Mechanisms of platelet-induced angiospastic reactions: potentiation of calcium sensitivity

BACKGROUND: Zatebradine is a new specific bradycardiac agent that selectively slows the depolarization in the pacemaker cells of the sinoatrial node. The purpose of our investigation was to determine whether the tachycardia induced by dobutamine can be attenuated by the administration of zatebradine. The results were compared with those produced by propranolol, which is used in the treatment of sinus tachycardia. METHODS: Twelve pigs were anesthetized with sodium pentobarbital, intubated, and ventilated. After baseline hemodynamic measurements were obtained, dobutamine was administered until the heart rate reached 25% above baseline. Animals were randomized to one of two groups. Group I received zatebradine, 0.5 mg/kg i.v., and Group II received propranolol, 0.5 mg/kg i.v. RESULTS: Dobutamine 10 micrograms.kg-1.min-1 increased the heart rate (FIR) by 25%, and increased mean arterial blood pressure (MAP) left ventricular (LV) dp/dt, and cardiac output (CO) (P < 0.05). Zatebradine decreased the HR to baseline (P < 0.05) without affecting left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), LV dP/dt, or CO. Stroke volume (SV) increased significantly (P < 0.05). Propranolol also reduced HR to baseline, but decreased LV dP/dt, LVSP, CO, and SV (P < 0.05). CONCLUSION: Zatebradine effectively attenuates the tachycardia caused by dobutamine in anesthetized pigs, without reducing cardiac performance.     

Pertussis toxin-sensitive G proteins influence nitric oxide synthase III activity and protein levels in rat heart

Inhibitory G protein activity (Gi) and nitric oxide (NO) modulate muscarinic-cholinergic (MC) inhibition of cardiac beta-adrenergic inotropic responses. We hypothesized that Gi mediates MC-NO synthase (NOS) signal transduction. Isoproterenol (0.2-0.8 microg/min) and acetylcholine (1 microM) were administered to isolated perfused rat hearts pretreated with saline (controls; n = 8) or pertussis toxin (PT; 30 microg/kg intraperitoneally 3 d before study; n = 20). PT abrogated in vitro ADP-ribosylation of Gi protein alpha subunit(s) indicating near-total decrease in Gi protein function. Isoproterenol increased peak +dP/dt in both control (peak isoproterenol effect: +2, 589+/-293 mmHg/s, P < 0.0001) and PT hearts (+3,879+/-474 mmHg/s, P < 0.0001). Acetylcholine reversed isoproterenol inotropy in controls (108+/-21% reduction of +dP/dt response, P = 0.001), but had no effect in PT hearts. In controls, NG-monomethyl-L-arginine (100 microM) reduced basal +dP/dt, augmented isoproterenol +dP/dt (peak effect: +4,634+/-690 mmHg/s, P < 0.0001), and reduced the MC inhibitory effect to 69+/-8% (P < 0.03 vs. baseline). L-arginine (100 M) had no effect in controls but in PT hearts decreased basal +dP/dt by 1, 426+/-456 mmHg/s (P < 0.005), downward-shifted the isoproterenol concentration-effect curve, and produced a small MC inhibitory effect (27+/-4% reduction, P < 0.05). This enhanced response to NO substrate was associated with increased NOS III protein abundance, and a three- to fivefold increase in in vitro calcium-dependent NOS activity. Neomycin (1 microM) inhibition of phospholipase C did not reverse L-arginine enhancement of MC inhibitory effects. These data support a primary role for Gi in MC receptor signal transduction with NOS in rat heart, and demonstrate regulatory linkage between Gi and NOS III protein levels.     

