Can we identify response markers to antihypertensive drugs? First results from the IDEAL Trial.

Current antihypertensive strategies do not take into account that individual characteristics may influence the magnitude of blood pressure (BP) reduction. Guidelines promote trial-and-error approaches with many different drugs. We conducted the Identification of the Determinants of the Efficacy of Arterial blood pressure Lowering drugs (IDEAL) Trial to identify factors associated with BP responses to perindopril and indapamide. IDEAL was a cross-over, double-blind, placebo-controlled trial, involving four 4-week periods: indapamide, perindopril and two placebo. Eligible patients were untreated, hypertensive and aged 25-70 years. The main outcome was systolic BP (SBP) response to drugs. The 112 participants with good compliance had a mean age of 52. One in every three participants was a woman. In middle-aged women, the SBP reduction from drugs was -11.5 mm Hg (indapamide) and -8.3 mm Hg (perindopril). In men, the response was significantly smaller: -4.8 mm Hg (indapamide) and -4.3 (perindopril) (P for sex differences 0.001 and 0.015, respectively). SBP response to perindopril decreased by 2 mm Hg every 10 years of age in both sexes (P=0.01). The response to indapamide increased by 3 mm Hg every 10 years of age gradient in women (P=0.02). Age and sex were important determinants of BP response for antihypertensive drugs in the IDEAL population. This should be taken into account when choosing drugs a priori.

Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers.

Statin use may be limited by muscle side effects. Although incompletely understood to date, their pathophysiology may involve oxidative stress and impairments of mitochondrial function and of muscle Ca(2+) homeostasis. In order to simultaneously assess these mechanisms, 24 male healthy volunteers were randomized to receive either simvastatin for 80 mg daily or placebo for 8 weeks. Blood and urine samples and a stress test were performed at baseline and at follow-up, and mitochondrial respiration and Ca(2+) spark properties were evaluated on a muscle biopsy 4 days before the second stress test. Simvastatin-treated subjects were separated according to their median creatine kinase (CK) increase. Simvastatin treatment induced a significant elevation of aspartate amino transferase (3.38±5.68 vs -1.15±4.32 UI/L, P<0.001) and CK (-24.3±99.1±189.3 vs 48.3 UI/L, P=0.01) and a trend to an elevation of isoprostanes (193±408 vs 12±53 pmol/mmol creatinine, P=0.09) with no global change in mitochondrial respiration, lactate/pyruvate ratio or Ca(2+) sparks. However, among statin-treated subjects, those with the highest CK increase displayed a significantly lower Vmax rotenone succinate and an increase in Ca(2+) spark amplitude vs both subjects with the lowest CK increase and placebo-treated subjects. Moreover, Ca(2+) spark amplitude was positively correlated with treatment-induced CK increase in the whole group (r=0.71, P=0.0045). In conclusion, this study further supports that statin induced muscular toxicity may be related to alterations in mitochondrial respiration and muscle calcium homeostasis independently of underlying disease or concomitant medication.

Autonomic nervous system activity imbalance in cardiomyopathic hamster.

There is strong evidence that autonomic imbalance plays an important role in progression of heart failure. Analysis of heart rate variability (HRV) has achieved substantial acceptance as a noninvasive method for the assessment of autonomic tone. The purpose of this investigation was to study HRV in an experimental model of heart failure using cardiomyopathic (BIO TO.2) hamsters. Animals showed an autonomic imbalance of cardiac control that seems due to attenuation of parasympathetic activity and an enhanced sympathetic tone. The reduction of parasympathetic activity in BIO TO.2 hamsters is suggested by (a) the reduction of the high-frequency (HF) spectrum, and (b) the lack of atropine to generate a response. The increased sympathetic activity is indicated by (a) the decreased time-domain indexes, (b) the increased LF/HF ratio of the power spectrum, and (c) the alteration of HRV indexes induced by propranolol. These results support the notion that in heart failure, there is a similar autonomic imbalance in both human and hamster and suggest that the cardiomyopathic hamster is a suitable experimental model for studying the involvement of the autonomic nervous system in the progression of heart failure.

