Effects of trapidil and nitroglycerin on coronary circulation in conscious dogs

Effects of trapidil and nitroglycerin (glyceryl trinitrate) on coronary blood flow or epicardial coronary diameter were studied in conscious dogs, instrumented with a Doppler flow probe or a pair of ultrasonic dimension crystals on the left circumflex coronary artery. Bolus intravenous injections of trapidil (0.5, 1.0 and 2.0 mg/kg i.v.) increased coronary blood flow, dose-dependently, such being comparable at the peak value seen with nitroglycerin (5, 10 and 20 micrograms/kg i.v.). Coronary blood flow following the intravenous administration of trapidil or nitroglycerin increased biphasically and returned to pre-drug levels in 1.4 +/- 0.2 min (trapidil 1 mg/kg i.v.) or 1.0 +/- 0.1 min (nitroglycerin 10 micrograms/kg i.v.), while the mean coronary diameter increased monophasically and approached the control level 5 min after drug administration. The first peak was observed before the maximal decrease in aortic pressure and the second peak was associated with concomitant increases in heart rate and myocardial contractility induced by a sudden hypotension. Propranolol, a beta-blocker, did not modify the initial peak but attenuated markedly the second peak (P less than 0.05) in case of trapidil (1.0 mg/kg i.v.) or nitroglycerin (10 micrograms/kg i.v.), which corresponded with reduced changes in reflex tachycardia and positive inotropism. Therefore, the direct effects of trapidil and nitroglycerin on coronary circulation of conscious dogs are an initial transient dilatation of the resistance vessels followed by a continuation of the dilatation of the conductance coronary vessels.     

Pharmacokinetics and pharmacodynamics of nitroglycerin and its dinitrate metabolites in conscious dogs: Intravenous infusion studies

Intravenous infusions of nitroglycerin (GTN), 1,2-glyceryl dinitrate (1,2-GDN), and 1,3-glyceryl dinitrate (1,3-GDN) were given to four conscious dogs at 10 g/min, 30 g/min, 50 g/min, and 70 g/min of GTN and 20 g/min and 100 g/min of GDNs. The steady state plasma concentrations (Css)of GTN were reached after about 60 min whereas for 1,2-GDN and 1,3-GDN the Csswere reached at about 150 min after the infusion began. Except for one dog, the Cssof GTN were not proportional to infusion rate, however, all dogs together showed a good linear relationship between Cssof GTN and infusion rates with an average correlation coefficient of 0.917±0.102. Large variability in GTN clearance after various infusion rates was observed in all dogs. The Cssratios of 1,2-GDN/GTN and 1,3-GDN/GTN yield overall averages of 31.5 ±17.2 and 5.47 ±3.19,respectively. Average Cssratios of metabolites 1,2-GDN/1,3-GDN were 5.78±1.23. This ratio is different from those obtained after iv bolus and oral dosing indicating that the biotransformation of GTN to 1,2-GDN and 1,3-GDN differs for each dosing route. The clearances for 1,2-GDN and 1,3-GDN were not changed over the dose range of 20 g/min to 100 g/min. Terminal half-lives of 1,2-GDN and 1,3-GDN postinfusion were similar to those values obtained after a single bolus dose (45 min). It appears that all the GTN dose at steady state can be accounted for by the formation of measurable 1,2-GDN and 1,3-GDN. Large intra- and interdog variations in systolic blood pressure decrease (SPD) following infusions of GTN were observed, however, all dogs showed a clear systolic blood pressure decrease when the highest infusion rate (70 g/min) was given. No significant systolic blood pressure drop was detected following 20 g/min infusions of 1,2-GDN or 1,3-GDN. It was clear that systolic blood pressure in all dogs decreased following 100 g/min infusions of 1,2-GDN or 1,3-GDN. When SPD values were plotted vs. log GTN concentrations following the infusion of 70 g/min of GTN in all four dogs, a counterclockwise hysteresis was observed indicating the significant contribution of the active dinitrate metabolites to GTN pharmacodynamics.This work was supported in part by NIH grant HL32243.     

