EFFECTS OF NEUROPEPTIDE Y ON LEFT VENTRICULAR FUNCTION IN THE CONSCIOUS RABBIT

1. Changes in arterial pressure, heart rate and left ventricular contractility induced by intravenous injections of neuropeptide Y (NPY; 1-30 micrograms/kg) were studied in the conscious rabbit. 2. NPY has a brief pressor effect associated with a bradycardia, an increase in left ventricular end diastolic pressure, and a prolonged fall in peak left ventricular dP/dt (LVdP/dt). 3. The haemodynamic changes increase substantially with increasing doses up to 10 micrograms/kg. Beyond 10 micrograms/kg there are only slight effects on heart rate or peak LV dP/dt.     

Relative inotropic and chronotropic activity of beta-adrenoceptor stimulants in anaesthetised, areflexic dogs

The use of different methods of measuring contractility and the effects of cardiovascular reflexes are among the factors which complicate the assessment of selective inotropic activity of beta-adrenoceptor agonists. The effects of dobutamine, prenalterol, noradrenaline and isoprenaline on heart rate, iliac blood flow, left ventricular pressure, max dP/dt and (dP/dt) divided by IIT (integrated isometric tension) were evaluated in anaesthetised dogs in which the hearts were denervated and blood pressure held constant. All the drugs caused dose-dependent increases in heart rate and contractility. The relative chronotropic and inotropic activity of each agonist was evaluated. At most doses studied the agonists exerted similar chronotropic and inotropic activity when compared to the non-selective agonist isoprenaline. It is likely that the inotropic selectivity observed with prenalterol and dobutamine in previous studies depends on factors other than direct drug action.     

The effects of a new β-adrenoceptor blocking compound, tolamolol, on haemodynamics and myocardial function in man

1 The effects of tolamolol on haemodynamics and myocardial contractility were investigated in two groups of six patients undergoing diagnostic cardiac catheterization.2 The intravenous administration of tolamolol (0.15 mg/kg) produced a significant fall in heart rate from a control value (87 +/- 7 to 62 +/- 3 beats/min) 5 min after administration and a concomitant fall in cardiac output from 4.7 +/- 0.9 to 3.5 +/- 0.8 litres/minute. There was no significant change in systemic blood pressure, pulmonary artery blood pressure or stroke volume.3 There was no change in left ventricular end diastolic pressure after tolamolol. There was a fall in the maximum rate of rise of the left ventricular pressure (LV dp/dt(max)) and the derived index of the left ventricular contractile state (V(max)).4 These results suggest that tolamolol has a predominantly negative chronotropic but also a lesser negative inotropic action on the heart.     

In vivo hemodynamic effects of endothelium-derived constricting factor in the dog

Primary cultures of bovine thoracic aortic endothelial cells release an endothelium-derived constricting factor (EDCF), which contracts isolated porcine, bovine, and canine coronary arteries and increases coronary perfusion pressure in isolated rabbit heart. We have tested the effect of theis EDCF on coronary and aortic flows, left ventricular dP/dt, and left ventricular end diastolic pressure, and mean arterial pressure in opern chest anesthetized dogs. Intracoronary administration of conditioned medium containing EDCF caused a reduction in coronary flow. The constrictor response was slow in onset, peaked 50 min after bolus injection, and was sustained during the rest of the observation period. Aortic flow, heart rate, left ventricular dP/dt, left ventricular end diastolic pressure, and mean arterial pressure were not significantly altered. Intracoronary administration of denatured conditioned medium or nonconditioned medium did not elicit any cardiovascular changes. The EDCF-induced reduction in coronary flow was inhibited by intracoronary administration of nitroglycerin. These findings suggest that conditioned medium from bovine aortic endothelial cells produces coronary vasoconstriction in the intact, anesthetized dog.     

The cardiovascular pharmacology of ICI 170777 ((6RS)-6-methyl-5-(pyrid-4-yl)-3H,6H-1,3,4- thiadiazin-2-one) a novel compound with positive inotropic and vasodilator effects.

