Intravenous administration of conivaptan hydrochloride improves cardiac hemodynamics in rats with myocardial infarction-induced congestive heart failure

We investigated the effects of intravenously administered conivaptan hydrochloride, a dual vasopressin V1A and V2 receptor antagonist, on cardiac function in rats with congestive heart failure following myocardial infarction, and compared results with those for the selective vasopressin V2 receptor antagonist SR121463A. Rats were subjected to left coronary artery occlusion to induce myocardial infarction, which in turn led to congestive heart failure. At 4 weeks after coronary occlusion, conivaptan (0.03, 0.1 and 0.3 mg/kg i.v.) dose-dependently increased urine volume and reduced urine osmolality in both myocardial infarction and sham-operated rats. SR121463A (0.3 mg/kg i.v.) also increased urine volume and decreased urine osmolality in myocardial infarction rats, to a degree comparable to that by conivaptan (0.3 mg/kg i.v.). At 6 weeks after surgery, myocardial infarction rats showed increases in right ventricular systolic pressure, right atrial pressure, left ventricular end-diastolic pressure and relative weights of the heart and the lungs, and a decrease in first derivative of left ventricular pressure (dP/dt(max))/left ventricular pressure, showing that congestive heart failure was well established. Conivaptan (0.3 mg/kg i.v.) significantly reduced right ventricular systolic pressure, left ventricular end-diastolic pressure, lung/body weight and right atrial pressure in myocardial infarction rats. Moreover, conivaptan (0.3 mg/kg i.v.) significantly increased dP/dt(max)/left ventricular pressure. SR121463A at a dose of 0.3 mg/kg i.v. significantly decreased left ventricular end-diastolic pressure and right atrial pressure, and tended to decrease right ventricular systolic pressure and relative lung weight in myocardial infarction rats. Although the aquaretic and preload-reducing effects of SR121463A were similar to those of conivaptan, SR121463A failed to improve dP/dt(max)/left ventricular pressure. These results suggest that dual vasopressin V1A and V2 receptor antagonists provide greater benefit than selective vasopressin V2 receptor antagonists in the treatment of congestive heart failure.     

Effect of conivaptan, a combined vasopressin V(1a) and V(2) receptor antagonist, on vasopressin-induced cardiac and haemodynamic changes in anaesthetised dogs.

The neurohormonal factor arginine vasopressin (AVP) produces potent systemic vasoconstriction as well as water retention in the kidneys via the V(1a) and V(2) receptors, respectively. Therefore, AVP may be considered as an aggravating factor of cardiac failure. In the present study, the effects of intravenous (i.v.) infusion of AVP on cardiovascular parameters and the effect of conivaptan (YM087, 4'-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride), a vasopressin V(1a)/V(2) receptor antagonist, on AVP-induced cardiac and haemodynamic changes were investigated in pentobarbitone-anaesthetised dogs. The i.v. infusion of AVP (0.12-4mUkg(-1)min(-1)) dose-dependently produced decreases in the cardiac contractility indicator LV dP/dt(max) and cardiac output (CO) and increases in left ventricular end-diastolic pressure (LVEDP) and total peripheral resistance (TPR). These changes accurately mimic the cardiovascular symptoms of congestive heart failure. The i.v. bolus injection of conivaptan (0.1mgkg(-1)) rapidly attenuated the AVP (4mUkg(-1)min(-1))-induced decrease in CO and reversed the AVP-induced elevation in both LVEDP and TPR. In conclusion, i.v. infusion of AVP produced cardiac dysfunction and vasoconstriction in pentobarbitone-anaesthetised dogs. Conivaptan demonstrated the ability to dramatically improve the impaired cardiovascular parameters induced by AVP. The results suggest the potential usefulness of conivaptan in treating congestive heart failure.     

