André A. Charlier

Effects of Nicardipine and Nisoldipine on Myocardial Metabolism, Coronary Blood Flow and Oxygen Supply in Angina Pectoris

The effects of the calcium antagonists nicardipine and nisoldipine on left ventricular (LV) metabolism were analyzed in 32 patients with angina pectoris. Measurements were made at a fixed heart rate under the basal state and during a cold pressor test (CPT). After administration of the drugs, coronary blood flow increased significantly and the mean aortic pressure decreased by 10% (p less than 0.01) in the basal state and by 11% (p less than 0.01) during CPT. Despite the reduction in pressure-rate product, myocardial oxygen consumption was unchanged in the basal state (18 +/- 4 vs 19 +/- 4 ml/min, difference not significant) and during CPT (21 +/- 5 vs 21 +/- 5 ml/min, difference not significant); this discrepancy between a reduced pressure-rate product and an unchanged oxygen consumption was also noted when nicardipine was given after propranolol (0.1 mg/kg; 12 patients). Both agents also increased LV lactate uptake, particularly during CPT (+13 mumol/min, p less than 0.05 vs control CPT) and reduced LV glutamine production. In 10 patients in whom 14C-lactate was infused, the chemical LV lactate extraction ratio increased more than the 14C-lactate extraction ratio after administration of the drugs, indicating a reduction in LV lactate production. The data are consistent with the hypothesis that nicardipine and nisoldipine improve perfusion and aerobic metabolism in chronically ischemic areas, resulting in an augmented oxygen consumption and in a reduced lactate production.

Force-velocity-length relations in hypertrophic cardiomyopathy: Evidence of normal or depressed myocardial contractility

To assess myocardial contractility in patients with hypertrophic cardiomyopathy (HC), force-velocity-length relations were analyzed during left ventricular (LV) ejection. LV pressure, volume and wall stress data in 15 patients with HC were analyzed and compared with values from 32 normal subjects. Patients with HC had a greater LV mass than did normal subjects (272 versus 96 g/m2, p less than 0.001), elevated LV end-diastolic pressure (17.5 versus 9.8 mm Hg, p less than 0.01) and impaired LV relaxation compared with those of normal subjects. Patients with HC also had a greater ejection fraction (84 +/- 7 versus 74 +/- 8%, p less than 0.01) and mean velocity of shortening than did normal subjects. However, in patients with HC, end-systolic stress (60 +/- 29 versus 187 +/- 61 kdyne/cm2, p less than 0.001) was significantly lower. End-systolic volume and stress data were linearly related in normal subjects (r = 0.88), and values from patients with HC fell either within the lowest part of the 95% confidence interval of this normal relation or outside it in the zone of depressed contractility (11 patients with HC). In addition, the slopes of the relations between end-systolic wall stress and ejection fraction or mean velocity of shortening were abnormal in patients with HC; the slope of the stress-volume trajectory during late ejection was also depressed in 12 patients with HC (average slope 2.6 versus 5.5 kdyne/cm5/m2, p less than 0.001). Thus, there is no evidence of a hypercontractile state in patients with HC; their high values of ejection phase indexes may be explained by a reduction in myocardial afterload.

Additional Hypotensive Effect of Endothelin-1 Receptor Antagonism in Hypertensive Dogs Under Angiotensin-Converting Enzyme Inhibition

BACKGROUND Endothelin-1 (ET-1) may play a role in hypertension. ET-1 receptor antagonism by bosentan lowers blood pressure in hypertension. We evaluated whether the effect of bosentan is still observed under ACE inhibitors (ACEI). METHODS AND RESULTS Thirty anesthetized and 18 conscious hypertensive dogs were studied randomly. Anesthetized dogs were divided into 4 groups: group 1 received cumulative doses of bosentan (bolus+30-minute infusion: 0.1 mg/kg+/-0.23 mg/kg per hour to 3 mg/kg+/-7 mg/kg per hour); group 2, the same dose-responses after 1 mg/kg enalaprilat; group 3, the vehicle after enalaprilat; and group 4, the dose responses to bosentan followed by enalaprilat. The conscious dogs were divided into 3 groups: group 5 received 2 cumulative doses of bosentan; group 6, the vehicle; and group 7, enalaprilat alone. In groups 1 and 2, bosentan produced dose-related decreases (P=.0001) in left ventricular systolic pressure and mean aortic pressure (AOP). In group 1, bosentan decreased mean AOP by 22%. In group 2, enalaprilat decreased mean AOP by 25% (from 173+/-26 to 130+/-25 mm Hg; P<.005); an additional 18% decrease was obtained with bosentan, the mean AOP reaching 98+/-21 mm Hg (P<.01). In group 3, the effect of enalaprilat alone was a 22% decrease in mean AOP (P<.005). The additive effect of the bosentan-ACEI association was also observed in group 4. In group 5, bosentan reduced mean AOP by 20% (P<.005), whereas mean AOP remained unchanged in group 6. The effect of ACEI alone (group 7) was similar to that of bosentan. CONCLUSIONS Bosentan produces an additional hypotensive effect to that of ACEI, which opens new therapeutic perspectives.

