dP Dt Research Articles

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.

Absolute continuity and mutual information for Gaussian mixtures

Absolute continuity, process representations, and the Shannon information are considered for problems involving a Gaussian mixture process (Nt ),tin [0,1] a.e. dP(ω)dt, where (Gt ) is a Gaussian process and Ais a positive random variable independent of (Gt ). Let (Yt )tin [0, 1], be a second process with υYand υNthe measures induced on and μYand μNthe measures induced on L2[0, 1] (when (Yt) has paths a.s. in L2[0, 1] The Cramer–Hida spectral representation and an extension of Girsanov's theorem are used to obtain results on absolute continuity and likelihood ratio in terms of similar results involving a Gaussian mixture local martingale, for which representations are given. These results are then applied to obtain the Shannon mutual information for a communication channel with feedback having (Nt ) as additive noise. Capacity is obtained for the no-feedback channel, subject to an average-energy type of constraint

Dependence of peak [formula omitted] and mean ejection rate on load and effect of inotropic agents on the relationship between peak [formula omitted] and left ventricular developed pressure — assessed in the isolated working rat heart and cardiac muscles

To examine the effects of preload (mean left atrial pressure) and afterload on two so-called “contractility indices” and the effects of inotropic agents (isoproterenol and calcium) on the relationship between left ventricular developed pressure and peak dP dt when afterload was increased, we used a modified working rat heart preparation (perfused with Krebs-Henseleit solution bubbled with a 95% O 2 - 5% CO 2 gas mixture at 37°C). The atrium was stimulated at a rate of 240/min. An increase in preload from 5 to 15 mmHg caused an increase in peak dP dt from 1,711 ± 293 mmHg/s to 1,971 ± 387 mmHg/s ( p < 0.001, n = 15), and an increase in the mean systolic ejection rate from 1.28 ± 0.31 ml/s to 2.74 ± 0.80 ml/s ( p < 0.001). An increase in afterload (left ventricular developed pressure) from 66 to 97 mmHg produced by elevating aortic pressure caused an increase in peak dP dt from 1,829 ± 222 mmHg/s to 2,449 ± 254 mmHg/s ( p < 0.001, n = 7), and a decrease in the mean systolic ejection rate from 2.12 ± 0.36 ml/s to 1.95 ± 0.33 ml/s ( p < 0.001). Studies using isolated rat papillary muscles ruled out the contribution of an increase in myocardial perfusion to the increase in peak dP dt , since the maximum rate of rise in tension ( dT dt ) increased with an increase in afterload during afterloaded isotonic contraction. Peak dP dt showed a linear relationship to left ventricular developed pressure when the latter was increased by elevating the aortic reservoir and then clamping the aortic outflow tube ( n = 8). The slope of the relation obtained with low-calcium perfusate (0.6 mmol/l) containing isoproterenol (2 × 10 −8 mol/l) was steeper than that obtained with low-calcium perfusate (25.0 ± 6.0/s vs 16.7 ± 4.0/s, p < 0.01) or high-calcium (2.5 mmol/l) perfusate without isoproterenol (17.8 ± 3.7/s). The relation was elevated by a high-calcium concentration ( p < 0.001). Our results indicate that peak dP dt is dependent on both preload and afterload, and that the slope of the relation between peak dP dt and left ventricular developed pressure is increased by isoproterenol, while the relation itself is elevated by calcium.

Effects of dietary fish oil on myocardial ischemic/reperfusion injury of Wistar Kyoto and stroke-prone spontaneously hypertensive rats

