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.     

Myocardial and haemodynamic effects of phentolamine

1. In cats anaesthetized with pentobarbitone, intravenous infusions of phentolamine ((10-50 mug/kg)/min for 5 min) increased heart rate, left ventricular dp/dt max (without increasing end-diastolic pressure), aortic dp/dt, cardiac output, myocardial blood flow and metabolic heat production.2. Phentolamine-induced increases in myocardial contractility occurred irrespective of the direction or magnitude of the blood pressure change and were maintained well beyond the actual infusion period.3. In cats treated with alprenolol, bretylium or reserpine there was no evidence of increased cardiac contractility following phentolamine administration.4. It is concluded that phentolamine, in doses less than those required to produce significant alpha-adrenoceptor blockade, increased myocardial contractility through an effect on the sympathetic nervous system.     

Myocardial and haemodynamic effects of the beta-adrenoceptor blocking drug alprenolol (H56/28) in anaesthetized cats

1. The effects of the beta-adrenoceptor blocking drug alprenolol (H56/28) on myocardial and general haemodynamics were studied in anaesthetized cats.2. Alprenolol (0.5 mg/kg and 1.0 mg/kg) reduced femoral systolic and diastolic pressures, heart rate and left ventricular systolic pressure. The rate of rise of the left ventricular pressure pulse (dp/dt) was reduced despite a significant elevation of left ventricular end-diastolic pressure. This is evidence for decreased myocardial contractility. On some occasions there was a transient initial increase in +ve dp/dt max. possibly indicative of moderate beta-adrenoceptor stimulant activity.3. Myocardial and liver blood flows were measured using a heated thermocouple technique. Alprenolol slightly decreased both myocardial and liver blood flows (mean of 17% and 15% respectively with a dose of 1.0 mg/kg). Myocardial and liver vascular resistances were only very slightly increased.4. Alprenolol had no direct effect on calculated myocardial and liver metabolic heat production.5. In doses up to 1.0 mg/kg alprenolol had no effect on airway resistance but occasionally decreased (in vivo) intestinal muscle movement.6. Since alprenolol (although reducing calculated myocardial oxygen consumption and the myocardial and metabolic heat stimulant effects of catecholamines) has no significant effect on myocardial vascular resistance, it is suggested that it would be a useful adjunct in the therapy of angina pectoris.     

The effect of catecholamine infusions on myocardial blood flow, metabolic heat production and on general haemodynamics, before and after alprenolol (H56/28), in anaesthetized cats

1. In cats anaesthetized with pentobarbitone sodium, infusions of adrenaline, noradrenaline (0.5 mug/kg per min) and isoprenaline (0.25 mug/kg per min) increased myocardial blood flow, myocardial heat production, left ventricular systolic and end-diastolic pressures, left ventricular +ve and -ve dp/dt max, and calculated cardiac output, effort and oxygen consumption. These effects (apart from the effect of noradrenaline on left ventricular systolic pressure) were markedly reduced by previous administration of alprenolol (0.5 or 1.0 mg/kg).2. Infusions of adrenaline and noradrenaline increased arterial diastolic blood pressure and isoprenaline reduced it. After alprenolol the effects of adrenaline and noradrenaline were potentiated and that of isoprenaline abolished; in some experiments isoprenaline increased arterial diastolic pressure after alprenolol. Alprenolol did not influence the increases in arterial systolic pressure which followed the administration of adrenaline and noradrenaline.3. Isoprenaline-induced tachycardia was markedly reduced and adrenaline tachycardia was converted to bradycardia after alprenolol. The bradycardia which occurred during noradrenaline infusions was unaffected.4. After blockade by alprenolol, recovery of the effects of isoprenaline on left ventricular dp/dt and on heart rate occurred more quickly than recovery of the effects on arterial diastolic pressure. This suggests that alprenolol has a greater affinity for beta(2)- than for beta(1)-adrenoceptors.5. Intravenous administration of acetylcholine decreased arterial blood pressure, left ventricular pressure and +ve and -ve dp/dt max. During recovery from these effects there was a marked increase in +ve dp/dt max. which was absent after the administration of alprenolol (0.5 mg/kg). Because this dose of alprenolol is thus able to block the effects of reflex sympathetic cardiac nerve stimulation but does not completely antagonize the effects of exogenous adrenaline on dp/dt, it is suggested that alprenolol may have some adrenergic neurone blocking activity.6. Increases in liver and myocardial blood flow and heat production produced by noradrenaline, adrenaline and isoprenaline were reduced after alprenolol.7. Isoprenaline reduced air-way resistance and this effect was abolished by alprenolol; increases in air-way resistance produced by adrenaline and nor-adrenaline were augmented. All three amines inhibited intestinal smooth muscle contractions in vivo. Only the effect of isoprenaline was reduced by alprenolol.     