Effect of the vasopressin receptor antagonist conivaptan in rats with heart failure following myocardial infarction

Myocardial infarction often induces congestive heart failure accompanied by a significant increase in plasma vasopressin concentration. To delineate the role of vasopressin in the pathogenesis of congestive heart failure, the acute hemodynamic and aquaretic effects of conivaptan (YM087, 4'-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride), a combined vasopressin V(1A) and V(2) receptor antagonist, were assessed in rats with heart failure induced by myocardial infarction. Left coronary artery ligation resulted in decreased left ventricular systolic pressure and first derivatives of left ventricular developed pressure, as well as increased left ventricular end-diastolic pressure, lung and right ventricular weight. Single oral administration of conivaptan (0.3 to 3.0 mg/kg) dose-dependently increased urine volume and decreased urine osmolality in heart failure rats. Furthermore, conivaptan (3.0 mg/kg) attenuated the changes in left ventricular end-diastolic pressure, lung and right ventricular weight induced by heart failure while reducing blood pressure. These results show that vasopressin plays a significant role in elevating vascular tone through vasopressin V(1A) receptors and plays a major role in retaining free water through vasopressin V(2) receptors in this model of congestive heart failure. Additionally, conivaptan, with its dual vasopressin V(1A) and V(2) receptor-inhibiting properties, could exert a beneficial effect on cardiac function in the congestive heart failure rat model.     

重组人脑钠肽对慢性心衰犬血流动力学和肾功能的影响

目的研究国产重组人脑钠肽(rhBNP)对慢性心衰犬血流动力学及肾功能的影响。方法用右心室快速起搏(RVP)或狭窄下腔静脉(TIVCC)形成犬的心衰模型。结果RVP心衰犬iv rhBNP后,平均动脉压(MAP)、左室内压(LVSP)、LVdp/dt、肺动脉压(PAP)、左室舒张末期压(LVEDP)、总外周阻力(TPR)及肾血管阻力(RVR)呈剂量依赖性下降,LVdp/dt/P、左室做功(LVW)、心输出量(CO)和心率(HR)无明显改变;TIVCC心衰犬在iv同剂量rhBNP后,MAP,LVEDP和CO下降,其他心功能指标无明显改变。两种心衰犬给药后尿量和尿钠排出量均增加。结论rhBNP有舒张血管和利尿作用,能明显降低心衰犬的心脏前后负荷,不影响心脏收缩功能。     

Effects of milrinone on systemic hemodynamics and regional circulations in dogs with congestive heart failure: comparison with dobutamine

Milrinone is a new bipyridine inotropic agent with direct vasodilator properties. To determine the role of the vasodilator action in mediating systemic and regional hemodynamic responses to milrinone, we administered two equipotent inotropic doses of either milrinone or dobutamine to dogs with chronic congestive right heart failure produced by tricuspid avulsion and pulmonary artery stenosis. Similar increases in cardiac output, right and left ventricular dP/dt, and left ventricular dP/dt/P were produced by milrinone and dobutamine; however, heart rate increased and mean aortic pressure decreased only with milrinone infusion. In addition, while total peripheral vascular resistance decreased with both agents, the decrease was greater with milrinone. Regional blood flows were measured by a radioactive microsphere method. Milrinone and dobutamine produced similar increases in myocardial blood flow and left ventricular oxygen consumption. Dobutamine infusion decreased quadriceps muscle vascular resistance and had no effect on renal and splanchnic circulations. In contrast, milrinone infusion increased vascular resistance in quadriceps muscle and decreased it in renal and splanchnic beds. Thus, when milrinone was used in inotropic doses similar to those of dobutamine, the responses in systemic and regional hemodynamics in congestive heart failure differed. Milrinone produced a greater decline in total peripheral, renal, and splanchnic vascular resistances, probably resulting from its direct vasodilator action.     

