Left Ventricular dP Dt Research Articles

Effects of Insulin on Coronary Blood Flow in Anesthetized Pigs

Insulin can influence the vasculature by a sympathetically mediated vasoconstriction and a vasodilatation; the latter effect predominates in the renal circulation of anesthetized pigs. We determined the effect of intravenous infusion of insulin on coronary blood flow in pentobarbitone-anesthetized pigs at constant heart rate, arterial pressure and blood levels of glucose and potassium. In 6 pigs, infusion of 0.004 IU kg^–1 min^–1 of insulin decreased coronary flow despite increasing left ventricular dP dt_max^–1; when the latter was abolished by propranolol, the coronary flow response was augmented. The mechanisms of this response were examined in 22 pigs given propranolol. Phentolamine changed coronary flow response to an increase (6 pigs) and this was abolished by intracoronary injection of N^ω-nitro-L-arginine methyl ester (L-NAME; 5 pigs). L-NAME augmented coronary flow response (6 pigs) and this was abolished by phentolamine (5 pigs). In 18 pigs given propranolol, three incremental doses of insulin caused graded coronary flow decreases whether L-NAME was given (6 pigs) or not (6 pigs) beforehand, and caused graded coronary flow increases after phentolamine (6 pigs). Thus insulin caused a coronary vasoconstriction mediated by sympathetic α-adrenergic effects and a vasodilatation related to the release of nitric oxide. The net effect was a coronary vasoconstriction.

Beneficial effects of ω-3 fatty acid treatment on the recovery of cardiac function after cold storage of Hyperlipidemic rats

Cardiac effects of ω-3 polyunsaturated fatty acids (PUFAs) were studied in female Wister rats fed a standard diet (control [C] diet) or a high-cholesterol (HC) diet. Subgroups of rats from these groups were treated with eicosapentaenoic acid-E (EPA) or docosahexaenoic acid-95E (DHA) for 5 weeks. Although plasma total cholesterol (TC) and triglyceride (TG) levels were higher in each group fed the HC diet versus each group fed the C diet, EPA administration with the HC diet (HC + EPA) significantly ( P < .05) reduced these levels. An isolated working-heart preparation was used to determine cardiac function. Cardiac output (CO) was lower in rats fed the HC diet and HC + DHA versus any of the groups fed the C diet ( P < .05). In addition, left ventricular (LV) maximum differentiation of pressure-time curve ( dp dt ) was lower in the rats fed the HC diet versus any of the C diet groups ( P < .05). After evaluation of cardiac function in each rat, the heart was stored in a histidine-tryptophanketoglutarate solution for 8 hours at 4°C. The heart was then reperfused, and recovery of cardiac function was evaluated. No significant differences were observed for post-preservative cardiac function within the C diet groups. However, within the HC diet groups, HC + EPA significantly ( P < .05) improved the recovery of cardiac function. In addition, HC + DHA also significantly ( P < .05) improved the recovery of coronary flow (CF) and LV dp dt . No significant differences were observed for plasma TC and TG concentrations in the C diet groups. EPA administration significantly decreased cardiac levels of palmitic, oleic, and linoleic acids in the HC diet groups. No significant differences were observed for cardiac levels of free fatty acids (FFAs) within the C diet groups. Cardiac EPA and DHA levels were significantly ( P < .05) elevated in EPA- or DHA-treated rats compared with the other diet-fed rats. Cardiac EPA levels were also elevated in DHA-treated rats compared with untreated rats ( P < .05). These results suggest that EPA attenuates coronary and myocardial preservation injuries through an increase in serum lipids and an accumulation of myocardial FFAs resulting from a HC diet.

Hemodynamic effects of the intravenous administration of cyclorirobuxine D in anesthetized pigs

