Disparate force-frequency effects of pimobendan and dobutamine in conscious dogs with tachycardia-induced cardiomyopathy

BACKGROUND: This study was designed to examine how a calcium sensitizer, pimobendan, affected a force-frequency response (FFR) as compared to the beta-adrenergic agonist dobutamine. METHODS AND RESULTS: Left ventricular (LV) contractility and relaxation were evaluated by the slope (Ees) of the LV end-systolic pressure-volume relation and the time constant (Tau) of LV pressure decay. Using 6 conscious dogs with tachycardia-induced heart failure, the FFR was examined before and after administration of dobutamine (6 microg/kg/min) or pimobendan (0.5 mg/kg). Despite the similar inotropic and lusitropic action at the baseline heart rate, pimobendan and dobutamine showed different FFR and relaxation-frequency responses. Before administration of these drugs, there was no significant increase in LV contractility and relaxation by increasing heart rate. However, dobutamine amplified FFR (Ees: +3.1 +/- 1.4, P <.05) as compared with Ees for a comparable increase in heart rate before administration of the drug. On the other hand, pimobendan showed relatively mild amplification of FFR compared with dobutamine (Ees: +1.9 +/- 1.1, P <.05). The relaxation-frequency response tended to increase with dobutamine but not with pimobendan. CONCLUSIONS: Mild amplification of FFR observed in pimobendan suggests that this agent could be used more safely than beta-adrenergic agent when heart rate is increased, as seen with exercise.     

Comparison of the effects of levosimendan,pimobendan, and milrinone on canine left ventricular-arterial coupling and mechanical efficiency

We examined and compared the effects of levosimendan, a new myofilament calcium sensitizer with phosphodiesterase inhibiting activity, pimobendan, and milrinone on left ventricular-arterial coupling and mechanical efficiency in 21 experiments performed in open-chest, barbiturate-anesthetized dogs instrumented for measurement of aortic and left ventricular (LV) pressure (micromanometer-tipped catheter), +dP/dt, and LV volume (conductance catheter). Myocardial contractility was assessed with the endsystolic pressure-volume relation (E_es) and preload recruitable stroke work (M_sw) generated from a series of differentially loaded LV pressurevolume diagrams. LV-arterial coupling and mechanical efficiency were determined by the ratio of E_es to effective arterial elastance (E_a; the ratio of end-systolic arterial pressure to stroke volume) and the ratio of stroke work (SW) to pressure-volume area (PVA), respectively. Levosimendan (0.75, 1.5, and 3.0 g·kg^–1·min^–1) significantly (p<0.05) increased heart rate, +dP/dt, and ejection fraction (EF) and decreased mean arterial pressure (MAP), pressurework index (PWI; an estimate of myocardial oxygen consumption), and LV systolic and end-diastolic pressures (LVSP and LVEDP) and volumes (EDV and ESV). Levosimendan-induced augmentation of myocardial contractility (E_es, M_sw, and+dP/dt) and reductions in LV afterload (E_a) caused increases in the E_es/E_a ratio (0.61±0.10 during control to 3.3±0.7 during the high dose) consistent with enhancement of LV-arterial coupling. Levosimendan increased SW/PVA (0.48±0.05 during control to 0.84±0.04 during the high dose), indicating this drug improves the transfer of myocardial potential energy to external work. Levosimendan also increased the ratio of SW to PWI (109±18 during control to 255±50 mmHg·min·100g during the high dose), suggesting that myocardial metabolic efficiency was improved as well. Like levosimendan, pimobendan and milrinone (10, 20, and 40 and 1.0, 2.0, and 4.0 g·kg^–1·min^–1, respectively) increased HR, +dP/dt, EF, E_es, and M_sw and decreased MAP, LVSP, LVEDP, EDV, ESV, and E_a. In contrast to levosimendan, neither agent reduced PWI. Pimobendan and milrinone caused dose-related increases in E_es/E_a, SW/PVA, and SW/PWI. The results indicate that levosimendan, pimobendan, and milrinone augment myocardial contractility, produce venous and arteriolar vasodilation, and enhance LV-arterial coupling and mechanical efficiency in open-chest, barbiturateanesthetized dogs.This work was supported by US PHS grant HL 54820 and Anesthesiology Research Training Grant GM 08377     

