ATTENUATION OF THE ANTIHYPERTENSIVE EFFECT OF CAPTOPRIL BY THE OPIOID RECEPTOR ANTAGONIST NALOXONE

To test a possible role of endogenous opioids in the blood pressure (BP) and heart rate (HR) responses to the converting enzyme inhibitor captopril in man, nine normal subjects were given captopril (50 mg) or placebo with and without the opioid antagonist naloxone (0.2 mg/kg i.v.). Treatments were given in random order and under double-blind conditions. BP and HR were measured supine and after a 5 min head-up tilt to 60 degrees before, 90, and 360 min after captopril. BP and HR responses to Valsalva's manoeuvre and isometric exercise (sustained hand grip) were also measured, as indirect tests of baroreceptor reflex function. After captopril alone, there was a significant decrease in supine diastolic and tilt systolic and diastolic BP at 90 min (7.8, s.d. = 6; 15.4, s.d. = 13; and 7.0, s.d. = 12 (s.d. = 9), 0 (s.d. = 15) and 3 (s.d. = 7) mmHg. The effect of naloxone on the changes in supine diastolic and tilt systolic BP were significant (P = 0.017, P = 0.030 respectively; analysis of variance). No significant effects of treatment on supine or tilt HR were seen. BP and HR changes during Valsalva's manoeuvre and isometric exercise were not altered by active treatment. These results suggest that the BP but not the HR responses to converting enzyme blockade are mediated by endogenous opioids.     

REPRODUCIBILITY OF PRESSOR RESPONSE TO HANDGRIP: INFLUENCE OF TIME INTERVALS, STRENGTH AND DURATION OF EXERCISE

1. The reproducibility of pressor response to handgrip performed at different time intervals and with different combinations of the product duration x strength of the exercise was evaluated in 14 normotensive subjects recording blood pressure with a noninvasive automatic device. 2. Subjects underwent five consecutive tests (30% of maximal voluntary contraction x 90 s) at 30 min, and 24 h intervals and repeated the test after 12 months. Furthermore, they underwent at 24 h intervals a randomized sequence of handgrip tests whose product strength x duration was combined in order to achieve either a constant or an increasing level of exercise. 3. Blood pressure response to exercise performed at 30 min intervals was much less reproducible than that induced by handgrip performed at time intervals greater than or equal to 24 h. 4. Increasing gradually the product strength x duration of the handgrip test there was a proportional blood pressure increase, whereas when the product was maintained constant diastolic blood pressure increase was also constant and reproducible within each subject. 5. This study shows that it is possible to obtain reproducible diastolic blood pressure responses to handgrip test measuring blood pressure with a non-invasive automatic device when the tests are performed at a time interval of at least 24 h. The choice of the strength and of the duration of the exercise is very important for the reproducibility of the test.     

FACTORS INFLUENCING THE EFFECTS OF INTRAVENOUS NALOXONE ON ARTERIAL PRESSURE AND HEART RATE AFTER HAEMORRHAGE IN CONSCIOUS RABBITS

The circulatory responses to different intravenous doses of naloxone were studied in conscious rabbits before and after haemorrhage, under different conditions including prior ganglion blockade. Unless there had been blood loss, naloxone elicited no pressor response, even in high dose. After bleeding so that arterial pressure fell to 40 mmHg, the dose-response relationship for naloxone had two components. Over a low-dose range (threshold 0.3 mg/kg) naloxone had a modest pressor effect but did not affect heart rate. Over a much higher dose range (threshold 0.6 mg/kg) naloxone caused a marked rise in arterial pressure and a profound bradycardia. The highest dose of naloxone examined (25 mg/kg) caused a rise in arterial pressure of 70 mmHg and a reduction in heart rate of 160 beats/min. The pressor and bradycardic effects of naloxone were the same whether post-haemorrhagic hypotension lasted 5, 10, 20 or 30 min. The responses to naloxone in low or high dose depended much more closely on the volume of blood removed than on the level to which arterial pressure fell. Even after non-hypotensive haemorrhage a high dose of naloxone had marked pressor and bradycardic effects. Ganglion blockade prior to haemorrhage abolished the pressor response to a low, but not to a high, dose of naloxone. It was concluded that prolonged and severe hypotension are not necessary to 'prime' the cardiovascular system to respond to naloxone after haemorrhage. In a high dose its pressor effects appear to be mediated post-ganglionically, but in a low dose it may act within the central nervous system.     

