COMPARATIVE HAEMODYNAMIC EFFECTS OF VERAPAMIL, FLECAINIDE, AMIODARONE AND SOTALOL IN THE CONSCIOUS RABBIT

1. The effect of intravenous boluses of verapamil (0.15 mg/kg), flecainide (2 mg/kg), amiodarone (5 mg/kg), and sotalol (l.5 mg/kg) on mean arterial pressure, heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), and peak rate of change of left ventricular pressure (LV dP/dt) were assessed in the conscious rabbit. 2. All four drugs had negative inotropic effects: verapamil reduced peak LV dP/dt by 19±4% (mean±s.e.m.; P<0.01), flecainide by 27 ± 9% (P<0.001), amiodarone by 11 ± 2% (P<0.01) and sotalol by 13 ± 3% (P<0.01). 3. The drugs had different effects on CO as a result of differences in their actions on peripheral blood vessels: verapamil and amiodarone produced, respectively, a 12 ± 4% (P<0.03) and 16 ± 6% (P<0.01) increase in CO associated with a substantial vasodilatory effect (TPR reduced 15 ± 7%[P<0.05] and 20 ± 5% [P<0.01], respectively). Flecainide caused only a small (6 ± 1%; P<0.01) increase in CO and sotalol had no effect on either CO or TPR. 4. Bolus intravenous injections of verapamil, flecainide and amiodarone produced an increase in HR, while sotalol reduced HR by 10 ± 2% (P<0.01). The increase in HR and cardiac output seen with verapamil, flecainide and amiodarone was in part secondary to reflex increase in sympathetic tone and these changes were abolished after total cardiac autonomic blockade. 5. The modest reduction in cardiac performance associated with sotalol was abolished by cardiac autonomic blockade, suggesting that the predominant effect of sotalol on contractility was mediated through its β-adrenoceptor blocking effect.     

Effects of neuropeptide Y on the heart and circulation of the conscious rabbit

The direct and reflex-mediated components of the cardiovascular response to administration of neuro-peptide Y (NPY) in intact conscious rabbits were determined by studies with cardiac beta adrenoceptor and vagal blockade, and during total autonomic blockade. Cardiac pacing was used to prevent bradycardia, and sinoaortic denervation (SAD) was used to remove afferent baroreflex input. In control animals, NPY (10 micrograms/kg bolus i.v.) caused arterial pressure to increase from 77.4 +/- 1.5 mm Hg (mean +/- SEM) to a maximum of 91.4 +/- 1.6 mm Hg (p less than 0.05). This pressor response was independent of autonomic effectors but was buffered by arterial baroreflexes. The fall in heart rate (HR) from 281 +/- 14 to 252 +/- 18 beats/min (p less than 0.05) was mediated in part through baroreceptor-dependent changes in cardiac autonomic efferent activity, but was in part independent of autonomic neural mechanisms. Peak left ventricular (LV)dP/dt fell from 5,551 +/- 342 to 4,182 +/- 394 mm Hg/s (p less than 0.05) following NPY in control rabbits. This reduction was maintained during pacing and following SAD, and was caused partly by a withdrawal of cardiac beta-adrenergic tone and partly through a non-beta-mediated myocardial depression. Small changes in cardiac output (CO) and in LV end-diastolic pressure (LVEDP) after NPY were secondary to bradycardia. Total autonomic blockade did not impair the NPY-induced rise in total peripheral resistance (TPR), suggesting a direct vasoconstrictor action that was independent of neural mechanisms.     