Systolic functional response of normal older and younger adult left ventricles to dobutamine

To determine the systolic functional response of the aged left ventricle to catecholamines, 16 healthy, physically active subjects aged 62 to 72 years (group A) and 19 healthy adults aged 18 to 28 years (group B) were evaluated before and during infusion of 8 micrograms/kg/min of dobutamine. Phonocardiograms, electrocardiograms and M-mode echocardiograms were recorded simultaneously with a carotid pulse tracing. End-diastolic dimension and end-systolic pressure remained unchanged in the 2 groups. End-systolic dimension decreased 0.3 cm (p less than 0.001) in group A and 0.5 cm (p less than 0.001) in group B. Fractional shortening increased (p less than 0.001) from 34 +/- 4% to 38 +/- 5% in group A and from 34 +/- 4% to 43 +/- 4% in group B. Mean velocity of circumferential fiber shortening (Vcf) increased 0.6 circ/s (p less than 0.001) in group A and 1 circ/s (p less than 0.001) in group B. End-systolic pressure/dimension ratio increased 3 mm Hg/cm (p less than 0.001) in group A and 8 mm Hg/cm (p less than 0.001) in group B. The changes in end-systolic dimension, fractional shortening, Vcf and end-systolic pressure/dimension ratio were more significant in group B (p less than 0.001). Thus, the left ventricular systolic functional response to dobutamine is diminished in healthy older persons.     

Quantitative comparison of the force-interval relationships of the canine right and left ventricles

We quantitatively compared the extrasystolic and postextrasystolic responses of the right ventricle and left ventricle of the same heart, which have vastly different geometries, architectures, and muscle masses. We studied nine isolated, supported canine hearts whose right and left ventricles were made to contract isovolumically with balloons placed in both chambers. The ventricles were paced with the following pattern: 20 regularly timed priming stimulations, followed by a test stimulation at a variable test pulse interval, and, finally, by a second test stimulation which was always delivered 1200 msec after the first test pulse. In each heart, approximately 15 different test pulse intervals between 300 and 1200 msec were investigated. Both the maximum developed pressure and maximum rate of pressure development, expressed as a percentage of their steady state values during the priming period were used to quantify the extra- and postextrasystolic responses. For each extrasystolic and postextrasystolic test beat, the normalized response of the right ventricle was plotted vs. that of the left ventricle. The regression line and correlation coefficient between the two were determined. The average result from nine hearts gave a slope of 0.96 +/- 0.05, an intercept of 4.52 +/- 4.05% and a correlation coefficient of 0.995 +/- 0.004. This analysis indicated that, despite the differences in right and left ventricular geometry, architecture, and mass, their force-interval behaviors were nearly identical.     

Effect of dobutamine on regional diastolic left ventricular asynchrony in patients with left ventricular hypertrophy.

Dobutamine improves systolic as well as diastolic function, but its effect on left ventricular (LV) asynchrony is unknown. An on-line automated segmental motion analysis (A-SMA) system was developed, based on an automatic border detection technique, to evaluate the effect of dobutamine on LV asynchrony in patients with LV hypertrophy (LVH). Low dose (5 microg x kg (-1) x min(-1)) dobutamine stress echocardiography was performed in 15 patients with LVH and in 15 healthy subjects. Short-axis LV views were obtained and divided into 4 wedge-shaped segments using A-SMA. The time - area curve and its first derivative curve in each segment were displayed. Total normalized peak filling rates (nPFR) were obtained. Systolic and diastolic asynchronies were assessed from the coefficient of variation (CV) of the regional time intervals from end diastole to the peak ejection rate (T-PER), and from end systole to the peak filling rate (T-PFR), respectively. At baseline, the CV of T-PER and T-PFR in patients with LVH were greater than those in healthy subjects (CV-T-PER: 18.8+/-9.2 vs 9.6+/-4.3%, CV-T-PFR: 19.5+/-7 vs 8.1+/-4.1%, both p<0.01). During dobutamine infusion, differences among groups at baseline disappeared and systolic and diastolic asynchronies improved (CV-T-PER: 7.3+/-4.8 vs 5.7+/-2.1%, CV-T-PFR: 6.8+/-3.5 vs 5.1+/-1.3%, both p>0.05). Total nPFR increased (from 3.2+/-1.0 /s to 5.6+/-1.3 /s, p<0.01) with dobutamine infusion in patients with LVH. Dobutamine improved LV diastolic asynchrony, as evaluated by A-SMA, in patients with LVH demonstrating that the lusitropic effect of dobutamine improved LV regional diastolic asynchrony, playing an important role in the improvement of global LV diastolic filling.     