Successful conservative surgery of acute ascending aortic dissection occurring during coronary angiography.

We reported the case of an acute aortic dissection complicating right guiding catheter manipulation during engagement in the right coronary ostium. Despite absence of hemodynamic deterioration, dissection progressed rapidly from the sinus of Valsalva to the ascending aorta along its entire length. At surgery, performed in emergency, the aorta was not dilated and the aortic wall did not appear pathologic. Therefore conservative surgery was performed, consisting of suture of the aortic tear and incollage of the false lumen, with good immediate and mid-term results.

Electrophysiologic and arrhythmogenic effects of the potassium channel agonist BRL 38227 in anesthetized dogs.

Although potassium channel openers have been demonstrated to induce arterial vasodilation and shortening of the QT interval, the complete in vivo hemodynamic and electrophysiologic profile of these drugs has not been fully established. We evaluated the effects of BRL 38227, the active enantiomer of cromakalim, on the electrophysiologic and hemodynamic parameters in anesthetized dogs. Four intravenous (i.v.) doses (0.01, 0.03, 0.1, and 0.3 mg/kg) of BRL 38227 (lemakalim) were given to four different groups of 6 anesthetized and mechanically ventilated dogs. Electrophysiologic and hemodynamic parameters were measured with bipolar catheters positioned in the right atria and the right ventricle and double micromanometers placed in the left ventricle and the aorta. Nine dogs died of ventricular fibrillation (VF; 6 of 6 after 0.3 mg/kg, 2 of 8 dogs after 0.1 mg/kg, and 1 of 7 dogs after 0.03 mg/kg BRL 38227). Three dogs had atrial tachycardia (1 had atrial flutter and 1 had atrial fibrillation after 0.03 mg/kg, and 1 had atrial fibrillation after 0.01 mg/kg BRL 38227). BRL 38227 did not modify heart rate (HR), corrected sinus recovery time (CSRT), and atrial or atrio-ventricular (A-V) conduction times. In contrast, PR interval, Luciani-Wenckebach cycle length (LW), HV interval, QRS duration, ventricular effective refractory period (VERP), QT interval, and monophasic action potential (AP) were significantly shortened in a dose-dependent manner. Left ventricular end-diastolic pressure (LVEDP) was not modified, whereas LVdP/dtmax decreased significantly at 0.1 mg/kg BRL 38227. Finally, there was a significant dose-dependent decrease in systolic, diastolic, and mean aortic blood pressure (SBP, DBP, MAP). We conclude that BRL 38227 shortens the ventricular parameters of conduction velocity and of repolarization and decreases BP, both in a dose-dependent manner. All doses were arrhythmogenic, suggesting that BRL 38227 has a low safety margin.

Lemakalim, a potassium channel agonist, reverses electrophysiological impairments induced by a large dose of bupivacaine in anaesthetized dogs.

We have examined the ability of lemakalim to correct bupivacaine-induced cardiac electrophysiological impairment in an experimental electrophysiological model in closed-chest dogs. Two groups (n = 6) of pentobarbitone-anaesthetized dogs were given atropine 0.2 mg kg-1 i.v., and bupivacine 4 mg kg-1 i.v. over 10 s. Group 2 received also lemakalim 0.03 mg kg-1 i.v. Bupivacaine induced bradycardia, prolonged PR and His-ventricle (HV) intervals, QRS duration, QTc and JTc intervals, decreased left ventricular (LV) dP/dt max and increased LV end-diastolic pressure. Lemakalim reversed bupivacaine-induced PR, HV, QRS, QTc and JTc prolongation, and did not worsen bupivacaine-induced bradycardia and haemodynamic depression. We conclude that lemakalim can antagonize the main deleterious electrophysiological effects induced by a large dose of bupivacaine in anaesthetized dogs.