硝酸甘油控制性低血压对罗库溴铵的药代动力学和药效动力学影响

目的 观察硝酸甘油(NTG)控制性低血压(DH)状态下罗库溴铵(肌肉松驰剂)体内效能变化.方法 选择全麻下择期鼓室成型术30例,随机分为DH组和对照组.诱导后单次给予罗库溴铵0.6 mg·kg-1,用高效液相色谱串联质谱法检测不同时间点罗库溴铵血药浓度.用非线性混合效应模型(NON-MEM)分析罗库溴铵的药代动力学和药效动力学.结果 当4个成串反应比值(TOFR)恢复至0.7和0.9时,DH组的罗库溴铵血浆浓度明显低于对照组(P<0.05).硝酸甘油控制性低血压对其药代动力学影响无显著性差异.药代动力学/药效动力学联合分析显示,对照组罗库溴铵的EC50和γ分别为1.42 mg·L-1,4.32;DH组罗库溴铵的EC50和γ显著降低(分别为1.11 mg ·L-1,2.92,P<0.05).结论 硝酸甘油控制性低血压能增强罗库溴铵效能,但对其药代动力学无明显影响.     

Effects of m-nisoldipine on ischemic arrhythmia in conscious rats

m-Nisoldipine iv 3, 5 and 10 micrograms/kg before coronary artery ligation markedly reduced the early ischemic arrhythmia in conscious rats. Nifedipine iv 5 and 10 micrograms/kg had the same effect on preventing ischemic arrhythmia. Nisoldipine was less effective than m-nisoldipine at equal doses. Myocardial infarct size was reduced and electrical stability of the myocardium was markedly improved as a result of the increment in VDT, VFT and VERP. These effects may be related to the mechanisms of their respective antiarrhythmic actions. It is unlikely that these calcium antagonists prevent ischemic arrhythmia by improving the blood supply to the ischemic myocardium.     

Effects of endothelin on regional hemodynamics in conscious rats

Endothelin is a potent vasoactive peptide in anesthetized rats and isolated vascular smooth muscle. This study was performed to describe the hemodynamic effects of endothelin in conscious, freely moving rats. Endothelin (0.067-2 nmol/kg i.v.) produced long-lasting, dose-dependent increases in arterial pressure, mesenteric and, to a lesser degree, hindquarters vascular resistances and decreases in heart rate. We suggest that endothelin may play an important role in regulation of arterial pressure by modulating peripheral vasomotor tone.     

Effects of prostaglandins and the autonomic nervous system on the vasodilatory properties of nitroglycerin in conscious dogs.

This study was designed to assess the respective roles of prostaglandins and the autonomic nervous system in the responses to nitroglycerin (NTG) in conscious dogs. In vivo, NTG (1, 10, and 100 micrograms/kg i.v.) induced dose-dependent decreases in blood pressure and increases in heart rate and cardiac output. Coronary and carotid blood flows increased simultaneously, whereas responses in renal blood flow were biphasic, i.e., an initial decrease was followed by an increase above control at 10 and 100 micrograms/kg. NTG responses were not changed by indomethacin but were affected by chlorisondamine alone or in combination with indomethacin; tachycardia was abolished, and increases in cardiac output after 10 and 100 micrograms/kg were reduced by 26 and 32%, respectively, after ganglionic blockade and by 19 and 32%, respectively, after chlorisondamine plus indomethacin. In addition, increases in carotid blood flow in doses of 100 micrograms/kg were reduced by 88% after chlorisondamine and 83% after chlorisondamine plus indomethacin. Finally, in the presence of chlorisondamine plus indomethacin, NTG induced a more pronounced hypotension associated with a more pronounced renal vasodilation at the highest dose. Independent of indomethacin pretreatment, NTG in vitro induced a dose-dependent relaxation of the carotid, coronary, and renal arteries. Depending on the vascular bed, the reflex and local controls of circulation are affected differently by NTG.     

Effects of different drugs on the cystometrogram in conscious rats.