Comparison of low-dose dobutamine ventriculography with low-dose dobutamine echocardiography for predicting regional improvement in left ventricular function after coronary artery bypass grafting

The demonstration of a contractile reserve during low-dose dobutamine echocardiography (LDDE) identifies viable myocardium and predicts recovery of left ventricular (LV) function after myocardial revascularization in patients with chronic coronary artery disease. However, a technically difficult transthoracic visualization may limit the use of LDDE, thus requiring an alternative diagnostic procedure. The present study compares LDDE with low-dose dobutamine ventriculography (LDDV) in predicting an improvement in regional LV function after surgical revascularization. We studied 18 patients with coronary artery disease and LV dysfunction who were to undergo coronary artery bypass grafting. Preoperatively, all patients were evaluated for the presence of viable myocardium using LDDE and LDDV. Follow-up echocardiography at rest and left ventriculography were performed 4 months after successful revascularization to assess recovery of LV function. The sensitivity and specificity of LDDE to identify dysfunctional segments capable of recovering function were 63% and 71%, respectively, with a diagnostic accuracy of 68%. The sensitivity, specificity, and diagnostic accuracy of LDDE improved to 81%, 72%, and 76% when patients with optimal transthoracic evaluation were selected, whereas they were 30%, 77%, and 57%, respectively, in those who underwent suboptimal evaluation. The sensitivity, specificity, and diagnostic accuracy of LDDV were 66%, 75%, and 71%, respectively, with no difference in subgroups of patients. This study demonstrates that LDDV can be considered a useful technique for identifying the presence of myocardial viability and may provide an advantage over LDDE in patients with suboptimal echocardiographic visualization.     

Different effects of prolonged exercise on the right and left ventricles

To examine the functional consequences of the greater increase in right ventricular work with exercise, the effects of prolonged exercise on the right and left heart chambers were compared in 41 athletes before, at the finish (13 min) and after recovery (28 h) from the Hawaii Ironman Triathlon (3.9 km swim, 180.2 km bike ride, 42.2 km run). Two-dimensional and Doppler echocardiograms were analyzed for left and right atrial and ventricular areas at end-diastole and end-systole, right and left ventricular inflow velocities and mitral and tricuspid regurgitation. After exercise, left ventricular and left and right atrial sizes were reduced, whereas right ventricular size increased (diastole: 21.4 to 24.2 cm2; systole: 15.8 to 18.2 cm2; p less than 0.01). The emptying fraction of all chambers was unchanged. Left but not right ventricular inflow showed an increase in peak velocity of rapid filling, whereas both atrial systolic velocities increased (26 to 38 cm/s tricuspid; 38 to 54 cm/s mitral; both p less than 0.01). Overall, the right ventricular early to atrial velocity ratio was reduced after exercise (1.56 to 1.17; p less than 0.05) and the left ventricular pattern was unchanged. The prevalence of tricuspid regurgitation was statistically unchanged (86% to 52%), although that of mitral regurgitation was greatly reduced (76% to 0%). Changes in all variables returned toward prerace values during recovery. Thus, in highly trained athletes, prolonged exercise causes differing responses of the right and left ventricles. These differences may be due to changes in right ventricular function, shape or compliance.     

Hemodynamic effects of dobutamine in children.