Experimental evidence in favor of role of intracellular actions of bupivacaine in myocardial depression.

Bupivacaine is more cardiodepressant than lidocaine. Nevertheless, the marked depression of contractility induced by bupivacaine cannot be completely explained by its electrophysiologic properties alone. Biophysical differences such as the greater lipid solubility of bupivacaine versus lidocaine must be taken into consideration. Perhaps more bupivacaine enters the cardiac cells and interacts with contractile processes. To test this hypothesis, the entry of lidocaine into the cells was facilitated by a membrane-permeant lipophilic anion, tetraphenylboron. We compared the spontaneous atrial rate and the contractile force of rabbit right atria bathing in solutions containing either 0.5 microgram/mL lidocaine or bupivacaine. Group 1 (n = 8) served to test the stability of the preparation. In group 2 (n = 6), tetraphenylboron (17 micrograms/mL) was added to Tyrode's solution; atrial rate was decreased by 8% and contractile force by 1.7%. In group 3 (n = 6), bupivacaine (0.5 microgram/mL) was added; bupivacaine decreased atrial rate by 11.3% and markedly depressed contractile force by 68.3%. In group 4 (n = 6), lidocaine (0.5 microgram/mL) was added; lidocaine did not change atrial rate but decreased contractile force by 6.0%. In group 5 (n = 6), both lidocaine and tetraphenylboron were added; atrial rate was decreased by 15.5% and contractile force was markedly depressed by 81.1%. In group 6 (n = 6), 0.2 mM adenosine triphosphate, tetraphenylboron, and then lidocaine were added; the addition of adenosine triphosphate partially counteracted the cardiodepressant effects of the combination of lidocaine and tetraphenylboron. Atrial rate was decreased by 10.4% and contractile force was depressed by 13.6%.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of electrophysiologic and hemodynamic effects induced by high dose of bupivacaine by the combination of clonidine and dobutamine in anesthetized dogs.

The ability of clonidine and dobutamine to correct bupivacaine-induced cardiac electrophysiologic and hemodynamic impairment was evaluated in an experimental electrophysiologic model on closed-chest dogs. Five groups (n = 6) of pentobarbital-anesthetized dogs were given atropine (0.2 mg/kg IV). Group 1 was given a saline solution; all other dogs were given bupivacaine (4 mg/kg IV) over a 10-s period. Group 2 was given only bupivacaine. Group 3 was given clonidine (0.01 mg/kg IV) over a 1-min period. Group 4 was given a dobutamine infusion at 5 micrograms.kg-1.min-1. Group 5 was given the combination of clonidine and dobutamine. Bupivacaine induced bradycardia, prolonged atrioventricular conduction time (PR interval), atrioventricular node conduction time (AH interval), His-Purkinje conduction time (HV interval), and QRS duration. Bupivacaine decreased left ventricular (LV) dP/dt max and increased LV end-diastolic pressure (LVEDP). Clonidine improved QRS duration and HV interval but enhanced AH interval, bradycardia, and hemodynamic depression induced by bupivacaine. Dobutamine infusion improved LV dP/dt max but did not modify bupivacaine-induced ventricular electrophysiologic impairment. The combination of clonidine and dobutamine corrected not only the electrophysiologic impairment induced by bupivacaine but also the hemodynamic depression. As the HV interval and the QRS duration could be correlated with ventricular conduction velocities, we conclude that (a) clonidine reversed the slowing of ventricular conduction velocities induced by bupivacaine, and (b) the combination of clonidine and dobutamine was able to correct the cardiac disturbances induced by bupivacaine in anesthetized dogs.

Succinylcholine does not worsen bupivacaine-induced cardiotoxicity in pentobarbital-anaesthetized dogs.