EFFECTS OF CONVERTING ENZYME INHIBITION WITH CAPTOPRIL ON RENAL FUNCTION IN NORMAL AND ACTH TREATED SHEEP

1. The effect on renal function in sheep of inhibiting converting enzyme with captopril was examined before and after 5 days ACTH administration. 2. Glomerular filtration rate, effective renal plasma flow, effective renal blood flow, mean arterial pressure and plasma sodium were all significantly incereased by ACTH treatment and plasma potassium was decreased. Captopril (20 mg i.v.) had no effect on renal function or blood pressure before or after ACTH treatment, although urinary potassium excretion decreased following captopril on day 6 of ACTH treatment. 3. The increase in glomerular filtration rate and effective renal plasma flow seen with ACTH treatment in sheep does not appear to be mediated by the renin-angiotensin system.     

CAPTOPRIL ANTAGONIZES THE HYPOTENSIVE ACTION OF ATRIAL NATRIURETIC PEPTIDE IN THE ANAESTHETIZED RAT

Atrial natriuretic peptide (8-33; ANP) caused a prolonged hypotensive response following intravenous injection in anaesthetized rats. This response was abolished by captopril treatment and restored by concomitant angiotensin II infusion. These results suggest that ANP exerts its hypotensive action in the anaesthetized rat by the antagonism of the vasoconstrictor action of endogenous angiotensin II.     

THE EFFECT OF QUATERNARY NALOXONE ON THE INCREASED NALOXONE POTENCY INDUCED BY MORPHINE

Using the abdominal constriction test in mice it was shown that the antinociceptive effect of morphine was inhibited by naloxone hydrochloride and its quaternary derivative naloxone methylbromide which presumably only acts peripherally. Pretreatment with a single dose of morphine 2.0 mg/kg s.c. did not alter the antinociceptive effect of a second dose of morphine given 3 h later. However, the antagonistic effect of naloxone against morphine was enhanced at this time. The development of increased naloxone potency was inhibited when naloxone hydrochloride was given together with morphine in the pretreatment. A similar inhibitory effect was observed when the quaternary derivative naloxone methylbromide was used instead of naloxone hydrochloride in the pretreatment regime. As there was no difference between the effects of naloxone hydrochloride and naloxone methylbromide in suppressing the development of increased naloxone potency induced by morphine pretreatment, it was concluded that this phenomenon may be mediated mainly through peripheral opiate receptors.     

THE EFFECTS OF NALOXONE, DEXAMETHASONE, DEOXYCORTICOSTERONE AND 17-HYDROXYPROGESTERONE ON BLOOD PRESSURE RESPONSES OF NORMAL AND ADRENALECTOMIZED RATS DURING HYPOVOLAEMIC SHOCK

The roles of, and interactions between, steroids and naloxone, an opioid antagonist, in the reversal of experimental hypotensive shock were studied in normal and adrenalectomized rats. In normal rats treated with dexamethasone or deoxycorticosterone or 17-hydroxyprogesterone the hypotension and shock caused by 1% bodyweight and 2% bodyweight haemorrhage could be substantially reversed by naloxone in a dose-related manner. In contrast, the reversal of hypotension by naloxone was markedly less in adrenalectomized rats. It is concluded that there is a co-ordinate release of pressor catecholamines and depressor enkephalins from adrenal glands in hypovolaemic shock. Eventually, the use of naloxone would be of much less value in the treatment of hypotension or shock in patients with Addison's disease.     