THE HAEMODYNAMIC EFFECTS OF QUAZODINE, A CARDIAC STIMULANT, IN EXPERIMENTAL E. COLI ENDOTOXIN SHOCK IN THE CAT

SUMMARY 1. Intravenous injections of quazodine (6,7-dimethoxy-4-ethylquinazoline, 0–5 mg/kg per min) in pentobarbitone-anaesthetized cats increased heart rate, the maximum rate of pressure development in the left ventricle (LV dP/dt max.), cardiac output and myocardial blood flow, and decreased systemic arterial blood pressure. The effects of this cardiac stimulant were examined 1, 2, and 3 h after the intravenous administration of 2 mg/kg of E. coli endotoxin.
2. During the endotoxin shock phase (> 1 h after endotoxin) the most pronounced effects were decreases in systemic blood pressure and cardiac output and a severe metabolic acidosis.
3. Quazodine failed to increase cardiac output during endotoxin shock and the effects on the heart rate and LV dp/dt max. were much reduced. In contrast, quazodine-induced vasodilatation was much more marked.
4. It is concluded that there is profound myocardial depression in severe endotoxin shock in the cat and that this cannot be significantly modified by quazodine.     

Pharmacology of LY195115, a potent, orally active cardiotonic with a long duration of action

Compound LY195115 is a novel cardiotonic with both inotropic and vasodilator activities. In cat papillary muscles, LY195115 increased contractility in a concentration-dependent manner; its actions were not blocked by either prazosin or propranolol. An intravenous dose of 7.0 micrograms/kg LY195115 resulted in a 50% increase in contractility in anesthetized dogs; comparable inotropic responses were observed in anesthetized cats receiving 10 micrograms/kg i.v. These doses of LY195115 increased heart rates of both dogs and cats by less than 10%. Oral administration of 25 micrograms/kg to conscious dogs was associated with a selective inotropic response that was maximal at 3 h and maintained in excess of 23 h. This effect was not accompanied by gross behavioral changes or emesis. The hemodynamic profile of LY195115 was evaluated in anesthetized beagle dogs. A 60-min infusion of 1.0 microgram/kg/min LY195115 followed by a 5-min infusion of 10 micrograms/kg/min resulted in dose-dependent increases in contractility (LV dP/dt60) and heart rate; doses that increased LV dP/dt60 by 50% increased heart rate by less than 10%. Doses of greater than 5.0 micrograms/kg decreased left ventricular end-diastolic pressure and systemic vascular resistance; mean arterial blood pressure and cardiac output were unchanged. Estimated myocardial oxygen consumption (heart rate times either systolic or mean arterial blood pressure) was not altered by doses as high as 110 micrograms/kg. This balance of inotropic/vasodilator activities may provide a means of improving cardiac function while maintaining myocardial oxygen supply/demand.     

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。     

Myocardial and circulatory effects of E. coli endotoxin; modification of responses to catecholamines

