Protective effects of betaglucin on myocardial tissue during myocardial infarction in rats and dogs

Aim： To test the protective effects of betaglucin, a novel beta-glucan, on models of myocardial infarction （MI） in rats and dogs. Methods： The left anterior descending （LAD） coronary artery occlusion model was used to induce an MI in rats and dogs. Three doses of betaglucin （10, 30 and 100 mg/kg）, propranolol （positive control, 1 mg/kg） and vehicle alone （5% glucose solution） were administered before LAD occlusion, and characteristics of the resulting MI were subsequently assessed. In anesthetized dogs, blood pressure heart rate, ventricular function, coronary artery blood flow and myocardial oxygen consumption were determined before and after the drug administration. Results： The MI mass in both rats and dogs was significantly reduced by betaglucin （30 and 100 mg/kg, P〈O.01） and propranolol （P〈O.01）. In anesthetized dogs, coronary artery blood flow was increased significantly by betaglucin （30 and 100 mg/kg, P〈O.01）, but blood pressure, heart rate and ventricular function were not changed （P〉O.05）. High-dose betaglucin （100 mg/kg） increased myocardial oxygen consumption, but not to a statistically significant level （P〉O.05）. The hemodynamic indexes were significantly changed by propranolol. Conclusion： Betaglucin has protective effects on myocardial tissue during MI in rats and dogs and has no influence on hemodynamic parameters at a therapeutic dose. The increase in coronary artery blood flow induced by betaglucin might be beneficial in the treatment of patients with MI.     

O16 Virtual dog for demonstrating the cardiovascular effects of drugs

Dogs are used for undergraduate medical, dental, pharmacy and veterinary practical classes to demonstrate the effects of drugs on the blood pressure （BP） and heart rate （HR）. This experiment can be replaced by simulating it on a computer using Computer Assisted Learning （CAL） software. Since CAL rather than the live experiment is sufficient to meet the objectives of a practical class, a CAL software to simulate the effects of drugs on dog BP and HR was developed. The software （developed in VisualBasic for Windows） displays a simulated chart recorder on which the animated tracings of BP and HR are recorded continuously. The user can choose any drug （and the dose） from the list provided, administer it to the virtual dog and measure its effects on BP and HR. When the software is run under the ‘ tutorial mode＇ , it allows the user to interactively test all the drugs in the list and observe their effects. In the‘examination mode＇ , an unknown drug is given and the student is asked to find out its nature by comparing its effects with those of known drugs. The software can serve as a replacement for the dog experiment. It is available free of cost at http ：//www. indphar, org and will be demonstrated.     

Influence of atropine on the cardiovascular effects of noradrenaline and tyramine in elder volunteers

The aim of this study, carried out in six elder healthy volunteers (mean age: 61 years), was to determine the influence of muscarinic receptor blockade with atropine (15 μg/kg i.v. loading dose followed by 0.15 μg/kg/min by i.v. infusion) on the effects of i.v. infusions of noradrenaline (5 incremental doses of 10-120 ng/kg/min) or tyramine, that releases endogenous noradrenaline (4 incremental doses of 5-20 μg/kg/min), on blood pressure, heart rate and systolic time intervals (STI’s, as a measure of positive inotropism). These results were compared with those recently published for young healthy volunteers (mean age: 26 years; Sch?fers et al. 1997). Noradrenaline caused increases in systolic and diastolic blood pressure, decreases in heart rate and a shortening of STI’s that were not different from those in young volunteers. Atropine did not significantly affect these hemodynamic responses to noradrenaline, while in young volunteers it significantly enhanced noradrenaline-induced blood pressure increases and converted the heart rate decrease into an increase. In the present study in elder volunteers, tyramine caused a smaller increase in systolic blood pressure than in the previous study in young volunteers; in addition, it slightly increased diastolic blood pressure while it decreased diastolic blood pressure in young volunteers. Atropine did not significantly affect the hemodynamic effects of tyramine in the elder volunteers, while in the young volunteers it enhanced the increase in systolic blood pressure and converted the decreases in diastolic blood pressure and heart rate into increases. These results indicate a) that ageing is accompanied by a blunted baroreflex-mediated parasympathetic activation resulting in reduced cholinergic vasodilation and decreases in heart rate, and b) that ageing is associated with a decreased responsiveness of (cardiac) β-adrenoceptors and (vascular) α₁-adrenoceptors which is only unmasked when the counterregulatory action of parasympathetic activation is removed. Received: 24 January 1997 / Accepted: 21 April 1997     