The effects on urodynamic parameters of i.v. administration of different drugs utilized in the therapy of detrusor instability, have been studied in conscious catheterized rats. Emepronium bromide, oxybutynin and nifedipine affected in a dose-dependent way the micturition pressure (MP), with sporadic changes in bladder volume capacity (BVC). Terodiline induced significant increases in BVC values in a wide range of doses. These changes, however, were always not dose-dependent. The drug significantly reduced MP only at the higher administered dose (10 mg/kg). Flavoxate induced increases of bladder capacity (BVC) not dependent on the administered doses, with no changes in micturition pressure (MP). Indomethacin significantly increased BVC and weakly reduced MP, but the effects were not dose-related. The effects of drugs on BVC were unrelated with the basal value of this parameter, whereas the decrease of MP seems to be related to high basal values before treatment. From a quantitative point of view, cystometrographic recordings in conscious normal rats can provide comparative data among drugs acting on bladder contractility (MP) such as anticholinergics and strong calcium antagonists.     

Effects of fenoldopam on alpha-methyl-p-tyrosine-stimulated prolactin secretion in conscious rats

Pituitary dopamine D-2 receptors participate in the regulation of prolactin (PRL) release. No dopamine D-1 receptors have so far been identified in the pituitary gland. The present study was designed to assess the effects of fenoldopam, a selective dopamine D-1 receptor agonist, on alpha-methyl-p-tyrosine-stimulated PRL release. Fenoldopam dose dependently reduced the alpha-methyl-p-tyrosine-stimulated PRL secretion. This inhibitory effect of fenoldopam was abolished after pretreatment with SCH 23390, a specific dopamine D-1 receptor antagonist, suggesting the involvement of a dopamine D-1 receptor in PRL secretion.     

Effects of various drugs on bladder function in conscious rats

In the present study, we attempted to evaluate the effects of various intravenous administered drugs, which had been shown to influence bladder function in anesthetized animals, on the cystometrogram in conscious rats placed in a restraining cage. Thiopental, diazepam, baclofen, clonidine and flavoxate, considered to act on the micturition center in the brain stem, hardly increased bladder capacity (time to micturition in cystometrogram) in conscious rats, but morphine, indomethacin and lidocaine, considered to act on the micturition center in the sacral cord or bladder mechanoreceptors, increased it. In a chronic conscious rat, histopathological findings show that the bladder tissue at 2 days after implantation of the catheter to the bladder showed experimental cystitis characterized by severe edema in the submucosa and an increase in prostaglandin E2 content, which is thought to stimulate directly and/or indirectly the capsaicin-sensitive sensory fiber in the afferent branch of the micturition reflex, and there was hyperreflexia characterized by decreases in both bladder capacity and urine volume. In conclusion, cystometrography in conscious rats placed in a restraining cage is thought to be a useful model for evaluating the true effect of a newly developed agent on bladder function.     

Effects of vasodilator drugs on venous tone in conscious rats

The dose-response effects of vasodilator drugs, nitroglycerin, sodium nitroprusside and hydralazine, on mean arterial pressure (MAP) and mean circulatory filling pressure (MCFP), an index of body venous tone, were investigated in conscious, unrestrained, intact rats as well as in rats treated with the ganglionic blocker, hexamethonium. The effects of these drugs were compared with those of the vehicle, normal saline, in control rats. In intact rats, i.v. infusion of nitroglycerin did not alter MAP while i.v. infusions of nitroprusside or hydralazine caused dose-dependent decreases in MAP. After ganglionic blockade, all three drugs decreased MAP. In intact rats, nitroglycerin and sodium nitroprusside did not affect MCFP but hydralazine increased MCFP. After treatment with hexamethonium, all three drugs decreased MCFP. The decreases in MCFP caused by nitroglycerin and nitroprusside, but not that by hydralazine, were significantly greater than the corresponding changes in control rats. Thus, in intact rats, the direct venodilator actions of nitroprusside and nitroglycerin were masked by endogenous sympathetic tone. When sympathetic nerve activity was attenuated, both nitroprusside and nitroglycerin have venodilator effects. Hydralazine, on the other hand, had insignificant venodilator effect both in the presence and absence of sympathetic reflexes.     