1. The predominant acute effect of E. coli endotoxin in anaesthetized, ventilated cats was pulmonary hypertension resulting from a 8-12 fold increase in pulmonary vascular resistance. This was followed by decreases in left ventricular (LV) and systemic arterial pressures and in LV dP/dt max. Recovery occurred within 2-4 min and was dependent upon increased sympathetic drive; recovery did not occur in cats treated with the beta-adrenoceptor blocking drug alprenolol.2. The pulmonary vasoconstriction was reduced in cats given compound 48/80 and evidence is presented that it results primarily from histamine release.3. Over the 2-3 h period following endotoxin injection, systemic arterial pressure tended to decrease and heart rate and myocardial metabolic heat production to increase. Myocardial blood flow and LV dP/dt remained fairly stable until the terminal stages of shock.4. The predominant delayed effect of E. coli endotoxin in cats were a markedly reduced stroke volume, an increase in peripheral vascular resistance and a severe metabolic acidosis (arterial base excess-20 mEq/litre). Arterial pO(2) and pCO(2) were not significantly affected. It is concluded that myocardial contractility is maintained at this time through the release of catecholamines and that endotoxin itself depresses contractility.5. The effects of adrenaline and noradrenaline infusions on systolic and diastolic blood pressures, heart rate, cardiac output, myocardial blood flow and LV dP/dt max were markedly reduced in the period 2-3 h after endotoxin. In a few animals some recovery of the response to noradrenaline occurred and was associated with a general circulatory improvement and a reduced metabolic acidosis.     

Haemodynamic effects of the carboxylic ionophore monensin when administered before and during shock induced by E. coli endotoxin.

The haemodynamic effects of the carboxylic ionophore monensin have been examined in cats anaesthetized with sodium pentobarbitone. Marked increases in left ventricular dP/dtmax (and dP/dt at fixed isovolumic pressures) and slight increases in cardiac output and stroke volume occurred, indicating increased myocardial contractility. Heart rate was unchanged but systemic arterial pressure was substantially increased. Satisfactory increases in contractility and arterial pressure were obtained when monensin was infused intravenously in a total dose of 0.25 mg kg-1 over 10 min. Larger doses, especially if rapidly injected, resulted in very marked increases in myocardial contractility leading eventually to cardiac failure. The haemodynamic effects of monensin were markedly reduced during shock induced by E. coli endotoxin and there was unfortunately no evidence to suggest that this extremely potent compound might be potentially beneficial in this form of profound cardiovascular shock.     

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.     

Hemodynamic actions of nicorandil, a new antianginal agent, in the conscious dog

We studied the hemodynamic effects of nicorandil (SG-75) and nitroglycerin in conscious dogs before and after beta-adrenergic receptor blockade. Nicorandil (25-300 micrograms/kg/min) and nitroglycerin (5-60 micrograms/kg/min) produced increases in heart rate and decreases in aortic and left ventricular pressures. In the doses studied, nicorandil caused greater decreases in aortic and left ventricular systolic pressure than nitroglycerin; however, nitroglycerin reduced left ventricular end-diastolic pressure to a greater degree. Nicorandil but not nitroglycerin produced an increase in cardiac output secondary to an increase in heart rate. Global contractility (peak positive dP/dt) was increased in a dose-related manner during nicorandil infusion before beta-blockade. In spite of marked hypotensive responses to higher doses, mean coronary blood flow and coronary conductance were increased by nicorandil. In contrast, both parameters were reduced during nitroglycerin infusion. The effects of nicorandil on coronary blood flow were unaltered by beta-adrenergic blockade, suggesting that metabolic autoregulation is not an important mediator of the response. Nicorandil (75-300 micrograms/kg/min) produced a dose-related increase in transmural myocardial blood flow with the greatest increases in perfusion occurring in the subepicardium and midmyocardium. The results of the present study demonstrate that despite structural similarities, nicorandil and nitroglycerin have varying hemodynamic spectra.     

Effects of amitriptyline on left ventricular function in conscious dogs

Amitriptyline (Am) is a frequently prescribed tricyclic antidepressant drug associated with an increased risk of sudden death that has been presumed to be arrhythmia related. Little has been known about the effects of Am on left ventricular function. We studied i.v. Am (0.5, 1.0, and 1.5 mg/kg) in 10 conscious, resting, chronically instrumented dogs. Heart rate (HR) increased up to 70%; this increase was only partially prevented by propranolol. Left ventricular end diastolic pressure (LVEDP) decreased without, but not with, propranolol. Mean arterial pressure (MAP) increased by 10-13% transiently. The maximum rate of rise of left ventricular pressure (dP/dtmax) decreased by 16-18% without propranolol and by 14-29% with propranolol, indicating a moderate decrease in myocardial contractility. Changes in stroke volume were similar to changes in dP/dt. Thus, i.v. Am, at levels similar to therapeutic blood levels, causes a moderate depression of myocardial contractility, which is accentuated by propranolol. Tricyclic antidepressants, therefore, could have adverse effects on cardiac performance in patients with underlying myocardial dysfunction.     