Cocaine significantly impairs myocardial relaxation

OBJECTIVES: To determine the immediate effects of intravenous "recreational" doses of cocaine on myocardial ventricular relaxation and contraction and on coronary blood flow. To determine the cardiac effects of cocaine after the administration of propranolol, as propranolol has been used to limit the cardiovascular effects of cocaine. DESIGN: Prospective study. SUBJECTS: Twenty mongrel dogs. INTERVENTIONS: We continuously recorded central aortic pressure, left atrial and ventricular pressures, coronary artery blood flow, and electrocardiograms in each dog. We determined from the left ventricular pressure waveforms the maximum rate of pressure increase [(dP/dt)max] and the time constant of isovolumic ventricular relaxation as our indices of ventricular contraction and relaxation. MEASUREMENTS AND MAIN RESULTS: In our initial series of experiments, we obtained pressure, coronary artery blood flow, and electrocardiographic recordings in ten anesthetized dogs before and for 40 mins after the intravenous administration of cocaine, in doses of 2.5 and then 5 mg/kg. In our second series of experiments in ten additional dogs, we injected 0.5 mg/kg of propranolol intravenously 30 mins before the injection of cocaine (2.5 mg/kg), and obtained hemodynamic and electrocardiographic recordings before and for 40 mins after the injection of propranolol and cocaine. Cocaine, 2.5 mg/kg, abruptly increased the time constant of isovolumic ventricular relaxation from 22.9 +/- 1.2 to 29 +/- 2.2 msecs at 1 min (p < .05) and to 35.3 +/- 2 msec at 40 mins (p < .01) but did not significantly change the mean arterial pressure, left atrial pressure, heart rate, coronary blood flow, or the maximum rate of left ventricular pressure increase [(dP/dt)max]. Cocaine also progressively displaced the electrocardiographic ST segments by 3.2 +/- 0.6 mm (p < .01) over 40 mins. Cocaine, 5 mg/kg, rapidly increased the time constant of isovolumic ventricular relaxation from 28.5 +/- 2.5 to 41 +/- 3 msecs in 1 min (p < .05) and to 48.7 +/- 4 msecs at 40 mins (p < .01) and reduced (dP/dt)max from 2905 +/- 370 to 1422 +/- 121 mm Hg/sec at 1 min (p < .01); (dP/dt)max returned to 2351 +/- 415 mm Hg/sec during the next 39 mins. Cocaine did not significantly change either the mean arterial or left atrial pressures. However, this dose of cocaine did decrease, over 40 mins, the heart rate from 184 +/- 11 to 139 +/- 11 beats/min (p < .01) and reduced coronary blood flow by 20% (p < .01). Cocaine also displaced the electrocardiographic ST segments by 3.3 mm over 40 mins (p < .05). Cocaine and propranolol abruptly increased the time constant of isovolumic ventricular relaxation from 26.4 +/- 1.3 to 43.2 +/- 2.1 msecs (p < .01) at 1 min and to 46.8 +/- 1.5 msecs at 3 mins (p < .01). The time constant of isovolumic ventricular relaxation remained abnormally increased at 43.0 +/- 1.4 msecs at 40 mins. Cocaine and propranolol reduced (dP/dt)max from 2760 +/- 458 mm Hg/sec to a minimum value of 1400 +/- 119 mm Hg/sec at 2 mins (p < .01). However, (dP/dt)max then returned to 2201 +/- 359 mm Hg/sec during the next 38 mins. Cocaine and propranolol did not significantly change the mean arterial and left atrial pressures, or heart rate, but did reduce coronary blood flow, over 40 mins, by 25% (p < .001). Cocaine also maximally displaced the electrocardiographic ST segments by 1 +/- 0.2 mm (p < .01). CONCLUSIONS: Cocaine substantially impairs myocardial ventricular relaxation for periods of at least 40 mins. Propranolol significantly intensifies cocaine's depressant effect on ventricular relaxation.     

Comparative hemodynamic effects of amiodarone, sotalol, and d-sotalol

The effects of intravenous boluses of amiodarone (5 mg/kg), racemic sotalol (enantiomeric ratio d/l-sotalol 1:1;1.5 mg/kg), and d-sotalol (0.75 mg/kg) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), left ventricular end-diastolic pressure (LVEDP), and peak rate of change of left ventricular pressure (LV dp/dt) were assessed in conscious rabbits. Amiodarone and sotalol had a modest negative inotropic effect: amiodarone reduced peak LV dp/dt by 8 +/ 2% (mean +/- SEM) (p < 0.05) and sotalol by 6 +/- 2% (p < 0.05). These two drugs had quite different effects on CO as a result of differences in their actions on peripheral blood vessels: amiodarone caused a 13 +/- 3% (p < 0.05) increase in CO associated with a substantial vasodilatory effect (TPR reduced 25 +/- 3%; p < 0.01); sotalol did not produce any substantial change in either CO or TPR. Bolus intravenous injection of amiodarone was associated with a significant increase in HR (12 +/- 3%; p < 0.01), whereas sotalol reduced HR by 7 +/- 1% (p < 0.05). In contrast, administration of the dextro-rotatory optical isomer, d-sotalol, produced no significant change in peak LV dp/dt, LVEDP, CO, TPR, or HR. These results confirm that amiodarone and racemic sotalol have a comparatively weak cardiodepressant action. The experiments also show that the reduction in cardiac performance associated with racemic sotalol is mediated predominantly through the beta-adrenoreceptor blocking action of the levo-rotatory isomer (l-sotalol) rather than any substantial cardiodepressant effect of the dextro-rotatory isomer.     

Assessment of the role of the renin-angiotensin system in cardiac contractility utilizing the renin inhibitor remikiren