The present study was undertaken in anesthetized pigs to determine the primary effects of cyclorirobuxine D given intravenously on hemodynamic variables. In eight pigs, the administration of 1.5 mg/kg of cyclorirobuxine D caused a small increase in aortic blood pressure. When this response was prevented, a decrease in heart rate was obtained in each of the eight pigs. When this response was also prevented, an increase in the maximum rate of change of left ventricular systolic pressure (left ventricular dP dt max ) was observed. In four pigs, the decrease in heart rate and the increase in left ventricular dP dt max were progressively augmented by graded increases in the dose of cyclorirobuxine D. In six pigs, the responses of hemodynamic variables to cyclorirobuxine D were not affected by blockade of cholinergic and adrenergic receptors. In a further six pigs, blockade of nitric oxide synthase with Nϖ-nitro-L-arginine methyl ester did not affect the decrease in heart rate caused by the drug, but abolished the increases in left ventricular dP dt max and aortic blood pressure. The present study showed that intravenous administration of cyclorirobuxine D primarily caused a decrease in heart rate and an increase in left ventricular inotropic state, which secondarily determined an increase in aortic blood pressure, and suggested that the response of heart rate involved a direct effect of the drug on the heart, while the response of left ventricular contractility was related to mechanisms dependent on the release of nitric oxide.

Vascular and myocardial protective effects of converting enzyme inhibition in experimental heart failure

Systemic vasoconstriction due to stimulation of the sympathetic and renin-angiotensin-aldosterone systems is a hallmark of heart failure and this is accompanied by impaired endothelium-dependent relaxations at the level of large arteries. This study investigated, in a rat model of heart failure, whether such an endothelial dysfunction also exists at the level of the resistance artery, and whether this is associated with morphologic changes, as well as the effects of chronic treatment with the angiotensin-converting enzyme inhibitor perindopril (2 mg/kg/ day). After 12 months, arterial pressure, left ventricular (LV) end diastolic pressure (LVEDP), and LV dP dt were measured in anesthetized rats. Responses to acetylcholine and nitroprusside were determined in isolated and perfused mesenteric artery segments (diameter: 280 ± 15 μm). After fixation, vessel diameter, media cross-sectional area, and media collagen and elastin densities were measured by image analysis. After 12 months, untreated rats showed signs of heart failure, i.e., reduced LV dP dt , and increased LVEDP, heart weight/body weight, LV cavity circumference, and myocardial collagen density. In mesenferic vessels the endothelium-dependent vasodilator response to acetylcholine was impaired, whereas the response to the nitric oxide donor nitroprusside was unaffected. Heart failure did not affect vascular morphological parameters. Perindopril decreased blood pressure and LVEDP without any modification of LV dP dt , and prevented cardiac remodeling. At the vascular level, perindopril improved the response to acetylcholine and reduced media crosssectional area and collagen density without affecting internal vessel diameter or elastin density. Thus, heart failure decreases endothelium-dependent vasodilator response to acetylcholine without modification of vessel structure. The heart-failure induced endothelial dysfunction could be prevented by angiotensin-converting enzyme inhibition.

Diltiazem and regional left ventricular function during graded coronary constriction and propofol anesthesia in the dog

Although calcium channel blockers may preserve function in ischemic myocardium, they may also produce myocardial depression and dysfunction in the presence of decreased coronary flow. This study was designed to examine the issue of possible protection afforded by diltiazem against ischemia-induced myocardial dysfunction during propofol anesthesia. In eight anesthetized and ventilated dogs, regional myocardial (ultrasonic crystals in both left anterior descending [LAD] and left circumflex [LC] perfusion areas) and global ventricular function were evaluated during progressively severe degrees of myocardial ischemia (LAD constriction) before and after intravenous diltiazem (150 μg/kg). As coronary flow decreased, heart rate increased, and arterial and coronary perfusion pressures, left ventricular dP dt , and cardiac output decreased. Systemic vascular resistance was unaffected. Diltiazem without coronary constriction increased heart rate, and decreased diastolic arterial pressures, left ventricular (LV) end-diastolic, coronary perfusion pressures, LV dP dt max, LAD coronary blood flow, stroke volume, and cardiac output. At all levels of coronary constriction following diltiazem, there were decreases in systolic and diastolic arterial pressures, stroke volume, cardiac output, LV dP dt , and coronary perfusion pressure. Heart rate increased at critical coronary constriction, and then remained constant relative to the prediltiazem state. The regional muscle effects of the reductions in coronary flow in the LAD perfusion territory included decreased systolic shortening and increased postsystolic shortening before and after diltiazem. Diltiazem did not alter the magnitude of the alterations in systolic or postsystolic shortening brought about by coronary constriction. No changes occurred in the LC area. In conclusion, diltiazem depressed global ventricular performance in the presence of propofol anesthesia, but did not worsen or protect regional myocardial function of the compromised LAD segment.