Dobutamine is useful for augmenting cardiovasuclar function in adults. However, no information is available on the action of dobutamine in children. To determine its hemodynamic effects in children, we infused dobutamine into 12 children with congenital heart disease during diagnostic cardiac catheterization. We administered dobutamine in two doses: first 2 and then 7.75 microgram/kg per min for 10 minutes each. We meaured heart rate, cardiac output, systemic and pulmonary arterial, right atrial and pulmonary capillary blood pressures before and during the infusion of dobutamine. Systemic and pulmonary vascular resistances, cardiac index and stroke index were calculated. Cardiac output, cardiac index, stroke volume, stroke index and systemic arterial phasic and mean blood pressures increased sugnificantly (P less than 0.05) and pulmonary capillary mean blood pressure decreased significantly (P less than 0.05) during the infusion of each dose of dobutamine compared with control values. Heart rate, pulmonary and right atrial mean blood pressure and systemic and pulmonary vascular resistance were unchanged with either dose of dobutamine. We noted no adverse effect from the drug.     

Cardiodynamic effects of experimental right bundle branch block in canine hearts with normal and hypertrophied right ventricles

Cardiodynamic effects of acute experimental right bundle branch block (RBBB) were studied in canine hearts: group A included 15 normal hearts; group B-1 had seven hearts with mild right ventricular hypertrophy (RVH), and group B-2 had 11 hearts with marked RVH. The main sequential changes following RBBB were marked prolongation of the Q upstroke interval of the right ventricle and striking shortening of right ventricular systolic time that affected right and left ventricular interaction, particularly in the hearts with RVH. Hemodynamic changes were: the right ventricular end-diastolic pressure was elevated markedly (4.4 +/- 2.2----9.8 +/- 2.6 mm Hg, p less than 0.001) in group B-2, moderately (p less than 0.01) in group B-1, and not at all in group A. The right ventricular positive peak dp/dt decreased remarkably (1036 +/- 151----827 +/- 152 mm Hg/sec, p less than 0.001) in group B-2 and negligibly in the other groups. A significant correlation existed between the percentage of decrease in right ventricular peak dp/dt and the QRS duration of RBBB in each group (p less than 0.01). The left ventricular peak negative dp/dt decreased distinctly (2570 +/- 326----+/- 2055 +/- 362 mm Hg/sec, p less than 0.01) in group B-2 and not at all in the other groups. The stroke volume showed 12% decrease in group B-2 (p less than 0.001), 8% decrease in group B-1 (NS), and no decrease in group A. In the presence of RVH, acute RBBB causes significant impairment of right and left ventricular function. The magnitude of the impairment invariably depends upon both the prior degree of RVH and the width of the QRS complex.     

Comparison of dobutamine echocardiography and positron emission tomography in patients with chronic ischemic left ventricular dysfunction

Objectives. The aim of this study was to correlate dobutamine-induced contractile reserve as detected by echocardiography with findings on positron emission tomography in patients with chronic ischemic left ventricular dysfunction.

Background. Contractile reserve induced by low dose dobutamine infusion has been proposed as a marker of myocardial viability.

Methods. Sixty patients with stable coronary artery disease and left ventricular dysfunction (mean ejection fraction [± SD] 29 ± 10%) underwent transthoracic echocardiography with dobutamine infusion (up to 10 μg/kg body weight per min) and positron emission tomography with nitrogen-13 ammonia and fluorine-18 (F-18) fluorodeoxyglucose as a perfusion and a metabolic tracer, respectively. Regional wall motion, perfusion and metabolism were analyzed semiquantitatively by using a 16-segment model. Segments with F-18 fluorodeoxyglucose uptake > 50% were considered viable on positron emission tomography.

Results. After dobutamine infusion, hemodynamic variables changed significantly, and myocardial ischemia was evident in 17 patients. All 60 patients had dysfunctional myocardium considered viable on positron emission tomography (8 ± 4 segments/patient), whereas 52 patients had dysfunctional myocardium with contractile enhancement by dobutamine echocardiography (4 ± 2 segments/patient, P = 0.01). The extent of dysfunctional myocardium with contractile reserve appeared to correlate less closely with the total extent of viable dysfunctional myocardium identified by positron emission tomography than with the number of such segments associated with a pattern of perfusion-metabolism mismatch.

Conclusions. In patients with chronic ischemic left ventricular dysfunction, echocardiography can be used to identify enhancement in the contractile function of viable dysfunctional myocardium after infusion of low dose dobutamine. In this study, the presence and extent of such enhancement were relatively less than the values obtained from positron emission tomography.     