1. The role of the renin-angiotensin system in the regulation of myocardial contractility is still debated. In order to investigate whether renin inhibition affects myocardial contractility and whether this action depends on intracardiac rather than circulating angiotensin II, the regional myocardial effects of systemic (i.v.) and intracoronary (i.c.) infusions of the renin inhibitor remikiren, were compared and related to the effects on systemic haemodynamics and circulating angiotensin II in open-chest anaesthetized pigs (25-30 kg). The specificity of the remikiren-induced effects was tested (1) by studying its i.c. effects after administration of the AT1-receptor antagonist L-158,809 and (2) by measuring its effects on contractile force of porcine isolated cardiac trabeculae. 2. Consecutive 10 min i.v. infusions of remikiren were given at 2, 5, 10 and 20 mg min-1. Mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), systemic vascular resistance (SVR), myocardial oxygen consumption (MVO2) and left ventricular (LV) dP/dtmax were not affected by remikiren at 2 and 5 mg min-1, and were lowered at higher doses. At the highest dose, MAP decreased by 48%, CO by 13%, HR by 14%, SVR by 40%, MVO2 by 28% and LV dp/dtmax by 52% (mean values; P < 0.05 for difference from baseline, n = 5). The decrease in MVO2 was accompanied by a decrease in myocardial work (MAP x CO), but the larger decline in work (55% vs. 28%; P < 0.05) implies a reduced myocardial efficiency ((MAP x CO)/MVO2). 3. Consecutive 10 min i.c. infusions of remikiren were given at 0.2, 0.5, 1, 2, 5 and 10 mg min-1. MAP, CO, MVO2 and LV dP/dtmax were not affected by remikiren at 0.2, 0.5 and 1 mg min-1, and were reduced at higher doses. At the highest dose, MAP decreased by 31%, CO by 26%, MVO2 by 46% and LV dP/dtmax by 43% (mean values; P < 0.05 for difference from baseline, n = 6). HR and SVR did not change at any dose. 4. Thirty minutes after a 10 min i.v. infusion of the AT1 receptor antagonist, L-158,809 at 1 mg min-1, consecutive 10 min i.c. infusions (n = 5) of remikiren at 2, 5 and 10 mg min-1 no longer affected CO and MVO2, and decreased LV dP/dtmax by maximally 27% (P < 0.05) and MAP by 14% (P < 0.05), which was less than without AT1-receptor blockade (P < 0.05). HR and SVR remained unaffected. 5. Plasma renin activity and angiotensin I and II were reduced to levels at or below the detection limit at doses of remikiren that were not high enough to affect systemic haemodynamics or regional myocardial function, both after i.v. and i.c. infusion. 6. Remikiren (10(-10) to 10(-4) M) did not affect contractile force of porcine isolated cardiac trabeculae precontracted with noradrenaline. In trabeculae that were not precontracted no decrease in baseline contractility was observed with remikiren in concentrations up to 10(-5) M, whereas at 10(-4) M baseline contractility decreased by 19% (P < 0.05). 7. Results show that with remikiren i.v., at the doses we used, blood pressure was lowered primarily by vasodilation and with remikiren i.c. by cardiac depression. The blood levels of remikiren required for its vasodilator action are lower than the levels affecting cardiac contractile function. A decrease in circulating angiotensin II does not appear to be the sole explanation for these haemodynamic responses. Data support the contention that myocardial contractility is increased by renin-dependent angiotensin II formation in the heart.     

Comparative efficacy of three indexes of left ventricular performance derived from pressure-volume loops in heart failure induced by tachypacing

OBJECTIVES: The purpose of this study was to serially evaluate the response and variability of the end-systolic pressure-volume relation, the left ventricular end-diastolic volume-peak positive first derivative of left ventricular pressure (dP/dt) relation and the left ventricular end-diastolic volume-stroke work relation in the development of progressive left ventricular dysfunction. BACKGROUND: Evaluation of systolic performance of the failing left ventricle may be enhanced by using relatively load-insensitive measures of left ventricular performance. The end-systolic pressure-volume, left ventricular end-diastolic volume-peak positive dP/dt and left ventricular end-diastolic volume-stroke work relations adequately define left ventricular performance under multiple loading conditions, but efficacy has not been fully assessed in the failing heart, particularly in the intact circulation. METHODS: Fourteen dogs underwent instrumentation and rapid pacing to heart failure. Variably loaded pressure-volume beats were produced by inferior vena cava occlusion. The dogs were evaluated at baseline and at three progressively more severe levels of left ventricular dysfunction. RESULTS: There was a progressive increase in left ventricular volumes at end-diastole ([mean value +/- SE] 60 +/- 28 to 73 +/- 29 ml, p < 0.001) and end-systole (39 +/- 19 to 61 +/- 27 ml, p < 0.001) during the 3 weeks of rapid pacing and a progressive decline in peak positive dP/dt (1,631 +/- 410 to 993 +/- 222 mm Hg/s, p < 0.001) and ejection fraction (37 +/- 8% to 16 +/- 11%, p < 0.001). There was a corresponding decline in the slope of each of the three relations: for end-systolic pressure-volume, 6.3 +/- 2.2 to 2.8 +/- 0.7 (p < 0.05); for left ventricular end-diastolic volume-stroke work, 61.9 +/- 9.1 to 26.5 +/- 2.4 (p < 0.05); and for left ventricular end-diastolic volume-peak positive dP/dt, 47.1 +/- 13.6 to 20.31 +/- 6.8 (p < 0.05). There was also a corresponding increase in position volumes: for end-systolic pressure-volume, 33.6 +/- 3.9 to 61.2 +/- 6.6 ml (p < 0.05); for left ventricular end-diastolic volume-stroke work, 46.2 +/- 3.6 to 89.3 +/- 7.6 ml (p < 0.05); and for left ventricular end-diastolic volume-peak positive dP/dt, 29.1 +/- 19.1 to 68.6 +/- 25.9 ml (p < 0.05). The relative degree of change in each of the three relations was similar as more severe heart failure developed. The coefficients of variation for position were significantly less than the variation for slopes. The response of volume intercepts was heterogeneous. For left ventricular end-diastolic volume-stroke work, the intercept increased as ventricular performance decreased. The intercept of the end-systolic pressure-volume relation was significantly more variable than the left ventricular end-diastolic volume-stroke work relation and did not change with progressive heart failure. The intercept for left ventricular end-diastolic volume-peak positive dP/dt was highly variable and showed no consistent changes as left ventricular function declined. CONCLUSIONS: All three relations consistently describe changes in left ventricular performance brought about by tachypacing. Evolution of left ventricular dysfunction causes a decline in slope and a rightward shift of these relations. The position of the relation is the most sensitive and least variable indicator of left ventricular systolic performance.     