Angiotensin II and endothelin-1 receptor antagonists have cumulative hypotensive effects in canine Page hypertension.

Objective To evaluate whether the cumulative hypotensive effect of the endothelin-1 receptor antagonist bosentan, previously demonstrated in the presence of an angiotensin converting enzyme inhibitor, persists under angiotensin II receptor blockade with losartan. Design The model of hypertension was canine renovascular hypertension (Page hypertension). Methods Ten conscious dogs, studied on two occasions, were administered losartan (a 0.1 mg/kg bolus plus 90 min infusion at 0.1 mg/kg per min) and then bosentan vehicle (experiment I) or losartan and then two cumulative doses of bosentan (a 0.3 mg/kg bolus plus 30 min infusion at 0.7 mg/kg per min; and a 3 mg/kg bolus plus 30 min infusion at 7 mg/kg per min; experiment II). Results At the end of the study, mean aortic pressure in dogs had decreased by 14% in experiment I (from 139 ± 4.7 to 119 ± 4.7 mmHg, P < 0.05), whereas a 28% reduction occurred in experiment II (from 145 ± 8.9 to 104 ± 5.0 mmHg, P < 0.005), corresponding to an additional 14% decrease after administration of bosentan (P < 0.005 between groups). This cumulative effect of bosentan was related to a decrease in systemic vascular resistance (from 1220 ± 119 to 847 ± 189 mmHg/ml per min per kg · 103, P < 0.05). Plasma angiotensin II level increased similarly in both experiments (in experiment I from 133 ± 43 to 622 ± 145 pg/ml, P = 0.01; in experiment II from 198 ± 63 to 771 ± 134 pg/ml, P < 0.005) whereas plasma endothelin-1 level increased only in experiment II (from 3.8 ± 0.4 to 32.7 ± 3.2 pg/ml, P < 0.001). Conclusion The cumulative hypotensive effect of bosentan suggests that, besides angiotensin II, endothelin-1 is independently involved in the pathophysiology of hypertension, which presents new therapeutic perspectives.

Assessment of thallium-201 redistribution versus glucose uptake as predictors of viability after coronary occlusion and reperfusion.

Both 201Tl redistribution and persistent glucose uptake have been proposed as markers of viability after reperfusion. In the present study, they have been compared in the same open-chest canine preparation of occlusion and reperfusion. Ten fasting dogs were subjected to 2 hr of left anterior descending coronary artery occlusion and 4 hr of reperfusion. Myocardial blood flow was determined by a microsphere technique 100 min after occlusion and 3 hr after reperfusion. 201Tl was injected intravenously 20 min before reperfusion. Serial biopsy samples were obtained from ischemic and normal areas. 18F-2-deoxyglucose, a tracer of exogenous glucose uptake, was injected 3 hr after reperfusion. Thirty minutes before the animals were killed, simultaneous blood samples were taken from the femoral artery and the regional coronary veins draining the reperfused and the remote areas. Dogs were killed 4 hr after reperfusion was established. Area at risk was assessed by dye injection in vivo and area of necrosis by triphenyl tetrazolium chloride (TTC) staining, with confirmation by electron microscopy. Immediately after death, endocardial and epicardial samples were taken from regions characterized as risk regions, areas of necrosis, areas of patchy necrosis, and normal areas. These samples were counted in a scintillation well counter. Four hours after reperfusion, in ischemic myocardium (TTC positive) the relative 201Tl gradient between ischemic and normal regions was 26 +/- 13%, whereas in necrotic samples, this gradient was 71 +/- 26%.(ABSTRACT TRUNCATED AT 250 WORDS)

Diastolic properties in canine hypertensive left ventricular hypertrophy: effects of angiotensin converting enzyme inhibition and angiotensin II type-1 receptor blockade.

OBJECTIVE Angiotensin II has been suggested to be involved in the pathogenesis of diastolic dysfunction in left ventricular hypertrophy (LVH). The purpose of this study was to asses the effects of enalaprilat and L-158,809, an angiotensin II type-1 receptor antagonist, on LV diastolic function in 16 normal control dogs and 20 LVH dogs with perinephritic hypertension. METHODS LV hemodynamics was studied before and after intravenous injection of enalaprilat (0.25 mg/kg) or L-158,809 (0.3 mg/kg). The hemodynamic data were analyzed in relation to the changes in myocardial blood flow (measured by radioactive microspheres) and in the circulating angiotensin II and norepinephrine levels. RESULTS AND CONCLUSIONS At baseline, significant increases were observed for LV/body weight ratio as well as LV systolic and end-diastolic pressure in the LVH dogs (all P < 0.01 vs. the control group). In addition, LV relaxation time constant was prolonged and the chamber and myocardial stiffness constants were increased (P < 0.01) in the LVH dogs, suggesting an impairment of LV diastolic function. Administration of enalaprilat or L-158,809 improved LV stiffness constants in the LVH dogs (P < 0.05). The diastolic LV pressure-diameter relation shifted downwards in the LVH dogs whereas diastolic distensibility was not altered in the control dogs. Although the circulating angiotensin II levels were significantly decreased by enalaprilat in the LVH dogs, they did not correlate with the changes in the stiffness constants. Furthermore, the alterations of LV diastolic properties in the LVH group could not be attributed to myocardial perfusion, which was rather decreased by administration of enalaprilat and L-158,809. These results suggest that angiotensin II, particularly at the local level, is involved in the pathogenesis of diastolic dysfunction in pressure-overload LVH. The data also support the concept that ACE inhibitors and angiotensin II receptor blockers are potentially beneficial in the treatment of the hypertrophied heart.