Usefulness of dobutamine in producing myocardial ischemia. Comparison with ergometry

Fifty six patients were studied while in the Coronary Care Unit: 17 with unstable angina and 39 with acute myocardial infarction. All patients underwent dobutamine stress testing (doses of 5, 10, 15 and 20 micrograms/kg/min every 5 min) and exercise testing (modified protocol to finish at an energy expenditure of approximately 5 METS): 4-5 days after the last crisis of angina or 6-8 days after the onset of noncomplicated acute myocardial infarction. The heart rate increased from 72 +/- 10 to 104 +/- 12 beat/min with dobutamine (p = 0.00001) and from 84 +/- 11 to 118 +/- 15 beat/min with exercise testing (p = 0.00001). The systolic blood pressure increased from 116 +/- 9 to 138 +/- 11 mmHg with dobutamine (p = 0.00001) and from 117 +/- 8 to 156 +/- 7 mmHg with exercise testing (p = 0.00001). Due to different reasons 33 patients did not finish the exercise protocol, while only 8 patients did not finish the dobutamine testing. The ST segment wast elevated in 22 cases with dobutamine and in 9 cases with exercise, eight of them coinciding in both tests. The ST segment was depressed in 36 cases with dobutamine and in 21 cases with exercise, 20 of them coinciding in both tests. Angina was present in 11 cases with dobutamine and in four exercise, three of them coinciding. If the unfinished tests or those with angina or ST segment depression are considered abnormal, there were 40 abnormal tests with dobutamine and 38 with exercise, 32 of them coinciding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transmural distribution of myocardial infarction: difference between the right and left ventricles in a canine model

The evolution of myocardial infarction 24 hours after ligating both the right coronary artery and the obtuse marginal branch of the left circumflex coronary artery was examined in 33 anesthetized dogs. Postmortem coronary angiography and a tracer microsphere technique were used to determine risk areas and their collateral blood flows, respectively. The mean weight of the risk areas was 11.3 +/- 0.5 g (mean +/- SEM) in the right ventricle and 10.5 +/- 0.9 g in the left ventricle (NS). The weight of infarcted tissue was 5.7 +/- 0.7 g in the right ventricle and 5.2 +/- 0.9 g in the left ventricle (NS). In both ventricles, infarct weight was linearly related to risk area size, and the percent of risk area necrosis was inversely correlated with the extent of collateral flow at 24 hours of coronary ligation, defined as the mean myocardial blood flow inside the central risk area. Ratios of infarct to risk area between the subendocardial and subepicardial layers were 0.76 +/- 0.06 and 0.28 +/- 0.05 in the right and left ventricles, respectively (p less than 0.01, between ventricles, n = 31), which coincided well with subendocardial-to-subepicardial-flow ratios at 24 hours, ie, 0.86 +/- 0.04 in the right ventricle and 0.32 +/- 0.06 in the left ventricle (p less than 0.01). The regional distribution of myocardial infarction correlated well with flow distribution inside the risk area; the slope of these relations was similar between the subendocardium and subepicardium in the right ventricle, whereas in the left ventricle it was larger in the subendocardium than in the subepicardium. Thus, in the dog, the inherent change in the regional distribution of coronary collateral blood flow is an important modifier in the evolution of myocardial infarction, especially in the left ventricle.     

Calcium equally increases the internal calcium recirculation fraction before and after β-blockade in canine left ventricles

Summary We studied whether intracoronary Ca administration after β-blockade would increase the internal Ca recirculation fraction (RF) analogously to the Ca administration before β-blockade. This was performed in excised cross-circulated canine hearts. We analyzed the exponential decay component of the postextrasystolic potentiation (PESP) following a spontaneous extrasystole. All the PESPs decayed in alternans with atrial pacing at a constant rate. We obtained the time constant (τ_e) of the monoexponential decay component of the alternans PESP. An increment of intracoronary Ca by 1.5mmol/1 enhanced the left ventricular contractility indexE _max (end-systolic maximum elastance) by 2.5 times before and after β-blockade with propranolol. The intracoronary Ca after β-blockade slightly but significantly increased τ_e, and hence increased RF calculated from τ_e by RF=exp(−1/τ_e). This was analogous to the slightly increased τ_c and RF with Ca before β-blockade. We speculate that the myocardial cyclic AMP-dependent phosphorylation level would not significantly alter the effect of intracoronarily administered Ca on myocardial Ca handling, in terms of τ_e and RF. This study was partly supported by Grants-in-Aid for Scientific Research (07508003, 09470009, 10770307, 10558136, 10877006) from the Ministry of Education, Science, Sports and Culture, a Research Grant for Cardiovascular Diseases (7C-2) from the Ministry of Health and Welfare, 1997 and 1998 Frontier Research Grants for Cardiovascular System Dynamics from the Science and Technology Agency, and research grants from the Ryobi Teien Foundation, the Mochida Memorial Foundation, and the Nakatani Electronic Measuring Technology Association, all of Japan.     