黄芪皂苷甲对血浆cAMP及再生肝DNA合成的影响

Astragalus saponin 1, one of the components isolated from Astragalus membranaceus Bge was found to induce accumulation of cAMP in rabbit plasma at the ip dose of 10mg/kg. The increase of cAMP started at 30 rain and reached maximum in 0.5～4h after a single injection. The effect of the component on DNA biosynthesis in partially hepatectomized mice seemed to be significant. The component was also shown to enhance the incorporation of [³H] TdR into the regenerating liver in mice.     

The interaction effect of grapefruit juice is maximal after the first glass

Objective: To compare the acute effect of grapefruit juice intake on the pharmacokinetics and haemodynamic effects of felodipine ER tablets with the interaction after 14 days′ intake of drug with juice. Methods: Twelve healthy male volunteers were included in this cross-over trial and randomly allocated to a daily intake of a 10-mg felodipine extended release tablet with water or grapefruit juice for 14 days. The two study periods were separated by at least 14 days. The pharmacokinetics of felodipine and dehydrofelodipine, as well as the haemodynamic effects of the drug, were studied during day 1 and 14 in each period. Results: Similarly to previous single-dose studies, the treatment during the first day with grapefruit juice increased the AUC (+73%) and C_max (+138%) of felodipine when compared with the control treatment. On day 14 a similar effect of grapefruit juice was observed, with an increased AUC₂₄ (+57%) and C_max (+114%) of felodipine compared with the control experiment. A significant accumulation of felodipine occurred during both the control (+37%) and grapefruit juice (+25%) period. The extent of accumulation was not significantly different in the two treatment periods. The pharmacokinetics of the metabolite dehydrofelodipine were affected to a similar extent by the juice on day 1 and day␣14. The first dose of felodipine together with grapefruit juice was associated with a significant additional increase in heart rate when compared with the control therapy, whereas there was no additional effect on blood pressure when therapy included grapefruit juice. On day 14 the intake of drug with juice resulted in an additional increase in heart rate and reduction in diastolic blood pressure in comparison with the control experiment. Furthermore, the vascularly related adverse events were more frequent in the period including grapefruit juice. Conclusion: The interaction between grapefruit juice and felodipine appears to be already fully developed after the first glass of grapefruit juice, as the change in pharmacokinetics in comparison with the control experiment is similar on day 1 and on day 14. Concomitant intake of 10 mg felodipine ER and the juice is associated with increased haemodynamic effects in healthy subjects both after a single dose and following 14 days of concomitant intake. Received: 6 June 1997 / Accepted in revised form: 12 November 1997     

Effect of Korean red ginseng on blood pressure and nitric oxide production

AIM: To investigate the effect of crude saponin and non-saponin fraction of Korean red ginseng (KRG) on the blood pressure and nitric oxide (NO) production in the conscious rats and cultured endothelial cell line, ECV 304 cells. METHODS: Systolic blood pressure and heart rate were monitored in the conscious rats. Nitric oxide levels and the expression of nitric oxide synthase were measured by a spectrophotometric assay using Griess reagents and Western blotting, respectively. Nitric-oxide synthase activity was measured based on the conversion rate of [3H]arginine to [3H]citrulline. RESULTS: Systolic blood pressure was decreased by crude saponin (100 mg/kg, iv) of KRG in the conscious control and one-kidney, one-clip Goldblatt hypertensive (IK, 1C-GBH) rats. The hypotensive effect induced by crude saponin of KRG reached maximum at 2 - 4 min and slowly recovered after 20 min to the initial level in both groups. Crude saponin of KRG induced tachycardia in the conscious rats but induced bradycardia in the a     

Effects of adenosine and adenosine analogues on mean circulatory filling pressure and cardiac output in anesthetized rats