Pharmacologic basis of the antiarrhythmic and hemodynamic effects of sotalol

Sotalol is a competitive β adrenoceptor antagonist devoid of membrane-stabilizing activity and intrinsic sympathomimetic activity that has no preferential actions on β 1 or β 2 responses. No other tested receptor systems are affected by sotalol. In addition to having class II (β blockade) effects, sotalol also has class III antiarrhythmic activity. It increases the action potential duration (APD) and prolongs atrial and ventricular repolarization. The effect on APD is independent of β blockade; the same effect is seen with similar concentrations of the d stereoisomer of sotalol, which does not have β-blocking activity. Sotalol prolongs the rate-corrected QT interval and ventricular and atrial refractoriness without affecting atrial, His-Purkinje, or ventricular conduction velocity. Atrioventricular nodal conduction is decreased, largely because of β blockade. Sotalol increases the fibrillation threshold and decreases the defibrillation threshold. Sotalol is an effective antiarrhythmic in various animal models of arrhythmia (e.g., chloroform, hydrocarbon—catecholamine, ouabain, and coronary ligation). In addition, it reduces the severity and frequency of arrhythmias induced by programmed electrical simulation. By comparison, metoprolol is ineffective and d-sotalol is as effective as the racemate in this model, indicating that this effect is independent of β blockade. Sotalol causes concentration-dependent increases in the contractility of isolated ventricular tissue that is not blocked by previous β or α blockade or catecholamine depletion. The positive inotropic effect may be related to inhibition of time-dependent K + current responsible for the increase in APD. Like propranolol, sotalol decreases contractile force, heart rate, arterial blood pressure, left ventricular dP dt , and cardiac output in intact animals due to blockade of circulating catecholamines. Sotalol consistently reduces the heart rate to a greater degree than propranolol and causes significantly less cardiac suppression than propranolol at a given heart rate.

Myocardial glutathione depletion impairs recovery of isolated blood-perfused hearts after global ischaemia

This study was performed to determine whether depletion of myocardial glutathione would impair recovery of left ventricular function of blood-perfused, isolated hearts after reversible ischaemic injury. Cats were treated with either vehicle or buthionine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the synthesis of glutathione. The feline isolated hearts were perfused with the blood of normal donor cats before and after 40 min of global myocardial ischaemia. The myocardial concentration of glutathione of the BSO group, 178±38 ng/mg tissue, was significantly less than that of the control group, 292±38 ng/mg tissue ( P<0.05). The peak left ventricular developed pressure (LVDP) 1 h after reperfusion, expressed as a fraction of the peak LVDP before ischaemia, was 0.87±0.10 for the control group and 0.64±0.08 for the BSO group ( P=0.05 vs. control). The peak left ventricular dP dt after reperfusion, expressed as a fraction of the peak dP dt before ischaemia, was 1.08±0.14 for the control group and 0.78±0.09 for the BSO group ( P=0.05 vs. control). The myocardial creatine kinase activity of the BSO group, 1046±46 U/g tissue, was not significantly different from that of the control group, 1038±17 U/g tissue ( P=0.87). Thus, depletion of myocardial glutathione resulted in impaired post-ischaemic contractile function that cannot be attributed to a greater extent of irreversible cell injury.

Beneficial effects of trandolapril on experimentally induced congestive heart failure in rats

Angiotensin-converting enzyme (ACE) inhibitors have been shown to prolong life expectancy in patients with congestive heart failure. In order to determine the relative contributions of the different factors involved in this beneficial effect, we investigated in an experimental model of postinfarction cardiac insufficiency in the rat over a 9–12-month period (1) the kinetics of the development of the hemodynamic, biologic, and morphologic alterations that accompany heart failure, and (2) the kinetics of the effects of a new, long-acting ACE inhibitor, trandolapril. Following induction of infarction, systolic blood pressure, left ventricular dP dt , and end-diastolic pressure were immediately decreased, decreased, and increased, respectively, and these modifications persisted throughout the study. Cardiac index, on the other hand, was only initially and transiently decreased. Cardiac remodeling (left ventricular dilation, myocardial hypertrophy, and fibrosis) occurred as early as 7 days after infarction and worsened throughout the study. Plasma atrial natriuretic factor (ANF) and urinary cyclic guanosine monophosphate (cGMP) were also increased. In this model, a 1-year oral treatment with trandolapril resulted in early hemodynamic and biologic beneficial effects (reductions in preand afterload, increase in cardiac index, and decrease in plasma ANF), and in a delayed reversal of the infarction-induced cardiac morphologic alterations. Hence, the trandolapril-induced increase in survival rate is due initially to the drug's hemodynamic effects and over the long-term to both its hemodynamic and cardiac morphologic (limitation of remodeling) effects.

