Comparison of development of tolerance between nicorandil and nitroglycerin in anesthetized, open-chest dogs

Development of tolerance to nicorandil (NCR), N-(2-hydroxyethyl) nicotinamide nitrate (ester), was compared with that to nitroglycerin (NTG) in dogs. An intra-coronary arterial (i.a.) injection of NCR (30 micrograms) or NTG (3 micrograms) produced coronary vasodilation. Development of tolerance (including cross tolerance) was determined by examining whether the coronary vasodilating effect of i.a. injection of these drugs was attenuated by a 2 hr-infusion of NCR or NTG. The effect of i.a. injection of NCR was not affected by either NCR infusion (10 micrograms/kg/min, i.v.) or NTG infusion (1 or 3 micrograms/kg/min, i.v.). The effect of i.a. injection of NTG, however, was attenuated by the NTG infusion, while it was not affected by the NCR infusion. Additionally, the coronary vasodilating effect of NCR infusion (30 micrograms/kg/min, i.v.) was not attenuated by NTG infusion (3 micrograms/kg/min, i.v.). These results suggest that NCR does not produce tolerance, whereas NTG does, and that there is no cross-tolerance between NCR and NTG in terms of the coronary vasodilating effect.     

硝酸甘油和尼可地尔对缺血区冠脉循环作用的比较

采用实验性冠脉狭窄犬模型,冠脉内恒流灌注硝酸甘油和尼可地尔(均为1μg·kg~(-1)·min~(-1)).发现硝酸甘油有两种作用:灌注5min时能扩张冠脉狭窄段(R_L)及狭窄远端小动脉(R_s),增加冠脉血流量(CBF),改善心肌缺血;但灌注10min后.却引起R_L的增加、CBF的减少,使冠状静脉全血粘度(Hb)、血细胞比容(Hct)增加。加重心肌缺血和恶化冠脉循环。尼可地尔能持久和缓和地扩张冠脉.使R_S降低,CBF增加,降低冠状静脉的Hb、Hct.改善缺血区冠脉循环。     

苦碟子注射液对犬心脏功能和血流动力学的影响

目的考察苦碟子注射液对麻醉开胸犬心脏功能和血流动力学的影响。方法采用麻醉开胸犬模型,测量其心率、心输出量、冠脉流量、心肌耗氧量以及血流动力学各参数。结果苦碟子注射液以2.0、4.0 g.kg-1静脉注射给药可显著增加戊巴比妥钠麻醉犬的心输出量和冠脉流量,降低平均动脉压、左心室内压和左心室舒张末期压力,减少左室内压力变化速度和心肌耗氧量(P<0.05,P<0.01)。结论苦碟子注射液能显著改善麻醉开胸犬血流动力学。     

Regional coronary haemodynamic effects of two inhibitors of nitric oxide synthesis in anaesthetized, open-chest dogs.

1. The role of endothelial nitric oxide synthesis from L-arginine in the regulation of coronary vascular tone and myocardial tissue perfusion was evaluated in anaesthetized, open-chest dogs. Coronary blood flow was measured with an electromagnetic flow probe placed around the left circumflex coronary artery. Coronary vascular resistance was calculated from mean arterial blood pressure and mean coronary blood flow, whereas regional myocardial tissue flow was determined by use of the radioactive microspheres technique. 2. NG-monomethyl L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME), administered directly into the left circumflex artery, induced a small increase in arterial blood pressure and an increase in coronary vascular resistance. However, myocardial tissue perfusion, assessed by the microspheres technique (whether subendocardial, subepicardial, or transmural), was unaffected by L-NMMA or L-NAME. 3. Acetylcholine, administered intracoronarily, induced an increase in left circumflex coronary blood flow and a decrease in coronary vascular resistance, without affecting systemic haemodynamics. This coronary vasodilator effect of acetylcholine was markedly inhibited by L-NMMA and L-NAME, the latter being a more potent antagonist than the former. 4. These results indicate that the endothelial L-arginine pathway is largely responsible for the coronary vasodilator effect of acetylcholine. However, although basal release of nitric oxide from L-arginine apparently contributes to the regulation of resting coronary vascular tone, blockade of this pathway does not affect myocardial tissue perfusion, possibly because of compensatory mechanisms occurring at the level of small arterioles and/or capillaries.     