Comparative haemodynamic effects of lidocaine, mexiletine, and disopyramide

The effect of intravenous boluses of lidocaine (5 mg/kg), mexiletine (3.5 mg/kg), and disopyramide (5 mg/kg) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance, left ventricular end-diastolic pressure, and peak rate of change of left ventricular pressure (peak LV dP/dt) were assessed in the conscious rabbit. Plasma levels for the three drugs corresponded to the human therapeutic range 3 min after administration. All three drugs had negative inotropic effects and reduced HR. Lidocaine reduced peak LV dP/dt by 26%, mexiletine by 41%, and disopyramide by 53%. The three drugs had quite different effects on CO as a result of differences in their actions on peripheral blood vessels: disopyramide caused a 21% fall in CO, associated with a significant vasoconstriction; mexiletine did not lower CO, as it caused a substantial vasodilation; and lidocaine did not produce any substantial change in either CO or vascular resistance. Cardiac autonomic blockade did not alter these changes. These results confirm that disopyramide has a marked cardiodepressant effect, and demonstrate that, although lidocaine depresses myocardial contractility in the conscious rabbit, it has little effect on other haemodynamic parameters. The experiments also show that mexiletine is a more profound negative inotrope than lidocaine, but that, as it produces a significant fall in MAP and thus a reduction in afterload, the CO is maintained.     

青藤硷对犬血流动力学的作用

麻醉开胸犬,静脉注射青藤硷0.5～2.0mg/kg后,立即出现心输出量、心率、收缩压(SBP)、舒张压(DBP)、左心室收缩期压力(LVSP)、dP/dt_(max)、心指数(CI)及外周阻力显著下降;VCE—+dP/dt_(max)无明显变化;在0.5mg/kg时,T值无明显变化,但2.0mg/kg时,T值明显升高。     

地奥心血康对肾性高血压大鼠血流动力学的影响

肾性高血压大鼠（ＲＨＲ）较对照假手术大鼠的ＳＢＰ，ＤＢＰ，ＬＶＥＳＰ，ＬＶＥＤＰ，＋ｄｐ／ｄｔ及｜－ｄＰ／ｄｔ｜值均显著增加（Ｐ均＜０．０１）。应用地奥心血康较用生理盐水对照的ＲＨＲ上述指标分别减少３１．２％，３５．９％，３２．６％，５０．８％，２５．７％和３０．２％（Ｐ均＜０．０１）。心率降低１７．５％（Ｐ＜０．０１）。提示地奥心血康对大鼠心脏具有负性变时、变力作用，可明显改善左心室的舒缩性能。     

Effects of betaxolol on cardiohemodynamics and coronary circulation in anesthetized dogs: comparison with atenolol and propranolol

Effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on cardiohemodynamics and coronary circulation were investigated in two kinds of anesthetized open-chest dog preparations in comparison with those of atenolol and propranolol. When administered intravenously, betaxolol, atenolol and propranolol produced dose-dependent decreases in the heart rate (HR), maximum left ventricular dP/dt [+)dP/dt), cardiac output (CO) and mean arterial pressure (MAP). Although all three drugs were almost equipotent in decreasing HR, betaxolol was much less potent than atenolol and propranolol in decreasing (+)dP/dt. Betaxolol decreased the total peripheral resistance (TPR), whereas atenolol and propranolol increased it. In another series of experiments, when administered intravenously, betaxolol, atenolol and propranolol all produced a decrease in the myocardial oxygen consumption (MVO2) and an increase in the atrioventricular conduction time (AVCT). All three drugs were nearly equipotent in decreasing MVO2, although betaxolol was less potent than the other two drugs at higher doses (greater than 300 micrograms/kg). Prolongation of AVCT with propranolol was stronger than those with betaxolol and atenolol. These results suggest that, unlike atenolol and propranolol, the decrease in TPR as well as beta 1-adrenoceptor blockade may be responsible for both the hypotensive effect of betaxolol and the decrease in MVO2 with betaxolol. The result that the cardiodepressant effect of betaxolol was much less potent than those of atenolol and propranolol suggests that betaxolol would be more beneficial than the others in the treatment of ischemic heart disease.     