1. This paper describes the cardiovascular effects of ICI 170777, a novel compound which enhances cardiac contractility and causes arterial and venous dilatation. 2. The positive inotropic effects of ICI 170777 on the heart were demonstrated by an increase in left ventricular dP/dtmax in the anaesthetized and conscious dog, and by an increase in tension development in isolated papillary muscles from the cat. 3. In the anaesthetized dog, the positive inotropic effects of ICI 170777 and of isoprenaline were attenuated by atenolol (5 mg kg-1, i.v.). Atenolol displaced the dose-response curve to ICI 170777 to the right by 4 fold but displaced the isoprenaline dose-response curve to the right by 247 fold. In vitro, however, atenolol (10 microM) had no significant effect on the positive inotropic response to ICI 170777. In the ganglion-blocked anaesthetized dog, infusion of a low dose of ICI 170777 which had no effect on the basal left ventricular dP/dtmax, selectively potentiated the positive inotropic effects of isoprenaline. These results indicate that ICI 170777 has both a non-adrenoceptor-mediated positive inotropic effect on the heart and also facilitates the beta-adrenoceptor-mediated control of contractility. 4. In the denervated and perfused hind-limb of the dog, ICI 170777 reduced arterial perfusion pressure and increased limb circumference at a constant arterial flow and venous pressure. This indicates that ICI 170777 has direct dilator actions on both arterial and venous vessels. In this preparation, diazoxide exerted an arterial selective vasodilator effect and sodium nitroprusside was a relatively selective venous dilator.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ca(2+)-sensitizing effect is involved in the positive inotropic effect of troglitazone

1. Troglitazone, an insulin sensitizing agent, has a direct positive inotropic effect. However, the mechanism of this effect remains unclear. Thus, we examined the inotropic effect of troglitazone while focusing on intracellular Ca2+ handling. 2. Troglitazone significantly increased peak isovolumic left ventricular pressure (LVP(max)), peak rate of rise of LVP (dP/dt(max)), peak rate of fall of LVP (dP/dt(min)) in isolated rat hearts perfused at a constant coronary flow and heart rate. This inotropic effect of troglitazone was not inhibited by pretreatment with carbachol (muscarine receptor agonist), H89 (protein kinase A inhibitor), U73122 (phospholipase C inhibitor), H7 (protein kinase C inhibitor), verapamil (L-type Ca2+ channel antagonist), thapsigargin (Ca(2+)-adenosine triphosphatase inhibitor) or ryanodine (ryanodine receptor opener). 3. Radioimmunoassay showed that the cyclic adenosine monophosphate concentration in the left ventricle was not increased by troglitazone. 4. Whole-cell patch clamp analysis revealed that troglitazone had no effect on inward Ca2+ currents in cardiomyocytes. 5. In fura-2 loaded perfused rat hearts, troglitazone exerted its positive inotropic effect without increasing Ca2+ concentration. 6. These results suggest that neither the inward Ca2+ currents nor Ca2+ handling in the sarcoplasmic reticulum was involved in the inotropic effect of troglitazone. Furthermore, troglitazone exerted its positive inotropic effect without affecting the intracellular concentration of Ca2+. 7. In conclusion, the positive inotropic effect of troglitazone is mediated by a sensitization of Ca2+.     

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。     

Negative inotropic and lusitropic effects of intravenous amiodarone in conscious rats

1. The acute effect of amiodarone on haemodynamics (mean arterial pressure and heart rate) and ventricular function (+dP/dt(max) and -dP/dt(max)) was investigated in conscious rats. In addition, the effects of amiodarone on dobutamine stress were determined. 2. Catheters were inserted in rats into the left ventricle and femoral artery and vein. Three groups of rats received 25 or 50 mg/kg, i.v., amiodarone or vehicle (a 1:1:8 mixture of Tween 80:99.5% ethanol:distilled water), followed by dobutamine (10 microg/kg). 3. The hypotensive effect of 50 mg/kg amiodarone was combined with marked bradycardia and attenuation of +dP/dt(max) and -dP/dt(max). A slight, but significant, hypotension was caused by 25 mg/kg amiodarone, without affecting heart rate, +dP/dt(max) and -dP/dt(max). However, although both doses of amiodarone attenuated the tachycardia caused by dobutamine, neither 25 nor 50 mg/kg amiodarone affected the increase in mean arterial pressure or the enhanced response of +dP/dt(max) and -dP/dt(max). 4. In conclusion, amiodarone caused hypotension, bradycardia, negative inotropic (+dP/dt(max)) and lusitropic (-dP/dt(max)) effects in conscious rats. In addition, amiodarone attenuated the tachycardia without affecting the hypertensive, contractile (+dP/dt(max)) and lusitropic (-dP/dt(max)) responses to dobutamine stress.     

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.     