The effects of adenosine and adenosine analogues, 2-[p-(2-[carboxyethyl) phenethylamino]-5’-N-ethylcarboxamidoadenosine (CGS 21680) and N⁶-2-(4-aminophenyl)-ethyladenosine (APNEA), on mean arterial pressure, cardiac output, mean circulatory filling pressure, arterial resistance, venous resistance and heart rate in untreated or treated (with ganglion-blockers mecamylamine and atropine) pentobarbital-anesthetized rats were examined. Infusion of adenosine (100, 300 and 900 μg/kg/min), CGS 21680 (0.1, 0.3 and 0.9 μg/kg/ min) or APNEA (1.0, 3.0 and 9.0 μg/kg/min) reduced mean arterial pressure and arterial resistance in all groups. Adenosine and APNEA also reduced mean circulatory filling pressure, venous resistance and heart rate in untreated animals. Furthermore, APNEA but not adenosine reduced cardiac output. In contrast, CGS 21680 increased cardiac output and heart rate but did not have any effect on mean circulatory filling pressure or venous resistance. In ganglion-blocked rats, APNEA reduced cardiac output, mean circulatory filling pressure and heart rate, while adenosine did not have any effect on these parameters. In addition, APNEA and adenosine reduced arterial resistance but were unable to alter venous resistance while CGS 21680 reduced mean circulatory filling pressure and arterial resistance but did not further affect cardiac output, heart rate and venous resistance in ganglion-blocked animals. The results of the present study suggest that adenosine and APNEA dilate arterioles and vein, whereas CGS 21680 causes arterial dilatation but not venodilatation in untreated animals due to hypotension-induced sympathetic activation. A possible explanation for the present observations could be differences in the distribution of vascular A₂ versus A₃ adenosine receptors in the venous circulation. Reza Tabrizchi Received: 17 September 1996 / Accepted: 27 March 1997     

Potassium diet as a determinant for the renal response to systemic potassium channel modulation in anesthetized rats

The role of potassium intake in the response of kidney function and plasma renin activity (PRA) to systemic application of U37883A (4-morpholinecarboximidine-N-1-adamantyl-N’-cyclohexyl-hydrochloride), a putative blocker of ATP-sensitive potassium channels (K_ATP), and P1075 (N-cyano-N’-(1,1-dimethylpropyl)-N’’-pyridylguanidine), an opener of K_ATP channels, was studied in the anesthetized rat. It was found that under normal potassium diet (0.7% K), U37883A (15 mg/kg, i.v.) increased urinary flow rate (UV) and sodium excretion (UNaV), decreased urinary potassium excretion (UKV), and significantly diminished heart rate (HR) without affecting mean arterial blood pressure (MAP) or glomerular filtration rate (GFR). P1075 (10 μg/kg, i.v.) lowered UV, UNaV and UKV, at least in part due to the fall in MAP and GFR.PRA was diminished by U37883A and increased by P1075.Variation in potassium diet (0.04 or 2% K) left the response in MAP, HR or GFR to both potassium channel modulators essentially unchanged. The reduction in renal excretion rates to P1075 also appeared unaffected, further supporting a predominant role of the change in MAP and GFR in this response. Variation in potassium diet, however, elicited the following alterations: (1) under both low and high potassium diet U37883A did no longer cause a significant natriuresis; (2) U37883A elicited a significant kaliuresis under high potassium diet, whereas potassium excretion remained essentially unchanged on very low levels under low potassium diet; (3) the increase in PRA to P1075 was blunted under low potassium diet. Additional experiments provided evidence that P1075 releases renin from freshly isolated juxtaglomerular cells of rats on normal but not on low potassium diet. In summary, systemic potassium channel modulation employing U37883A or P1075, respectively, exerts distinct effects on blood pressure and heart rate independent of potassium diet. In contrast, potassium diet appears to be a determinant for the concomitant reponses in plasma renin activity and renal sodium and potassium excretion. Received: 3 December 1997 / Accepted: 23 April 1998     

Cardiovascular actions of Radix Stephaniae Tetrandrae: a comparison with its main component, tetrandrine

A comparison of the cardiovascular actions of the extract of Radix Stephaniae Tetrandrae (RST), the root of a Chinese herb Stephania tetrandra S Moore, in rats with those of tetrandrine (Tet), the best known active component of RST was reviewed. The RST extract inhibits Ca2 influx into the myocyte and reduces protein release during reperfusion with a Ca2 containing solution following perfusion with a Ca2 free solution (Ca2 paradox) , and arrhythmia during reperfusion in the isolated perfused heart. It also reduces the infarct size induced by ischemia/reperfusion in vitro and in vivo. In addition, the RST extract suppresses elevation of arterial blood pressure in DOCA-salt hypertensive rats. It does not further reduce the heart rate and coronary flow significantly during myocardial ischemia. The effects are similar to those of Tet. When compared with the same doses of Tet alone, the RST extract, of which 9 % is Tet, produces equally potent effects on infarction, arrhythmias, coronary flow and heart r     