Effects of adrenomedullin 2 on regional hemodynamics in conscious rats

The present study aimed to assess the effects of rat adrenomedullin 2 on systemic and regional hemodynamics in conscious Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Intravenous infusion of rat adrenomedullin 2 (0.25-5 micro g/kg/min) decreased blood pressure, and increased heart rate in a dose-dependent manner in both types of rats. Rat adrenomedullin 2 (5 micro g/kg/min) increased heart rate and cardiac output. As a result, total peripheral resistance significantly decreased. In SHRs, adrenomedullin 2 significantly increased regional blood flow in the heart, liver, spleen, kidneys, and adrenal glands. Especially, effects on heart, liver, and kidneys were remarkable. Regional hemodynamic changes were reproduced in WKY rats, and there was no qualitative difference in regional responses to rat adrenomedullin 2 between SHRs and WKY rats. Thus, rat adrenomedullin 2 predominantly increased flow rates in organs that were richly blood-supplied from cardiac output. Rat adrenomedullin 2 may contribute to the regulation of the cardiovascular system, by acting as a local vasodilatory hormone as well as a circulatory hormone.     

Effects of water deprivation on the pharmacokinetics and pharmacodynamics of bumetanide in rats

The effects of temporary water deprivation for 48 h on the pharmacokinetics and pharmacodynamics of bumetanide were examined after intravenous (i.v.) administration of bumetanide, 8 mg kg^?1 to control and water deprived rats (n = 7). The values of AUC, t_1/2 and MRT increased 79.0, 417, and 633 per cent, respectively, and CL and CL_NR decreased 44.0 and 41.2 per cent, respectively, in water deprived rats. They were all significantly different. The decreased CL_NR in water deprived rats could be due to decreased nonrenal metabolism of bumetanide; it could be supported that the amounts of glucuronide conjugate of bumetanide (52.5 vs 12.9 μg), desbutylbumetanide (170 vs 113 μg) and its glucuronide conjugation (191 vs 125 μg), and sum of the three metabolites (414 vs 229 μg), which are expressed in terms of bumetanide excreted in 24 h urine, decreased significantly in water deprived rats. The 8-h urine outputs per 100 g body weight (4.32 vs 1.34 ml) also reduced significantly in water deprived rats, and it might be due to significantly reduced amounts of bumetanide excreted in 8 h urine (90.9 vs 25.7 μg) and/or reduced kidney function in water deprived rats. The kidney function based on CL_lot (9.87 vs 2.14 ml min^?1 kg^?1) reduced significantly in water deprived rats. The 8-h urinary excretions of sodium (0.430 vs 0.0818 mmol), potassium (0.567 vs 0.270 mmol), and chloride (0.549 vs 0.0624 mmol) per 100 g body weight also reduced significantly in water deprived rats.     

Effects of safflower injection on the pharmacodynamics and pharmacokinetics of warfarin in rats

1.?Safflower injection (SI) is extracted from Chinese herbal medicine safflower that comprises many active components. Warfarin is a common anticoagulant and has exhibited drug interactions with several herbal products. This study aimed to investigate the effects of SI on pharmacodynamics and pharmacokinetics of warfarin in rats.

2.?Wistar rats were randomly divided into blank control group, SI group, warfarin control group and SI?+?warfarin group, respectively. In SI and SI?+?warfarin groups, rats were injected with SI (1.6?mL/kg/d, i.p.) for 14?days. Warfarin (0.2?mg/kg) was given orally on the eighth day. Saline was given as control. The blood samples were collected at various time points. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were measured. UPLC-MS/MS was used to determine the plasma concentrations of S(R)-warfarin, and the pharmacokinetic parameters were calculated.