β-Adrenergic contractile reserve as a predictor of clinical outcome in patients with idiopathic dilated cardiomyopathy

To examine the ability of β-adrenergic contractile reserve assessment to predict the outcome of patients with heart failure, a prospective study was undertaken in 35 patients with idiopathic dilated cardiomyopathy and radionuclide ejection fraction below 40%. During right- and left-sided catheterization, right atrial and left ventricular (LV) pressures, peak positive LV dp dt , cardiac index, and plasma norepinephrine and epinephrine concentrations were measured at baseline. After a left main intracoronary infusion of dobutamine (25 to 200 μg · min −1), β-adrenergic contractile responsiveness was assessed as the net increase in peak positive LV dp dt (Δ LV dp dt ). After the initial examination, patients were treated with diuretics, digitalis, and angiotensin converting enzyme inhibitors and then followed-up. After a mean follow-up period of 13 ± 7 months, two groups of patients were distinguished: those who responded to medical therapy (group A, n = 26) and those with clinical deterioration (group B, n = 9) leading to death ( n = 4) or heart transplantation ( n = 5). Initial peak positive LV dp dt , LV end-diastolic pressure, cardiac index, and LV ejection fraction were better in group A than in group B ( p < 0.001). Initial plasma norepinephrine and epinephrine concentrations were significantly higher and Δ LV dp dt was lower in group B than in group A ( p < 0.001). Multivariate stepwise logistic regression analysis showed that Δ LV dp dt ( p < 0.0001) and LV ejection fraction ( p = 0.0001) were independently related to prognosis. At threshold values of either 250 mm Hg · sec −1 for Δ LV dp dt or 20% for LV ejection fraction, their prognostic predictive values were 69% and 53%, respectively. When the same threshold values were used, a combination of these two parameters led to a positive predictive value of 100%. In conclusion, patients who do not respond to medical therapy were those with the lowest β-adrenergic contractile reserve. Regarding clinical outcome, low- and high-risk populations may be discriminated by combining LV ejection fraction and β-adrenergic contractile reserve assessment.

Regional redistribution of myocardial perfusion by UL-FS 49, a selective bradycardic agent

The effects of UL-FS 49, a specific bradycardic agent, on systemic hemodynamics, regional myocardial function (sonomicrometry, percentage of segment shortening), and regional coronary blood flow (radioactive microspheres) were studied in open-chest, anesthetized dogs with severe left circumflex coronary artery (LCX) stenosis. UL-FS 49 was administered as two sequential bolus injections of 0.25 mg/kg. Heart rate decreased from 149 ± 13 beats/min to 102 ± 6 and 77 ± 4 beats/min after 0.25 and 0.5 mg/kg cumulative doses of UL-FS 49, respectively. The reduction in heart rate was not associated with any significant change in left ventricular pressure or mean arterial pressure, left ventricular dp dt , or coronary vascular resistance. Similarly no hemodynamic changes occurred with atrial pacing to the initial heart rate. Application of an LCX stenosis of sufficient severity to produce a 50% reduction in mean LCX blood flow (44 ± 4 to 22 ± 2 ml/min) resulted in a significant reduction in the percentage of segment shortening in the ischemic zone (9.8 ± 1.6% to 6.5 ± 1.1%). The percentage of segment shortening in the ischemic zone progressively improved to 8.4 ± 1.2% and 9.4 ± 0.5% after 0.25 and 0.5 mg/kg UL-FS 49, respectively. Subepicardial perfusion in the ischemic zone was decreased and subendocardial perfusion was increased after administration of UL-FS 49. Consequently the ischemic zone endocardial/epicardial ratio increased from 0.43 ± 0.08 to 1.12 ± 0.22 and 1.48 ± 0.32 with low and high doses of UL-FS 49. Atrial pacing to the control heart rate abolished the effects of UL-FS 49 on regional myocardial blood flow and percentage of segment shortening. These data indicate that UL-FS 49 is a selective bradycardic agent that can improve ischemic myocardial function distal to severe coronary stenosis. The data suggest that UL-FS 49 improves the relationship between myocardial oxygen supply and demand by negative chronotropic actions and by favorably redistributing ischemic blood flow.