Mechanisms of nitrate accumulation in plasma during pacing-induced heart failure in conscious dogs

The goal of this study was to understand the mechanisms behind the changes in plasma NOx during heart failure. Heart failure is associated with an increase in plasma nitrate levels, and yet most experimental evidence demonstrates a reduction in endothelial nitric oxide production during heart failure. Dogs were chronically instrumented for measurement of systemic hemodynamics and left ventricular (LV) dimensions. Hearts were paced at 210 bpm for 3 weeks (n = 14) and then 240 bpm for 1 week (n = 7). Hemodynamics, arterial blood gases, plasma NOx, and creatinine levels were monitored weekly. Heart failure was evidenced by cachexia, ascites, and hemodynamic alterations. Resting heart rate rose (94 +/- 6 to 135 +/- 9 bpm), and LV dP/dt fell (2810 +/- 82 to 1471 +/- 99 mm Hg/s), while LV end diastolic pressure quadrupled (5.8 +/- 0.7 to 25 +/- 0.8 mm Hg), and diastolic wall stress quadrupled (11 +/- 1.3 to 43 +/- 6.0 g/cm2, all P < 0.05). These changes occurred during a doubling in plasma NOx (5.5 +/- 1.5 to 10 +/- 1.6 microM, P < 0.05). There were no changes in plasma NOx through 3 weeks of pacing. Plasma creatinine levels increased 450% (from 0.27 +/- 0.32 to 1.21 +/- 0.63 mg%). Stimulated nitrite production by agonists in sieved coronary microvessels was unchanged after 3 weeks of pacing but was reduced after heart failure. Plasma NOx did not correlate with LV dP/dt or systolic wall stress but correlated directly with LV EDP or diastolic wall stress and inversely with cardiac work. Plasma NOx rose in direct relation to plasma creatinine levels (Y = 4.8X + 2.8, r2 = 0.84), suggesting that the rise in plasma NOx during heart failure is due to decreased renal function not increased NO production.     

Hemodynamic effects of sub-chronic NO synthase inhibition in conscious dogs: role of EDRF/NO in muscular exertion

Acute and chronic administration of nitric oxide (NO) synthase (NOS) inhibitors increase mean arterial blood pressure (MAP) in rats but their hemodynamic effects in other species remain unknown. Moreover, the role of NO in the control of exercise-induced vasodilation is still debated. To answer these questions, six dogs were instrumented for the continuous measurement of cardiac output (CO, electromagnetic flow probe on the aorta), MAP (aortic catheter) and left ventricular pressure (Konigsberg gauge). Total peripheral resistance (TPR) was calculated as MAP/CO ratio and dP/dt was used as an index of cardiac inotropism. The dogs were treated from day 0 (D0) to 7 (D7) by the NOS inhibitor, N omega-nitro-L-arginine (L-NNA), 20 mg/kg/day (IV). Such a dose regimen resulted in NOS inhibition evidenced (a) in vivo by a reduction of the hypotensive responses to graded doses of acetylcholine and bradykinin, (b) ex vivo by a decrease in the relaxation of the femoral artery to acetylcholine (EC 50 = 2.2 +/- 0.6 10(-7) M after L-NNA vs 2.2 +/- 0.8 10(-8) M in controls). One month after instrumentation, the dogs being conscious, MAP measured at rest remained unchanged following one week L-NNA treatment (from 90 +/- 2 at D0 to 91 +/- 5 mmHg at D7). However, TPR increased (from 3,600 +/- 290 at D0 to 6,300 +/- 510 dyn.s.cm-5 at D7) and CO decreased (from 2.1 +/- 0.2 at D0 to 1.2 +/- 0.1 l/min at D7) (all p < 0.01), partly as the result of a marked bradycardia (from 100 +/- 7 at D0 to 60 +/- 7 beats/min at D7). L-NNA induced-increase in TPR was completely reversed by a bolus injection of nitroglycerin (10 micrograms/kg). During treadmill exercise (12 km/h), heart rate (251 +/- 9 at D0 vs 226 +/- 11 beats/min at D7), CO (6.3 +/- 0.9 at D0 vs 4.3 +/- 0.7 l/min at D7) and stroke volume remained significantly lower, and TPR significantly higher (1,662 +/- 278 at D0 vs 2,621 +/- 489 dyn.s.cm-5 at D7) after L-NNA than in the control state. Thus, NOS inhibition in resting conscious dogs by L-NNA markedly increases peripheral resistance but does not increase arterial pressure. In addition, L-NNA blunts both exercise-induced peripheral vasodilation and increase in cardiac output, despite metabolic vasodilation.     

Hypothesis of the compression of morbidity: an example of theoretical development in epidemiology]

To assess the usefulness of the tissue Doppler imaging variables for the evaluation of left ventricular (LV) systolic function, we compared variables obtained by the pulsed Doppler method with the LV ejection fraction (%EF) and the maximum value for the first derivative of LV pressure (peak dP/dt). We examined 65 patients, including 15 patients with noncardiac chest pain, 15 with ischemic heart disease, 15 with dilated cardiomyopathy, 10 with hypertensive heart disease, and 10 with asymmetric septal hypertrophic cardiomyopathy. The subendocardial systolic wall motion velocity patterns were recorded for LV posterior wall and ventricular septum in the parasternal LV long-axis view. The peak dP/dt was significantly lower in the hypertensive heart disease, hypertrophic cardiomyopathy, and dilated cardiomyopathy groups. The peak systolic velocity was lower and the time from the electrocardiographic Q wave to the peak of the systolic wave for the posterior wall was longer in the hypertensive heart disease (5.9 +/- 0.5 cm/sec and 215 +/- 21 msec, respectively), hypertrophic cardiomyopathy (6.2 +/- 0.9 cm/sec and 217 +/- 17 msec, respectively), and dilated cardiomyopathy (5.2 +/- 0.8 cm/sec and 235 +/- 26 msec, respectively) groups than in the noncardiac chest pain (7.7 +/- 0.9 cm/sec and 187 +/- 24 msec, respectively) and the ischemic heart disease (7.6 +/- 0.8 cm/sec and 184 +/- 22 msec, respectively) groups. In all groups, the peak systolic velocity and the time from the electrocardiographic Q wave to the peak of the systolic wave for the posterior wall correlated directly and inversely, respectively, with the %EF (r = 0.59, p < 0.0001; r = -0.59, p < 0.0001) and the peak dP/dt (r = 0.75, p < 0.0001; r = -0.68, p < 0.0001). Both tissue Doppler variables for the ventricular septum did not correlate with the %EF but roughly correlated with peak dP/dt. We conclude that the systolic LV wall motion velocity parameters obtained by pulsed tissue Doppler imaging may be useful for noninvasive evaluation of global LV systolic function in patients with no regional asynergy.     