Circulatory effects of deep inspirations, blocked expirations and positive pressure inflations at equal transpulmonary pressures in conscious dogs

1. Circulatory effects of deep inspirations, blocked expirations and constant endotracheal positive pressure inflations were studied in six conscious dogs under comparable geometries of the pulmonary vascular bed, i.e. at equal transpulmonary pressures (around 10·2 cm H2O) and similar lung volumes.

Effects of pimobendan (UD-CG 115) on the contractile function of the normal and "postischemic" canine myocardium.

Summary: Pimobendan (UD-CG 115) is a long-acting positive inotropic drug with arterio- and venodilator properties. To determine to what extent this new agent is able to affect contractile function in previously ischemic areas of the left ventricle (LV), the effects of pimobendan on global and regional LV function were studied in eight conscious dogs, 2 days after a 2-h coronary occlusion followed by reperfusion. Before pimobendan, percentage of systolic shortening and mean velocity of shortening were lower in reperfused segments than in control areas (0.41 ± 0.17 vs. 0.93 ± 0.07 s−1 and 7 ± 3 vs. 15 ± 1%, respectively; both p < 0.05). Infusion of 1 mg of pimobendan significantly improved peak + dP/dt (3202 ± 372 to 3848 ± 498 mm Hg/s; p < 0.05) and ejection time (166 ± 13 to 156 ± 15 ms; p < 0.05). Cumulative infusion up to 2.5 mg further improved these indexes to 5199 ± 934 mm Hg/s and to 125 ± 11 ms, (respectively; both p < 0.05) without affecting mean arterial pressure (91 ± 14 to 93 ± 22 mm Hg; NS). Mean velocity of shortening rose to 1.18 ± 0.09 s−1 (p < 0.05) in control segments and to 0.62 ± 0.18 s−1 (p < 0.05) in reperfused segments. The ratio between end-systolic pressure and length increased by 26 ± 9% (p < 0.05) in the reperfused segments and by 20 ± 8% (p < 0.05) in control areas. Coronary flow increased slightly in reperfused areas (endo, 111–149; epi, 78–100 ml/min/100 g; NS) as well as in control areas (endo, 126–155; epi, 92–122 ml/min/100 g; NS) during pimobendan infusion and the ratio (endo/epi) flow remained unchanged. No loss of benefit was seen in reperfused areas up to 5 h after pimobendan infusion. In conclusion, pimobendan improved global and regional indexes of contractility in postischemic myocardium. These results suggest that pimobendan might be useful to treat heart failure after reperfusion.

Early changes in sodium and water balances in patients with acute myocardial infarction: relationship to haemodynamics and creatine kinase

Abstract. The changes in sodium and water balances during the first 4 days after an uncomplicated transmural myocardial infarction (MI) were determined in forty patients. The sodium balance was positive 4 days after MI in 80% of the patients but negative in 20%. Neither in anterior (n= 23) nor in inferior (n= 17) MI were rank correlations found between the haemodynamic parameters (cardiac index, mean arterial pressure, mean right atrial or pulmonary capillary pressures, right or left ventricular work indices) and sodium balance. However, the sodium balances correlated with the total creatine kinase (CK) release in anterior MI after 1 day (r= 0·60; P < 0·002) and after 4 days (r= 0·65; P < 0·001) but not in inferior MI. Furthermore, in anterior and inferior MI matched for their CK release, the sodium handling was different both after 1 day (– 70 in anterior v.+ 44 mmol (24 h)‐1 in inferior MI; P < 0·001) and after 4 days (–36 v.+ 147 mmol (72 h)‐1; P < 0·01), a difference unexplained by differences in medical management or in sodium intake. Finally, sodium balance correlated with the changes in left ventricular stroke work index (LVSWI) observed during this period (r= 0·48, P < 0·001), LVSWI being more stable when sodium balance was more positive.

Hemodynamic and Thermal Aspects of Prolonged Intermittent Exercise

Summary9 young normal subjects were studied during two types of prolonged intermittent exercise requiring periods of heavy work (12 min at 80%