海洛因依赖者心血管功能微机检测分析

本文报告１００例海洛因依赖者心血管功能微机检测结果分析。具体选择心肌收缩、舒张功能指标：ＣＯ，ＣＩ，ＣＷＩ，ＨＩ．ｄＱ／ｄｔ，ｄｐ／ｄｔ，ＥＩ，ＩＲＴ，ＬＶＥＤＶ，ＬＶＥＤＰ；血管功能指标：ＴＰＲ，ＡＣ，ＤＢＰ，ＳＢＰ，ＣａＦＰ，ＭＡＰ。实测结果与标测值对照，除ＣＯ，ＣＩ，ＨＩ，ＬＶＥＤＶ，ＴＰＲ，ＳＢＰ外，均有显著性差异。提示海洛因依赖者心脏泵功能开始减退，心排血量减少。舒张压、平均动脉压和冠状动脉灌注压降低，其结果会影响组织血流灌注，甚至可能出现心肌缺血。因此，在戒断和康复治疗中要注意心血管疾病的辅助治疗。     

胃复安对豚鼠心肌生理特性及犬血液动力学的作用

胃复安(MCP)30～100μmol/L能抑制豚鼠心室乳头状肌收缩力和肾上腺素诱发的自律性,降低兴奋性,延长功能不应期。此外,对豚鼠右心房收缩力和自律性有抑制作用。麻醉开胸犬iv MCP5mg/kg立即出现HR减慢,SBP,DBP,MAP,LVSP,CI,dP/dt_(max)和TPR增加;iv 10mg/kg MCP后,除CI仍增加外,上述各参数均降低;ivMCP5～10mg/kg对V_((?)e)～+dP/dt_(max)和T值无显著影响。     

CARDIOVASCULAR EFFECTS OF NEUROMUSCULAR BLOCKADE DURING INDUCED HYPOTHERMIA

Young lambs were used to study the effects of progressive cooling and rewarming on cardiovascular function during neuromuscular blockade induced by gallamine. Initially, it was shown that gallamine exerted no immediate, direct haemodynamic effect in normothermic or hypothermic lambs (cooled by 10 degrees C). By comparison with hypothermic controls, neuromuscular blockade was associated with increases in left ventricular (LV) max dP/dt (153%; P less than 0.02) as cooling progressed, and even greater increases (232%; P less than 0.001) during rewarming. It was concluded that these changes seem likely to represent enhanced myocardial contractility since preload did not closely follow LV max dP/dt (heart rate and mean aortic pressure fell gradually during cooling but values were restored in the rewarming phase). LV max dP/dt in lambs given gallamine only after cooling also showed a similar response during rewarming. Results of this study may have clinical relevance relating to the mechanical recovery of the hypothermic heart in patients receiving neuromuscular blockade during cardiac surgery, and they argue against using gallamine as such an agent.     

Role of endothelin-1 receptors in healthy anaesthetized rabbits

1. Many diseases are associated with elevated endothelin (ET)-1 plasma concentrations. In order to understand the consequence of this elevation, in the present study the effects of exogenous ET-1 on the entire organsim were investigated, in particular with respect to the role of ETA and ETB receptors in the cardiovascular system. In open-chest rabbits, left ventricular (LV) pressure (LVPmax, LVPed), dP/dtmax and dP/dtmin were recorded in ejecting and isovolumically beating hearts to determine cardiac function. In addition, heart rate (HR), aortic pressure (AoP) and aortic flow (AoF) were measured. Total peripheral resistance (TPR) was calculated from mean AoP and AoF. 2. In the first series of experiments (n = 11), ET-1 (0.5 nmol/kg; bolus) produced a non-significant reduction in HR. Systolic function, in terms of AoF, LVPmax and dP/dtmax, was improved; for example, LVPmax was increased significantly (69 +/- 10 vs 106 +/- 20 mmHg for control and ET-1, respectively; P < 0.05). Similarly, early relaxation (dP/dtmin) was improved. In parallel, TPR rose significantly (0.25+/-0.07 vs 0.35+/-0.1 mmHg/min per mL for control and ET-1, respectively; P < 0.05). Isovolumic measurements showed corresponding responses. 3. In the second series of experiments (n = 7), animals were pretreated with an ETA receptor antagonist (330 nmol/min per kg FR 139317). After ETA receptor blockade, the administration of ET-1 had no significant effect on cardiac function or vasomotion. 4. In the third series of experiments (n = 6), animals were pretreated with an ETB receptor antagonist (10 nmol/min per kg BQ 788). In this series of experiments, the effects of ET-1 on cardiac function and vasomotion were the same as in the first series of experiments, except for the effect on HR, which decreased by 35% after ET-1. 5. In our experimental model, exogenous ET-1 exerted a clear-cut positive inotropic effect, together with the anticipated peripheral vasoconstriction via ETA receptors.     