The intravascular injection of a large dose of bupivacaine induces electrophysiological cardiac impairment, mainly by slowing ventricular conduction velocity, and haemodynamic depression, by a decrease in myocardial contractility. When cardiotoxicity occurs, succinylcholine rapidly stops convulsions. However, the possible interactions between bupivacaine and succinylcholine on cardiac electrophysiology and haemodynamic status have never been investigated. Thus, we used an experimental electrophysiological model involving closed-chest dogs. Three groups (n = 6) of pentobarbital-anaesthetized dogs were given 0.2 mg.kg-1 atropine iv. Dogs in Group 1 were given saline. The others received 4 mg.kg-1 bupivacaine iv over ten seconds. Dogs in Group 2 were then given saline and those in Group 3 were then given 2 mg.kg-1 succinylcholine iv from one to two minutes after the administration of bupivacaine. The following electrophysiological variables were measured: heart rate represented by RR interval (RR), PR, atria-His (AH), and His-ventricle (HV) intervals, QRS duration, and QT interval corrected for heart rate (QTc). The following haemodynamic variables were measured: mean aortic pressure (MAoP), the peak of the first derivative of left ventricular pressure (LV dP/dt max), and LV end diastolic pressure (LVEDP). Comparison between Groups 1 and 2 showed that bupivacaine induced more than 100% HV interval lengthening and QRS widening (P less than 0.01), prolonged QTc interval by more than 25% (P less than 0.01), and decreased LV dP/dt max by more than 50% (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction by carbachol of ventricular conduction impairments induced by various class I antiarrhythmic drugs in anesthetized dogs.

A common property of all Class I antiarrhythmic agents is the inhibition of the fast inward current INa. Consequently, ventricular conduction velocities are impaired and reentrant phenomena are counteracted. Unfortunately, these conductive pathway disturbances may also induce proarrhythmic effects and reduce cardiac contractility. Recent evidence indicates that a cholinergic agonist, carbachol, is able to correct in vitro both the duration of the action potential and the partial depolarization induced by lidocaine and quinidine in rabbit atria. In the present study, we demonstrated that i.v. carbachol is also a powerful agent in vivo for correcting conductive disturbances previously induced by four different Class I antiarrhythmic agents. The electrophysiological and hemodynamic parameters of ten groups of atropinized-anesthetized dogs, including six animals per group, were investigated. QRS duration, HV and V-St intervals were selected as in vivo indexes of ventricular conduction. Quinidine, procainamide, cibenzoline and flecainide were selected as representative agents of Class Ia and Ic antiarrhythmic drugs. In all treated groups, carbachol (1 mg/kg) was able to correct the indexes of ventricular conduction previously impaired by the antiarrhythmic drug used.

Bupivacaine-induced slow-inward current inhibition: a voltage clamp study on frog atrial fibres.

The effects of various concentrations of bupivacaine on the characteristics of the slow-inward current (isi) were studied over a ten-minute period on isolated frog atria. At a concentration of 10(-7) M, bupivacaine did not modify isi. At 10(-6) M, the maximal amplitude of the slow-inward current (i max) was depressed by 11 per cent. At 10(-5) M, i max was depressed by 24.5 per cent, the time-to-peak current value (tpeak) was increased by 13.4 per cent and the inactivation time constant (tau in) by 29.8 per cent. At 10(-4) M, i max was depressed by 32.9 per cent, tpeak increased by 30.4 per cent and tau in by 58.7 per cent. In conclusion, bupivacaine produced only moderate inhibition of the slow-inward current. The findings might explain the decline in sinus impulse formation with sinus bradycardia, and the slowing of atrio-ventricular node conduction produced by bupivacaine. However, the decrease in contractility previously reported does not seem to be due only to inhibition of the slow-inward current.

Class IC drugs: propafenone and flecainide.