Effects of cromakalim, pinacidil and nicorandil on cardiac refractoriness and arterial pressure in open-chest dogs

The cardiac electrophysiologic effects of the potassium channel activators cromakalim, pinacidil and nicorandil were determined in anesthetized open-chest normotensive dogs using conventional surface electrogram recording techniques. Intravenous administration of cromakalim (0.025-0.5 mg/kg), pinacidil (0.1-2.0 mg/kg) and nicorandil (0.1-2.5 mg/kg) produced large dose-dependent decreases in arterial blood pressure accompanied by smaller reductions of atrial and ventricular effective refractory periods. The shortening of refractoriness was more pronounced in the atrium than in the ventricle and was similar for all three compounds at a given level of hypotension. Effects on other electrophysiological parameters were minimal. Atrial arrhythmias could be induced during electrical pacing at doses of cromakalim and pinacidil producing excessive (greater than or equal to 40%) decreases in mean arterial pressure. No arrhythmias were observed with nicorandil. Induction of the arrhythmias appeared to be closely coupled to the extrastimuli (S2) used to determine refractory periods and was associated with a significant reduction in atrial refractory period (greater than or equal to 30%). No ventricular arrhythmias were observed in this study with any of the compounds tested. Although the plasma levels reached in this study are likely to be higher than those seen clinically, the results nevertheless suggest the potential for cardiac electrophysiologic effects by these agents.     

Hemodynamic effects of zinc sulfate on anesthetized open-chest dogs

ZnSO4 3-5 mg/kg iv decreased systolic blood pressure, diastolic blood pressure and mean arterial blood pressure, +dP/dtmax, -dP/dtmax, VCE- +dP/dtmax, and left ventricular systolic pressure. However, ZnSO4 had no significant effects on T values and total peripheral resistance. In addition, ZnSO4 obviously decreased heart rate and cardiac index. These results suggest that iv ZnSO4 may cause hypotension via cardiac inhibition.     

Comparison of vasodilating effects of nisoldipine and nifedipine in anesthetized open-chest dogs

Hemodynamic effects of nisoldipine (Bay k 5552) were compared with those of nifedipine in anesthetized open-chest dogs. Both nisoldipine and nifedipine produced a fall in aortic pressure and increases in aortic, vertebral and coronary blood flows. After administration of nisoldipine, renal blood flow, heart rate and left ventricular enddiastolic pressure were not changed, but left ventricular dP/dt was increased. After administration of nifedipine, renal blood flow and left ventricular dP/dt were decreased, and left ventricular enddiastolic pressure was elevated. Heart rate was hardly changed. Durations of increases in aortic, vertebral and coronary blood flows were about 3 times longer after nisoldipine than after nifedipine. Percent decrease in coronary vascular resistance was greater and percent decrease in renal vascular resistance was smaller than that in total peripheral vascular resistance with both nisoldipine and nifedipine. Results indicate that nisoldipine and nifedipine produce marked coronary vasoldilation and the vasodilating effect of nisoldipine lasts longer than that of nifedipine.     

Cardiovascular effects of flesinoxan in anaesthetized and conscious dogs

Summary Stimulation of 5-HT_1A receptors is known to decrease the arterial blood pressure in anaesthetized rats, cats and dogs. We investigated the hypotensive activity of flesinoxan (0.1 + 0.2 + 0.7 mol/kg), a 5-HT_1A-receptor agonist, in dogs anaesthetized with either morphine and pentobarbital or enflurane and also in the conscious state. Flesinoxan led to a decrease in arterial blood pressure in anaesthetized, but not in conscious dogs. In the conscious state the marked increase in heart rate, which can be taken as an indicator of sympathetic tone, may have masked the consequences of vasodilatation. These different haemodynamic responses to flesinoxan may be dependent on side effects of the drug in the conscious dogs, in particular hyperventilation and salivation combined with anxiety, and on the magnitude of the decrease in baroreceptor reflex activity during anaesthesia with morphine and pentobarbital on the one hand and enflurane on the other hand.     