Age-dependent effects of high fat-diet on murine left ventricles: role of palmitate

Obesity-associated heart disease results in myocardial lipid accumulation leading to lipotoxicity. However, recent studies are suggestive of protective effects of high-fat diets (HFD). To determine whether age results in differential changes in diet-induced obesity, we fed young and old (3 and 18 months) male C57Bl/6 mice control diet, low-fat diet (both 10 kcal% fat) or HFD (45 kcal% fat) for 16 weeks, after which we analyzed LV function, mitochondrial changes, and potential modifiers of myocardial structure. HFD or age did not change LV systolic function, although a mildly increased BNP was observed in all old mice. This was associated with increased myocardial collagen, triglyceride, diacylglycerol, and ceramide content as well as higher caspase 3 activation in old mice with highest levels in old HFD mice. Pyruvate-dependent respiration and mitochondrial biogenesis were reduced in all old mice and in young HFD mice. Activation of AMPK, a strong inducer of mitochondrial biogenesis, was reduced in both HFD groups and in old control or LFD mice. Cardiomyocytes from old rats demonstrated significantly reduced AMPK activation, impaired mitochondrial biogenesis, higher ceramide content, and reduced viability after palmitate (C16:0) in vitro, while no major deleterious effects were observed in young cardiomyocytes. Aged but not young cardiomyocytes were unable to respond to higher palmitate with increased fatty acid oxidation. Thus, HFD results in cardiac structural alterations and accumulation of lipid intermediates predominantly in old mice, possibly due to the inability of old cardiomyocytes to adapt to high-fatty acid load.     

Cardiodynamic effects of dopamine and dobutamine.

On 11 patients undergoing coronary surgery, at the end of the surgical intervention, the inotropic responses to 0.4 and 0.8 microgram x kg-1 x min-1 dopamine and dobutamine given via the aorto-coronary bypass directly into the coronary artery were compared. These dosages correspond to ones 10 times greater applied intravenously. The measurements were made using needle force probes which were implanted into the myocardial offstream area in the left ventricular wall. Bypass flow was measured simultaneously by an electromagnetic flow probe. There is a significant increase in coronary bypass flow induced by both rates of 0.4 and 0.8 microgram x kg-1 x min-1 dobutamine, but there was no significant effect on bypass flow induced by dopamine. Developed myocardial force is raised more by dobutamine medication than by dopamine. However, the rate of contraction increases significantly and relaxation is significantly accelerated by dopamine at both dosages. A significant increase in rate of contraction and relaxation was only induced by the higher dosage of 0.8 microgram x kg-1 x min-1 dobutamine.     

Comparison of exercise electrocardiography and dobutamine echocardiography.

It is uncertain whether dobutamine echocardiography is a better test than exercise electrocardiography for the detection of coronary disease in patients who can exercise. We compared the hemodynamics, sensitivity, and specificity of these tests in 24 patients, 16 with coronary disease and 8 controls. The tests were performed within six weeks of one another and were interpreted without knowledge of other clinical data. The exercise electrocardiogram was considered abnormal if the patient developed one mm of ST-segment depression, while the dobutamine test (up to 40 micrograms/kg/min) was considered abnormal if the patient developed ST-segment depression or a left ventricular wall motion abnormality. Exercise testing resulted in a higher heart rate (145 +/- 29 vs. 110 +/- 24, p less than 0.001) and blood pressure (176 +/- 31 vs. 148 +/- 24, p less than 0.001). Dobutamine testing was 25% more sensitive than exercise testing (94 vs. 69%, 95% confidence interval for difference is 0 to 50%, p = 0.09), while exercise testing was 38% more specific (88 vs. 50%, 95% confidence interval for difference is -3 to 79%, p = 0.14). We conclude that exercise results in a higher heart rate and blood pressure than dobutamine infusion. Differences in sensitivity and specificity are inconclusive, but indicate that the sensitivity of exercise testing is, at best, equivalent to dobutamine testing, while any increase in specificity with dobutamine testing, compared with exercise testing, would not be clinically significant.     