Calcium channel blockade limits cardiac remodeling and improves cardiac function in myocardial infarction-induced heart failure in rats

Calcium channel antagonists (CCAs) have been proposed to prevent cardiac events after myocardial infarction (MI). However, unwanted effects, such as negative inotropy, limit their use in many cases. The aim of this study was to compare the effects of long-term treatment with the CCAs, mibefradil, verapamil, and amlodipine, administered before and after chronic MI on myocardial remodeling and cardiac function. MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Infarcted animals were treated with placebo, mibefradil (10 mg/kg/d po), verapamil (8 mg/kg bid po), or amlodipine (4 mg/kg/d po). Treatment was started 7 days before or 3 h after MI induction. Six weeks after MI, mean arterial blood pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), and cardiac contractility (dP/dt(max)) were measured. Morphometric parameters such as infarct size (IS), left ventricular dilation (LVD), septal thickness (ST), and cardiac fibrosis were determined in picrosirius red-stained hearts. Six weeks after MI, MAP and dP/dt(max) were decreased, whereas LVEDP and HR were increased in placebo-treated controls. The hearts featured an IS of 45%, left ventricular dilation, cardiac fibrosis, and septal thinning. MAP of all CCA-treated animals was increased, whereas LVEDP was decreased and dP/dt(max) increased 7-day pre- and 3-h post-MI started in mibefradil- and amlodipine-treated animals, but not in verapamil-treated animals. In contrast to amlodipine treatment, before and after MI started mibefradil and verapamil treatment decreased HR. Pretreatment with all CCA reduced IS and increased ST, whereas only mibefradil and amlodipine pretreatment prevented LVD and cardiac fibrosis. After MI started treatment with mibefradil and amlodipine reduced IS and cardiac fibrosis, and increased ST. Long-term treatment with the CCAs mibefradil, verapamil, and amlodipine reduced myocardial remodeling and improved cardiac function in MI-induced heart failure in rats.     

Influence of autonomic blockade on the reduction in myocardial performance produced by clonidine

Clonidine (15 μg/kg, i.v.) induced an increase followed by a long-lasting decrease in blood pressure and reduced heart rate and cardiac output of dogs. All the indices of myocardial performance were decreased: maximal rate of rise in left ventricular pressure, max dP/dt/I.P. (I.P. = ventricular pressure at max dP/dt), pressure time index. The left ventricular end diastolic pressure was increased even when stroke work was decreased. The curve relating dP/dt to the developed pressure was flattened. These facts indicate that clonidine decreased myocardial contractility. Ventricular volumes were not altered. Pacing of the heart after clonidine did not lead to a recovery of cardiac output and myocardial contractility.To analyze the role of the sympathetic and vagal tones on these factors, 5 groups of dogs were used: (1) reserpinized, (2) reserpinized with both vagus nerves cut, (3) with β-adrenoceptor (S 2395, 50 μg/kg) and muscarinic receptor (atropine, 50 μg/kg) blockade, (4) with both vagus nerves cut, and (5)_with both carotid sinus nerves cut.Heart rate was markedly reduced in group 1 but not change in group 2 and 3 3; in groups 4 and 5, heart rate was decreased but to a smaller extent than in control dogs. Therefore the decrease in sympathetic tone and the increase in vagal tone were responsible for the bradycardia. The increase in the vagal tone was apparently due to potentiation of the influence of baroreceptor impulses.The maximal rate of rise in left ventricular pressure did not change in groups 1,2, and 3, but was decreased in groups 4 and 5, indicating that the loss of the sympathetic tone was responsible for the reduction in myocardial contractility.Cardiac output was not changed significantly in groups 2,3 and 4, but decreased in groups 1,3 and 5. The loss of the sympathetic tone and the bradycardia when very marked appear to reduce cardiac output.Left ventricular end diastolic pressure rose in groups 1 and 2, and was increased only transiently in groups 4 and 5. The decrease in myocardial contractility, the changes in blood pressure, the bradycardia and possibly the reduced venous return appear to be the factors influencing this parameter.Blood pressure shows the usual biphasic changes, an increase followed by a decrease in groups 3,4 and 5, did not change in group 1, and was only increased in group 2. The loss of the sympathetic tone was therefore responsible for this effect.     