Recently published clinical data on the efficacy and side-effect profiles of flecainide and propafenone are reviewed. Both compounds appear to be clinically effective for the control of a variety of cardiac arrhythmias, both ventricular as well as supraventricular. These include termination of atrial fibrillation, control of junctional tachycardias, and control of ventricular arrhythmias. While the incidence of noncardiac side effects appeared to be similar for both compounds, proarrhythmic effects appeared to be higher on flecainide than on propafenone, especially with doses higher than 400 mg.

[Do beta adrenergic receptor blockaders increase bupivacaine cardiotoxicity?]. / Les bêta-bloquants aggravent-ils la cardiotoxicité de la bupivacaïne?

Bupivacaine is known to impair the electrophysiology of the heart as well as haemodynamic parameters. Administration of calcium channel blockers prior to bupivacaine enhances its cardiotoxicity. This study assessed the effects of bupivacaine at toxic dose in dogs with previous beta-adrenergic receptor blockade. It included 12 dogs anaesthetized with thiopentone, allocated in a control group (n = 6) receiving a bolus of bupivacaine (4 mg.kg-1) and a study group (n = 6) treated with the sequence propranolol (0.2 mg.kg-1) and bupivacaine (4 mg.kg-1), 15 min later. Infranodal conduction (HV conduction times and QRS durations) was worsened in both groups. Previous propranolol administration had no potentiating effects on these parameters. Conversely the latter was responsible of a greater decrease in heart rate, and increase in atrio-ventricular conduction time (77.9% vs 18.7%, p less than 0.05), as well as a more severe hypotension. Moreover, 3 out of the 6 animals in the study group suffered a cardiac arrest between the 5th and the 10th min. It is concluded that in anaesthetized dogs the cardiac and circulatory effects of a toxic dose of bupivacaine are increased in case of preexisting blockade of beta adrenergic receptors.

In vitro study on mechanisms of bupivacaine-induced depression of myocardial contractility.

Although several mechanisms have been proposed to explain bupivacaine cardiotoxicity, the predominant effect remains to be determined. In this study, we used an isolated rabbit right atrial model that reproduces the effects on inotropic and chronotropic functions induced by 0.5 micrograms/mL bupivacaine; then we tried to counteract these events by electrical stimulation or by addition of CaCl2 or adenosine triphosphate (ATP) to the bathing solution. Contractile force was dramatically depressed by bupivacaine alone (-68%), even when the preparation was paced (-59%). CaCl2 partially counteracted this decrease (-37%). Inotropic function was almost completely restored (-9%) when ATP was added before administration of bupivacaine. Inhibition of energy metabolism seems to be a major explanation for bupivacaine cardiotoxicity.

A potent radiolabeled human renin inhibitor, [3H]SR42128: enzymatic, kinetic, and binding studies to renin and other aspartic proteases.

The in vitro binding of [3H]SR42128 (Iva-Phe-Nle-Sta-Ala-Sta-Arg), a potent inhibitor of human renin activity, to purified human renin and a number of other aspartic proteases was examined. SR42128 was found to be a competitive inhibitor of human renin, with a Ki of 0.35 nM at pH 5.7 and 2.0 nM at pH 7.4; it was thus more effective at pH 5.7 than at pH 7.4. Scatchard analysis of the interaction binding of [3H]SR42128 to human renin indicated that binding was reversible and saturable at both pH 5.7 and pH 7.4. There was a single class of binding sites, and the KD was 0.9 nM at pH 5.7 and 1 nM at pH 7.4. The association rate was 10 times more rapid at pH 5.7 than at pH 7.4, but there was no difference between the rates of dissociation of the enzyme-inhibitor complex at the two pHs. The effect of pH on the binding of [3H]SR42128 to human renin, cathepsin D, pepsin, and gastricsin was also examined over the pH range 3-8. All the aspartic proteases had a high affinity for the inhibitor at low pH. However, at pH 7.4, [3H]SR42128 was bound only to human renin and to none of the other aspartic proteases. Competitive binding studies with [3H]SR42128 and a number of other inhibitors on human renin or cathepsin D were used to examine the relationships between structure and activity in these systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiologic effects and pharmacokinetics of intravenous penticainide (CM 7857).