N-乙酰半胱氨酸和L-NAME对磷化铝诱导的大鼠心血管毒性的作用(英文)

AIM: To investigate the protective effects of N-acetyl-cysteine (NAC) and N~ω-Nitro-L-arginine methyl ester(L-NAME) on aluminium phosphide (AlP) poisoninginduced hemodynamic changes, myocardial oxygen freeradical in injury and on survival time in rats. METH-ODS: AlP (12.5 mg/kg) was administered intragastri-cally under urethane anaesthesia. The effect of pre- andpost-treatment with NAC and L-NAME alone and incombination was studied on haemodynarnic parameters[blood pressure (BP), heart rate (HR), and electrocar-diogram (ECG) ] and biochemical parameters (malonyl-     

Modification of cardiovascular responses to intravenous phenytoin by dopamine in dogs: Evidence against an adverse interaction

Phenytoin (sodium diphenylhydantoin) was studied for its blood pressure and heart rate effects in conscious and anesthetized dogs, alone and in combination with dopamine HCl. In conscious dogs phenytoin administered intravenously (0.15–1.0 mg/kg/min) at different infusion rates (total dose, 25 mg/kg) produced consistent central nervous system (CNS) excitation (agitation, emesis, incoordination) at doses below those required to produce hypotension. Concomitant administration of phenytoin (total dose, 23–32 mg/kg) and dopamine (2.5, 10, or 25 μg/kg/min) did not produce adverse effects on blood pressure and heart rate. In the anesthetized dog, iv infusions of phenytoin (0.88–1.0 mg/kg/min for 70 min) produced a progressive lowering of blood pressure and heart rate, and four of seven dogs died (total dose, 55–70 mg/kg). When dopamine (25 μg/kg/min) and phenytoin were infused simultaneously, the blood pressure and heart rate changes were reduced, and only one of seven dogs died (total dose, 71 mg/kg). When the dopamine infusion was started after phenytoin had already produced a severe hypotension or after the total dose of phenytoin had been given, dopamine raised the blood pressure and heart rate in four of seven dogs. Three dogs failed to respond and died (total dose, 65–77 mg/kg). These experiments show that phenytoin and dopamine do not adversely interact to produce cardiovascular collapse in dogs and suggest that dopamine may be supportive in phenytoin-induced hypotension, thus supporting the simultaneous use of these agents where clinically indicated in man.     

General pharmacological actions of traxanox sodium. II. Effects on the cardiovascular system

The effects of traxanox, an anti-allergic drug, on the cardiovascular system were studied in both anesthetized dogs and cats and in isolated heart preparations from guinea-pigs. In anesthetized dogs, a very small dose of traxanox (0.01 mg/kg, i.v.) had no effect, but 0.1--30 mg/kg caused an increase in respiratory rate, hypotension, bradycardia, a transient decrease followed by an increase in renal blood flow, and a decrease in femoral blood flow. These effects were abolished by vagal block, indicating they are mediated via vagal afferents. In contrast, oral administration of traxanox (100 mg/kg) had no effect on the blood pressure or heart rate of anesthetized dogs. In anesthetized cats, traxanox (3 and 30 mg/kg, i.v.) caused a slight increase in blood pressure, but showed no effect on respiratory rate and heart rate. Both traxanox and theophylline (10(-4)M) caused increases in the beat rate of the atria and the contractile force of the papillary muscle in isolated preparations from guinea-pigs, and they potentiated the positive chronotropic and inotropic responses induced by isoproterenol. On the other hand, in anesthetized and vagotomized dogs, traxanox (3 and 10 mg/kg, i.v.) affected neither the left ventricular contractile force nor the hypotension and positive inotropic and chronotropic responses produced by isoproterenol. Administration of theophylline alone (3 and 10 mg/kg, i.v.) caused hypotension and increases in contractile force and heart rate, but it did not enhance the responses produced by isoproterenol. At doses of 1 and 10 mg/kg (i.v.), traxanox had little effect on either pressor or chronotropic responses to norepinephrine, epinephrine, DMPP and stellate cardiac nerve stimulation. The same doses of traxanox slightly reduced the depressor and chronotropic responses to isoproterenol, acetylcholine and vagus nerve stimulation. These findings suggest that traxanox had no effect on the cardiovascular systems of the animals studied in the dose range (1--5 mg/kg, p.o.) showing anti-allergic activity.     