Cellular basis of ventricular remodeling after myocardial infarction

To determine whether acute left ventricular failure associated with myocardial infarction leads to architectural changes in the spared nonischemic portion of the ventricular wall, large infarcts were produced in rats, and the animals were sacrificed 2 days after surgery. Left ventricular end-diastolic pressure was increased, whereas left ventricular dP dt and systolic pressure were decreased, indicating the presence of severe ventricular dysfunction. Absolute infarct size, determined by measuring the fraction of myocyte nuclei lost from the left ventricular free wall, averaged 63%. Transverse midchamber diameter increased by 20%, and wall thickness diminished by 33%. The number of mural myocytes in this spared region of the left ventricular free wall decreased by 36% and the capillary profiles by 40%. Thus, side-to-side slippage of myocytes in the myocardium occurs acutely in association with ventricular dilation after a large myocardial infarction. In order to analyze the chronic consequences of myocardial infarction on ventricular remodeling, a second group of experiments was performed in which the left coronary artery was ligated and the functional and structural properties of the heart were examined 1 month later. In infarcts affecting an average 38% of the free wall of the left ventricle (small infarcts), reactive hypertrophy in the spared myocardium resulted in a complete reconstitution of functioning tissue. However, left ventricular end-diastolic pressure was increased, left ventricular dP dt was decreased, and diastolic wall stress was increased 2.4-fold. After infarctions resulting in a 60% loss of mass (large infarcts), a 10% deficit was present in the recovery of viable myocardium. Functionally, ventricular performance was markedly depressed, and diastolic wall stress was increased 9-fold. The alterations in loading of the spared myocardium were due to an increase in chamber volume and a decrease in the myocardial mass/chamber volume ratio that affected both infarct groups. Thus, decompensated eccentric ventricular hypertrophy develops chronically after infarction and growth processes in myocytes are inadequate for normalization of wall stress when myocyte loss involves nearly 40% or more of the cells of the left ventricular free wall. The persistence of elevated myocardial and cellular loads may sustain the progression of the disease state toward end-stage congestive heart failure.

Acute hemodynamic effects of terazosin in hypertensive and normotensive patients

Terazosin, a selective α 1-adrenergic antagonist, was administered intravenously to 10 patients undergoing cardiac catheterization to determine its short-term hemodynamic effects. Hemodynamic measurements were performed before and 30 minutes after three doses of the drug: 1, 1, and 3 mg. One milligram of terazosin reduced the blood pressure (systolic/diastolic, mean) from a mean of 152.0 86.3 , 110.7 mm Hg by −24.3 −9.4 , −15.3 mm Hg ( p < 0.05). In the five patients who received 5 mg of the drug, blood pressure declined in a dose-dependent manner by −21.8 −3.8 , −11.6 mm Hg after 1 mg, and by −35.8 −14.8 , −22.8 mm Hg ( p < 0.05) after all 5 mg of the drug. The changes in blood pressure paralleled the terazosin-induced decrease in systemic resistance. Similar changes were recorded for pulmonary artery and capillary wedge pressures and pulmonary vascular resistance. The greatest hemodynamic response was noted with the first drug dose; succeeding doses had a progressively diminished incremental effect. Cardiac output, heart rate, and maximum left ventricular dp dt demonstrated little change, whereas left ventricular end-diastolic pressure decreased after all three doses, reaching significance after 2 mg (−3.4 ± 0.9 mm Hg, p < 0.05), and left ventricular ejection fraction tended to increase (+ 5.6% ± 2.4%, p < 0.05 after 1 mg) and showed a dose dependence analogous to that of systemic resistance. Although not generally reaching statistical significance, indexes of aortic stiffness and compliance displayed a favorable effect. These data are consistent with terazosin's specific α 1-antagonism. Left ventricular performance is improved by afterload reduction, since terazosin demonstrated no direct effect on cardiac contractility. The reduction of systemic vascular resistance, coupled with reduction in blood pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance, and improved left ventricular performance without myocardial depression after intravenous terazosin, makes this agent a useful adjunct in antihypertensive therapy.