Hemodynamic and myocardial energetic effects of CK-3197, a selective positive inotropic agent.

CK-3197 was developed as a selective positive inotropic agent for the treatment of congestive heart failure. We compared the hemodynamic and myocardial energetic effects of CK-3197 to ouabain in the pentobarbital-anesthetized dog. Fifteen minutes after intravenous (i.v.) administration of CK-3197 (0.1, 0.3, and 1.0 mg/kg) to five dogs, mean left ventricular (LV) dP/dt increased by 24, 68, and 109% and mean arterial pressure (MAP) decreased by 4, 9, and 18%, respectively, from basal values. CK-3197 was 11 times more potent as a positive inotropic agent than as a vasodilator. Heart rate (HR) increased by 5, 14, and 24% after these doses of CK-3197, whereas LV end diastolic pressure (LVEDP) decreased by 4 mm Hg after the highest dose of compound. LV oxygen consumption (MVO2) and stroke MVO2 increased by 9, 25, and 102% and 1, 8, and 58%, respectively, at the peak of the increases in LV dP/dt. Ouabain (0.02 and 0.03 mg/kg, i.v.) increased MAP (12 and 22%), HR (2 and 20%), and LV dP/dt (19 and 36%), with a 14 and 16% increase in LV MVO2 and a 12 and -6% change in stroke MVO2. Thus, CK-3197 is a selective, positive inotropic agent with preload reducing activity in the dog. CK-3197, similar to ouabain, produced energy-efficient positive inotropic responses with either no increase in MVO2 or increases in myocardial oxygen consumption that were less than the expected 1:1 ratio with LV dP/dt. Therefore, CK-3197 may have significant utility in the clinical treatment of congestive heart failure.     

Effects of intravenous endothelin on hemodynamics and cardiac contractility in conscious Milan normotensive rats.

The effects of endothelin-1 (ET-1) on hemodynamics and cardiac contractility were compared with the responses to angiotensin I (AI) and phenylephrine (PE) in Milan normotensive rats. Intravenous (i.v.) injection of ET-1 (0.8 nmol/kg) initially decreased mean blood pressure (MBP), total peripheral resistance (TPR), and dP/dt (-28 +/- 2, -34.8 +/- 3.7, and -9.4 +/- 1.3%, p less than 0.01, respectively), and increased heart rate (HR), cardiac output (CO), and the velocity of myocardial anterior wall shortening (dL/dt) (11.8 +/- 2.1, 10.4 +/- 2.9, and 28.3 +/- 8.3% p less than 0.05, respectively). These effects were followed by a sustained increase in MBP and TPR and a decrease in CO. As compared with AI (0.25 nmol/kg) and PE (35 nmol/kg), which produced a similar degree of increase in TPR, the reduction in CO induced by ET-1 was more prominent (-25 +/- 2 by ET-1 vs. -14 +/- 2 by AI and -14 +/- 3% by PE, p less than 0.05, respectively). Moreover, ET-1 induced a significant decrease in dP/dt, shortening fraction (SF), and dL/dt (-6.1 +/- 1.6, -35.0 +/- 3.8, and -38.6 +/- 5.5%, p less than 0.01, respectively), whereas these indexes of left ventricle performance were not affected by either AI or PE. Furthermore, the reduction in SF induced by ET-1 was mainly due to the decrease in myocardial diastolic segment length, suggesting reduction in diastolic filling volume.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of tumour necrosis factor-α on the cardiovascular system of anaesthetized rats