Chronic ouabain treatment enhances cardiac myosin ATPase activity in rats

1. Chronic ouabain administration increases blood pressure and produces a positive inotropic effect. However, the temporal changes capable of affecting both arterial and ventricular pressures and myosin ATPase activity during the induced hypertension have not been determined. 2. The aim of the present study was to investigate the time-course of the induction of hypertension to define when changes occur in Wistar rats treated with 25 mg/kg per day, s.c., ouabain for 3, 7, 15 or 30 days. 3. In anaesthetized rats, diastolic blood pressure increased after 7 days treatment with ouabain and after 15 and 30 days treatment, increases were observed in systolic blood pressure, left ventricular systolic pressure and myosin ATPase activity. After 15 days treatment, heart rate (HR) also increased, but after 30 days treatment HR returned to control levels. However, only after 30 days treatment did the left ventricular positive and negative first derivatives of intraventricular pressure (dP/dt(max) and dP/dt(min), respectively) increase. Increased arterial and left ventricular systolic pressures and myosin ATPase activity observed after 15 days treatment maintained similar levels as those after 30 days treatment. 4. The results suggest that changes in arterial and left ventricular pressures, HR and myosin ATPase activity induced by chronic ouabain treatment are time dependent, increasing after 15 days treatment. After 30 days treatment, the increase in systolic and diastolic arterial and ventricular pressures remained stable, as did inotropism. Normalization of HR after 30 days treatment suggests that during the period from Day 16 to Day 30 ouabain-induced hypertension is dependent, at least in part, on increased sympathetic activity.     

dP/dt(max) - A measure of 'baroinometry'

dP/dt(max) is the maximal rate of rise of (usually) left ventricular pressure (LVP), but it is determined by myocardial contractility and the loading conditions on the ventricle, thus it is an imperfect and sometimes incorrect predictor of the inotropic state (myocardial contractility). The value of dP/dt(max) to represent contractility may be improved by adjusting it to ventricular end-diastolic volume (pre-load) or by calculating dP/dt as a function of LVP during isovolumetric contraction and determining the maximal value. Every investigator who uses dP/dt(max) should record this parameter while venous return is changed in order to observe how dependent dP/dt(max) is on pre-load. Since dP/dt(max) does not represent only the inotropic state, we coined the term baroinometry to represent that dP/dt(max) is determined by aortic pressure (baro), the inotropic state (ino), and the length (meter). dP/dt(max) measures the inotropic state only when loading conditions are unchanged.     

An analysis of the stimulant effects of 5-hydroxytryptamine on isolated, blood-perfused rat heart.

In rat isolated hearts perfused at a fixed low rate, single injections of 5-hydroxytryptamine (5-HT) (0.1--3 microgram) into the coronary perfusion produced dose-dependent increases in left ventricular (LV) dP/dt max and perfusion pressure (PP), but no clear changes in heart rate. The increases in the LVdP/dt max and PP were not significantly affected by treatment with propranolol, while they were abolished by methysergide. The present study indicates that the positive inotropic and vasoconstrictor responses of the rat heart to 5-HT are not mediated by endogenous catecholamine release, but are induced by a direct action on 5-HT receptors.     

Inotropic selectivity of salbutamol and terbutaline in anaesthetised, areflexic dogs

The cardiovascular effects of the selective beta 2-adrenoceptor agonists salbutamol and terbutaline have been evaluated in anaesthetised, areflexic dogs. The preparation was designed to reduce the effects of changes in cardiac function mediated via reflex responses to changes in blood pressure. The effects of the selective beta 2-adrenoceptor agonists on heart rate, hindlimb blood flow, left ventricular pressure, max dP/dt and (dP/dt)/IIT (integrated isometric tension) were compared to those of isoprenaline, while blood pressure was held constant. All three drugs produced dose-dependent increases in heart rate, myocardial contractility and iliac blood flow. When equiactive inotropic doses of isoprenaline and salbutamol were compared, salbutamol produced a significantly lower chronotropic effect. A similar inotropic selectivity was found when terbutaline was compared to isoprenaline. beta 2-Adrenoceptor blockade abolished this selectivity. It is concluded that, in the absence of autonomic reflex activity, the beta 2-selective adrenoceptor agonists are relatively selective inotropic stimulants.     

The haemodynamic effects of subcutaneous sumatriptan, a 5HT1-receptor agonist

Aims Previous in vivo studies with sumatriptan, a 5HT₁-receptor agonist, have demonstrated vasopressor responses in the pulmonary and systemic arterial circulation. Pulmonary artery wedge pressure (PAWP) also increases after sumatriptan injection, raising the possibility of an additional venoconstrictive action or a negative inotropic effect. The mechanism for the rise in PAWP was investigated in the study.
Methods Ten patients undergoing diagnostic coronary arteriography underwent haemodynamic monitoring.
Results There was a significant rise ( P <0.05) in systemic and pulmonary arterial pressure and total systemic and pulmonary vascular resistance. There was a similar rise ( P <0.05) in PAWP and left ventricular end diastolic pressure (LVEDP). There was no change in cardiac output nor in peak rate of left ventricular pressure rise (dP/dt).
Conclusions The sumatriptan induced rise in PAWP and LVEDP appears consequent upon increased afterload although a negative inotropic effect cannot be excluded.     