Cardiac adenosine production is linked to myocardial pO 2

Experiments were performed on isolated perfused guinea-pig hearts ( n=45) to further evaluate the stimulus that triggers cardiac adenosine production. Stimulation of hearts with isoproterenol (4 n m, 20 min) enhanced left ventricular dP dt max , heart rate and myocardial oxygen consumption within 1 min to new steady state values, whereas coronary venous adenosine concentration only transiently increased reaching its maximum between 1 and 3 min of stimulation. Rate of accumulation of S-adenosylhomocysteine (SAH), a measure of the free cytosolic adenosine concentration, was steepest immediately following onset of stimulation and then progressively declined. Similar to adenosine, changes in coronary venous pO 2 were phasic and adenosine release and pO 2 closely correlated. Norepinephrine (20 n m) which increased myocardial oxygen consumption to a comparable extent as isoproterenol (4 n m) further decreased coronary venous pO 2 and increased coronary venous adenosine. When myocardial oxygen supply was systematically varied by changing coronary perfusion pressure from 60 to 90 and 35 cmH 2O, respectively, the adenosine release during isoproterenol (2n m) was markedly enhanced at 35 cmH 2O but blunted at 90 cmH 2O. Similarly SAH accumulation was greatest at 35 cmH 2O and smallest at 90 cmH 2O. It is concluded that changing myocardial oxygen consumption is not a sufficient cause to enhance adenosine formation. Myocardial oxygenation as reflected by changes in coronary venous pO 2 closely correlates with changes in free cardiac adenosine as evidenced by two independent indices: tissues SAH and coronary venous adenosine concentration. The stimulus triggering cardiac adenosine formation is most likely the imbalance of oxygen supply and oxygen demand.

Adverse effects of cocaine on cardiovascular dynamics, myocardial blood flow, and coronary artery diameter in an experimental model

Smoking “crack” is currently popular; this results in rapidly peaking, high blood levels of cocaine. Our purpose was to investigate the effects of rapid cocaine administration. Hemodynamics, myocardial blood flow, and left ventricular cavity end-systolic and end-diastolic areas were measured in pentobarbital-anesthetized dogs before and 15 minutes after (1) a bolus intravenous injection of cocaine ( n = 6), or (2) a 10-minute infusion of cocaine ( n = 6), or (3) saline ( n = 6) administration. In both treated groups cocaine caused a significant reduction in heart rate and left ventricular dP dt compared with baseline measurements, and an increase in left ventricular end-diastolic pressure. Cocaine also caused dilation of the left ventricle and a fall in regional myocardial blood flow. In nine other dogs, proximal circumflex artery diameter, assessed by angiography, and regional myocardial blood flow were measured before and 3 to 5 minutes after cocaine ( n = 7) or saline ( n = 2). In treated animals, circumflex artery diameter was reduced 15 ± 4% (range 2% to 29%, p < 0.01 versus baseline) after cocaine. We conclude that in this model, rapid administration of cocaine depresses left ventricular function, causes left ventricular dilation, and is associated with coronary artery vasoconstriction and reduced myocardial blood flow.

Interactions of pyridostigmine with cardiopulmonary systems and their relationships to plasma cholinesterase activity

Three dose levels of pyridostigmine (0.5, 2, and 5 mg/kg) were given iv to dogs anesthetized with sodium pentobarbital. Hemodynamic measurements made were cardiac output, blood pressure, left ventricular dP dT , and heart rate. Pulmonary function data obtained were airway resistance, respiratory rate, and tidal volume. Activity of blood cholinesterase was also measured. Increasing doses of pyridostigmine promptly and progressively lowered the acetylcholinesterase activity of blood to a minimum of 40% of control at the 5 mg/kg dose. Airway resistance was most sensitive to the drug. Resistance increased significantly with 2 mg/kg, and the 5 mg/kg dose resulted in more than a 10-fold increase, which persisted for more than 2 hr. Tidal volume was decreased and minute volume was increased due to an increase in respiratory rate. With the higher doses, heart rate decreased and stroke volume rose sufficiently to compensate so that cardiac output was unchanged. The lowest dose produced minimal effects on both cardiovascular and respiratory systems, and since this dose is greater than that proposed for organophosphate poisoning in humans, it seems likely that this drug would not cause important effects in normal humans when used as a protective agent.