THE EFFECT OF CHLORPROMAZINE PRETREATMENT ON MORPHINE ANALGESIA AND NALOXONE POTENCY IN ADRENALECTOMIZED MICE

Morphine pretreatment (2.0 mg/kg s.c.) induced no overt tolerance to its antinociceptive effect in mice 3 h later, but enhanced the antagonistic potency of naloxone. 2 Pretreatment with chlorpromazine slightly potentiated the antinociceptive effect of morphine measured 3.5 h later. The antagonistic effect of naloxone was also enhanced. 3 The observed effect of chlorpromazine on naloxone potency was augmented when naloxone was administered in the pretreatment regime. 4 The enhanced naloxone potency induced by morphine pretreatment was inhibited by chlorpromazine administered 0.5 h before the morphine pretreatment. 5 Adrenalectomy sensitized the animals to the antinociceptive effect of morphine. However, the naloxone potency was similar to that of the sham-operated controls. 6 Adrenalectomy greatly attenuated the effect of chlorpromazine pretreatment on naloxone potency. However, the effect of combined pretreatment with either chlorpromazine plus naloxone or morphine remained unaffected. 7 These results indicate that the increased naloxone potency after chlorpromazine pretreatment may be partly mediated through an adrenal-linked process. However, it appears that this process is not essential for the development of increased naloxone potency induced by morphine pretreatment and for the interaction between chlorpromazine, naloxone and morphine.     

EFFECTS OF CAPTOPRIL ON THE SLEEP EEG OF SPONTANEOUSLY HYPERTENSIVE RATS

Intracerebroventricular captopril produces significantly different effects on the sleep electroencephalogram (EEG) of normotensive Wistar-Kyoto (WK) and spontaneously hypertensive rats (SHR). The compound produces a definite pattern of decrease in the percentage and power of the lower frequency EEG of the SHR. Corresponding action on the WK was confined to a general decrease in the power of the EEG. These findings suggest that certain components of the central renin-angiotensin system in the SHR are abnormal.     

THE EFFECT OF PHENTOLAMINE ON ACTIVE AND INACTIVE RENIN RELEASE IN HUMAN RENOVASCULAR HYPERTENSION

1. Phentolamine was infused at low increasing doses (0.2, 0.3, 0.4 and 0.5 mg/min) in five patients with unilateral renal artery stenosis measuring active and inactive (cryoactivable) renin in the renal veins from the stenosed and nonstenosed kidney and in a peripheral vein. 2. PRA values from the stenosed kidney (11.59, s.e.m. = 5.79 pmol ang I/ml per h) were higher than those in the peripheral vein (5.19, s.e.m. =2.64) while these latter were similar to those from the contralateral kidney (5.09, s.e.m. =2.93). Phentolamine significantly increased PRA from the stenosed kidney and in the peripheral vein in a dose-related manner. PRA changes were unrelated both to blood pressure decrements and to heart rate increments induced by the drug. 3. Before phentolamine, inactive renin from the stenosed kidney (5.19, s.e.m. = 2.84 pmol ang I/ml per h) did not differ significantly from that on the contralateral side (3.15, s.e.m. = 1.96) and in the peripheral vein (4.40, s.e.m. = 1.96). Phentolamine induced significant (P < 0.005) increments of inactive renin only from the stenosed kidney at the doses of 0.3, 0.4 and 0.5 mg/min. Inactive renin from the contralateral kidney was unchanged and it tended to increase, but not to a significant extent, in the peripheral vein. A highly significant relationship was found between active and inactive renin from the stenosed kidney (r = 0.79, P < 0.001, n= 25) and in peripheral blood (r = 0.71, P < 0.001, n= 25) but not from the stenosed kidney (r = 0.29, n= 25). 4. These results suggest that phentolamine, infused at low increasing doses causes an increase of PRA only in the stenosed kidney, an action which does not seem to be wholly explained by either sympathetic nervous system activation or decrease of renal perfusion pressure, and which suggests an action on intrarenal a-adrenoreceptors. Furthermore, phentolamine stimulated inactive renin release only from the stenosed kidney without evidence of intrarenal conversion of the inactive into the active form.     