The purpose of the present study was to determine whether 15 weeks of dietary fish oil supplementation to Wistar Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SP-SHR) would alter cardiac contractile performance. Isolated perfused working hearts were used to determine the effects of varying left atrial filling pressures on cardiac pump output and pressure development. In addition, the ability of these hearts to recover cardiac output after a 60-minute period of low-flow ischemia followed by 30 minutes of reperfusion was assessed. Myocardial high-energy phosphate levels and long-chain acylcarnitine content were measured. Fish oil supplementation had no effect on indirect tail-cuff systolic blood pressure of WKY rats, but produced a small decrease in systolic blood pressure of SP-SHR. In response to varying left atrial filling pressures, hearts from WKY rats and SP-SHR exhibited no major differences in aortic flow, left intraventricular diastolic pressure, systolic pressure, positive and negative rate of pressure change per unit of time ( dP dt ), or relaxation time; however, coronary flow values were lower in SP-SHR groups relative to respective WKY groups. Fish oil supplementation had no effect on these cardiac parameters. When these hearts were subjected to ischemia and reperfusion, the recovery of cardiac contractile performance was significantly improved in fish oil-fed WKY and SP-SHR groups, compared with their corn oil-fed counterparts. There were no differences in the recovery of the above cardiac hemodynamic parameters between corn oil-fed WKY and SP-SHR. These results provide further support to the hypothesis that dietary fish oil can significantly reduce the mortality risk from cardiovascular disease.

Relationship between cytosolic calcium and oxygen consumption in isolated rat hearts

Maximum oxygen consumption was attained in isolated perfused rat hearts using high perfusate calcium and/or isoproterenol, or phenylephrine. The amplitude of calcium transients was directly related to oxygen consumption until oxygen consumed per beat reached maximum. At saturating oxygen consumption the amplitude of [Ca 2+] i transients continued to increase, indicative of a calcium overload. In all cases +dP dt correlated proportionately with +dCa 2+ dt . Augmented developed pressure, related to isoproterenol-induced increase in cytosolic cAMP, cannot be attributed totally to elevated levels of [Ca 2+] i transients. Adenosine (10 −5 M) added to the medium containing isoproterenol (10 −6 M) negated the isoproterenol-induced increase in cAMP and returned cardiac performance, oxygen consumption, and amplitude of [Ca 2+] i transients to control state.

Myocardial Na +,K +-ATPase in tachycardia induced cardiomyopathy

Na +,K +-ATPase is a major determinant of myocyte homeostasis and excitation-contraction. Cardiac glycosides such as digitalis and ouabain increase the inotropic state of the heart through the inhibition of Na +,K +-ATPase. While cardiac glycosides are commonly used in the setting of congestive heart failure, optimal therapy would depend upon an intact Na +,K +-ATPase system. Changes in Na +,K +-ATPase activity and glycoside receptor density with the development of cardiomyopathy have not been well defined. Accordingly, left ventricular (LV) function and Na +,K +-ATPase activity and glycoside binding were examined in 7 pigs with dilated cardiomyopathy and in 7 controls. Dilated cardiomyopathy was produced by pacing induced supraventricular tachycardia (SVT) for 3 weeks at 240 bpm. Left ventricular function was examined by simultaneous echocardiography and catheterization. Left ventricular fractional shortening significantly decreased with SVT (34 ± 2 vs. 10 ± 2%, P<0.05) and LV diastolic dimension and pressure significantly increased (3.8 ± 0.3 vs. 5.1 ± 0.4 cm, and 8 ± 2 vs. 27 ± 2 mmHg, respectively, P<0.05) as compared to controls. Na +,K +-ATPase activity was assayed as potassium dependent p-nitrophenol-phosphatase activity. Glycoside receptor density ( B max) and affinity ( K D) was determined using [ 3H]-ouabain binding assays. Na +,K +-ATPase activity, B max, and K D all significantly fell from control values with SVT induced cardiomyopathy (0.64 ± 0.06 vs. 0.45 ± 0.12 μg pNP/mg/h, 5.5 ± 0.4 vs. 1.9 ± 0.4 pmol/mg, and 15 ± 3 vs. 9 ± 3 n m, respectively, P<0.05). The distribution of Na +,K +-ATPase in LV sections taken from control and SVT hearts were examined using immunohistochemical techniques. A patchy distribution of Na +,K +-ATPase along the sarcolemma in SVT sections was observed as opposed to a more uniform distribution in control myocytes. There was no observable change in the relative content and distribution of the Na +,K +-ATPase isoforms α2 and α3 in the SVT sections as compared to controls. In an additional set of experiments, changes in LV as well as isolated myocyte responsiveness to ouabain were examined. Left ventricular fractional shortening and peak dP dt were measured following administration of 20–60 μg/Kg of ouabain in control ( n = 3) and SVT ( n = 3) pigs. In the control group, 40 μg/Kg caused a 25% in LV fractional shortening and a 60% increase in peak dP dt from baseline. Cumulative doses of 60 μg/Kg in the control pigs resulted in over a 75% increase in peak dP dt from baseline values. Administration of 40 μg/Kg of ouabain produced only a 16% and 20% increase in LV fractional shortening and peak dP dt in the SVT group respectively; both significantly lower than controls ( P<0.05). In contrast to controls, cumulative doses of 60 μg/Kg in the SVT group were not tolerated and resulted in irreversible ventricular fibrillation. Myocyte contractile responsiveness to cumulative doses of ouabain (0.05–8 μ m) was examined in cardiocytes isolated from 3 additional control and SVT hearts. In control myocytes, 2 μm ouabain produced over a 50% increase and 4 μ m caused over a 100% increase in velocity of shortening from baseline values. In contrast, there was no significant increase in the velocity of shortening of SVT myocytes at any ouabain concentration. In summary, SVT induced cardiomyopathy caused a reduction in glycoside receptor density and Na +,K +-ATPase activity. These changes were associated with an attenuated LV and myocyte responsiveness to ouabain as well as increased sensitivity to the toxic effects of this cardiac glycoside. These changes in Na +,K +-ATPase activity and glycoside responsiveness may have important implications in the treatment of dilated cardiomyopathies.

