in the guinea-pig ileum bioassay by obtaining pKB values for naloxone and for the kappa-selective antagonist nor-binaltorphimine. Both racemic compounds and the (-)-enantiomers displayed high selectivity for the kappa-receptor with (-)-PD123475 the most selective. The (+)-enantiomer, PD123497, was approximately equipotent at mu-/kappa-sites while (+)-U63639 displayed a 140-fold mu-receptor selectivity. Bioassay studies showed each compound to be interacting at the kappa-receptor, with the exception of (+)-U63639 which displayed a profile consistent with that of a weak mu-receptor agonist.     

Effects of nicardipine in rats subjected to endotoxic shock.

1. The calcium channel blocker, nicardipine, produced a dose-dependent reduction in the mortality caused by endotoxin in rats. 2. The drug also reduced most of the hematological and gross pathological manifestations of disseminated intravascular coagulation (DIC) caused by endotoxin. 3. The endotoxin-induced monocytopenia but not the granulocytopenia, lymphocytopenia or thrombocytopenia was inhibited by the drug. 4. The results suggest that the protective action of nicardipine is causally related to prevention of the endotoxin-induced DIC and that an effect of the drug on monocytes may be of importance.     

Effects of osutidine (T-593) and its enantiomers on gastric mucosal hemodynamics and mucosal integrity in anesthetized rats

T-593 (osutidine, CAS 140695-21-2) is a new anti-ulcer agent that consists of two enantiomers, (+)-(R)-T-593 and (-)-(S)-T-593. The present study was designed to investigate the effects of T-593, (+)-(R)-T-593 and (-)-(S)-T-593 on ethanol-induced gastric damage in rats. Rats were given intraperitoneal administration of vehicle, racemic T-593, (+)-(R)-T-593 or (-)-(S)-T-593. 30 min later, the rats intragastrically received a 1-ml solution of 40% ethanol, and 30 min thereafter, they were sacrificed for assessment of gastric damage. Gastric hemodynamics were assessed by reflectance spectrophotometry and laser Doppler flowmetry during the experiment. Gastric damage was significantly suppressed by racemic T-593 in a dose-dependent manner. While 60 mg/kg of (+)-(R)-T-593 and (-)-(S)-T-593 also suppressed ethanol-induced gastric injury, the same dose of racemic T-593 exerted the most potent anti-ulcerative activity. Both (+)-(R)-T-593 and racemic T-593 increased gastric mucosal blood flow and abolished gastric mucosal blood flow stasis induced by 40% ethanol. Although (-)-(S)-T-593, which antagonizes histamine H2-receptors, exerts an antiulcerative effect, (+)-(R)-T-593 also protects the gastric mucosa from ethanol-induced injury, possibly by influencing gastric mucosal hemodynamics. Thus racemic T-593 may protect the gastric mucosa by antagonizing H2-receptors and by enhancing gastric circulation in rats.