THE EFFECT OF FOOD ON CABERGOLINE PHARMACOKINETICS AND TOLERABILITY IN HEALTHY VOLUNTEERS

The effect of food on the pharmacokinetics and tolerability of cabergoline in man was investigated. For this purpose an open, randomized, single-dose study was conducted in 12 healthy male volunteers who received 1 mg cabergoline as tablets both under fasting conditions and after a breakfast containing a substantial amount of carbohydrates, fat, and proteins, in a crossover fashion. The two treatments were separated by a 4 week washout period. Plasma and urine were collected up to 336 and 168 h respectively after administration and cabergoline concentration was measured in both fluids using a validated radioimmunoassay. Tolerability assessment included haematology, blood chemistry, and urinalysis, blood pressure and heart rate measurements, and ECG. Under both fasting and fed conditions low but persistent cabergoline plasma levels were observed in the present study up to 2 weeks after drug intake, in agreement with the long-lasting prolactin-lowering activity of the drug. In subjects receiving cabergoline under fed or fasting conditions, C_max values averaged 44 and 54 pg mL⁻¹, AUC_{(0–336 h)} averaged 6392 and 5331 pg h mL⁻¹, Ae_{(0–168 h)} averaged 12·7 and 11·9 μg, and t_1/2 averaged 109·7 and 101·3 h, respectively. No statistically significant difference was found when C_max, AUC_{(0–336 h)}, t_1/2, and Ae_{(0–168 h)} from subjects treated under fasting and fed conditions were compared. Median t_max values in subjects treated under fasting or fed conditions were identical (2·5 h). The statistical analysis applied to the parameters chosen to evaluate the variations in the blood pressure profiles observed either supine or standing did not show any significant difference between the fed and fasting conditions. Heart rate values were not significantly modified after cabergoline under either fed or fasting conditions. Laboratory evaluation showed some minor deviations from normal, which were not clinically relevant (only one subject showed an occasional and transient elevation in alkaline phosphatase which disappeared in the subsequent laboratory evaluations) and were considered for the most part not to be drug related. Eleven subjects reported adverse events (one after both treatments, five only after drug intake under fasting conditions, and five only after drug intake with food). Side-effects, typical of the pharmacological class, included headache, somnolence, dizziness, nausea, light-headedness, feeling of faintness, and slowing of thought. They were reported mostly on the day of the first drug administration, were mainly short lasting, and were all mild or moderate in severity. In conclusion, the comparison of the pharmacokinetic and tolerability parameters evaluated in the present study indicates that the pharmacokinetics, as well as the safety, of cabergoline are not modified by food intake.     

PREVENTION AND REVERSAL OF OUABAIN-INDUCED CARDIOTOXICITY BY NALOXONE IN THE GUINEA-PIG

The effects of pre- and post-treatment with naloxone on the cardiotoxicity of ouabain in the guinea-pig were studied. After pretreatment with naloxone, the dose of ouabain required to induce ventricular arrhythmias and cardiac arrest were significantly increased, in a dose-dependent manner, compared with the control, indicating a protective effect of naloxone against digitalis intoxication. Administration of naloxone at the onset of cardiac arrhythmias induced by a lethal dose of ouabain restored the cardiac rhythm and consequently saved life in seven out of eight animals, indicating an antiarrhythmic effect of naloxone in digitalis-intoxicated guinea-pigs. The protective and antiarrhythmic effects of naloxone against digitalis intoxication have clinical implications.     