Myocardial contractile behavior of a new sotalol derivative.

The effects of E4031, a new class III antiarrhythmic agent similar to sotalol, were tested in isometrically contracting rabbit papillary muscles and in anesthetized, open-chest dogs. In papillary muscles, E4031 caused a modest dose-dependent increase of 26 +/- 8% in developed tension and 38 +/- 8% in its maximal rate of rise. Since there was no significant change in the maximal rate of relaxation, the ratio between both maximal velocities increased from 0.92 +/- 0.03 to 1.19 +/- 0.10. Time to peak tension did not change significantly, whereas time to half relaxation increased from 72 +/- 3 to 85 +/- 4 ms. The effective refractory period in the rabbit papillary muscles increased from 179 +/- 10 to 414 +/- 45 ms. In the open-chest dog, the i.v. administration of E4031 did not induce significant changes in heart rate, mean arterial pressure, or left ventricular end diastolic pressure. +dP/dt increased from 1,839 +/- 162 to 2,470 +/- 247 mm Hg/s with no significant change in -dP/dt after 100 micrograms/kg of E4031. Consequently, (+dP/dt)/(-dP/dt) increased from 0.97 +/- 0.07 to 1.18 +/- 0.08. To further evaluate the effects of E4031 on myocardial relaxation, the time constant of isovolumic left ventricular pressure decay was measured by two different methods (tau 1 and tau 2) before and after administering 10 micrograms/kg E4031. Tau 1 increased from 27 +/- 1.8 to 33 +/- 1.6 ms and tau 2 increased from 30 +/- 2.3 to 41 +/- 3.3 ms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chemistry and positive inotropic effect of pelrinone and related derivatives. A novel class of 2-methylpyrimidones as inotropic agents

A novel series of pyrimidine derivatives was synthesized and evaluated for positive inotropic activity. Inotropic and chronotropic effects were determined in vitro in cat papillary muscle and right atrium, respectively. Selected compounds were then evaluated in vivo in a dog heart failure model. Changes in ventricular dP/dt, heart rate, and blood pressure were monitored. Several of these agents produced relatively minor changes in heart rate. This class of agents demonstrated a varying degree of vasodilator effects concomitant with increases in ventricular contractility. The most potent analogues, 9, 48, and 49, were evaluated orally in conscious dogs with implanted Konisberg pressure transducers, and their effect on left ventricular dP/dt was compared with that of milrinone. Mechanistically, the agents of this novel class appear not to mediate their effect via beta-receptors or inhibition of Na+/K+-ATPase. A major component of their inotropic effect is mediated by the inhibition of cardiac phosphodiesterase (PDE)-Fr. III. This was clearly demonstrated by 9, 48, and 49. Compound 48 was found to be the most potent inhibitor of PDE-Fr. III from among the compounds tested in this assay.     

The effect of (minus)-delta 9-trans-tetrahydrocannibinol on myocardial contractility and venous return in anesthetized dogs

Administration of (?)-Δ⁹-trans-tetrahydrocannabinol (Δ⁹-THC, 2.5 mg/kg i.v.) to pentobarbital-anesthetized dogs in which heart rate was maintained constant by electrical pacing, decreased aortic blood pressure, cardiac output, left ventricular peak pressure and left ventricular end diastolic pressure and dP/dt. However, the contractility index (max. dP/dt)/I.P. was not altered by the compound. Furthermore, it was shown that the decrease in cardiac output due to Δ⁹-THC could be restored to original levels by an infusion of saline-dextran in quantities sufficient to elevate the left ventricular end diastolic pressure to pre-Δ⁹-THC level.In dogs in which cardiac output was maintained constant by a right heart bypass procedure Δ⁹-THC decreased blood pressure and total peripheral resistance and augmented intravascular blood volume. This increase in intravascular blood volume was significantly less (74%) in animals in which the splanchnic (superior, inferior and celiac) arteries were ligated prior to the administration of Δ⁹-THC. On the other hand, in spinal dogs Δ⁹-THC was devoid of any measurable cardiovascular effects.These observations clearly support the hypothesis that the diminution of cardiac output induced by Δ⁹-THC in animals with constant cardiac rate is primarily due to diminished venous return to the heart and not to an impaired ability of the myocardium.     