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.

Correlation between myocardial ischemia and changes in arterial resistance during coronary artery bypass surgery

The arterial resistometer provides continuous on-line monitoring of changes in arterial resistance. Resistance index (Ri), which bears a direct relationship to systemic vascular resistance (SVR), is defined by the equation Ri = P′ ( dP′ dt ) , where dP′ dt is the peak dP dt of the arterial waveform, and P′ is the pressure at dP′ dt . In 42 patients with unstable angina, changes in Ri were studied at six periods during aortocoronary bypass surgery before tracheal intubation, during tracheal intubation, leg elevation, presternotomy, sternotomy, and dissection of the internal mammary artery. Thirty-four episodes of ischemia (0.1 mV ST segment changes) were observed in 26 patients. All ischemic episodes were associated with increased Ri (mean increase, 102 ± 52%). Elevation of the pulmonary capillary wedge pressure correlated with ischemia during the preintubation, intubation, and sternotomy periods, but not in the remaining periods. Changes in arterial pressure and heart rate were not good predictors of ischemia. The prevalence of ST segment changes increased markedly during all periods of anesthesia with increase in Ri ( P < 0.05). Ninety-one percent of ST segment changes were associated with a 25% increase from the baseline Ri. Raising the cutoff point to a ≥ 75% increase in Ri improved the specificity of Ri in ischemia detection from 61 to 92%. An increase of ≥ 75% in Ri occurred in only 8% of cases without ST segment changes. It was found that an increase in Ri as depicted by the arterial resistometer was the best hemodynamic correlate of myocardial ischemia.

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 haemodynamic effects of dopexamine in patients with coronary arterial disease