On the mechanism of the protective effects of nitroglycerin and nicorandil in cardiac anaphylaxis

Previous investigations have shown that nitric oxide donors and nicorandil can suppress allergic reaction. In the present study, the protective effects of nitroglycerin and nicorandil on cardiac anaphylaxis were examined. Presensitized guinea-pig hearts challenged with specific antigen caused a marked decrease in coronary flow (CF), left ventricular pressure (LVP) and its derivatives (+/-dp/dtmax), increase in heart rate, and prolongation of P-R interval. Nitroglycerin (300 nM) or nicorandil (100 microM) markedly increased the content of calcitonin gene-related peptide (CGRP) concomitant with a significant improvement of the cardiac dysfunction and alleviation of the extension of P-R interval. Nicorandil at a concentration of 100 microM also inhibited the sinus tachycardia and histamine release. The protection afforded by nitroglycerin was abolished by glibenclamide, a blocker of ATP-sensitive potassium channels, or by CGRP8-37, the selective CGRP receptor antagonist, or by pretreatment with capsaicin, which depletes endogenous CGRP. The inhibitory effect of nicorandil on cardiac anaphylaxis was abolished only by glibenclamide but not by pretreatment with capsaicin. These results suggest that nitroglycerin and nicorandil possess a protection of cardiac anaphylactic injury. The present study also suggests that the protective effect of nitroglycerin may be related to stimulation of CGRP release and opening the KATP channel, and that the effect of nicorandil is mainly due to the activation of the KATP channel.     

卡维地洛对麻醉犬血流动力学的影响

目的　观察国产卡维地洛（ｃａｒｖｅｄｉｌｏｌ,Ｃａｒ）对动物血流动力学的影响,全面了解该药对心血管系统的作用。方法　杂种家犬麻醉下ｉｖ０－１、０－３、１ｍｇ·ｋｇ－１Ｃａｒ,记录心电、血压、左心室内压、心输出量。结果　Ｃａｒｉｖ给药可引起麻醉犬平均动脉压、心率、左心室内压及其最大变化速率、左心室做功及总外周血管阻力明显下降,给药后１ｍｉｎ即开始起效,给药后１～５ｍｉｎ达最大效能,并具有剂量依赖性,１ｍｇ·ｋｇ－１剂量药效可持续至给药后４５ｍｉｎ,Ｃａｒ对心输出量及左室舒张末压无明显影响。结论　Ｃａｒ具有较广泛的心血管效应,除通过扩张外周阻力血管降低血压外,尚具有降低心率、抑制心肌收缩性能的作用;试验结果同时提示国产Ｃａｒ兼具α肾上腺素受体和β肾上腺素受体拮抗作用,支持该药为具有Ｓ（－）和Ｒ（＋）构型的外消旋化合物。     

Positive inotropic effects of histamine in anaesthetized dogs.

1 The cardiovascular effects of histamine were examined in dogs anaesthetized with pentobarbitone 2 The effect of histamine on heart rate, blood pressure, left ventricular pressure, dP/dtmax and dP/dt: IIT (integrated isometric tension) was compared in the presence and absence of autonomic reflexes and blood pressure control. 3 In innervated animals with no attempt to control blood pressure, histamine produced dose-dependent decreases in blood pressure and heart rate and either positive or negative inotropic actions. 4 When autonomic reflexes were abolished, this variability in inotropic response was reduced and histamine produced a slight positive inotropic response. There was a decrease in blood pressure and a positive chronotropic response to histamine. 5 When blood pressure was controlled and the cardiac nerves were intact, histamine produced a decrease in heart rate. However, in the denervated animals, there was a slight increase in heart rate. 6 Inotropic responses to histamine in the blood pressure controlled groups were less variable than when blood pressure was uncontrolled. In all of these animals there was an increase in contractility, the increase being more marked in the denervated group. 7 The H2-receptor agonist impromidine produced a positive inotropic action in intact animals with uncontrolled blood pressure.     