Comparative effects of dobutamine and corwin, a beta 1-adrenergic partial agonist, in experimental left ventricular failure

Corwin is a new, long-acting beta 1-adrenergic partial agonist for oral and intravenous (i.v.) use. The effects of corwin were compared with those of dobutamine in acute ischemic left ventricular failure in dogs. Failure was produced by embolization of the left main coronary artery with 50 micron plastic microspheres. This induced severe depression in left ventricular function, as evidenced by a marked increase in left ventricular end-diastolic pressure, reduction in left ventricular dP/dtmax, and cardiac output. After 45 min was allowed for stabilization, the 27 dogs were randomly assigned to three groups: control (n = 9), dobutamine-treated (5-10 micrograms/kg/min i.v., n = 9), and corwin-treated (0.025-0.10 mg/kg i.v., n = 9). The doses of dobutamine and corwin were adjusted to give an increase in left ventricular dP/dtmax of 50%. Both drugs similarly increased cardiac output (p less than 0.01), lowered left ventricular end-diastolic pressure (p less than 0.01) and total peripheral vascular resistance (p less than 0.01), but did not affect the heart rate. Only dobutamine increased the mean arterial pressure (p less than 0.01). Both drugs also increased the arterial concentrations and myocardial uptake of fatty acids (p less than 0.05) but caused only a small and nonsignificant increase in myocardial oxygen consumption. Our findings indicate that the hemodynamic and metabolic profiles of corwin and dobutamine are similar, and both drugs should be of special value in the treatment of congestive heart failure. Since corwin can be given orally and has a longer duration of action, it is potentially useful in the long-term treatment of heart failure.     

Haemodynamic and coronary effects of quazodine in cats with developing myocardial infarcts

Acute ligation of the descending branch of the left coronary artery in anaesthetized cats resulted, within 1–2 h, in a 30% decrease in local blood flow in the region mainly supplied by the ligated vessel, a fall in systemic blood pressure, in cardiac output, and in left ventricular dP/dt max (LVdP/dt). There was electrocardiographic evidence of myocardial ischaemia (pronounced ST elevation). In these animals with developing myocardial infarcts, intravenous infusions of quazodine (MJ1988; 6,7-dimethoxy-4-ethyl-quinazoline) markedly increased myocardial contractility and local myocardial blood flow in the developing infarct, and decreased systemic arterial pressure, peripheral vascular resistance and left ventricular end-diastolic pressure, effects similar to those observed in normal cats. The increase in cardiac contractility (cardiac output and LVdP/dt) occurred without a concomitant increase in myocardial metabolic heat production. This ‘oxygen sparing effect’ probably results from a decrease in left ventricular wall tension. It is suggested that quazodine warrants further investigation as a cardiac stimulant in power failure following myocardial infarction in man.     

Vasodilators in myocardial infarction: rationale and current status.

While digitalis and diuretics constitute conventional therapy of congestive heart failure due to acute myocardial infarction, systemic vasodilator drugs offer an innovative approach of decreasing left ventricular systolic wall tension (afterload) by reducing aortic impedance and/or by reducing cardic venous return. Thus, vasodilators increase lowered cardiac output by diminishing peripheral vascular resistance and/or decreasing increased left ventricular end-diastolic pressure (ventricular preload) by reducing venous tone. Concomitantly, there is a reduction of myocardial oxygen demand thereby potentially limiting infarct size and ischaemia. The vasodilators produce disparate modifications of cardiac function depending on their differing alterations of preload versus impedance: nitrates principally cause venodilatation (decrease left ventricular end-diastolic pressure); sodium nitroprusside, phentolamine and prazosin produced relatively balanced arterial and venous dilatation (decrease left ventricular end-diastolic pressure while increasing cardiac output, provided upper limits of normal left ventricular end-diastolic pressure are maintained); and hydrallazine solely effects arteriolar dilatation (increases cardiac output). Combined sodium nitroprusside and dopamine therapy synergistically enhances cardiac output and decreases left ventricular end diastolic pressure. In addition, sodium nitroprusside is aided by mechanical counterpulsation which sustains myocardial perfusion pressure in acute myocardial infarction.     