3.?PT, APTT in SI and SI?+?warfarin rats increased significantly compared with corresponding control rats. The pharmacokinetic parameters including C_max, t_1/2, AUC_0-t and AUC_0-∞ of S-warfarin and R-warfarin in SI?+?warfarin rats were higher than those in warfarin control rats.

4.?These findings suggest that SI significantly increases the anticoagulant effect of warfarin by affecting its pharmacodynamic and pharmacokinetic parameters.     

Prazosin potentiates the acute hypotensive effects of nitroglycerin but does not attenuate nitrate tolerance in normal conscious rats

Sympathetic activation has been suggested as a mechanism of acute nitrate tolerance, but the available literature is not definitive. We investigated the effects of prazosin, an alpha1-adrenoceptor antagonist, on acute nitroglycerin (NTG) hemodynamics and tolerance development in normal conscious rats. The effect of prazosin bolus injection (300 microg/kg) on NTG hemodynamics was first determined after acute dosing. The extent of maximal mean arterial pressure (MAP) response and the duration of drug-induced hypotension to NTG bolus doses (5, 15, and 30 microg) were measured before and after prazosin. In separate studies, the effects of prazosin on NTG tolerance development were examined. Rats received either 10 microg/min NTG or vehicle infusion for 5 hours after predosing with prazosin (300 microg/kg). Maximal MAP response to the hourly 30-microg NTG i.v. bolus challenge dose (CD) was determined before and after prazosin, and during NTG or vehicle infusion. Our results showed that bolus doses of NTG (at 5, 15, and 30 microg) dose-dependently decreased maximal MAP by 20.8 +/- 5.8, 26.1 +/- 5.0, and 30.6 +/- 5.7 mm Hg, respectively. Prazosin caused an average of 16 mm Hg depression in MAP, and it only slightly potentiated the hypotensive effects of bolus doses of NTG both after acute dosing and during continuous infusion. Prazosin treatment prolonged the duration of NTG-induced MAP response by about 4-fold for all NTG doses examined (P < 0.01 versus corresponding dose before prazosin, ANOVA). In both prazosin-treated and untreated groups, NTG infusion significantly attenuated the MAP response of the NTG CD starting from 1 hour of infusion (P < 0.001 versus 0 hour response, ANOVA), confirming tolerance development. In the presence of NTG tolerance development, prazosin no longer enhanced the apparent duration of NTG action. The hypotensive effect produced by the 30-microg NTG CD lasted for 7 +/- 2 and 10 +/- 2 seconds for prazosin-treated and untreated groups, respectively (P > 0.05, ANOVA). Our results showed that, in both NTG-tolerant and control animals, prazosin only slightly potentiated the maximum hypotensive effects of a challenge NTG dose, but did not significantly alter the pharmacodynamics of NTG-induced hemodynamic tolerance. Thus, in our animal model, sympathetic blockade by prazosin neither prevented nor attenuated in vivo tolerance induced by NTG.     

Effects of glibenclamide on systemic and splanchnic haemodynamics in conscious rats.

1. The effects of the sulphonylurea, glibenclamide (20 mg kg-1, i.v.), at a dose that blocks vascular potassium channels, on systemic and splanchnic haemodynamics (radioactive microspheres) were studied in conscious rats. 2. Glibenclamide significantly decreased cardiac index and hepatic artery blood flow while it significantly increased vascular resistance in systemic, portal and hepatic arterial territories. 3. In rats with suppressed cardiovascular reflexes, glibenclamide induced vasoconstriction in systemic, portal and hepatic arterial territories. 4. Intracerebroventricular administration of glibenclamide did not alter systemic or regional vascular tone. 5. Glibenclamide blunted the vasodilator effect of the potassium channel opener, diazoxide but not that of the L-type calcium channel blocker, nicardipine. 6. Another sulphonylurea, glipizide (20 mg kg-1, i.v.), induced significant systemic and splanchnic vasoconstriction. 7. Thus, the glibenclamide-induced blockade of vascular potassium channels caused a vasoconstriction in the systemic and splanchnic vascular beds. In these territories, therefore, the opening of glibenclamide-sensitive potassium channels might be responsible for a basal vasodilator tone.     