Cardiovascular and bronchial actions of famotidine in anesthetized dogs

The effects of famotidine (Gaster; CAS 76824-35-6) and cimetidine on cardiovascular and bronchial functions were investigated in anesthetized dogs. Famotidine did not affect heart rate, blood pressure, left ventricular pressure (LVP), max. dLVP/dt, cardiac output or coronary blood flow at i.v. doses of 1 to 30 mg/kg in open-chest dogs anesthetized with pentobarbital or a combination of nitrous oxide, oxygen and halothane (GOF). No hemodynamic changes were either observed after famotidine in pentobarbital anesthetized dogs whose cardiac function was depressed by propranolol (1 mg/kg i.v.). On the contrary, cimetidine dose-dependently decreased heart rate and blood pressure at doses greater than 3 mg/kg, and left ventricular pressure, cardiac output and coronary blood flow at the dose of 30 mg/kg. Regarding the electrocardiogram (ECG), famotidine did not produce any remarkable change at doses up to 30 mg/kg with the exception of a transient increase or decrease in the T-wave amplitude at a dose of 30 mg/kg. Cimetidine prolonged Q-T intervals of ECG in addition to changing the T-wave at a dose of 30 mg/kg. Neither famotidine nor cimetidine showed any effect on resting and histamine-increased bronchoresistance at doses up to 30 mg/kg. It is concluded that famotidine is superior to cimetidine with regard to safety because famotidine has no significant effects on cardiovascular functions in anesthetized dogs.     

Hemodynamic effects of labetalol in the dog. Comparative study in the anesthetized open-chest dog and in the conscious dog

Hemodynamic effects of labetalol, an alpha- and beta-adrenoceptor blocking drug, were investigated in the conscious dog and in the anesthetized open-chest dog. In the conscious dog, intravenous injection of labetalol, in a dose of 0.5 mg/kg, decreased the total peripheral resistance by approximately 20% (P less than 0.01) in association with falls in blood pressure and heart rate. The total peripheral resistance of the anesthetized open-chest dog was not affected by labetalol in the presence of the same extent of blood pressure fall as results of the conscious dog. In contrast, agents which have beta-adrenoceptor blocking effect alone provided substantial elevation of the total peripheral resistance in the anesthetized dog. These results indicate that the different responses of the resistance to labetalol probably result from the vascular alpha-adrenoceptor blocking action, and also show that in the conscious state alpha-adrenoceptor blocking action of labetalol is enhanced in comparison with the effect in the anesthetized open-chest dog.     

Cardiovascular effects of intravenous pentazocine and cyclazocine in conscious, curarized-conscious, and anesthetized dogs

The cardiovascular effects of intravenous pentazocine and cyclazocine in dogs were studied under conscious, curarized-conscious (paralyzed by gallamine), and anesthetized states. In the conscious state, blood pressure and heart rate were dose-dependently increased by pentazocine (1, 2, 3 mg/kg) and to a lesser extent by cyclazocine (0.3 mg/kg). In all subsequent experiments on dogs, the results were obtained using 3 mg/kg pentazocine and 0.3 mg/kg cyclazocine. Pentazocine accelerated breathing, peaking at about 10 min, whereas cyclazocine reduced breathing to a minimum in 1 min, followed by a gradual recovery thereafter. In the curarized-conscious state, the blood pressure response to pentazocine was biphasic, namely an initial decrease followed by an increase; chronotrophic activity was stimulated. Pretreatment with either ganglionic or alpha andrenergic blocking agents not only significantly antagonized the pressory responses to the drug but also potentiated the initial decreases in blood pressure and unmasked a bradycardic component, but these parameters were not altered by 0.3 mg/kg naxalone. In open-chest anesthetized dogs, blood pressure, heart rate, contractility, and mean peripheral vascular resistance were simultaneously decreased by both pentazocine and cyclazocine, initially accompanied by increases in aortic blood flow. During the later stages of drug action, only the blood pressure and contractility were increased above control levels (biphasic effect). A comparison of blood pressure and heart rate responses to pentazocine in dogs kept under differing experimental conditions revealed that conscious dogs were more sensitive than curarized conscious and anesthetized animals to pentazocine action. In isolated guinea pig atria, the effect of adrenaline (0.1, 0.3, or 1 mg/mL) on the spontaneous breathing rate was significantly augmented by 10 mg/mL pentazocine (p < 0.02 for 0.3 g/mL; p < 0.01 for 0.1 g/mL adrenaline). In dogs, however, adrenaline (1 mg/kg)-induced increases in heart contractility, aortic blood flow, and blood pressure remained almost unaltered in the presence of pentazocine. We concluded that the abovementioned cardiovascular responses to pentazocine and cyclazocine are a consequence of the sum of the two following opposing effects: (i) an indirect reflex activation of sympathetic neuromediation in the periphery, and (ii) a direct membrane effect on the heart leading to bradycardia and a depression in myocardial contractility.     