Cardiovascular profile of pimobendan, a benzimidazole-pyridazinone derivative with vasodilating and inotropic properties

Intravenous infusions of 0.01-0.1 mg X kg-1 X min-1 of pimobendan, a benzimidazole-pyridazinone derivative in pigs with normal coronary circulation caused dose-dependent changes in heart rate (10-35%), left ventricular systolic pressure (-5 to -45%), left ventricular filling pressure (-20 to -40%) but had only a minor effect on the maximum rate of rise of left ventricular pressure (max LVdP/dt; 10-20%). The decrease in mean arterial blood pressure was primarily due to systemic vasodilation; peripheral resistance and cardiac output decreased by up to 40 and 14%, respectively. Vasodilation occurred in several vascular beds, but was particularly pronounced in the adrenals, stomach, small intestine and myocardium. Although the increase in myocardial blood flow favoured the epicardium, vascular conductance in both the endo- and epicardial layers was significantly increased. Myocardial O2 consumption (MVO2) was not affected despite the increase in heart rate. Bolus injections of 0.1-0.5 mg X kg-1 pimobendan produced similar changes in all haemodynamic variables, except max LVdP/dt which now increased by 30-70%. As in the infusion experiments, cardiac output tended to decrease due to a pronounced reduction in ventricular preload probably as a result of venodilation and the consequent reduction in cardiac filling. However, in animals where max LVdP/dt and cardiac output were reduced and pre- and/or after-load were increased by partial occlusion of the left anterior descending coronary artery, pimobendan clearly increased both max LVdP/dt and cardiac output. Pretreatment with propranolol did not modify any of the cardiovascular responses to pimobendan, thereby excluding the involvement of a beta-adrenoceptor mechanism. Pimobendan is thus a compound with vasodilator and positive inotropic properties that improves cardiac output in animals with severe myocardial ischaemia. The finding that the mild tachycardia caused by pimobendan was not accompanied by an increase in MVO2 warrants investigation to evaluate its usefulness in the treatment of heart failure.     

Congestive heart failure model in rabbits: effects of digoxin and a drug containing toad venom.

A low-output-type heart failure model was established in rabbits by protease treatment of the surface of the left ventricular anterior wall. Heart rate, aortic blood flow (AoF), left ventricular pressure (LVP) and maximal rate of rise of LVP (max dP/dt) in this model were maintained at lower levels than in normal rabbits, while left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance (SVR) were maintained at higher levels, and mean blood pressure (MBP) remained at a normal level. Intraduodenal administration of digoxin and a drug containing toad venom (Kyushin:KY) improved the hemodynamic parameters by increasing the AoF, LVP and max dP/dt and by decreasing the LVEDP and SVR without a significant change in MBP. These results suggest that the beneficial effects of digoxin and KY on this heart failure model originate from their cardiotonic activity.     

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.     

Cardiovascular effects of the calcium sensitizer, levosimendan, in heart failure induced by rapid pacing in the presence of aortic constriction.

1. The haemodynamic effects of a novel cardiotonic drug, levosimendan, which has both calcium-sensitizing and phosphodiesterase III (PDE III) inhibitory properties, were studied in conscious dogs in which heart failure had been induced by prolonged cardiac pacing in the presence of aortic constriction. These effects were compared with those in sham-operated dogs with essentially normal cardiac function. 2. Eighteen mongrel dogs were instrumented for the measurement of left ventricular pressure (LVSP, LVEDP) and contractile function (dP/dt; dP/dt/P). In twelve dogs a balloon catheter, positioned in the thoracic aorta, was inflated producing an approximate 60% reduction in effective aortic diameter. Twenty min later rapid ventricular pacing (240 beats mean-1) was commenced and maintained for 48 h by means of a bipolar pacing electrode introduced into the right ventricle. This electrode served also for recording changes in the endocardial electrogram in the absence of pacing. Six of these dogs were used to evaluate the haemodynamic changes of pacing-induced heart failure; a further six of these dogs the haemodynamic changes elicited by levosimendan under these conditions. Six sham-operated dogs (group 2) served as controls. 3. In six dogs (group 1) the haemodynamic alterations were assessed after the development of heart failure. In the presence of aortic constriction, 48 h continuous rapid cardiac pacing resulted in a marked deterioration in left ventricular function which remained stable for at least 48 h after cessation of pacing. Thus, there was a marked reduction in LVSP (15%), +dP/dtmax (35%), -dP/dtmax (36%) and also in dP/dt/P (29%), whereas LVEDP was increased considerably (from 6.4 +/- 1.4 to 20.0 +/- 2.2 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic, renal, and hormonal effects of 8-Br-cyclic GMP in conscious dogs with and without congestive heart failure

