Effects of moxonidine vs. metoprolol on blood pressure and metabolic control in hypertensive subjects with type 2 diabetes.

Subjects with type 2 diabetes experience an increased cardiovascular morbidity and mortality, related to a high prevalence of hypertension, dyslipidemia, and obesity. Antihypertensive treatment with beta-adrenergic receptor blockers may have deleterious metabolic consequences, including worsening of lipid profiles and insulin sensitivity. The centrally-acting sympatholytic agent moxonidine may improve these variables. In this randomised, double-blind multicenter study, the effects of two widely used antihypertensive agents--moxonidine (MOX) and the beta (1)-selective adrenergic receptor blocker metoprolol (MET)--on blood pressure and metabolic control were directly compared in hypertensive subjects with type 2 diabetes. Patients received either MOX (0.2 - 0.6 mg/d) or MET (50 - 150 mg/d) for 12 weeks, intending comparable blood pressure control. In total 200 patients were randomized. Here we report results from the per protocol population consisting of 127 patients (MOX 66, MET 61) but similar results were found in the ITT population. Reductions in systolic (SBP) and diastolic (DBP) blood pressures after 12 weeks were similar in both groups: In the MOX group, mean SBP (+/- SD) decreased from 154 +/- 12 to 142 +/- 17 mmHg and mean DBP from 91 +/- 9 to 83 +/- 9 mmHg. In the MET group, mean SBP decreased from 152 +/- 13 to 140 +/- 15 mmHg, and mean DBP from 90 +/- 8 to 84 +/- 10 mmHg. Mean HbA (1C) values did not differ between groups after 12 weeks (MOX 8.1 +/- 1.4 Hb%, MET 8.1 +/- 1.5 Hb%, intention-to-treat population). However, fasting plasma glucose decreased in the MOX group (median change - 5 mg/dl), but increased in the MET group (+ 16 mg/dl; p < 0.05). Median changes in the insulin resistance index (HOMA (IR)) were + 0.56 micro IU x mol/L (2) in the MET group, and - 0.27 micro IU x mol/L (2) in the MOX group. Correspondingly, fasting triglycerides increased with a median change of + 29.5 mg/dL in the MET group, but decreased in the MOX group (- 27.5 mg/dl; p < 0.05). These results indicate that MOX, unlike MET, may elicit beneficial adaptations in glucose and lipid metabolism in hypertensive subjects with type 2 diabetes, although mean HbA (1c) values did not differ. In long-term treatment in this high-risk population, MOX thus may decrease global vascular disease risk to a greater extent than MET.

Antihypertensive agent moxonidine enhances muscle glucose transport in insulin-resistant rats.

The sympatholytic antihypertensive agent moxonidine, a centrally acting selective I1-imidazoline receptor modulator (putative agonist), may be beneficial in hypertensive patients with insulin resistance. In the present study, the effects of chronic in vivo moxonidine treatment of obese Zucker rats--a model of severe glucose intolerance, hyperinsulinemia and insulin resistance, and dyslipidemia--on whole-body glucose tolerance, plasma lipids, and insulin-stimulated skeletal muscle glucose transport activity (2-deoxyglucose uptake) were investigated. Moxonidine was administered by gavage for 21 consecutive days at 2, 6, or 10 mg/kg body weight. Body weights in control and moxonidine-treated groups were matched, except at the highest dose, at which final body weight was 17% lower in the moxonidine-treated animals compared with controls. The moxonidine-treated (6 and 10 mg/kg) obese animals had significantly lower fasting plasma levels of insulin (17% and 19%, respectively) and free fatty acids (36% and 28%, respectively), whereas plasma glucose was not altered. During an oral glucose tolerance test, the glucose response (area under the curve) was 47% and 67% lower, respectively, in the two highest moxonidine-treated obese groups. Moreover, glucose transport activity in the isolated epitrochlearis muscle stimulated by a maximally effective insulin dose (13.3 nmol/L) was 39% and 70% greater in the 6 and 10 mg/kg moxonidine-treated groups, respectively (P<.05 for all effects). No significant alterations in muscle glucose transport were elicited by 2 mg/kg moxonidine. These findings indicate that in the severely insulin-resistant and dyslipidemic obese Zucker rat, chronic in vivo treatment with moxonidine can significantly improve, in a dose-dependent manner, whole-body glucose tolerance, possibly as a result of enhanced insulin-stimulated skeletal muscle glucose transport activity and reduced circulating free fatty acids.