Negative inotropic effect of a CB2 agonist A-955840 in isolated rabbit ventricular myocytes is independent of CB1 and CB2 receptors

A-955840, a selective CB2 agonist, has been shown to elicit concentration-dependent decreases in cardiac contractility in the anesthetized dog (decreased maximal velocity of left ventricular pressure development [LV dP/dt max]). However, it is unknown whether this represents a direct effect or a response dependent on other factors (such as autonomic tone and neurohumoral factors) present in vivo. This study examined if A-955840 had a direct effect on contractility of isolated cardiac myocytes, and if so to determine the potential mechanisms. Contractility was assessed in vitro using percent changes in maximal shortening velocity of sarcomeres (dL/dt max) and fractional shortening of sarcomere length (FS) in rabbit left ventricular myocytes. L-type calcium current in myocytes was recorded using wholecell voltage-clamp techniques. A-955840 reduced dL/dt max and FS in a reversible and concentration-dependent manner with an IC50 of 11.4 μg/mL (based on dL/dt max) which is similar to the estimated IC50 value of 9.8 μg/mL based on the effects of A-955840 on LV dP/dt max in anesthetized dogs. A-955840 (4.1 μg/mL) reduced myocyte contractility (%FS) to a similar extent in the absence and presence of a CB2 antagonist, SR-2 (24.0 ± 3.4 vs 23.1 ± 3.0 %, n=5) or a CB1 antagonist, Rimonabant (18.8 ± 2.3 vs 19.8 ± 2.7 %, n=5). A-955840 (4.1 μg/mL) also reduced L-type calcium current of rabbit ventricular myocytes (1.05 ± 0.11 vs 0.70 ± 0.12 nA, n=5, P < 0.01). These results suggest that A-955840 exerts direct negative inotropic effects on isolated rabbit ventricular myocytes, which is mediated by neither CB2 nor CB1 receptors, and consistent with off-target negative inotropy mediated by inhibition of the cardiac L-type calcium current.     

The actions of a new β-adrenoceptor blocking drug, ICI 66082, on the rabbit papillary muscle and on the dog heart

1 The actions of 4-(2-hydroxy-3-isopropylaminopropoxy) phenyl acetamide (ICI 66082), a new beta-adrenoceptor blocking drug, on the twitch response of the isolated papillary muscle of the rabbit and on dP/dt max and free heart rate of a denervated dog heart preparation, are described.2 ICI 66082 (up to 1 mg/ml) did not produce any depression of the twitch response of the rabbit papillary muscle. ICI 66082 antagonized the action of isoprenaline on this preparation at a concentration of 0.01 mug/ml.3 ICI 66082 (0.5-1.0 mg/kg intravenously) reduced the control value of dP/dt max in four dog preparations by a mean value of 529 mmHg/s (s.e. mean +/- 139 mm Hg/s), with no significant change in free heart rate. Antagonism of the effect of isoprenaline on dP/dt max and on free heart rate was demonstrated with ICI 66082 (0.1 mg/kg).4 ICI 66082 (1.0-1.5 mg/kg) produced no significant changes in dP/dt max or in free heart rate in four dogs pretreated with reserpine. A significant reduction (16% of the control value) in dP/dt max was observed with ICI 66082 at a high dose of 40-50 mg/kg.5 It is concluded that ICI 66082 is a competitive antagonist against the actions of isoprenaline on cardiac muscle, has no negative inotropic action (unless the dose exceeds 40 mg/kg) and lacks intrinsic sympathomimetic activity.     

Comparative effects of inotropic agents on coronary and systemic hemodynamics of conscious dogs: actions of milrinone, dopamine, ouabain and MCI-154

The hemodynamic actions of a new inotropic agent, MCI-154, were compared to dopamine, ouabain and milrinone in conscious, chronically instrumented dogs. MCI-154 and milrinone produced similar hemodynamic changes: increases in heart rate, diastolic coronary blood flow velocity and peak positive dP/dt. Neither agent had significant effects on arterial pressure while both drugs reduced left ventricular end-diastolic pressure in a dose-related fashion and myocardial segment length, indicating a decrease in diastolic left-ventricular size. MCI-154 was found to be approximately twice as potent as milrinone. In contrast, dopamine and ouabain produced little change in left ventricular end-diastolic pressure or myocardial segment length during diastole, while both drugs produced increases in arterial and left ventricular systolic pressures. An increase in left ventricular afterload was not observed with either MCI-154 or milrinone, highlighting an important advantage of the latter compounds.