In conscious dogs, we examined the hypothesis that the effects of atrial natriuretic peptide (ANP) are mediated by cyclic GMP and tested whether stimulation of the intracellular pathway beyond the ANP receptor level still exerts ANP-like effects during tolerance to ANP in heart failure. We studied the hemodynamic, renal, and hormonal effects of the cyclic GMP analogue 8-bromo-cyclic GMP (8-Br-cyclic GMP) in conscious dogs before and after induction of congestive heart failure by right ventricular pacing. In healthy dogs, 8-Br-cyclic GMP (1-100 micrograms/kg/min) dose-dependently decreased mean arterial pressure (MAP -19% by 100 micrograms/kg/min) and total peripheral resistance (TPR -22%) with no change in cardiac output (CO) and right atrial pressure, increased urine flow (UF 52%), and sodium excretion (UNaV 135%). Plasma renin (62%) and norepinephrine (NE 24%) were increased. In dogs with heart failure, 8-Br-cyclic GMP induced a similar arteriolar dilation (MAP -16%, TPR -23%) with no change in CO and preload. However, the effects on renal excretory function were abolished or markedly attenuated (UF -4%, UNaV 7%). Plasma renin (163%) and aldosterone (40%) were increased. Our findings support the hypothesis that the renal effects of ANP are mediated by cyclic GMP in vivo. The attenuation of renal effects of 8-Br-cyclic GMP in heart failure does not prove but is in agreement with the hypothesis that an intracellular defect beyond cyclic GMP production might be involved in the tolerance to ANP in heart failure.     

Cardiovascular effects of endothelin in dogs: positive inotropic action in vivo

Endothelin, administered i.v. to anesthetized dogs, dose dependently increased the cardiac output, left ventricular systolic pressure (LVSP), and maximum upstroke velocity (max dp/dt) of the LVSP for about 10 min without changing the heart rate. Thereafter the cardiac output decreased to below the control level but max dp/dt decreased to the control level. The arterial pressure and total peripheral resistance showed an initial, transient decrease followed by a sustained increase. These results suggest that endothelin has positive inotropic and long-lasting vasoconstrictive effects preceded by transient vasodilatation in vivo.     

Combined atorvastatin and coenzyme Q10 improve the left ventricular function in isoproterenol-induced heart failure in rat

The effect of atorvastatin on cardiac remodeling, function, and homodynamic parameters in isoproterenol-induced heart failure was evaluated in the present study. A subcutaneous injection of isoproterenol (5mg/kg/day) for 10 days was used for the induction of heart failure. Isoproterenol administration produced intensive myocardial necrosis and fibrosis with a significant decrease in the arterial pressure indices, heart rate, contractility (LVdP/dt(max)) and relaxation (LVdP/dt(min)), but an increase in the left ventricular end-diastolic pressure. Rats were randomly assigned to control, treatment with only atorvastatin, and treatment with atorvastatin plus coenzyme Q10. Histopathological analysis showed a marked attenuation of myocyte necrosis and interstitial fibrosis in all atorvastatin treated groups (P<0.001). A low dose of atorvastatin (5mg/kg/day) significantly improved the left ventricular systolic pressure, contractility and relaxation (P<0.01). On the contrary, a high dose of atorvastatin (20mg/kg/day) worsened the isoproterenol-induced left ventricular dysfunction by a further reduction of LVdP/dt(max) from +2780 ± 94 to +1588 ± 248 (mmHg/s; P<0.01) and LVdP/dt(min) from -2007 ± 190 to -2939 ± 291 (mmHg/s; P<0.05). Co-administration of coenzyme Q10 with atorvastatin reversed the hemodynamic depression and the left ventricular dysfunction to a high level (P<0.001). There was a lower level of LVEDPs in the atorvastatin+coenzyme Q10 treated groups (3 ± 1 and 4 ± 1.4 versus 8 ± 3.5 and 14 ± 3.6 mmHg, respectively), thereby suggesting improvement in the myocardial stiffness by the combined coenzyme Q10 and atorvastatin treatment. The atorvastatin therapy attenuated myocardial necrosis and fibrosis in isoproterenol-induced heart failure. However, a high dose of the drug considerably worsened the left ventricular dysfunction and hemodynamic depression, which was reversed by coenzyme Q10 co-administration.     