We assessed the acute haemodynamic effects of dopexamine 1 μg/kg/min and 3 μg/kg/min in 21 patients with coronary arterial disease following routine catheterisation. Patients were aged 38 to 72 years and left ventricular ejection fraction ranged from 23 to 79%. Dopexamine was well tolerated in all patients except one in whom transient ventricular arrhythmias occurred with 3 μg/kg/min. No patient developed angina. Dopexamine increased cardiac index (2.6 ± 0.4 to 3.2 ± 0.1 ( P < 0.001) and 4.0 ± 1.0 l/min/m 2 ( P < 0.001), control to 1 μg/kg/min and 3 μg/kg/min, respectively) and decreased systemic vascular resistance index (3356 ± 1506 to 2318 ± 809 ( P < 0.001) and 2252 ± 1973 dyne · sec · cm −5/m 2 ( P < 0.001)), but did not affect systemic arterial, pulmonary arterial or right atrial pressure. Maximum positive dP dt was increased (1294 ± 324 to 1597 ± 505 ( P < 0.001) and 2199 ± 819 mmHg/sec ( P < 0.001)) as was left ventricular stroke work index (44 ± 20 to 51 ± 21 ( P < 0.05) and 56 ± 27 g · m/m 2 ( P < 0.001) control to 1 μg/kg/min and 3 μg/kg/min, respectively). Left ventricular end diastolic pressure fell with 3 μg/kg/min from 19.8 ± 6.9 to 12.4 ± 4.6 mmHg ( P < 0.05) in patients with preserved left ventricular ejection fraction (> 50%, n = 6), but not in those with impaired left ventricular ejection fraction (< 50%, n = 15), otherwise the effects in these two subgroups were similar. We conclude that dopexamine has both inotropic and vasodilator properties. Despite increasing left ventricular stroke work index and contractility it is well tolerated by patients with ischaemic heart disease, and would therefore be useful in the treatment of acute cardiac failure in this group of patients.

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.

Effects of hemoperfusion during percutaneous transluminal coronary angioplasty on left ventricular function

The effect of autologous blood perfusion, delivered through an angiographic power injector, on alleviating left ventricular (LV) hemodynamic deterioration during percutaneous transluminal coronary angioplasty (PTCA) was examined. LV systolic and diastolic pressures, LV peak positive and peak negative first derivative of LV pressure ( dP dt ), and ST-segment shift were recorded in 9 patients with and without hemoperfusion. Hemoperfusion resulted in an improved LV hemodynamic profile during balloon occlusion, as reflected in LV systolic pressure (127 ± 14 vs 120 ± 15 mm Hg, p = 0.01), LV end-diastolic pressure (17 ± 14 vs 25 ± 6 mm Hg, p < 0.001), peak positive (1,237 ± 240 vs 1,149 ± 225 mm Hg/s, p < 0.05) and peak negative (1,666 ± 357 vs 1,485 ± 385 mm Hg/s, p = 0.003) dP dt . Hemoperfusion provides substantial protection for significant LV dysfunction induced by conventional PTCA in 1-vessel angioplasty and is a feasible option to protect against potential cardiovascular collapse in high-risk PTCA.

Relationship between adenylate cyclase activity and regional myocardial energetics in experimental left ventricular hypertrophy

The aim of this study was to examine the responsiveness of the hypertrophied left ventricle to β-adrenergic stimulation in a pressure overload model produced by valvular aortic stenosis and characterized by reduced β-adrenoceptor number. The study was designed to correlate changes in global and regional cardiac work and energetics in response to isoproterenol with adenylate cyclase activity. Eleven anesthetized dogs with left ventricular hypertrophy and 11 controls were studied at rest and during 0.5 and 1.0 μg/kg/min isoproterenol infusion. We measured regional work from segment length and force changes with ultrasonic dimension crystals and miniature force gauges in addition to arterial and left ventricular blood pressure and cardiac output. Regional myocardial oxygen consumption was calculated from O 2 extraction using microspectrophotometry and blood flow using radioactively labeled microspheres. Adenylate cyclase activity was assayed at baseline and after stimulation with forskolin. Isoproterenol significantly increased heart rate, dP dt max , cardiac output, and external work to similar levels in control and hypertrophied animals. Similarly, regional work increased from 463 ± 115 to 995 ± 584 g × mm/min for controls and from 392 ± 156 to 1175 ± 577 for hypertrophied dogs with high dose isoproterenol. Regional O 2 consumption also increased to similar levels (20.3 ± 14.7 vs 16.2 ± 6.3 ml O 2/min/100 g) in both groups. Adenylate cyclase activity was lower in hypertrophy at baseline (23.9 ± 7.3 vs 62.9 ± 14.2 p M/min/mg protein for controls), but was the same as for controls with forskolin stimulation. The results indicate that the retained stimulated activity of adenylate cyclase compensated for the decreased β-adrenoceptor number in this model of hypertrophy thereby sustaining responsiveness to β-adrenergic stimulation.