The effects of two vasoactive agents (adenosine A2A agonist, CGS 21680, and adrenoceptor agonist, noradrenaline) were examined on cardiac output (CO), heart rate (HR), blood pressure (BP), mean circulatory filling pressure (Pmcf), resistance to venous return, arterial resistance, dP/dt, plasma levels of NO2-/NO3-, and inducible nitric oxide synthase (iNOS) activity in lungs ex vivo, following treatment with tumour necrosis factor-alpha (TNF-alpha; 30 microg/kg) in anaesthetized rats. Treatment with TNF-alpha produced significant reduction in CO (41+/-2%), dP/dt (26+/-3%), BP (26+/-2%) and Pmcf (27+/-4%; n=6; mean+/-SEM), but increased arterial resistance. There were no significant changes in the plasma levels of NO2-/NO3-levels over time following treatment with TNF-alpha, but there was a significant increase (approximately twofold) in the activity of the iNOS in the lungs of animals treated with TNF-alpha. Administration of CGS 21680 (1.0 microg/kg per min) significantly increased CO (44+/-6%), HR (12+/-2%), Pmcf (24+/-4%) and dP/dt (24+/-5%) in TNF-alpha-treated rats. CGS 21680 also significantly reduced arterial resistance (33+/-2%) without altering resistance to venous return in TNF-alpha-treated rats. While noradrenaline (1.0 microg/kg per min) infusion did not significantly increase CO, it did significantly increase HR (12+/-1%), BP (55+/-9%), Pmcf (47+/-5%), dP/dt (65+/-7%), resistance to venous return (64+/-20%), and arterial resistance (41+/-16%) in TNF-alpha-treated animals. The reduction in BP due to administration of TNF-alpha is the result of significant reduction in CO. Consequently, the decline in CO can be attributed to a combination of a negative inotropic effect as well as a reduction in Pmcf. It is evident that infusion with CGS 21680 could reverse the negative impact of TNF-alpha on CO by increasing dP/dt, Pmcf and HR as well as a reduction in arterial resistance. The fact that noradrenaline did not significantly increase CO in TNF-alpha-treated rats can be attributed to increased arterial resistance as well increase in resistance to venous return.     

Haemodynamic effects of endothelin receptor antagonist,tezosentan, in tumour necrosis factor-α treated anaesthetized rats

Administration of tumour necrosis factor-alpha (TNF-alpha) produces progressive reduction in cardiac output (CO) by affecting preload, afterload and cardiac contractility. We have examined the effect of an endothelin receptor antagonist, tezosentan (1, 3 or 10 mg/kg), on CO, heart rate (HR), blood pressure (BP), mean circulatory filling pressure (P(mcf)), resistance to venous return (RVR), arterial resistance (AR), dP/dt, stroke volume (SV), plasma levels of NO(2)(-)/NO(3)(-), and inducible nitric oxide synthase (iNOS) activity in lungs, ex vivo, following treatment with TNF-alpha (30 microg/kg) in anaesthetized rats. Treatment with TNF-alpha alone resulted in significant reduction in CO (40+/-4%), dP/dt (24+/-2%), P(mcf) (24+/-2%), BP (21+/-3%) and SV (38+/-5%) ( n=6; mean +/- SEM), and significant increases in RVR (38+/-9%) and AR (45+/-6%). There were no significant changes in HR or in plasma levels of NO(2)(-)/NO(3)(-) in animals treated with TNF-alpha but there was a modest but significant increase in iNOS activity. Tezosentan alone did not have any effect on haemodynamics, plasma levels of NO(2)(-)/NO(3)(-) or iNOS activity. Tezosentan at the highest dose abolished the effects of TNF-alpha on dP/dt, AR, and RVR. In animals treated with a combination of TNF-alpha and highest dose of tezosentan CO, P(mcf), BP, and SV were reduced by 28+/-5%, 16+/-3%, 21+/-4%, and 27+/-5%, respectively. Tezosentan was able to inhibit the negative impact of TNF-alpha on AR and dP/dt but not on P(mcf). It is likely that the negative impact of TNF-alpha on CO in tezosentan-treated animals could be entirely attributed to reduction in preload.     

Haemodynamic profile of an inhibitor of phosphodiesterase III, adibendan (BM 14.478): comparison with nitroprusside and dobutamine in conscious dogs.