Experimental study on the effects of the extracorporeal ultrafiltration method in advanced congestive heart failure

The effects of the extracorporeal ultrafiltration method were studied in an experimental canine model of advanced congestive heart failure with mitral regurgitation, coronary artery occlusion and overhydration. With the application of this technique, cardiac output, stroke work, systemic vascular resistance and left ventricular dp/dt increased significantly associated with reduction in the right atrial and left ventricular filling pressures. Serum electrolytes were stable throughout the procedure, and there were significant elevations in serum protein and hematocrit levels. The composition of the ultrafiltrate indicated that excessive extracellular fluid was removed. Five out of seven cardiogenic shock subjects also benefited. The clinical application of this approach using recently developed dialyzers to treat intractable heart failure with overhydration under close hemodynamic monitoring is warranted.     

Cardioprotective effects of carbocromen in awake and anesthetized dogs with amitriptyline poisoning

We studied the effects of the antianginal drug carbocromen (4 mg/kg bolus plus 80 micrograms/kg/min i.v.) on amitriptyline (400 micrograms/kg/min i.v.) toxicity. In anesthetized dogs, amitriptyline increased heart rate, left ventricular (LV) end-diastolic pressure, and the PR and QT intervals, the QRS complex, and the S-T segments of the peripheral electrocardiogram. Blood pressure, LV pressure, and LV dP/dtmax fell considerably. Survival time was 37 +/- 4 min in amitriptyline-treated dogs and 64 +/- 3 min (p less than 0.05) in those receiving amitriptyline plus carbocromen. The amount of amitriptyline consumed until death increased from 14.8 to 25.6 mg/kg (p less than 0.05) with carbocromen. In conscious dogs, the hemodynamic impact of intraatrial amitriptyline was similar to that in anesthetized animals, and changes in stroke volume resembled those of dP/dt. Cardiac output was not altered, and peripheral resistance decreased moderately. Carbocromen prevented most of the typical amitriptyline effects on the heart and circulation. Sustained ventricular arrhythmia occurred at 29 +/- 4 min with amitriptyline infusion but was delayed to 58 +/- 3 min (p less than 0.05) when carbocromen was added. These experiments demonstrate (a) amitriptyline intoxication produced ventricular tachyarrhythmia and cardiac failure if high agent concentrations were achieved; (b) these rhythm disorders were associated with slowing of intraventricular conduction, which could be enhanced by carbocromen; and (c) carbocromen might be an effective therapy for amitriptyline-caused arrhythmia with cardiovascular collapse.     