Cardiomyoplasty: hemodynamic benefit to normal and depressed canine left ventricular function

This study examined the effects of cardiomyoplasty with vascular delay on canine normal and depressed left ventricular (LV) function. To improve viability of the latissimus dorsi muscle (LDM), vascular delay was performed 2 weeks before cardiomyoplasty in 10 mongrel dogs. Two weeks after cardiomyoplasty, LV function was evaluated by simultaneously measuring LV and aortic pressure, and aortic flow. The LDM was stimulated at a ratio of 1:4-1:7 synchronously with ventricular systole. Microspheres (90 mu) were sequentially injected into the left coronary artery to depress LV function. Data were acquired and analyzed on a beat to beat basis. Results were as follows: LDM stimulation significantly augmented LV systolic pressure (LVSP) from 138 +/- 2 to 161 +/- 2* mmHg, the peak rate of change of LV pressure (+dP/dt) from 1888 +/- 46 to 2584 +/- 43* mmHg/sec, aortic systolic pressure (AoSP) from 140 +/- 2 to 159 +/- 2* mmHg, stroke volume (SV) from 11.2 +/- 0.3 to 13.3 +/- 0.3* ml, stroke work (SW) from 19 +/- 1 to 26 +/- 1* gm.m, peak aortic flow (P Qa) from 5542 +/- 142 to 7190 +/- 161* ml/min, and decreased -dP/dt from -1683 +/- 31 to -1689 +/- 49* mmHg/sec (* = p < 0.05). Microsphere injections depressed LV function, but did not affect the magnitude of the net changes between stimulated and nonstimulated beats. However, the percent changes significantly increased. Preconditioning of LDM with vascular delay augments cardiac function in LDM assisted beats. This improved performance was present in both normal as well as depressed LV function groups. Thus, investigations of cardiomyoplasty may not necessarily require a model of severe myocardial dysfunction. Vascular delay offers an important preconditioning method of LDM to augment cardiac function in cardiomyoplasty.     

Early hemodynamic effects of olprinone hydrochloride after coronary artery bypass grafting

Our purpose was to evaluate the hemodynamic effects of olprinone hydrochloride early after coronary artery bypass grafting (CABG). Fifteen patients undergoing CABG were administered a constant infusion of 0.1 microgram/kg/min of olprinone and continued for 4 hours. No bolus infusion of olprinone was administered before continuous infusion. Systolic systemic arterial pressure, systolic pulmonary arterial pressure, systemic vascular resistance and pulmonary vascular resistance were significantly decreased. There were no significant changes in heart rate, mean central venous pressure, mean left atrial pressure and left ventricular stroke work index. Cardiac index was significantly increased, but a correlation between cardiac index and mixed venous blood oxygen saturation was not found. Double product was significantly decreased, which described above suggest that olprinone achieved improvement of left cardiac function without more myocardial oxygen consumption. Severe transient hypotension (systolic arterial pressure < 80 mmHg) after infusion of olprinone was observed in three patients. Olprinone administered soon after CABG surgery had beneficial effects in terms of improvement of hemodynamic status without more oxygen consumption and reduction of pulmonary vascular resistance. However transient hypotension was a serious clinical problem in patients after open heart surgery, especially in CABG patients who need suitable systolic arterial pressure to keep enough blood perfusion of arterial bypass grafts.     

Hemodynamic effects of a calcium channel promoter, BAY y 5959, are preserved after chronic administration in ischemic heart failure in conscious dogs

BAY y 5959 is a dihydropyridine derivative that binds to L-type calcium channels in a voltage-dependent manner and promotes calcium entry into the cell during the plateau of the action potential by influencing mean open time. Because myofilament responsiveness to calcium is preserved in congestive heart failure (CHF), the inotropic responsiveness to this compound should be preserved in CHF, and tolerance should not develop despite long-term treatment. To test these hypotheses, CHF was induced in 14 chronically instrumented dogs by daily (30 +/- 5 days) intracoronary microsphere injections. The effects of BAY y 5959 (2-h i.v. infusions of 3 microg/kg/min and 10 microg/kg/min) were determined before heart failure, after heart failure was established and then 2 h after the end of a 5-day continuous BAY y 5959 intra-atrial infusion. Before CHF, the positive inotropic effect of BAY y 5959 at a dose of 10 microg/kg/min [left ventricular dP/dt (LVdP/dt) increased from 2955 +/- 132 mmHg to 4897 +/- 426 mmHg, P < .05] was associated with bradycardia (HR decreased from 92 +/- 4 to 78 +/- 6 b/min, P <.05), slight increases in mean arterial pressure (it increased from 100 +/- 2 mmHg to 113 +/- 5 mmHg, P <.05) and did not alter left ventricular end-diastolic pressure. In CHF, BAY y 5959 continued to induce dose-dependent increases in left ventricular systolic pressure, LVdP/dt and mean arterial pressure, as well as causing bradycardia and a significant decrease in left ventricular end-diastolic pressure. After a 5-day infusion of BAY y 5959, base-line LVdP/dt and left ventricular end-diastolic pressure improved. The responses of LVdP/dt and mean arterial pressure to BAY y 5959 were similar to those of the control state. The sustained responses in CHF and after long-term infusion suggest that BAY y 5959 may be an effective and potent inotropic agent for treatment of CHF that does not lead to tolerance to its positive inotropic effects.     