THE EFFECT OF CHLORPROMAZINE PRETREATMENT ON THE NARCOTIC ANTAGONISTIC POTENCY OF NALOXONE IN MICE

Morphine pretreatment (8.0 mg/kg s.c.) induced no overt tolerance to its antinociceptive effect in mice 4 h later, but enhanced the antagonistic potency of naloxone. Pretreatment with chlorpromazine hydrochloride (0.5–2.0 mg/kg s.c.) potentiated the antinociceptive effect of morphine measured 4.5 h later. The antagonistic effect of naloxone was also enhanced. The observed effect of chlorpromazine on naloxone potency was augmented when naloxone hydrochloride 0.2 mg/kg was administered in the pretreatment regime. The enhanced naloxone potency induced by morphine pretreatment was inhibited by chlorpromazine administered 0.5 h before the morphine pretreatment. These results indicate that pretreatment with either morphine or chlorpromazine increased the antagonistic potency of naloxone. However, it appears that these two drugs act by different mechanisms.     

THE EFFECT OF NALOXONE ON PRESSOR RESPONSES TO ANGIOTENSIN II IN ANAESTHETIZED GREYHOUNDS

In greyhounds anaesthetized with morphine and chloralose, vertebral artery infusions of angiotensin II resulted in a similar pressor response but smaller tachycardia than in greyhounds anaesthetized with chloralose alone. The pressor responses to intravenous infusions of angiotensin II were significantly larger in the morphine premedicated greyhounds. In greyhounds anaesthetized with morphine and chloralose, pressor responses to vertebral artery angiotensin II were potentiated following the administration of naloxone via either a vertebral artery or intravenously although the effect was more consistent with the former route. No such effect was seen in greyhounds anaesthetized with chloralose alone. Naloxone had no effect on the pressor responses to intravenous angiotensin II or carotid artery occlusion. The heart rate responses to vertebral artery angiotensin II in greyhounds anaesthetized with morphine and chloralose were potentiated by naloxone such that they were not significantly different from the responses obtained in greyhounds anaesthetized with chloralose alone before naloxone. As was observed with the pressor responses, the potentiation was more apparent with the vertebral artery route of administration of naloxone. There was no potentiation of the heart rate responses in the chloralose group of greyhounds. It is suggested that morphine premedication may repress the vagal withdrawal mechanism while potentiating the sympathetic vasomotor mechanism mediating the central cardiovascular actions of angiotensin II.     

ARTERIAL PRESSURE AND HEART PERIOD IN THE CONSCIOUS RABBIT: DIURNAL RHYTHM AND INFLUENCE OF ACTIVITY

Mean-arterial pressure (MAP), heart period (HP) and the level of physical activity were measured in conscious rabbits and averaged over one-hour periods during 14 consecutive days. Serial autocorrelation coefficients and serial crosscorrelation coefficients were computed, to analyse periodicity. Measurements were started immediately after implantation of the cannula (group A, n = 11) or 10-46 days after implantation of the cannula (group B, n = 6). In the course of 14 days, in group A, MAP decreased 9 mmHg and HP increased 21 ms (P less than 0.05). In group B, MAP decreased and HP increased in a similar way. Percentage activity did not show a trend. Significant diurnal rhythms were found. MAP and percentage activity reached the lowest values at noon, and the highest late in the evening. HP reached the highest values at noon and the lowest late in the evening. MAP and HP fluctuated exactly in antiphase. This suggests a common origin for both rhythms. During physical activity MAP was 10-15 mmHg higher and HP was 35-40 ms shorter than during rest. These differences did not show a trend or a diurnal variation. In individual animals MAP and HP varied greatly from hour to hour. These biological variations in MAP and HP as well as the influence of activity should be taken into account when conclusions are drawn from short-term measurements.     

NALOXONE ATTENUATES AUGMENTATION OF cAMP LEVELS AND ARRHYTHMIAS FOLLOWING MYOCARDIAL ISCHAEMIA AND REPERFUSION IN THE ISOLATED PERFUSED RAT HEART

The effects of myocardial ischaemia and reperfusion on arrhythmias and cAMP levels were studied using the Langendoff isolated perfused rat heart preparation. Myocardial ischaemia and reperfusion caused arrhythmias and augmentation of cAMP levels concurrently, supporting the suggestion that myocardial cAMP is related to arrhythmias. Pretreatment with naloxone attenuated both arrhythmias and augmentation of cAMP levels to a similar extent. The results suggest that the anti-arrhythmic effect of naloxone may involve myocardial cAMP.     