EFFECTS OF ENDOTHELIN-1 ON ARTERIAL PRESSURE AND MYOCARDIAL CONTRACTILITY IN THE CONSCIOUS NORMOTENSIVE RABBIT

1. We studied the effects of an intravenous bolus of endothelin-1 on arterial pressure and myocardial contractility in the conscious rabbit. 2. Endothelin produced an initial fall in arterial pressure accompanied by an increase in heart rate. This was followed by a dose-dependent increase in arterial pressure, peaking about 7 min after injection, accompanied by a reciprocal fall in heart rate. 3. Left ventricular rate of change of pressure (LV dP dt) increased with endothelin except at higher doses (0.8 and 1.6 nmol/kg), where in some animals it decreased.

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.

The effects of high (sodium meglumine diatrizoate, Renografin-76) and low osmolar (sodium meglumine ioxaglate, Hexabrix) radiographic contrast media on diastolic function during left ventriculography in patients

Although a majority of studies indicate superior hemodynamic and clinical profiles of low osmolar compared with high osmolar contrast media, the effect of these agents on diastolic left ventricular function has not been examined. We prospectively examined hemodynamic, electrocardiographic, and echocardiographic indices of left ventricular function in patients undergoing contrast ventriculography with a high osmolar, ionic, monomeric contrast, diatrizoate (Renografin-76) compared with a low osmolar, ionic, dimeric contrast, ioxaglate (Hexabrix). Thirty patients were randomized to each group. There were no clinical differences between the two groups. The decrease in systemic pressures was significantly greater with diatrizoate after left ventriculography (−38.5 ± 3.5 versus −18.2 ± 2.3, p < 0.001) and selective left coronary angiography (−29.5 ± 2.4 versus −17.4 ± 2.6, p < 0.001). In addition, left ventricular end-diastolic pressure increased significantly more with diatrizoate (7.3 ± 0.9 versus 2.7 ± 0.8 mm Hg for ioxaglate, p < 0.001). QT interval prolongation occurred in both patient groups. Diatrizoate decreased systemic vascular resistance, and increased cardiac output and left ventricular ejection fraction more than ioxaglate, while simultaneously increasing left ventricular end-diastolic volume and altering the peak atrial filling velocity. Negative dp dt ( p < 0.05), but not Tau, computed by the logarithmic or derivative methods, was reduced by diatrizoate. These data indicate that significant alteration of diastolic filling patterns occurs with high osmolar compared with low osmolar contrast agents. Although the clinical significance of this observation is currently unknown, these data further support the reported hemodynamic superiority of the low osmolar, dimeric contrast agent ioxaglate during contrast angiography.

Acute hemodynamic effects of intravenous diperdipine, a new dihydropyridine derivative, in coronary heart disease

The acute hemodynamic effects of a new dihydropyridine calcium channel blocker, diperdipine, which is suitable for intravenous administration, were studied by right and left cardiac catheterization in 16 patients with coronary heart disease. Diperdipine markedly reduced systemic vascular resistance and improved stroke index and left ventricular ejection fraction. Mean pulmonary artery and wedge pressures were slightly increased as a possible consequence of enhanced venous return, whereas right atrial and left ventricular end-diastolic pressures were not significantly changed. Nevertheless, an increase in preload was clearly indicated by an augmented left ventricular end-diastolic volume index after administration of diperdipine. Left ventricular contractility, which was estimated by the end-systolic pressure-volume ratio and by dP dt max was not significantly changed, though analysis of individual data suggests a minimally negative inotropic effect. However, such a minor effect on left ventricular contractility was largely counterbalanced by the marked reduction of afterload, which produced a sharp improvement of stroke index. Enhancement of left ventricular ejection fraction and reduction in systemic vascular resistance were inversely and directly correlated to control values. Overall, diperdipine was well tolerated, but one patient had a major untoward reaction that consisted of an ischemic episode that was possibly related to drug administration. In conclusion, intravenous diperdipine appears to be a potent arteriolar dilating agent that does not affect left ventricular contractility.