Improved oxygen utilization during mild exercise in heart failure

In heart failure with low cardiac output, exercise tolerance is reduced despite modulated regional blood distribution and oxygen extraction. However, low cardiac output does not necessarily lead to reduced exercise tolerance especially during mild exercise. In the present study, in order to understand the mechanisms regulating exercise tolerance in heart failure, we measured oxygen consumption (VO2) and cardiac output (CO) during both mild and intense exercise. Patients with heart failure were divided into 2 groups; group L (n = 8) consists of patients with low anaerobic threshold (AT) < 13 ml/min per kg and group H (n = 7) consisting of patients with AT > 13 ml/min per kg. At rest, VO2 was similar between groups L and H, whereas CO was lower in group L than in group H (3.5 + 0.3 vs 4.8 + 1.4 ml/min, p < 0.01). Increase in VO2 during warm-up exercise was not significant between the 2 groups (7.4 +/- 0.5 (group L) vs 6.2 +/- 0.3 ml/min per kg (group H), ns), but increase in CO was lower in group L than in group H (2.5 +/- 0.6 vs 3.4 +/- 0.4 ml/min, p < 0.01). After warm-up to the AT point, however, the increase in not only VO2 but also CO was markedly reduced in group L than in group H (VO2: 0.5 +/- 0.4 vs 3.7 +/- 0.8 ml/min per kg, p < 0.01, CO: 0.2 +/- 0.3 vs 1.1 +/- 0.3 L/min, p < 0.01). Based on these measurements, we calculated the arteriovenous oxygen difference (c(A-V)O2 difference) during exercise in individual patients using Fick's equation. The c(A-V)O2 difference was markedly increased in severe heart failure during the warm-up stage, but between the end of warm-up and the AT point, it remained at the same level as that of group H. These results suggest the presence of a unique mechanism regulating the c(A-V)O2 difference in severe heart failure patients, activation of which may, at least during mild exercise, contribute to efficient oxygen delivery to the peripheral tissues thus compensating for the jeopardized exercise tolerance in those patients.     

The rate of force generation by the myocardium is not influenced by afterload

The influence of afterload on the rate of force generation by the myocardium was investigated using two types of preparations: the in situ dog heart (dP/dt) and isolated papillary muscle of rats (dT/dt). Thirteen anesthetized, mechanically ventilated and thoracotomized dogs were submitted to pharmacological autonomic blockade (3.0 mg/kg oxprenolol plus 0.5 mg/kg atropine). A reservoir connected to the left atrium permitted the control of left ventricular end-diastolic pressure (LVEDP). A mechanical constriction of the descending thoracic aorta allowed to increase the systolic pressure in two steps of 20 mmHg (conditions H1 and H2) above control values (condition C). After arterial pressure elevations (systolic pressure C: 119 +/- 8.1; H1: 142 +/- 7.9; H2: 166 +/- 7.7 mmHg; P < 0.01), there were no significant differences in heart rate (C: 125 +/- 13.9; H1: 125 +/- 13.5; H2: 123 +/- 14.1 bpm; P > 0.05) or LVEDP (C: 6.2 +/- 2.48; H1: 6.3 +/- 2.43; H2: 6.1 +/- 2.51 mmHg; P > 0.05). The values of dP/dt did not change after each elevation of arterial pressure (C: 3,068 +/- 1,057; H1: 3,112 +/- 996; H2: 3,086 +/- 980 mmHg/s; P > 0.05). In isolated rat papillary muscle, an afterload corresponding to 50% and 75% of the maximal developed tension did not alter the values of the maximum rate of tension development (100%: 78 +/- 13; 75%: 80 +/- 13; 50%: 79 +/- 11 g mm-2 s-1, P > 0.05). The results show that the rise in afterload per se does not cause changes in dP/dt or dT/dt.     