Regional and global biventricular function during dipyridamole stress testing

This study assesses the relation between regional ventricular performance (using 2-dimensional echocardiography) and global systolic and diastolic indexes of biventricular myocardial function (using hemodynamic monitoring) during dipyridamole stress testing. Simultaneous 2-dimensional echocardiographic and biventricular hemodynamic monitoring during dipyridamole infusion (0.56 mg/kg over 4 minutes) was performed in 19 patients. All patients had a normal resting function. Eleven of the 19 patients had a positive echocardiography test (new wall motion dyssynergy with dipyridamole) and they formed group 1. Eight patients had a negative echocardiography test (group 2). During baseline conditions, no significant differences were found in the 2 groups: rate pressure product ( 107 ± 16 vs 108 ± 13 mm Hg × beats/min × 1 100 ), positive left ventricular (LV) dP dt (1,950 ± 473 vs 2,262 ± 430 mm Hg/s), negative LV dP dt (−2,069 ± 620 vs −2,205 ± 245), LV end-diastolic pressure (8.2 ± 4.4 vs 9.6 ± 4.0 mm Hg), right ventricular positive dP dt (368 ± 133 vs 400 ± 190 mm Hg/s) and negative dP dt (−281 ± 89 vs −383 ± 147). At peak dipyridamole, the 2 groups were different for LV end-diastolic pressure (20 ±10 vs 8 ± 5 mm Hg, p < 0.01), LV positive dP dt (2,100 ± 688 vs 3,013 ± 851 mm Hg/s, p < 0.01) and negative dP dt (−1,868 ± 518 vs −2,564 ± 272, p < 0.01). At peak ischemia, LV positive dP dt increased slightly, but not significantly, while negative dP dt decreased significantly (p < 0.01) in comparison with resting values. In the absence of ischemia, the effect of dipyridamole on LV function consists of an increase in peak positive and negative LV dP dt . Alterations in regional myocardial performance and global LV diastolic function provide more sensitive indexes of dipyridamole-induced ischemia than global systolic function.

The effects of phospholipase A 2 inhibition on experimental infarct size, left ventricular hemodynamics and regional myocardial blood flow

It has been reported that activation of phospholipase A 2 and the subsequent degradation of membrane phospholipids are responsible for irreversible myocardial injury. Thus, we examined whether a phospholipase A 2 inhibitor 1-(benzylmethyl-amino)-3-[(α,α,α-trifluoro-m-tolyl)oxy]-2-propanol hydrochloride, can reduce myocardial necrosis after coronary artery occlusion. In 14 anesthetized dogs, 1 minute after coronary occlusion, 99mTc-labeled albumin microspheres (8 mCi) were injected into the left atrium for future assessment of the hypoperfused zone. After 15 minutes, the dogs were randomized to a control group ( n = 7) and a treated group ( n = 7, 2 mg/kg i.v.). After 6 hours, infarct size and hypoperfused zones were measured using triphenyltetrazolium chloride staining and autoradiography, respectively. The hypoperfused zone, as a percentage of the left ventricle, was 26 ± 3% and 23 ± 1% in the control and the treated groups (NS), respectively. The percentage of the hypoperfused zone that evolved to necrosis was 98 ± 4% in the control group and 45 ± 10% in the treated group ( P < 0.001) showing a reduction of 54%. By weight, in the control group, necrosis involved 26 ± 4 g of the left ventricle while in the treated group it was 9 ± 2 g ( P < 0.005). In 6 additional dogs, left ventricular hemodynamics and regional myocardial blood flow were studied before and after treatment i.e., 15 and 30 minutes after coronary occlusion, respectively. Phospholipase A 2 inhibitor did not acutely change heart rate, aortic pressure, left ventricular end-diastolic and systolic pressures, left ventricular dP dt and regional myocardial blood flow. Thus, phospholipase A 2 inhibitor salvaged the acutely ischemic myocardium, reducing necrosis by over 50% in the canine model. It is postulated that since this effect was not related to the studied hemodynamic parameters and regional myocardial blood flow, it may be related to the preservation of membrane integrity.