1. This study was performed to investigate whether cardiac positive inotropic as well as peripheral vasodilator properties of adibendan contribute to its overall haemodynamic profile in conscious dogs. 2. Haemodynamic measurements were carried out in conscious chronically instrumented dogs after administration of adibendan, sodium nitroprusside or dobutamine. 3. The cardiovascular changes induced by adibendan (0.01 and 0.03 mg kg-1) resembled those of dobutamine (1.0-4.0 micrograms kg-1 min-1): left ventricular dP/dt60 (LV dP/dt60), stroke volume (SV) and cardiac output (CO) increased to a similar extent, but mean arterial pressure (MAP) and heart rate (HR) remained unchanged. 4. In contrast to dobutamine, higher doses of adibendan (0.1-1.0 mg kg-1) decreased MAP and LVEDP. These effects were of a similar magnitude to those observed following nitroprusside administration (0.5-12.5 micrograms kg-1 min-1). In contrast to nitroprusside, adibendan still showed additional effects on LV dP/dt60 and CO. 5. From these results, it is concluded that both the peripheral vasodilator and the cardiac positive inotropic action of adibendan contribute to its overall haemodynamic profile.     

A novel orally active dopamine prodrug TA-870. III. Positive inotropic effect and cardiorenal selectivity in anesthetized dogs.

The effect of TA-870, a novel dopamine prodrug, on the cardiovascular system was studied in anesthetized open- and closed-chest dogs. Intraduodenal administration of less than or equal to 12 mg/kg TA-870 to anesthetized dogs increased left ventricular (LV) dP/dtmax and dP/dt/Pmax. Furthermore, at a lower dose of TA-870 (2 mg/kg), renal vascular resistance (RVR) decreased and renal blood flow (RBF) increased. Similarly, total peripheral resistance (TPR) decreased and cardiac output (CO) increased at less than 4 mg/kg. In an intravenous cumulative dose-response study of TA-870, the plasma-free-dopamine concentration was elevated depending on the dose of TA-870. Renal vasodilation occurred at a low plasma-free-dopamine concentration, whereas a positive inotropic action required higher plasma-free-dopamine. However, the dose-response curve for LVdP/dt/Pmax was steeper than that for RBF or CO. Heart rate was less affected than LVdP/dt/Pmax in open-chest dogs and decreased in closed-chest dogs. Propranolol strongly inhibited the effect of TA-870 on LVdP/dt/Pmax. It also inhibited the effects of TA-870 on TPR and CO to a lesser extent, and the remaining effects were almost completely inhibited by an additional treatment with the dopamine blocker, RS-sulpiride. In conclusion, TA-870 increased myocardial contractility and output by the enteral route, and the latter effect was produced at lower doses with the help of peripheral vasodilation due to the activation of dopamine receptors.     

Effects of isosorbide 5-mononitrate on cardiovascular function. (II). Effects on pre-load and after-load

Effects of isosorbide 5-mononitrate (5-ISMN) on cardiovascular function were compared with those of verapamil hydrochloride and propranolol hydrochloride in anesthetized open-chest dogs. Intravenous injection of 5-ISMN (3 mg/kg) considerably lowered systolic blood pressure (SBP). Especially, stroke volume (SV), cardiac output (CO), cardiac work (CW) and systolic right ventricular pressure (SRVP) were significantly decreased. 5-ISMN also produced a continuous reduction in mean pulmonary artery pressure (MPAP), mean pulmonary capillary wedge pressure (MPCWP) and mean right atrium pressure (MRAP), while heart rate (HR) and total peripheral resistance (TPR) were not altered significantly. Intravenous injection of verapamil (0.3 mg/kg) considerably lowered diastolic blood pressure (DBP). Verapamil also caused a significant decrease in HR, CW and TPR and a slight decrease in SRVP and MPCWP. However, SV was significantly increased, and slight increases in MPAP and MRAP were also observed. Propranolol (0.5 mg/kg, i.v.) greatly decreased HR together with CO, CW, SRVP and MPAP and slightly decreased MPCWP, while it caused a considerable increase in 3V and a slight increase in TPR. The finding that administration of 5-ISMN resulted in reduction of pre-load and after-load suggests the possibility that this drug might decrease venous return and thereby reduce myocardial oxygen requirements.     