Human isosporiasis in an AIDS patient--report of first case in Malaysia

Splanchnic and systemic hemodynamics and plasma levels of aldosterone, glucagon and plasma renin were investigated in 12 patients with advanced cirrhosis before and 2 wk (14.6 +/- 2.8 days) and 2 mo (60.8 +/- 10.5 days) after orthotopic liver transplantation. Liver transplant was followed by significant (p < 0.01) changes in systemic hemodynamics at 2 wk, with a marked reduction in cardiac index (4.9 +/- 0.8 vs. 3.7 +/- 0.7 L/min.m2) and increases in mean arterial pressure (79 +/- 8 vs. 101 +/- 11 mm Hg) and peripheral vascular resistance (721 +/- 149 vs. 1,274 +/- 253 dyn.sec.cm-5). Two months after liver transplant, we saw further significant increases in peripheral vascular resistance (1,700 +/- 341 dyn.sec.cm-5; p < 0.05) without changes in cardiac index. Hepatic venous pressure gradient, very high before transplantation, was normal 2 wk after liver transplant (18.7 +/- 3.0 vs. 2.1 +/- 0.8 mm Hg; p < 0.01). Hepatic blood flow rose markedly from 1.03 +/- 0.46 to 2.25 +/- 0.79 L/min (p < 0.01) and was still elevated at 2 mo (1.84 +/- 0.74 L/min). Azygos blood flow had not changed after 2 wk with respect to pretransplant values (0.65 +/- 0.26 vs. 0.69 +/- 0.39 L/min) but had decreased significantly at 2 mo (0.39 +/- 0.16 L/min; p < 0.05). The elevated aldosterone, plasma renin and glucagon levels found in our cirrhotic patients before transplantation decreased to near-normal values 2 wk after the procedure. These results suggest that most of the hemodynamic and humoral abnormalities characteristic of advanced cirrhosis are reversed after liver transplant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preconditioning improves myocardial function and reflow, but not vasodilator reactivity, after ischaemia and reperfusion in anaesthetized dogs

1. The present study examines whether three cycles of brief coronary artery occlusion and reperfusion (i.e. ischaemic preconditioning; PC) can prevent vasodilator dysfunction and the impairment of myocardial reflow caused by prolonged ischaemia. Coronary blood flow, left ventricular dP/dt, systemic arterial blood pressure and heart rate were measured in open-chest anaesthetized dogs. 2. Sixty minute occlusion of the left circumflex coronary artery (LCx) and 60 min LCx reperfusion (ISC/REP; group 1) significantly reduced resting coronary blood flow (CBF, initial 29 +/- 3 mL/min; ISC/REP 20 +/- 3 mL/min, P < 0.05 vs initial) and increased coronary vascular resistance (CVR, initial 4.1 +/- 0.6 mmHg/min per mL; ISC/REP 5.8 +/- 1.0 mmHg/min per mL, P < 0.05 vs initial). By contrast CBF and CVR were not affected in dogs subjected to preconditioning before ischaemia (group 2: CBF, initial 24 +/- 4 mL/min; PC+ISC/REP 23 +/- 4 mL/min; CVR, initial 4.7 +/- 0.6 mmHg/min per mL; PC+ ISC/REP 5.3 +/- 1.0 mmHg/min per mL). These data suggest that ischaemic preconditioning prevents the ischaemia-induced impairment of myocardial reflow. 3. Ischaemia and reperfusion impaired coronary dilator responses to the endothelium-dependent dilator acetylcholine (delta CBF, after ISC/REP: 50 +/- 6% of initial) and the endothelium-independent dilator glyceryl trinitrate (delta CBF, ISC/REP: 46 +/- 6% of initial). Despite the improvement in reperfusion in the preconditioned group, there was no significant improvement in responses to acetylcholine (PC+ISC/REP 52 +/- 6% of initial) or glyceryl trinitrate (PC+ISC/REP 59 +/- 6% of initial) after ischaemia and reperfusion. 4. The reduction in left ventricular dP/dt after ischaemia and reperfusion was significantly smaller in the preconditioned group indicating a lower level of impairment of cardiac contractility. In addition, we confirmed that preconditioning caused a significant reduction in infarct size and a reduction in the release of lactate dehydrogenase indicating less cardiac injury. 5. These results suggest that although ischaemic preconditioning was able to improve both myocardial reperfusion and contractility, it was not able to preserve vasodilator function. Such a reduction in vasodilator reserve could prevent adequate myocardial perfusion under conditions of elevated oxygen demand.     

Effect of hemofiltration on hemodynamics and systemic concentrations of anaphylatoxins and cytokines in human sepsis

OBJECTIVE: To determine whether hemofiltration (HF) can eliminate cytokines and complement components and alter systemic hemodynamics in patients with severe sepsis. DESIGN: Prospective observation study. SETTING: Surgical intensive care unit of a university hospital. PATIENTS: 16 patients with severe sepsis. INTERVENTIONS: Continuous zero-balanced HF without dialysis (ultrafiltrate rate 2 l/h) was performed in addition to pulmonary artery catheterization, arterial cannulation, and standard intensive care treatment. MEASUREMENTS AND MAIN RESULTS: Plasma and ultrafiltrate concentrations of cytokines (the interleukins IL-1 beta, IL-6, IL-8, and tumor necrosis factor alpha) and of complement components (C3adesArg, C5adesArg) were measured after starting HF (t0) and 4 h (t4) and 12 h later (t12). Hemodynamic variables including mean arterial pressure (MAP), mean central venous pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output were serially determined. During HF, cytokine plasma concentrations remained constant. However, C3adesArg and C5adesArg plasma concentrations showed a significant decline during 12-h HF (C3adesArg: t0 = 676.9 +/- 99.7 ng/ml vs t12 = 467.8 +/- 71, p < 0.01; C5adesArg: 26.6 +/- 4.7 ng/ml vs 17.6 +/- 6.2, p < 0.01). HF resulted in a significant increase over time in systemic vascular resistance (SVR) and MAP (SVR at t0: 669 +/- 85 dyne.s/cm5 vs SVR at t12: 864 +/- 75, p < 0.01; MAP at t0: 69.9 +/- 3.5 mmHg vs MAP at t12: 82.2 +/- 3.7, p < 0.01). CONCLUSIONS: HF effectively eliminated the anaphylatoxins C3adesArg and C5adesArg during sepsis. There was also a significant rise in SVR and MAP during high volume HF. Therefore, HF may represent a new modality for removal of anaphylatoxins and may, thereby, deserve clinical testing in patients with severe sepsis.     