Cardiovascular effects of nicorandil and nitroprusside in furosemide plus digoxin pretreated dogs

In support of human congestive heart failure (CHF) trials, the cardiovascular effects of the vasodilators nicorandil (NIC) and nitroprusside (NP) were examined in anesthetized and conscious dogs pretreated with the diuretic furosemide (FURO) and the cardiac glycoside digoxin (DIG). In anesthetized control dogs, iv NP (2–19 μg/kg/min) and NIC (24–105 μg/kg/min) maximally reduced mean arterial pressure (MAP) by 43 and 40 mmHg, respectively, with moderate increases in heart rate (HR). These hypotensive responses to NP and NIC were unmodified by iv FURO (2.65 mg/kg) + DIG (0.075 mg/kg) pretreatment (PT). FURO + DIG reduced central venous pressure (CVP) BY 3 mmHg, masking the separate effects of NP and NIC. In a third group, FURO's fluid volume depletion and DIG's plasma concentrations were unaffected by adjunctive NIC infused for 2.5 h at a mean 17 μg/kg/min iv. No untoward interactions were seen with any combination. In conscious dogs, the hypotension and tachycardia seen with iv NP (2–20 μg/kg/min) and NIC (20–160 μg/kg/min) were also unchanged after 5 days of oral FURO (5 mg/kg/day) and DIG (0.0125 mg/kg/day), with no intolerance. Repeated oral NIC (7.5 mg/kg/day × 3 days) in these chronic FURO + DIG dogs ws consistently hypotensive but steadily more tachycardiac. This study offers a prototype of 3-way CHF drug interaction, demonstrates that NIC and NP can be safely combined with acute and chronic FURO and DIG, and shows that these CHF agents minimally affect the cardiovascular responses to NIC and NP in dogs.     

The effects of caerulein on insulin secretion in anaesthetized dogs

1. Insulin concentration changes in pancreatico-duodenal venous plasma were studied in anaesthetized dogs injected with caerulein.2. Rises in insulin concentration were elicited by rapid intravenous injection of caerulein, as well as by intravenous infusion. Threshold doses were 10 ng/kg and 0.5-1 (ng/kg)/min respectively.3. At the highest dose used (500 ng/kg by rapid intravenous injection and (25 ng/kg)/min by intravenous infusion) the increase in immuno-reactive insulin release was approximately 7 to 9 times the base levels.4. Adrenalectomy potentiated the effects of intravenous infusion of caerulein.5. On a molar basis, caerulein was 2-3 times as active as pancreozymin.6. It is concluded that caerulein is a potent stimulant of pancreatic islets in the dog and that it may be considered as a model peptide, capable of being substituted for pancreozymin in any experiment.7. The mechanism of the insulin stimulating effect of caerulein is discussed. The possibility of a direct "beta-cytotropic" effect of the peptide is suggested.     

The effects of molsidomine on intracranial pressure in anaesthetized dogs

Summary Measurements of intracranial liquor pressure were made during i.v. molsidomine administration in pentobarbital anaesthetized beagle dogs without thoracotomy, and compared with those after nitroglycerin. The administration of 100 g/kg molsidomine decreased blood pressure by 14 mmHg and increased intracranial pressure by 3.7 cm H₂O (p<0.05). No changes in heart rate and the alveolar endtidal CO₂ concentration were noted. The i.v. administration of 5 g/kg nitroglycerin, however, decreased systolic blood pressure by 41 mmHg (p<0.05), increased heart rate by 40 bpm (p<0.01), elevated intracranial pressure by 3.2 cm H₂O (p<0.05), and caused marked hyperventilation indicated by increased end-tidal CO₂ concentration. Larger increases in intracranial pressure were related to larger pressure reductions. Thus, molsidomine produced significant increase in intracranial liquor pressure of longer duration (60 to 90 min of observation time). Nitroglycerin increased liquor pressure with a short duration of action and was about twenty times more effective with respect to intracranial pressure increase. In contrast to molsidomine, this was accompanied by significant decrease in systolic peripheral blood pressure.     

Parallel tolerance between platelet cyclic GMP and preload effects of nitroglycerin in anaesthetized mini-pigs.

