Test of the Usefulness of a Paradigm to Identify Potential Cardiovascular Liabilities of Four Test Articles With Varying Pharmacological Properties in Anesthetized Guinea Pigs

Abstract

The evaluation of proarrhythmic and hemodynamic liabilities for new compounds remains a major concern of preclinical safety assessment paradigms. Contrastingly, albeit functional liabilities can also translate to clinical morbidity and mortality, lesser preclinical efforts are focused on the evaluation of drug-induced changes in inotrope and lusitrope, particularly in the setting of concomitant hemodynamic/arrhythmic liabilities. This study aimed to establish the feasibility of an anesthetized guinea pig preparation to assess functional liabilities in the setting of simultaneous drug-induced electrocardiographic/hemodynamic changes, by evaluating the effects of various compounds with known cardiovascular properties on direct and indirect indices of left ventricular function. In short, twenty nine male guinea pigs were instrumented to measure electrocardiograms, systemic arterial pressure, and left ventricular pressure-volume relationships. After baseline measurement, all animals were given intravenous infusions of vehicle and two escalating concentrations of either chromanol 293B (n = 8), milrinone (n = 6), metoprolol (n = 7), or nicorandil (n = 8) for 10 minutes each. In all cases, these compounds produced the expected changes. The slope of preload-recruitable stroke work (PRSW), a pressure-volume derived load independent index, was the most sensitive marker of drug-induced changes in inotropy. Among the indirect functional indices studied, only the "contractility index" (dP/dtmax normalized by the pressure at its occurrence) and the static myocardial compliance (ratio of end diastolic volume and pressure) appeared to be adequate predictors of drug-induced changes in inotropy/lusitropy. Overall, the data confirms that both electrophysiological and mechanical liabilities can be accurately assessed in an anesthetized guinea pig preparation.

Acute effects of intravenous dronedarone on electrocardiograms, hemodynamics and cardiac functions in anesthetized dogs

“…negative lusitrope) may result from β-blocking effect of dronedarone which prevents phosphorylation of phospholamban; therefore, less calcium is resequestrated through the SERCa 2+ channel resulted in slow relaxation [4]. This result is also in accordance with our previous study in which dP/dt min and tau were lengthened when metoprolol was given to anesthetized guinea pigs [17]. The end-diastolic pressure-volume relationship (EDPVR) has been used as an index of lusitrope, since it measures the relationship between pressure and volume at the end-diastole [5].…”

“…Similar to the results of tau and dP/dt min , EDPVR was elevated at an escalating dose of 2.5 mg/kg compared to baseline, suggesting diastolic dysfunction due to acute effect of β-blockade. The similar result was observed when escalating doses of metoprolol were given intravenously in anesthetized guinea pigs [17]. …”

“…RAP=right atrial pressure, PAP=pulmonary arterial pressure, LVP=left ventricular pressure, AoP=aortic pressure, CO=cardiac output, PVL=pressure-volume loop). Pressure-volume loops were obtained at 30 min after the beginning of infusion as previously described [17]. Briefly, at a given time point after dosing, left ventricular preload was acutely reduced by means of brief (~8–10 beats) caudal vena caval occlusions in order to generate a family of pressure-volume curves; approximately three occlusions were performed at each time point, allowing for hemodynamic recovery between occlusions.…”

Transmural dispersion of repolarization and cardiac remodeling in ventricles of rabbit with right ventricular hypertrophy

“…Recent studies in anesthetized guinea pigs and dogs demonstrated that contractility index is more reliable for assessment of inotropic state of the heart than dP/dt max (Kijtawornrat et al, 2014). The relaxation of the right and left ventricle of rabbit with RVH also decreased significantly as assessed by tau (for only the left ventricle).…”

Cardiovascular safety risk assessment for new candidate drugs from functional and pathological data: Conference report

“…Ultimately however, an in vivo risk assessment is required to build on in vitro data (Hamlin & Del Rio, 2010). While the measurement of left ventricular pressure in small and/or large animal models can be used as an index of effects on drug-induced contractility (Hamlin & del Rio, 2012;Kijtawornrat et al, 2014), for compounds with a significant effect, translatable data such as ejection fraction obtained via echocardiography in repeat-dose toxicology studies represent the final step for an integrated risk assessment (Redfern et al, 2013). These types of data were illustrated with examples from in-house discovery projects.…”