Effects of tetramethylpyrazine on heart rate and pupil diameter in rats

The alpha-adrenergic nature of tetramethylpyrazine (TMPZ), a commonly used cardiovascular drug in China, was studied with a combined bradycardia and mydriasis model in the pentobarbital anesthesized rat. Intravenous injections of TMPZ at 1-30 mg/kg failed to change heart rate or pupil size, whereas iv injections of both clonidine (alpha 2-adrenoceptor agonist, 1-30 micrograms/kg) and methoxamine (alpha 1-adrenoceptor agonist, 10-300 micrograms/kg) caused dose-dependent bradycardia and mydriasis. Pretreatment of rats with TMPZ (30 mg/kg) did not significantly change clonidine- or methoxamine-induced bradycardia or mydriasis. However, when TMPZ was injected 2 min after clonidine administration (30 micrograms/kg), while the mydriasis reached a maximum, it slightly but significantly reversed the clonidine-induced mydriasis for 15-20 s. In contrast, the alpha 2-adrenoceptor antagonist idazoxan (6 micrograms/kg) caused the same degree of reduction of the clonidine-induced mydriasis for greater than 2 min. Our results suggested that TMPZ at the doses studied did not have alpha-adrenoceptor agonistic activities, but may have slight alpha 2-adrenoceptor antagonistic activities.     

General pharmacology of IY-81149, a new proton pump inhibitor

IY-81149 (2-[(4-methoxy-3-methyl)-2-pyridinyl]methylsulfinyl -5-(1H-pyrrol-1-yl)-1H-benzimidazole, CAS 172152-36-2) is a new proton pump inhibitor and expected to be an antiulcer drug. Its general pharmacological effects were studied in this paper. The doses given were vehicle control, 0.3, 1, 3, 100, 300 and 1000 mg/kg and were administered orally. The animals used in this study were mouse, rat, guinea pig and beagle dog. IY-81149 decreased spontaneous locomotor activity at 1000 mg/kg and showed a weak effect in motor performance at 300 and 1000 mg/kg. IY-81149 prolonged the hexobarbital-induced sleeping time dose dependently at 100, 300 and 1000 mg/kg. Oral administration of IY-81149 caused a dose-dependent hypothermic effect up to 300 mg/kg and showed analgesic effect at 1000 mg/kg. IY-81149 produced an antisecretory effect in pylorus ligated rats. The total gastric volume and acidity were significantly decreased at doses ranging from 1 to 3 mg/kg. However, IY-81149 had no effects on general behavior, did not show anticonvulsant activity, and did not affect blood pressure and heart rate, LVP (left ventricular peak systolic pressure), LVEDP (left ventricular end diastolic pressure), LVDP (left ventricular developing pressure), DP (double product), HR (heart rate), CFR (coronary flow rate), smooth muscle contraction, respiration, intestinal transport and renal function. These findings demonstrate that IY-81149 possesses weak central nervous system action and inhibitory effects on microsomal enzymes and gastric secretion after single administration. The results suggest that IY-81149 does not exert any notable pharmacological effects on the cardiovascular system, autonomic nerve system or smooth muscle function at all doses tested.     