The effects of acute intravenous nitroglycerin (NTG) administration on platelet cyclic GMP in relation to changes in indices of preload (end-diastolic volume) and afterload (effective arterial elastance) were evaluated in the anaesthetized mini-pig, using pressure-volume analysis. NTG (1-30 micrograms kg-1 min-1, i.v.) elicited a dose-dependent fall in preload and afterload, and an increase in arterial blood platelet cyclic GMP. Repeated doses of NTG (30 micrograms kg-1 min-1) resulted in tolerance to the preload but not afterload effects. The increases in platelet cyclic GMP were also attenuated, being highly correlated with the preload changes. Therefore, platelet cyclic GMP appears to reflect NTG-induced venous tolerance, rather than arterial responsiveness. The measurement of platelet cyclic GMP may represent a simple approach for monitoring the degree of venous tolerance to NTG in animals or patients, facilitating further mechanistic investigations.     

Cardiovascular effects of the new calcium antagonist isradipine and of diltiazem in anesthetized open-chest dogs

Cardiovascular effects of the new calcium antagonist, isradipine (PN 200-110), were compared with those of diltiazem in anesthetized open-chest dogs. Isradipine 5 micrograms/kg i.v. produced significant decreases in systolic, diastolic and mean aortic blood pressure (AoP) concomitant with a decrease in mean renal blood flow (RBF) and increases in mean vertebral blood flow (VBF), mean coronary blood flow (CBF) and left ventricular dP/dt (LVdP/dt), but almost unchanged heart rate (HR) and left ventricular enddiastolic pressure (LVEDP). Diltiazem 300 micrograms/kg i.v. also produced decreases in AoP and RBF and increases in AoF, VBF and CBF. LVdP/dt and LVEDP were not significantly changed, but HR was decreased by this drug. Duration of increase in AoF, VBF and CBF was significantly longer in isradipine than in diltiazem. The decrease of coronary vascular resistance relative to total peripheral resistance was significantly greater than 1.0 for diltiazem, but not for isradipine. Results indicate that isradipine produces effects on AoP, AoF, VBF, CBF, RBF and LVEDP similar to diltiazem and the drug increases LVdP/dt without a decrease in HR in contrast to diltiazem, and that the effects of isradipine were long sustained when compared with those of diltiazem.     

异钩藤碱的降压及血流动力学作用(英文)

在清醒正常血压大鼠,iv Isorhy2.5 mg/kg对BP及HR均无明显影响,iv5 mg/kg则使DAP和HR降低,但SAP无变化,剂量加大至10 mg/kg时,上述各项指标均明显降低。经十二指肠内给Isorhy10 mg/kg后20 min出现BP及HR降低,而20mg/kg剂量组于10 min开始出现BP及HR的进一步下降.Isorhy(10mg/kg和2 mg/kg,iv)亦能分别降低肾性高血压清醒大鼠和麻醉犬的BP。icv表明中枢不是降压作用的主要部位,在体条件下无α-受体和神经节阻断作用。Isorhy使清醒大鼠和麻醉犬的LVSP,dP/dt_(max),V_(max)等左室收缩性能指标短暂下降,而BP呈持久性降低。在麻醉犬给药后CO,CI,HR及LVWI下降的同时SV和SI不变,TPVR降低,反映心肌氧耗的TTI明显减少.结果提示Isorhy具有肯定的降压作用,其持续降压与扩张血管及减慢心率导致CO下降有关,而其负性肌力作用亦可能参与了早期的降压机理.Isorhy能减少心肌氧耗对高血压心肌劳损可能有保护意义。     

Cardiovascular effects of delta9-tetrahydrocannabinol in conscious and anaesthetized dogs.

1. Temporal effects of delta9-tetrahydrocannabinol (THC) on heart rate and blood pressure in conscious dogs were compared to those in anaesthetized dogs. 2. In conscious dogs, THC in doses of 0.25 and 0.1 mg/kg resulted in maximal heart rate reductions of 48 and 41%, respectively, and in no significant change in blood pressure. 3. In anaesthetized animals THC in doses of 0.5 and 0.25 mg/kg caused a peak reduction in heart rate of 38 and 34%, and of blood pressure of 24 and 8%, respectively. 4. The results demonstrate that the bradycardia in response to THC in dogs is independent of the concomitant anaesthesia. 5. We conclude that the discrepancy between heart rate response to THC in dogs and in man is due to a species difference.