Effects of acute renal failure and ganciclovir on the pharmacodynamics of levofloxacin-induced seizures in rats

Seizures have been reported in patients receiving fluoroquinolones, including levofloxacin (LVFX). In the present study, we investigated the effects of experimental renal failure and the concomitant treatment with ganciclovir on the pharmacodynamics of LVFX-induced seizures to identify whether these factors can alter the pharmacokinetics or the pharmacodynamics of LVFX. Male Wistar rats received an intravenous infusion of LVFX at 250, 500, or 1000 mg/h/rat until the onset of seizures, and samples of serum, brain, and cerebrospinal fluid (CSF) were obtained. The concentration of LVFX in CSF at the onset of seizures was not affected by the infusion rate, whereas that in serum and brain increased with increasing infusion rate. This suggests that the concentration of LVFX in CSF is an appropriate index of the drug concentration at the site of action. The concentration of LVFX in CSF at the onset of seizures was significantly lower in rats with renal failure than in the control rats. Pretreatment with methylguanidine, an uremic toxin, at 600 mg/h/rat for 8 min reduced the concentration of LVFX in CSF at the onset of seizures and the total body clearance of LVFX after the intravenous injection. In rats pretreated with ganciclovir at 500 mg/h/rat for 1 h, the concentration of LVFX in CSF at the onset of seizures was significantly lower than the control rats. These results suggest that renal failure and ganciclovir can be the risk factors for LVFX-induced seizures, and that they increase the sensitivity of the central nervous system to LVFX-induced seizures.     

Effects of Ginkgo biloba extract on the pharmacokinetics and pharmacodynamics of tolbutamide in protein-restricted rats

Objectives Effects of repeated administration of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide were examined in rats fed a low‐protein diet. Methods Rats were given a low (7% casein) or control (20% casein) protein diet for 21 days and administered Ginkgo biloba extract (100 mg/kg per day) for the last 5 days. Tolbutamide was co‐administered on the last day. Blood glucose and plasma tolbutamide concentrations were determined over the subsequent 12 h and the activity of hepatic cytochrome P450s were determined at 12 h after dosing. Key findings There were significant decreases in body weight, the ratio of liver to body weight, and plasma albumin concentrations in rats on the low‐protein diet compared with controls. The hypoglycaemic effect of tolbutamide was significantly greater and the concentration of the drug in plasma was higher in the former group. The repeated administration of Ginkgo biloba extract had little influence on the hypoglycaemic effect of tolbutamide, but tended to decrease the drug concentration in plasma of control rats, while it reduced significantly the hypoglycaemic action and plasma concentration of tolbutamide in the protein‐restricted rats. Conclusions The effects of Ginkgo biloba extract on the pharmacokinetics and pharmacodynamics of tolbutamide were significantly enhanced in rats on the low‐protein diet.     

ketanserin对慢性心肌梗死大鼠血流动力学的影响

目的　研究ketanserin对慢性心肌梗死大鼠血流动力学的影响。方法　设假手术组、心肌梗死组和心肌梗死治疗组。治疗组在冠脉结扎后饮水中给予ketanserin 10mg·kg-1·d-1,持续 4～ 5wk。在清醒自由活动条件下连续监测血压 ,并采用改良Symth法测定动脉压力感受性反射敏感性(BRS)。结果　与假手术组比较 ,心肌梗死大鼠血压下降、心动间期波动性 (HPV )升高、BRS降低 ,而血压波动性(BPV)和心动间期无明显改变。ketanserin长期治疗可降低心肌梗死大鼠的血压、BPV和改善BRS。心肌梗死组室性心律失常发生率为 60 % (12 / 2 0 ) ,经ketanserin治疗后降至2 8 6% (6/ 2 1)。治疗或未治疗心肌梗死大鼠如果存在心律失常 ,则HPV升高 ,否则正常。结论　ketanserin可能作为改善心肌梗死预后的治疗药物。心肌梗死大鼠HPV增加与心律失常有关