Haemodynamic effects of the carboxylic ionophore monensin when administered before and during shock induced by E. coli endotoxin

The haemodynamic effects of the carboxylic ionophore monensin have been examined in cats anaesthetized with sodium pentobarbitone. Marked increases in left ventricular dP/dt_max (and dP/dt at fixed isovolumic pressures) and slight increases in cardiac output and stroke volume occurred, indicating increased myocardial contractility. Heart rate was unchanged but systemic arterial pressure was substantially increased. Satisfactory increases in contractility and arterial pressure were obtained when monensin was infused intravenously in a total dose of 0·25 mg kg^?1 over 10 min. Larger doses, especially if rapidly injected, resulted in very marked increases in myocardial contractility leading eventually to cardiac failure. The haemodynamic effects of monensin were markedly reduced during shock induced by E. coli endotoxin and there was unfortunately no evidence to suggest that this extremely potent compound might be potentially beneficial in this form of profound cardiovascular shock.     

Intrapericardial beta-adrenergic blockade with esmolol exerts a potent antitachycardic effect without depressing contractility

Hyperadrenergic states of various etiologies can contribute to tachycardias. Systemic beta-adrenergic blockade suppresses sinus tachycardia but may adversely affect arterial blood pressure and contractility, because the drug gains access to myocardial cells as well as to the sinoatrial node. We examined whether intrapericardial beta-adrenergic blockade with esmolol could suppress tachycardia without reducing contractility as a result of limited drug diffusion, which would be sufficient to penetrate the superficial sinoatrial node but not the deeper myocardial layers. In five anesthetized pigs, we provoked a reflex heart rate increase of 50 beats/min with hemorrhage. The rapidly acting beta-adrenergic blocking agent esmolol (1 mg/kg) was administered intrapericardially using a new percutaneous transatrial access method and a catheter system that can be rapidly and safely introduced. Esmolol equivalently suppressed hemorrhage-induced sinus tachycardia when administered intrapericardially (from 192 to 158 beats/min at 5 min, p < 0.05) or intravenously (from 177 to 151 beats/min at 1 min, p < 0.05). The antitachycardic effect of intrapericardial esmolol was prolonged compared with intravenous esmolol (10 min vs. 3 min, p < 0.05). Intrapericardial esmolol did not affect blood pressure or left ventricular dP/dt max, an index of contractility, whereas intravenous esmolol decreased blood pressure at 1 min for 2 min (p < 0.05) and simultaneously decreased left ventricular dP/dt max at 1 min for < 2 min (p < 0.05). Intrapericardial esmolol suppresses adrenergically induced sinus tachycardia without decreasing contractility or blood pressure. The transatrial approach for intrapericardial delivery of certain 1-adrenergic blocking agents could be employed to control tachycardias in emergency care and surgical settings in patients with impaired cardiac contractility and propensity to hypotension.     

Effects of intravenous azimilide on cardiac performance, fibrillation threshold, and hemodynamics in anesthetized dogs