Penticainide is a new class I antiarrhythmic agent. Its electrophysiological effects and pharmacokinetic properties were studied in 28 patients undergoing endocavitary exploration for paroxysmal supraventricular tachycardia (10 cases), WPW syndrome involving an accessory pathway (5 cases), and unexplained dizziness (13 cases). Increasing doses of penticainide were infused in the first 18 patients (0.12 up to 3.5 mg kg-1). The next ten patients received 4 mg kg-1 over a 30 minute period. Penticainide shortened the sinus cycle length and increased the transnodal conduction time. The ventricular conduction time tended to increase. Atrial functional refractory period increased when atrioventricular nodal and ventricular refractory periods remained unchanged. In patients with previous supraventricular tachycardias all triggered arrhythmias were prevented with dosages higher than 2 mg kg-1 and related blood levels higher than 3 mg l-1. A dose-dependency of plasma and renal clearance was documented. Average Cmax values after 4 mg kg-1 was 7.37 +/- 1.28 mg l-1. No adverse events occurred during the trial and penticainide proved to be well tolerated.

Effect of amiodarone on myosin isoenzymic distribution in rat ventricular myocardium.

Rats were given amiodarone (50 mg X kg-1 X day-1, orally) for 4 weeks and the distribution of ventricular isomyosins, a sensitive index of the effects of thyroid hormones on cardiac tissue, was analyzed. Amiodarone treatment induced a marked increase in both T4 and rT3 and tended to decrease T3 serum levels. At the pharmacologically active dosage we used, the drug induced a moderate redistribution of ventricular isomyosins in favour of V, at the expense of V1. Our results do not support the hypothesis that the major mechanism of action of amiodarone is mediated through hypothyroid-like effects.

Electrophysiological studies of penticainide (CM 7857), a new antiarrhythmic agent, in mammalian myocardium.

The intracellular electrophysiologic properties of a new antiarrhythmic substance, penticainide, were studied in isolated rabbit, dog, and guinea pig myocardial preparations superfused or perfused with oxygenated Tyrode's solution. "Therapeutic" concentrations of penticainide (1.5 to 3 X 10(-5) M) had little effect on sinus node automaticity; sinoatrial conduction was slightly delayed. In atrial, Purkinje and ventricular fibers, amplitude, and maximal rate of rise of phase O (dV/dtmax) were decreased by penticainide; Purkinje-ventricle conduction velocity was depressed. Penticainide did not significantly modify action potential duration (APD) of rabbit atria and dog ventricle and reduced APD and effective refractory period (ERP) of dog Purkinje and guinea pig ventricular fibers. Penticainide reduced APD heterogeneity of Purkinje-ventricle junction with a preferential effect at the gate and decreased tension amplitude of perfused papillary muscle in dog heart. The effect of penticainide on dV/dtmax was voltage and rate dependent; the resting block was weak. Thus, penticainide is a class 1 antiarrhythmic agent with properties of class 1B agents such as APD reduction and properties of class 1C agents such as slow recovery kinetic of rate-dependent block.

Binding of a tritiated pepstatin analog to human renin.

The interaction between human renin and a potent pepstatin analog, SR 42128, has been investigated using binding studies. Binding and enzymatic assays were performed at pH 5.7 and pH 7.4. We found one specific inhibitor binding site per molecule of renin at both pH's. The dissociation constant (KD) obtained at equilibrium was 14-fold lower at pH 5.7 than at pH 7.4, showing a pH effect on binding of [3H]SR 42128. A similar decrease was measured in enzymatic studies. In nonequilibrium conditions, we demonstrated that only association kinetic constants have been affected by pH variations. Radioligands provided interesting tools to investigate enzyme-inhibitor relationships.