Pharmacological effects of the antianxiety compound suriclone and its principal metabolites

The pharmacodynamic effects of 4-methyl-1-piperazinecarboxylic acid ester with (+/-)-6-(7-chloro-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-7-h ydr oxy-5H-p- dithiino[2,3-c]pyrrol-5-one (suriclone, RP-31264) and its principal metabolites M1 and M2 on respiration, cardiovascular system, autonomic nervous system, smooth muscle and other physiological parameters were investigated in various animal species. Suriclone, 1 mg/kg i.v., increased the amplitude of respiratory movement, decreased the respiratory rate and blood pressure and increased the heart rate in conscious rabbits. The respiratory and depressor effects were more evident in pentobarbital anesthetized rabbits. In anesthetized dogs, suriclone, 0.05 or 0.5 mg/kg i.v., produced essentially the same effects as seen in the anesthetized rabbits. The ECG pattern was not significantly changed in any animal. Such effects on respiration and on the cardiovascular system of metabolites M1 and M2 in the rabbits were weak. In the isolated guinea-pig atria, suriclone, 10(-6) g/ml, had no effect but increased contractility and decreased heart rate at a high concentration of 10(-5) g/ml. Both M1 and M2 had weak effects. Suriclone had no action on flow rate of the perfusate through the blood vessels of the isolated rabbit ear. In anesthetized dogs, suriclone 0.5 mg/kg i.v., did not affect the responses to vagal stimulation or to pre- and postganglionic stimulation of cardiac ganglion. Suriclone instilled onto the eye or i.v. had no appreciable effect on pupillary diameter or the miotic response in rabbits, but an abnormal oculogyration was evoked when the drug was given i.v. at 1 mg/kg. M1 or M2 had no such effect. Suriclone did not exert analgesic effects in mice.(ABSTRACT TRUNCATED AT 250 WORDS)     

General pharmacological studies on N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate. 3rd communication: effect on cardiovascular system

In this general pharmacological study of N-[2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate (SUN 1165), its effects on the cardiovascular and respiratory systems were studied. SUN 1165, at doses of up to 1.0 mg/kg i.v., had almost no effect. SUN 1165, at doses of 3.0 and 6.0 mg/kg i.v., caused dose-dependent decreases in blood pressure, common carotid, vertebral, coronary, hepatic and femoral artery and portal vein blood flows, cardiac contractility, heart rate and myocardial oxygen consumption. SUN 1165 increased urine volume and urinary excretion of electrolytes in rats at a dose of 100 mg/kg p.o. SUN 1165 decreased renal plasma flow and urinary excretion of electrolytes in anesthetized dogs at 6.0 mg/kg i.v., but at the antiarrhythmic doses (1.0-3.0 mg/kg i.v. in dogs), it had almost no effects on renal function. SUN 1165 had almost no effect on the autonomic nervous systems in anesthetized dogs. These results suggest that SUN 1165 at the antiarrhythmic doses do not have any effects on the respiratory and cardiovascular systems, renal function and autonomic nervous systems in rats and dogs, but that when administered at high doses, it has inhibitory effects on respiratory and cardiovascular system and renal function. In conclusion, SUN 1165 seems to be a novel antiarrhythmic drug relatively free of cardiovascular, respiratory, renal and autonomic effects.     

Pulmonary and cardiovascular effects of mefloquine methanesulfonate

Mefloquine methanesulfonate (WR-142, 490·CH₃SO₃H), a highly effective antimalarial agent, when infused at a dose rate of 1 mg/kg/ min for 20 min in the anesthetized dog, caused either little or no effect on the pulmonary and cardiovascular parameters measured during this drug infusion or in the following 3-hr observation period. However, dose rates of 2 and 3 mg/kg/min of mefloquine MS for 20 min did produce pulmonary and cardiovascular changes. The respiratory parameters which were observed to change were: (1) tidal volume, which fell during the drug infusion but then returned to control values during the remaining portion of the observation period; (2) respiratory rate, which rose during the drug infusion, but returned to control values; (3) dynamic airways resistance, which decreased during drug administration, but then rose above control values; (4) small gradual changes in blood p_O2 and p_CO2. The cardiovascular parameters observed to change were: (1) arterial blood pressure, which decreased during the drug infusion, but returned rapidly to control values; (2) cardiac contractile force, which diminished during the drug infusion and returned toward control values later in the observation period; (3) central venous pressure, which rose transiently during drug administration; (4) pulmonary artery pressure, which rose initially, but tended to decrease late in the observation period and returned to control values within a 24-hr period. The magnitude of the effects of mefloquine MS appeared to be more dependent on the dose rate of drug delivery than on the total dose delivered.