The class III antiarrhythmic azimilide (E-1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]-amino]-3-[4-(4-methyl-1- piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride; WHO No. 7299, CAS 149888-94-8), by slow infusion or stepwise bolus doses, was evaluated for effects on heart rate, blood pressure, and cardiac pump function, excitability, and refractoriness in anesthetized dogs. Infusion (0.6 mg/kg/min) in male beagles (n = 5) to a maximum dose of 54 mg/kg increased QTc more than 20 ms at 2.0 mg/kg. At a dose of 8.9 mg/kg i.v., QTc increased 34% above baseline and remained elevated throughout the subsequent infusion and for at least 60 min postinfusion. At this maximum class III dose, azimilide increased heart contractile force (HCF) 10% and +dP/dt 34% and decreased heart rate (HR) 12%, without significantly changing mean blood pressure (MBP), left ventricular end diastolic pressure, -dP/dt, stroke volume (SV), or cardiac output (CO). At the mean maximum 47 mg/kg i.v. dose, QTc remained elevated, but decreases were observed in HCF (-27%), +dP/dt (-24%), -dP/dt (-35%), SV (-16%), and CO (-52%). Cumulative intravenous bolus injections of azimilide (0.3, 1, 3, 10, and 30 mg/kg) in male mongrels (n = 5) increased effective refractory period (ERP) and +dP/dt (18% and 16%, respectively, at 10 mg/kg) as a function of dose and significantly decreased HR (-22% at 10 mg/kg). MBP decreased significantly (-23%) only at the highest dose. Ventricular fibrillation threshold (VFT) was unchanged at 30 mg/kg. Effects of dl- (n = 3) and d-sotalol (n = 4) on ERP and HR were similar to azimilide's, but both compounds caused a greater MBP depression and VFT elevation. These results suggest that azimilide is well tolerated by the cardiovascular system, providing an increase in contractility and a slight decrease in HR at intravenous doses that produced a large or maximum increase in cardiac refractoriness.     

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.     

Influence of nifedipine on ventricular function and myocardial hypertrophy in spontaneously hypertensive rats

We compared left ventricular (LV) hemodynamics, LV muscle mass (LVMM), and LV geometry of 13 spontaneously hypertensive rats (SHRs) treated for 20 weeks with nifedipine (30 mg/kg/day) with those of 11 age-matched untreated SHRs. LVMM, LVMM related to end-diastolic volume (LVMM/EDV), LV pressure (PLV), systolic wall stress (Tsyst), ejection fraction (EF), cardiac index (CI), and isovolumetric contractility indices (dP/dtmax, IP, t-dP/dtmax, and VCE) were determined. Nifedipine treatment lowered PLV from 170 to 136 mm Hg and Tsyst from 222 to 194 10(3) dyn/cm2. LVMM and LVMM/EDV decreased moderately from 800 to 744 mg and from 2.56 to 2.29 mg/microliter, respectively. Left ventricular ejection was markedly increased (EF from 52 to 64%; CI from 154 to 178 ml/min X kg), whereas isovolumic contractility indices remained unchanged. Thus, nifedipine reduced but did not totally prevent myocardial hypertrophy and enhanced LV function. These effects seem to result from reduction in LV afterload and not from altered myocardial contractility.     

Effects of platelet-activating factor on myocardial contraction and myocardial relaxation of isolated perfused guinea pig hearts.

Platelet-activating factor (PAF) is an important mediator of cardiovascular shock owing to immunologic reactions, including anaphylaxis and endotoxaemia. Previous studies have shown that PAF is a potent cardio-depressive agent causing a marked coronary constriction and a sustained impairment of myocardial contractility. In this study, we attempted to characterize further the prolonged PAF effects on coronary circulation and myocardial contractile force in isolated guinea pig hearts perfused at constant pressure (60 cm H2O) or constant flow which was adjusted to a level of 100% above basal flow. In addition, the PAF-induced changes of ventricular systolic and diastolic function were distinguished. In the hearts perfused at constant pressure, PAF induced a dose-dependent (0.57, 5.7, and 57 pmol/min) decrease of coronary flow rates, left ventricular pressure (LVP), LV contraction (peak positive dP/dt) and LV relaxation (peak negative dP/dt). The decrement of peak negative dP/dt was more pronounced than that of peak positive dP/dt. Maintenance of coronary flow rates only attenuated, but did not suppress, the PAF-induced ventricular malfunction, and it improved ventricular relaxation less than it did ventricular contraction. Pretreatment with the PAF antagonist WEB 2086 (19.7 nmol/min) almost completely abolished the effects of the highest PAF dose on coronary circulation and ventricular contractile parameters. We conclude that the cardiodepressive effects of PAF are due to coronary constriction and direct contractile events. Furthermore, PAF impairs ventricular diastolic function more than ventricular systolic function.