沙丁胺醇气雾剂在健康受试者体内的药代动力学及生物利用度研究

目的研究沙丁胺醇气雾剂在健康受试者体内的药代动力学及其相对于口服水溶液的生物利用度.方法以10名健康男性志愿者为研究对象,采取随机分组、自身对照、开放实验设计,在吸入或口服沙丁胺醇1.2mg后,定时采血,用HPLC方法测定血浆药物浓度,通过PCNONLIN软件进行房室模型拟合,求算药代动力学参数,用非房室模型计算相对生物利用度.结果沙丁胺醇气雾剂的人体内动力学过程符合二室开放模型.两种给药方式的T_max分别为(0.22±0.07)h和(1.8±0.6)h,C_max分别为(3.4±1.1)ng·mL^-1和(3.9±1.4)ng·mL^-1,T_1/2β分别为(4.5±1.5)h和(4.6±1.1)h.AUC_{0-20 min (inhal)}为AUC_{0-20 min (po)} 的7.94倍.相对生物利用度为57.23%.结论所建立的HPLC方法灵敏、专一、准确、精密.沙丁胺醇气雾剂在人体内的吸收过程与口服水溶液有显著差异.     

国产依诺沙星在健康人体内的药代动力学和制剂生物利用度研究

本文报道18例健康志愿者口服依诺沙星后的药代动力学参数和制剂的生物利用度。用高效液相色谱仪测定服药后15小时内的血浆药浓,结果表明:该药吸收迅速、分布相短暂,体内过程符合线性动力学。口服原粉(553mg)后主要药代动力学参数为:t_(max)=1.10±0.49h;C_(max)=4.37±0.82mg/L;K_α=2.89±1.10h~(-1);tlag=0.18±0.08h;AUC_(-noit)=31.71±6.84h·mg/L;其中13例为二室模型:K_(12)=0.51±0.36h~(-1);K_(21)=0.46±0.12h_(-1);t_(1/2)α=0.72±0.27h;t_(1/2)β=6.77±1.12h;另5例为一室模型:t_(1/2)Ke=4.98±0.55h。随机交叉口服片剂(600mg)和胶囊剂(1200mg),未发现血药浓度消除呈现剂量依赖性。供试3种片剂和1种胶囊剂与原粉比较,均具有较高的相对生物利用度,其范围为98.3％～101. 6％。     

左旋氧氟沙星对氨茶碱药物动力学的影响

采用荧光偏振免疫分析法(FPIA),在7名志愿者身上,对氨茶碱单用及与左旋氧氟沙星合用后,血中氨茶碱浓度的变化进行观测.结果表明,合用左旋氯氟沙星后氨茶碱消除速率常数k降低13.6%,清除率CL下降15.6%,半衰期T_1/2延长16.5%(P<0.05),但对峰浓度C_(max)、曲线线下面积AUC,表观分布容积V_d无显著影响(P相似文献   

NALOXONE BLOCKS THE CARDIAC EFFECTS OF MYOCARDIAL ISCHAEMIA AND REPERFUSION IN THE RAT ISOLATED HEART

The effects of naloxone on contractility and cardiac rhythm were studied in the rat isolated perfused heart during myocardial ischaemia and reperfusion. Pretreatment of the rat isolated perfused heart with naloxone abolished the reduction in left ventricular pressures and attenuated greatly the arrhythmias due to myocardial ischaemia and reperfusion. Administration of naloxone into the fibrillating rat isolated heart induced by myocardial ischaemia and reperfusion also attenuated the arrhythmias in a dose-dependent manner. The results indicate a possible involvement of the endogenous opioid peptides in the cardiac effects due to myocardial ischaemia and reperfusion. The antiarrhythmic effect of naloxone has great clinical implications.