Cardiovascular Effects of the Novel Cardiotonic Agent DPI 201–10. in the Anaesthetized Rat

Abstract: DPI 201–10. (4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1H-indole-2-carbonitrile) was given intravenously to anaesthetized male rats. DPI caused an increase in left ventricular dP/dt (LV dP/dt), giving a significant increase at 0.03 μmol/kg. At this dose DPI had no effect on either mean arterial pressure (MAP) or heart rate (HR). At higher doses, MAP decreased transiently. At 0.3 and 1 μmol/kg, HR was decreased. The results indicate that DPI produces positive inotropic and negative chronotropic effects in the anaesthetized rat.     

Hemodynamic effects of cibenzoline on normal myocardium and after pretreatment with DL-sotalol.

The circulatory and myocardial effects of cibenzoline were investigated in 78 open-chest rats during and after a 7-min intravenous (i.v.) infusion. Measurements were performed in the intact circulation, and myocardial function was also examined by isovolumic registrations independent of circulatory changes. In the first part of the study, the dose-dependent effects of cibenzoline were investigated (2, 4, and 8 mg/kg vs. NaCl controls). Cibenzoline caused a dose-dependent decrease in heart rate (HR) (-16, -34, -37% vs. preinfusion values), mean aortic blood pressure (AoPm) (-8, -20, -30%), cardiac output (CO) (-6, -29, -39%), and dP/dtmax (+1, -21, -59%). The isovolumic peak left ventricular systolic BP (LVSBP) (-6, -6, -17%) and peak dP/dtmax (-8, -18, -54%) were also reduced. In the second part of the study, we examined the effects of 2 mg cibenzoline/kg after pretreatment with 2 mg DL-sotalol/kg: HR was -22% AoPm was -12%, CO was -29%, dP/dtmax was -40%, isovolumic LV pressure (LVP) was -12%, and peak dP/dtmax was -41%. Cibenzoline caused dose-dependent bradycardia, which cannot be explained by beta-adrenoceptor blockade. The auxotonic and isovolumic measurements indicate that cibenzoline possesses a dose-dependent negative inotropic effect: 2 mg cibenzoline/kg caused only a slight decrease in myocardial performance, but this effect was aggravated after pretreatment with DL-sotalol. Cibenzoline also increased peripheral resistance. The observed combination of negative inotropism and vasoconstriction caused by cibenzoline should be taken into consideration especially in patients with reduced LV function. This is of particular importance if cibenzoline is combined with DL-sotalol.     

Effect of the novel orally active angiotensin converting enzyme inhibitor alacepril on cardiovascular system in experimental animals

Effects of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219) a new orally active angiotensin converting enzyme (ACE) inhibitor, on cardiovascular system in experimental animals were examined. In conscious renal hypertensive dogs, alacepril (3 mg/kg p.o.) caused a marked reduction in systolic and diastolic blood pressure (SBP and DBP) and total peripheral vascular resistance (TPR), but did not change significantly heart rate (HR), cardiac output (CO), stroke volume (SV), cardiac work (CW) and electrocardiogram (ECG). Captopril (3 mg/kg, p.o.) showed similar changes in cardiovascular parameters as alacepril. In anesthetized open-chest normotensive dogs, alacepril (3-100 micrograms/kg/min for 10 min, i.v. infusion) tended to decrease DBP and TPR, but did not change significantly CO, stroke work (SW), left ventricular end diastolic pressure (LVEDP), dp/dt and HR. Captopril also showed similar effects but these changes were greater in extent than those of alacepril. In conscious renal hypertensive rats, alacepril did not affect the regional cerebral blood flow in the frontal cortex and the dorsal hippocampus after single (3 and 10 mg/kg) and successive (3 mg/kg/d for 7 days) oral administration. Captopril (10 mg/kg) significantly decreased blood flow in the frontal cortex after single oral administration. In conscious normotensive dogs, alacepril (3 and 30 mg/kg p.o.) increased renal plasma flow (RPF), urine volume (UV), urinary sodium excretion (UNaV) and urinary Na+/k+ ratio, but did not change glomerular filtration rate (GFR) and urinary potassium excretion (UKV). Captopril (3 and 30 mg/kg p.o.) also showed similar changes as alacepril. These effects of alacepril on cardiovascular system resemble those of captopril and might be considered as a favourable profile for the antihypertensive agent.