[Clinical safety using the thrombocyte aggregation inhibitor c7E3 in interventional cardiology in 520 patients]. / Klinische Sicherheit der Anwendung des Thrombozytenaggregationshemmers c7E3 in der Interventionellen Kardiologie bei 520 Patienten.

The monoclonal antibody c7E3 (ReoPro) is a highly selective inhibitor of platelet aggregation that binds to the fibrinogen receptor (GP IIb/IIIa) on the surface of platelets and leads to a dose-dependent, nearly complete inhibition of platelet aggregation. The clinical value of c7E3 to reduce ischemic events after PTCA in addition to heparin and aspirin has been demonstrated in the EPIC-, EPILOG-, and CAPTURE-trial. In these studies, c7E3 was associated with an increased bleeding risk after the coronary intervention. The DTREO-Trial (German trial with c7E3) was designed as a prospective study to investigate the clinical safety of c7E3 in the daily routine of a cath lab. From April 1995 through September 1996 520 patients were enrolled at 30 German sites. c7E3 was mainly used in patients with acute coronary syndromes (55% unstable angina Braunwald Class I-III and C; 28% in acute myocardial infarction) and in patients with complex coronary lesions (AHA/ACC classification type B and C lesion in 84% of the study group). In 51% of the interventions a stent was implanted (25% in bailout-situations and in 26% as an elective intervention) and c7E3 was used as an adjunctive to prevent sub-acute stent thrombosis. The incidence of "major" bleeding events (TIMI-classification) was less frequent in this study as in the EPIC-trial and comparable to the results of the EPILOG- and CAPTURE trial. In conclusion this study confirms the positive risk profile of c7E3 in patients undergoing high-risk percutaneous revascularization procedures.

Functional interaction between local anaesthetics and calcium antagonists in guineapig myocardium: 2. Electrophysiological studies with bupivacaine and nifedipine.

The negative inotropic effect of local anaesthetics is potentiated by several calcium antagonists in guineapig myocardium [1]. Therefore, we studied which effects on cardiac ionic currents could be responsible for this interaction. Concentration-response curves for bupivacaine were studied in isolated guineapig atria and papillary muscles (slow action potentials). Effects on action potentials were assessed in the absence (n = 7 atria, n = 8 papillary muscles) or presence of nifedipine (8 x 10(-8) mol litre-1 in n = 8 atria, 10(-8) mol litre-1 in n = 8 papillary muscles). The effect on the Ca2+ current was assessed directly using the patch-clamp technique in guineapig ventricular myocytes. Bupivacaine reduced contractile force and upstroke velocity of atrial action potentials. Only the negative inotropic effect was potentiated in the presence of nifedipine. Force and upstroke velocity of slow action potentials were diminished by bupivacaine. Both variables were affected at significantly smaller concentrations of bupivacaine when given in combination with nifedipine. The Ca2+ current was reduced significantly by bupivacaine 5 x 10(-5) mol litre-1 (mean -18 (SD 7)%, n = 9). Its effect was accentuated in the presence of nifedipine 10(-9) mol litre-1 (-47 (4)%, n = 7). Bupivacaine 3 x 10(-4) mol litre-1 given alone exerted a comparable effect (-53 (4)%, n = 4). Variables indicative of Ca2+ channel function (contractile force, upstroke of slow but not normal action potentials, Ca2+ inward current) revealed potentiation of the effects of bupivacaine by nifedipine.

[The potential dependence of the effect of bupivacaine and ropivacaine on the heart. In-vitro studies on the effect of local anesthetics on the force of contraction and the action potential in left guinea pig atria]. / Die Potentialabhängigkeit der Wirkung von Bupivacain und Ropivacain am Herzen. In vitro-Untersuchungen zur Wirkung der Lokalanästhetika auf die Kontraktionskraft und das Aktionspotential an linken Meerschweinchenatrien.