Myocardial dysfunction and norepinephrine release in the isolated rat heart injured by electrolysis-induced oxygen free radicals

In the present investigation, we used electrolysis as a source of oxygen free radicals to test their possible role in norepinephrine release, as well as in the mechanism of cellular injury, cardiac dysfunction and arrhythmias. In the isolated rat heart perfused under constant pressure, according to the Langendorff technique, electrolysis of the Krebs-Henseleit solution (10 mA d.c. current for 1 min) produced myocardial irreversible dysfunction within 5 min. Fifteen minutes after electrolysis, significant falls in the left ventricular pressure (from 87.5 ± 6.8 to 33.7 ± 5.2 mmHg), dP dt max (from 1230 ± 90 to 375 ± 59 mmHg/s), heart rate (from 287 ± 18 to 119 ± 13.5 beats/min) and coronary flow (from 14.8 ± 9 to 3·4 ± 1.7 ml/min) were observed, along with an increase in left ventricular end diastolic pressure from 10 to 50 ± 3.5 mmHg ( n = 8, P < 0.01). AV conduction block and/or sinus bradycardia were noted in all preparations. An increase in norepinephrine washout from 298.5 ± 84 at baseline to 610 ± 110 pg/min/g 5 min after electrolysis was measured ( n = 8, P < 0.05) and a 44.8 ± 9·2% and 35 ± 7.5% reduction, respectively in right and left ventricular tissue norepinephrine content was also found at 30 min ( n = 5, P < 0.05). Pretretment of the hearts 10 min before electrolysis and throughout the experimental period by superoxide dismutase (SOD; 100 U/ml), catalase (150 U/ml), a combination of SOD + catalase or mannitol (50 m m) partially blocked the deleterious effect of free radicals and permitted a functional recovery of 50 to 60%, mannitol being the more potent protective agent. Furthermore, these scavengers also significantly reduced norepinephrine washout. Thus, it appears that electrolysis-generated free radicals may injure sympathetic neuronal as well as myocardial membranes, hence induce norepinephrine release, rhythm disturbances and cardiac dysfunction.

Altered responsiveness of hypertrophied rat hearts to alpha- and beta-adrenergic stimulation

Inotropic responsiveness to α- and β-adrenergic agents was examined in pressure-overload hypertrophied rat hearts. Pressure overload was induced in rats by abdominal aortic constriction. Three weeks post-constriction, hearts were isolated and perfused with buffer containing various concentrations of (1) calcium (2) isoproterenol (3) forskolin, or (4) phenylephrine. The change in rate of left ventricular pressure development ( Δ + dP dt ) with increasing perfusate calcium concentrations was comparable in hypertrophied hearts of aortic-constricted rats (AC) and hearts of sham-operated rats (SO). However, with isoproterenol or forskolin stimulation, inotropic responsiveness ( Δ + dP dt ) was 50% lower in hypertrophied hearts of AC. This was associated with significantly lower tissue cAMP levels. Beta-adrenoceptor number and affinity were unchanged in the hypertrophied myocardium. Maximum inotropic responsiveness to phenylephrine was also lower in hypertrophied hearts and was associated with reduced α-adrenoceptor numbers. The data suggest that altered inotropic responsiveness to α-adrenergic stimulation may, in part, be due to reduced cardiac α-adrenoceptor density. However, post-receptor mechanisms including alterations in cAMP metabolism may contribute to the reduced responsiveness to β-adrenergic stimulation in hypertrophied hearts of AC.