Acute hemodynamic effects of intravenous isradipine

The acute hemodynamic effects of isradipine, a new dihydropyridine calcium antagonist, were evaluated in 16 men referred for elective cardiac catheterization. Low-dose (0.007 mg/kg, n = 8) and highdose (0.015 mg/kg, n = 8) isradipine was administered intravenously over 10 minutes and the hemodynamic alterations assessed 10 minutes after completion of infusion. Low-dose isradipine caused increases in heart rate (68 ± 9 to 79 ± 12 beats/ min, p < 0.001) (mean ± standard deviation), cardiac index (3.0 ± 0.7 to 4.1 ± 0.9 liter/min/m 2, p < 0.001) and coronary sinus blood flow (114 ± 27 to 162 ± 74 ml/min, p < 0.01), and significant decreases in mean aortic pressure (104 ± 17 to 92 ± 10 mm Hg, p < 0.01), systemic and coronary vascular resistance. High-dose isradipine caused similar effects: the heart rate increased (72 ± 6 to 84 ± 14 beats/min, p < 0.005), as did the cardiac index (3.0 ± 0.6 to 4.6 ± 0.9 liter/min/m 2, p < 0.001) and coronary sinus blood flow (122 ± 48 to 166 ± 47 ml/min, p < 0.025). In addition, there were increases in the stroke volume index (43 ± 10 to 55 ± 8 ml/m 2, p < 0.001) and left ventricular stroke work index (69 ± 12 to 79 ± 12 g-m/m 2, p = 0.05) after the high-dose infusion. Vascular resistance declined significantly in the systemic, pulmonary and coronary beds. Neither isradipine infusion changed the left ventricular end-diastolic pressure or myocardial O 2 consumption, but the peak positive left ventricular dP dt increased significantly at both infusion levels. Intravenous isradipine is a potent arterial vasodilator with a rapid onset of action. As with other drugs in this class, negative inotropic effects may have occurred, although they were masked by reflex sympathetic activation. These hemodynamic properties should make isradipine efficacious for the therapy of certain cardiovascular disorders.

Effect of increasing heart rate on left ventricular performance in patients with normal cardiac function

The influence of an increase in heart rate on left ventricular (LV) contractile performance was assessed in patients with normal LV function. In 19 patients (3 men, 16 women) ages 55 ± 9 years (mean ± standard deviation) with normal global and segmentai LV function and normal coronary arteries, LV dP dt max was measured at baseline heart rate and during atrial pacing at baseline +5, baseline +25 and baseline +45 beats/min. In 10 of the patients, intravascular volume was not altered during pacing and, as a result, echocardiographically measured LV end-diastolic dimension decreased (5.4 ± 0.4 at baseline vs 4.9 ± 0.5 cm at baseline +45 beats/min, p < 0.05). In these patients, LV dP dt max increased modestly (1,571 ± 237 at baseline vs 1,760 ± 199 mm Hg/s at baseline +45 beats/min, p < 0.05). In the other 9 patients, intravascular volume was expanded rapidly (by saline infusion) during pacing and, as a result, LV end-diastolic dimension was held constant (5.2 ± 0.6 at baseline vs 5.1 ± 0.6 cm at baseline +45 beats/min, difference not significant). In these patients, LV dP dt max increased substantially with pacing (1,505 ± 228 at baseline vs 2,050 ± 258 mm Hg/s at baseline +45 beats/min, p < 0.05). Thus, an increase in heart rate induces a modest increase in LV dP dt max in patients in whom LV preload (as reflected by end-diastolic dimension) is allowed to decrease; in contrast, it causes a marked increase in LV dP dt max in those in whom LV preload is maintained constant.

Potential mechanisms of improved left ventricular function with enoximone in severe congestive heart failure

Enoximone, a phosphodiesterase inhibitor, is a potent inotropic vasodilator agent that causes a marked improvement in systemic hemodynamics in patients with severe chronic congestive heart failure. Cardiac index, stroke volume index and stroke work index increase, and there is a significant decrease in pulmonary capillary wedge pressure. Left ventricular dP dt increases, despite a decrease in arterial pressure and systemic vascular resistance and without any significant change in heart rate, indicating a positive inotropic effect. A marked decrease in systemic vascular resistance indicates that decreased left ventricular outflow resistance resulting from peripheral vasodilation also contributes to improvement in left ventricular function. In some patients, left ventricular end-diastolic volume increases despite a marked decrease In pulmonary capillary wedge pressure, suggesting an improvement in apparent left ventricular compliance, which may also be contributory to improved left ventricular function.