Henri Van Mechelen

Hemodynamic and cardiac effects of nicardipine in patients with coronary artery disease

The hemodynamic and cardiac effects of the calcium antagonist nicardipine,1 alone (n = 10 patients) or combined with propranolol (0.1 mg/kg i.v.; n = 9 patients), were assessed in patients with coronary artery disease. In the absence of β-blockade, nicardipine (5 or 10 mg i.v.) increased heart rate (+ 23 and + 15 beats/min after 5 and 10 mg, respectively; p < 0.01) and cardiac output (from 4.7 ± 1.1 to 7. 4 ± 1.3 L/min after 5 mg and from 5.1 ± 1.1 to 8.6 ± 1.6 L/min after 10 mg; p < 0.005). Systemic vascular resistance decreased with both doses (−46 and −57%; p < 0.005), whereas mean aortic pressure decreased by 14 mm Hg after 5 mg and by 28 mm Hg after 10 mg (p < 0.004); left ventricular end-diastolic pressure was unchanged. Nicardipine also decreased significantly end-systolic left ventricular volume and increased ejection fraction (from 63 to 71% after 5 mg and from 54 to 63% after 10 mg; p < 0.008) and velocity of shortening. Peak (+) dP/dt and (dP/dt)/DP40(value of dPIdt at a developed pressure of 40 mm Hg) were unchanged, and Emax, the maximal left ventricular pressure/volume ratio, improved slightly (+8%; p < 0.05). After β-blockade, nicardipine (2.5 mg i.v.) still decreased mean aortic pressure (−16 mm Hg; p < 0.05) and systemic vascular resistance, and irnproved the ejection phase indices; cardiac output and ventricular relaxation, both depressed after propranolol administration, were also normalized after infusion of nicardipine. Further, after infusion of propranolol, nicardipine did not modify the isovolumic indexes of inotropic state or Emax. In conclusion, nicardipine is a powerful arteriodilator without detectable negative inotropic effects in vivo.

Role of Endogenous Endothelin-1 in Experimental Renal Hypertension in Dogs

BACKGROUND Endothelin-1, a vasoconstrictive peptide released by endothelium, may be involved in the pathophysiology of hypertension. The goal of the present study was to evaluate the role of endogenous endothelin-1 in renal hypertension in dogs. The model of hypertension consisted of silk tissue wrapping of the left kidney, which produced hypertension associated with perinephritis after 6 to 8 weeks. METHODS AND RESULTS Thirty-two anesthetized open chest dogs were studied randomly: 8 dogs with perinephritic hypertension received the nonpeptidic ETA-ETB receptor antagonist bosentan (group 1); 8 other hypertensive dogs received the vehicle solution (group 2); 8 healthy dogs received bosentan (group 3); and 8 healthy dogs received the vehicle solution (group 4). Bosentan was injected as an intravenous bolus (3 mg/kg) followed by a 1-hour infusion at a rate of 7 mg.kg-1.h-1. In hypertensive dogs, bosentan produced a similar decrease (P = .0001) of both left ventricular systolic and mean aortic pressures, which averaged 38 mm Hg (-22% and -24%, respectively). These parameters remained unchanged with the vehicle solution. Left ventricular end-diastolic and left atrial pressures also declined significantly with bosentan (P = .0005 and P < .05, respectively). Left ventricular lengths tended to decrease. The other cardiovascular parameters (heart rate, peak [+]dP/dt, time constant of relaxation, and coronary vascular resistance) did not change significantly. In healthy dogs, bosentan decreased mean aortic pressure by 19 mm Hg (P = .004). Vehicle solution had no effect. Plasma endothelin-1 levels, similar under basal conditions in healthy and hypertensive dogs, increased 30-fold with bosentan (P = .0001). CONCLUSIONS Specific endothelin-1 receptor antagonism markedly lowers blood pressure in experimental hypertension but is less effective on blood pressure of healthy animals. This suggests that endothelin-1 plays a role in the pathophysiology of hypertension but contributes to a lesser extent to the maintenance of normal blood pressure. This role of endothelin-1 is unrelated to its plasma levels. The increase of plasma endothelin-1 with bosentan, due either to a displacement of endothelin-1 from its receptor or to a feedback mechanism, does not prevent this blood pressure reduction.

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.

Cardiovascular effects of beta 3-adrenoceptor stimulation in perinephritic hypertension.

Background A new beta 3‐adrenoceptor (β3‐AR) has been shown to mediate peripheral vasodilation. This study was conducted to evaluate effects of the β3‐AR agonist, SR58611 in normal and hypertensive dogs.

Effects of endothelin-1 at pathophysiologic concentrations on coronary perfusion and mechanical function of normal and postischemic myocardium.