Remodeling of the rat right and left ventricles in experimental hypertension.

Pathological left ventricular hypertrophy in renovascular hypertension is associated with the accumulation of fibrillar collagen within the extracellular space and around intramyocardial coronary arteries. Even though the angiotensin converting enzyme inhibitor captopril was previously found to attenuate this interstitial and perivascular fibrosis, the relative importance of arterial and ventricular systolic pressures versus circulating angiotensin II (AII) and aldosterone (AL) in promoting hypertrophy and collagen accumulation in renovascular hypertension is uncertain. By drawing on the in-parallel arrangement of the right and left ventricles, with respect to their coronary circulation, and the in-series mechanical alignment of the ventricles, with a pressure-overloaded left and a normotensive right ventricle, this study sought to address this uncertainty. Three models of experimental hypertension, each having a different circulating AII and AL profile, were examined and compared with their controls: renovascular hypertension, where both AII and AL are increased; infrarenal aorta banding, where AII and AL are normal; and a chronic infusion of AL, where AII is suppressed or normal and AL is increased. In renovascular hypertension, as well as with AL, we found a significant rise in the interstitial collagen volume fraction and perivascular collagen area of the pressure-overloaded, hypertrophied left ventricle as well as the normotensive, nonhypertrophied right ventricle. This remodeling was not seen in either ventricle with infrarenal aorta banding despite comparable systemic hypertension and left ventricular hypertrophy. Thus, in experimental arterial hypertension in the rat, myocyte and nonmyocyte compartments of the myocardium are under separate controls: myocyte hypertrophy is most closely related to ventricular loading while circulating AII and AL, acting alone or in concert with other humoral factors, regulate the accumulation of collagen within the right and left ventricles.     

Comparison of the haemodynamic effects of dopexamine and dobutamine in patients with severe congestive heart failure

Dopexamine hydrochloride is a novel compound with properties of DA1-dopaminergic and beta 2-adrenergic receptor agonism and neuronal noradrenaline uptake inhibition. It has been shown to produce beneficial renal and haemodynamic effects in patients with severe heart failure. We compared the haemodynamic effects of dopexamine (0.5 to 6 micrograms/kg/min) with those of dobutamine (5 to 25 micrograms/kg/min) in 9 patients with severe congestive heart failure. The two drugs were similar in their effects at peak infusion rates: heart rate increased (dopexamine 87 +/- 17 to 100 +/- 14; dobutamine 91 +/- 18 to 103 +/- 17 min-1), cardiac index increased (dopexamine 1.7 +/- 0.5 to 2.8 +/- 1.1; dobutamine 1.8 +/- 0.5 to 3.0 +/- 1.1 l.min-1.m-2) and systemic vascular resistance decreased (dopexamine 1553 +/- 221 to 1117 +/- 432; dobutamine 1721 +/- 347 to 1280 +/- 433 dyne.s.cm-5). Neither drug affected pulmonary artery wedge pressure (dopexamine 24 +/- 6 to 22 +/- 6; dobutamine 25 +/- 9 to 24 +/- 10 mm Hg). Dopexamine had significantly lower peak effects on left ventricular stroke work index (dopexamine 20 +/- 9, dobutamine 27 +/- 15 g.m.m-2, P less than 0.05) and cardiac power output (dopexamine 0.71 +/- 0.36, dobutamine 0.93 +/- 0.46 W, P less than 0.05). These haemodynamic effects, due largely to vasodilatation but with some contributory positive inotropy, indicate that dopexamine will be useful in the acute treatment of congestive heart failure.