Effects of a new angiotensin converting enzyme inhibitor, enalapril, in acute and chronic left ventricular failure in dogs

Enalapril (MK-421) is a new angiotensin converting enzyme inhibitor which effectively lowers elevated blood pressure and might also be useful in heart failure. Enalapril was infused into six awake dogs 2 hours after left circumflex coronary artery embolization (acute failure group) and into six other awake dogs two to six months after coronary embolization (chronic failure group). In the acute failure group 2 hours after embolization, increased left ventricular end-diastolic pressure and reduced cardiac output remained unchanged during enalapril infusion. In the chronic failure group, increased left ventricular end-diastolic pressure also remained unchanged during enalapril infusion, but cardiac output, which had fallen to 131.8 +/- 11.9 (S.D.) from 165.8 +/- 17.9 ml/min/kg (P less than 0.01) by two to six months in this group rose during enalapril infusion to 154.5 +/- 27.7 ml/min/kg (P less than 0.05). Heart rate and blood pressure were not changed during enalapril in either group, but stroke volume rose (26.0 +/- 5.9 to 29.2 +/- 6.9 ml, P less than 0.01) and systemic vascular resistance fell (58.5 +/- 10.3 to 39.3 +/- 4.3 units, P less than 0.01) during enalapril only in the chronic failure group. Plasma renin activity after embolization was slightly but not significantly higher in the acute failure group. Thus, enalapril appears to be an arterial vasodilator in dogs with chronic but not acute left ventricular failure.     

Comprehensive evaluation of cardiovascular function in the anesthetized rat.

The present report describes methods and procedures which have been developed and used in the intact, anesthetized rat for cardiovascular functional evaluation. Integrative hemodynamic mechanisms are ascertained under resting conditions by measuring arterial blood pressure, cardiac output and heart rate. Stroke volume and total peripheral resistance are derived from the above measurements. In addition, left ventricular pressure is determined by direct cardiac puncture. Derived rates of left ventricular pressure development (+dP/dt) and left ventricular pressure decline (-dP/dt) provide estimates of myocardial contractility and cardiac relaxation, respectively. Hemodynamic responses to isoproterenol infusion test the functional adequacy of the beta-adrenergic receptor, adenylate cyclase, cyclic AMP system. Ventricular function curves relating stroke volume and end-diastolic pressure during rapid volume infusion provide useful indices of cardiac pump performance in the intact heart. Peak left ventricular +dP/dt in response to brief aortic occlusion provides an index of cardiac contractile performance. Cardiac cellular/subcellular mechanisms relating (a) myofibrillar ATPase with heart contractility and (b) sarcoplasmic reticulum calcium handling properties with myocardial relaxation can be assessed. Thus, the methods and procedures described represent an experimental animal preparation which should prove useful for comprehensive evaluation of cardiovascular function.     

Cardiovascular effects of AR-L115 BS in conscious dogs with and without chronic congestive heart failure

AR-L115 BS is a phenyl-imidazo-pyridine derivative that combines positive inotropic and vasodilator properties. To analyze the mechanisms of action of AR-L115 in the presence or absence of heart failure, we administered it intravenously to conscious dogs (seven normals and eight with a volume-overload heart failure). In normals, at a plasma level around 1,000 ng/ml, AR-L115 BS increased left ventricular (LV) peak (+) dP/dt (+48%; p less than 0.02) and heart rate (+29 beats/min; p less than 0.05) without altering significantly cardiac filling pressures or cardiac output. The mean aortic pressure and the systemic vascular resistances (-20%; p less than 0.02) were reduced, but plasma renin activity (PRA) was unchanged. In heart failure, the same plasma level increased peak (+) dP/dt by 36% (p less than 0.01), but heart rate stayed unchanged. Mean aortic pressure, systemic vascular resistances (-20%; p less than 0.01), and LV end-diastolic pressure (-9.1 mm Hg; p less than 0.01) all dropped significantly, while cardiac output increased slightly; PRA did not rise significantly. After beta-blockade, the increases in peak (+) dP/dt and the changes in systemic vascular resistances were markedly reduced. In conclusion, AR-L115 BS has strong positive inotropic and vasodilator effects, both of which are partially dependent on the level of the sympathetic tone in the intact animal. These combined properties improve hemodynamics in heart failure; this improvement is already significant at relatively low plasma levels, at which deleterious changes in heart rate or PRA are absent.