The cardiotoxicity of long acting local anaesthetics is still a matter of controversy. Therefore, the effects of bupivacaine and ropivacaine on cardiac contractility and electrophysiologic parameters were evaluated in the presence of different extracellular potassium concentrations. METHODS. In strips from left atria of guinea pigs action potentials were induced to obtain cumulative dose response curves for bupivacaine (racemic mixture) and ropivacaine (S-enantiomer). Effects on force of contraction and parameters of the action potential (especially maximum upstroke velocity, dV/dtmax, as an indirect measure of fast sodium channel function) were compared for low (2.7 mM) and high (8.7 mM) extracellular K+ concentrations (n = 7-8). RESULTS. At low K+ concentration, bupivacaine and ropivacaine depressed force of contraction and dV/dtmax in a dose-dependent manner. At higher local anaesthetic concentrations, action potential amplitude decreased and action potential duration was prolonged. There was no influence on the resting membrane potential (Tables 2, 3). At high K+ concentration, both local anaesthetics induced effects similar to those observed with low K+, but the dose-response curves for contractility and dV/dtmax were shifted leftward. The EC50 of bupivacaine for the negative inotropic effect and, analogously, for dV/dtmax was approximately 10 times lower. Similar results were observed for ropivacaine (Figs. 1, 2). CONCLUSION. This study confirms the dependence of the cardiodepressive effects of bupivacaine on the extracellular K+ concentration (i.e. membrane potential). The present investigation shows a similar dependence for the effects of ropivacaine, a new long-lasting local anaesthetic. Our results concerning the potential dependency of dV/dtmax depression are compatible with the binding of bupivacaine to the inactivated state of the sodium channel protein preferentially (modulated receptor hypothesis). Thus accumulation of block will occur if stimulation frequency is in an appropriate range. Though we found striking analogies between potential dependency of dV/dtmax depression and negative inotropic effect, there is no firm evidence that the sodium channel block by bupivacaine or ropivacaine substantially participates in the latter effect. An influence on other ionic channels such as the calcium channel remains to be evaluated.

Enantioselectivity of asocainol studied at different conditions: a novel approach to check the feasibility of molecular models of antiarrhythmic drug action.

In terms of the "guarded receptor" hypothesis, changes in potency of Na+ channel blocking drugs reflect alterations in drug access to and/or egress from a compartment facing a binding site with constant affinity. Potency is therefore assumed to be determined by changes in drug diffusion, its mobility in the electric field, protonation etc. Hence, the potencies of enantiomers, i.e. compounds with identical physicochemical properties, should be influenced in a parallel manner by the condition. To test this prediction, actions of the enantiomers of the stereoselective antiarrhythmic drug asocainol were compared at various membrane potentials and stimulus frequencies. Several experimental models indicative of Na+ channel block were used: the elevation of the rectangular pulse stimulation threshold (RPT) and the suppression of alternating-current induced arrhythmia (ACT) were studied in guinea-pig atria. The reduction of the upstroke velocity of action potentials was measured in guinea-pig papillary muscles. The inhibition of whole-cell Na+ currents was investigated in isolated guinea-pig ventricular myocytes. In all these assays, (+)-asocainol was more potent than the (-)-enantiomer. Lowering the membrane potential and/or increasing the stimulus frequency enhanced the effects of both enantiomers. However, over a certain range of conditions, the potency of (+)-asocainol was more markedly affected than that of (-)-asocainol, indicating that the eudismic ratio between potencies of the two drugs is not constant. Accordingly, these findings are inconsistent with the guarded receptor hypothesis.

The polycationic compound gentamicin inhibits the calcium paradox in guinea-pig hearts.

The polycationic drug gentamicin and two calcium antagonists were studied with respect to their protecting action against the calcium paradox in perfused guinea-pig hearts. Besides the mechanograms the release of creatine kinase was recorded; in parallel experiments the Na(+)-content of the hearts was measured before and at the end of the Ca(2+)-lack period, and during re-exposure to normal [Ca2+]0. The calcium paradox was induced by perfusion, for 50 s, with Ca(2+)-free solution containing EGTA (3 x 10(-4) M). Nifedipine and verapamil in concentrations which reduced the equilibrium contractile force by 50%, only mitigated the extent of the calcium paradox, whereas gentamicin applied in a concentration also reducing the contractile amplitude by 50% was able to suppress the calcium paradox completely. The dose-response curves for nifedipine, with respect to the reduction of contractile force and contracture, were identical. In contrast, gentamicin was more effective in attenuating the contracture of the paradox than in reducing the equilibrium contractile force. The large gain of Na+ during the Ca(2+)-lack period was diminished by both nifedipine and gentamicin. The partial protection of calcium antagonists can be related to their interference with the uptake of Na+ through L-type Ca(2+)-channels during the Ca(2+)-lack period, whereas gentamicin seems to act by an additional inhibition of the Na/Ca exchange during the re-exposure to normal [Ca2+]0.