We assess hemodynamic, vascular, and hormonal effects of endothelin-1 (ET-1) at pathophysiologic levels on normal and ischemic myocardium. Thirty conscious chronically instrumented dogs were studied before, during, and after a 10-min coronary artery occlusion (CAO) performed either during ET-1 infusion (2.5 ng/ kg min, n = 15) or during placebo infusion (n = 15). ET-1 infusion produced an increase in plasma ET-1 (from 1.3 ± 0.1 to 11.5 ± 1.1 pAf, p < 0.0001) during CAO (pathophysiologic value). Left anterior descending artery (LAD) blood flow (measured by Doppler flow probe) decreased similarly during CAO with ET-1 or placebo (p = 0.0001, NS, ET-1 vs. placebo). Both endocardial and epicardial blood flows in ischemic regions also decreased (p = 0.0001) during CAO but were threefold greater with ET-1 than with placebo (endocardium 42 ± 7 vs. 14 ± 2 ml/min/100 g, p = 0.003). No significant difference in myocardial blood flows between groups was observed in control regions. CAO produced increases (p < 0.005) in heart rate (HR), mean aortic pressure (AOP), and ventricular pressures but no change in atrial pressures. The changes in these parameters were comparable in the ET-1 and placebo groups. Despite the greater residual flow during CAO, however, ET-1 decreased the function of the ischemic zone during reperfusion as assessed by systolic shortening (p < 0.05). Atrial natriuretic factor (ANF), unchanged during CAO with placebo, increased from 38.3 ± 6.1 to 53.3 ± 10 pM with ET-1 (p = 0.02). Thus, ET-1, at pathophysiologic levels, increases collateral blood flow in ischemic myocardium without affecting perfusion of normal myocardium. It decreases postischemic myocardial recovery and directly stimulates ANF release.

Effects of intravenous epinine administration on left ventricular systolic performance, coronary hemodynamics, and circulating catecholamines in patients with heart failure.

Summary Twenty-six patients with mild to moderate heart failure were studied to determine the effects of epinine infusion (at a rate producing plasma levels similar to those measured after oral administration of 100 mg of the prodrug ibopamine) on left ventricular (LV) function (14 patients), and coronary flow and circulating catecholamines (12 patients). The only significant hemodynamic change at an infusion rate of 0.5 μg/kg/min was a 9% (p < 0.05) decrease in systemic vascular resistance (SVR). At an infusion rate of 1 μg/kg/min (mean free epinine plasma levels 14.3 ± 3.7 ng/ml), heart rate (HR), dP/dtmax (1,405 ± 255 to 1,490 ± 320 mm Hg, NS), (dP/dt)/DP40, and the relaxation rate remained unchanged, but the ejection fraction (EF) increased from 32 to 38% (p < 0.001), cardiac output (CO) increased, and SVR decreased by 22% (p < 0.05). In a separate group of 12 patients, epinine infusion at rates of 0.5–1 μg/kg/min produced no significant changes in coronary blood flow or myocardial oxygen uptake. At these infusion rates, arterial norepinephrine (NE) and dopamine (DA) levels decreased slightly and arterial and coronary sinus epinephrine increased. In conclusion, epinine, at concentrations similar to those achieved during therapeutic use of ibopamine, had negligible effect on myocardial contractility and relaxation rate in heart failure patients. Cardiac pump function was improved by a decrease in SVR rather than by inotropic stimulation. The data also suggest that these low concentrations of epinine may modulate the sympathetic nervous system, but further studies are needed to determine whether this effect could have clinical significance.

Effects of pimobendan (UD-CG 115 BS) on left ventricular inotropic state in conscious dogs and in patients with heart failure.

The purpose of this study was to examine the time course of the changes in left ventricular inotropic state after intravenous pimobendan administration. In conscious dogs, cuμlative doses of 1 and 2.5 mg of pimobendan significantly increased heart rate and the isovolumic indices of inotropic state and relaxation. The maximal effect, however, required 2 h to be present. The changes in cardiac index and capillary wedge pressure after the intravenous administration of 5 mg to patients with heart failure confirmed this slightly delayed action of pimobendan. Accordingly, the effects of pimobendan on left ventricular inotropic state in patients with moderate to severe heart failure were determined during cardiac catheterization 130–150 min after injection of 5 (n = 3) or 2.5 (n = 4) mg. After drug administration, heart rate increased slightly (+7 beats/min: NS) while left ventricular end-diastolic and systolic pressure both decreased significantly (from 22.7 to 9.2 mm Hg, p < 0.007 and from 123 to 90 mm Hg, p < 0.025, respectively). The isovolumic index of contractility (dP/dt) DP40 increased by 19.6 ± 14.7%. (p < 0.02) and the slope of the late systolic stress-volume relationship improved by 48% P < 0.05). It is concluded that pimobendan is a positive inotropic agent in the failing human heart as well as a powerful veno- and arteriodilator

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.

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.