Does the choice of antihypertensive therapy influence haemodynamic responses to induction, laryngoscopy and intubation?

We have measured haemodynamic responses to induction of anaesthesia, laryngoscopy and intubation in 103 mild-moderate hypertensive patients (83 patients (diastolic pressures < or = 110 mm Hg) currently receiving one of four monotherapies (ACE inhibitors, group A; beta adrenoceptor blocking drugs, group B; calcium channel antagonists, group C; diuretics, group D) and 24 were untreated hypertensive patients). Anaesthesia was induced with fentanyl 1.5-2.0 micrograms kg-1 and thiopentone 3-5 mg kg-1. Tracheal intubation was facilitated by vecuronium 0.1 mg kg-1 and anaesthesia maintained with enflurane and nitrous oxide in oxygen. Systolic and diastolic pressures (SAP, DAP) were measured at 1-min intervals by a non-invasive oscillometric method and cardiac output (CO) and stroke volume (SV) by thoracic bioimpedance. Induction of anaesthesia was associated with a decrease in SAP, DAP and CO in groups A-D (P < 0.05). Heart rate (HR) decreased in groups A and D (P < 0.01) and systemic vascular resistance (SVR) decreased in groups A and B (P < 0.05). SAP and HR increased in all groups after laryngoscopy and intubation (P < 0.01) as did SVR in groups A, B and D (P < 0.02). CO was unaltered. Similar changes occurred in the untreated hypertensive patients, although nine of 24 patients exhibited HR > or = 100 beat min-1 after laryngoscopy and intubation. Comparison of the changes in SAP, DAP, CO and SVR with time showed no differences in the five treatment groups; changes in HR were significantly less in group B compared with the other groups (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prognostic indicators in adult cerebral malaria: a study in Burundi, an area of high prevalence of HIV infection

Many authors link increased mortality in course of bronchial asthma (BA) with the administration of excessive doses of beta-2 agonists, one of the causes considered being their cardiotoxic effect. The aim of the present study was to evaluate the effect of 0.5 mg intravenous bolus of salbutamol (S) on left ventricular (LV) function assessed by echocardiography and on the selected biochemical parameters: the activity of creatinine kinase (CK) and its cardiac specific isoenzyme (CK-MB), potassium (K+) and free fatty acids (FFA) serum concentration as well as partial arterial oxygen pressure (PaO2). The studied group consisted of 16 patients (pts)--12 males and 4 females, aged 36-60 yrs, mean 49.0 +/- 7 yrs with BA and moderate airway obstruction (FEV1%VC--60 +/- 7%). Pts with cardiac disorders were excluded from the study. Echocardiographic examination was performed before and 30 min after S injection. Biochemical determinations were carried out at 5 min., 30 min, 2 h, and 4 h following S administration. We found mean HR increase by 20 beats per min (p < 0.001) and mean systolic blood pressure elevation by 19 mmHg at 30 min (p < 0.001) after S. It was accompanied by significant increase of cardiac output (CO) from 5.7 +/- 1.5 to 8.4 +/- 1.8 l/min (p < 0.001) and mean rate of circumferential shortening (mVcf) from 1.48 +/- 0.27 to 1.88 +/- 0.43 (circ/sec), p < 0.01. Stroke volume (SV), ejection fraction (EF%), fractional shortening of LV (FS%) increased nonsignificantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of clonidine on cerebral blood flow velocity, carbon dioxide cerebral vasoreactivity, and response to increased arterial pressure in human volunteers

BACKGROUND: Because patients may be taking clonidine chronically or may be receiving it as a premedication before surgery, the authors investigated its effect on cerebral hemodynamics. METHODS: In nine volunteers, middle cerebral artery mean blood flow velocity (Vm) was measured using transcranial Doppler ultrasonography (TCD). CO2 vasoreactivity was measured before clonidine administration (preclonidine), 90 min after clonidine, 5 microg/kg orally, then following restoration of mean arterial pressure (MAP) to the preclonidine level. In addition, Vm was measured after a phenylephrine-induced 30-mmHg increase in MAP. RESULTS: After clonidine administration, Vm decreased from 62 +/- 9 to 48 +/- 8 cm/s (P < 0.01), and MAP decreased from 86 +/- 10 to 63 +/- 5 mmHg (P < 0.01; mean +/- SD). Clonidine decreased the CO2 vasoreactivity slope from 2.2 +/- 0.4 to 1.2 +/- 0.5 cm x s(-1) x mmHg(-1) (P < 0.05); restoring MAP to the preclonidine level increased the slope to 1.60 +/- 0.5 cm x s(-1) x mmHg(-1), still less than the preclonidine slope (P < 0.05). CO2 vasoreactivity expressed as a percentage change in Vm, decreased after clonidine, 3.5 +/- 0.8 versus 2.4 +/- 0.8 %/mmHg (P < 0.05); this difference disappeared after restoration of MAP, 3.1 +/- 1.2 %/mmHg. With a 30-mmHg increase in MAP, Vm increased by 13% before and after clonidine (P < 0.05). CONCLUSIONS: Clonidine, 5 microg/kg orally, decreases Vm and slightly attenuates cerebral CO2 vasoreactivity, therefore decreased cerebral blood flow and mildly attenuated CO2 vasoreactivity should be anticipated.