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Promising approach for the preclinical assessment of cardiac risks using left ventricular pressure-volume loop analyses in anesthetized monkeys.

Abstract：

INTRODUCTION:Load-independent cardiac parameters obtained from the ventricular pressure-volume relationship are recognized as gold standard indexes for evaluating cardiac inotropy. In this study, for better analyses of cardiac risks, load-independent pressure-volume loop parameters were assessed in addition to load-dependent inotropic, hemodynamic and electrocardiographic changes in isoflurane-anesthetized monkeys. METHODS:The animals were given milrinone (a PDE 3 inhibitor), metoprolol (a β-blocker), or dl-sotalol (a β+IKr blocker) intravenously over 10min at two dose levels including clinically relevant doses (n=5/drug). RESULTS:Milrinone and metoprolol produced positive and negative inotropy, respectively. These effects were detected as changes in the slope of the preload-recruitable stroke work, which is a load-independent inotropic parameter. However, dl-sotalol did not alter the slope of the preload-recruitable stroke work. That means dl-sotalol produced no inotropy, although it decreased load-dependent inotropic parameters, including maximal upstroke velocity of left ventricular pressure, attributable to decreased heart rate and blood pressure. Other typical pharmacological effects of the compounds tested were also detected. Both β-blockers produced PR prolongation, decreased left ventricular end-systolic pressure, increased left ventricular end-diastolic pressure, and increased maximal descending velocity of left ventricular pressure and time constant for isovolumic relaxation. dl-Sotalol also prolonged heart-rate-corrected QT interval. Milrinone induced reflex tachycardia, PR shortening, and decreased left ventricular end-diastolic pressure. DISCUSSION:The overall assessment by not only load-dependent inotropic parameters but also load-independent parameters obtained from the ventricular pressure-volume loop analysis using monkeys can provide further appropriate information for the assessment of drug-induced cardiac risks.

journal_name

J Pharmacol Toxicol Methods

journal_title

Journal of pharmacological and toxicological methods

authors

Ishizaka T,Yoshimatsu Y,Maeda Y,Takasaki W,Chiba K,Mori K

doi

10.1016/j.vascn.2016.10.004

subject

Has Abstract

pub_date

2017-01-01 00:00:00

pages

1-10

eissn

1056-8719

issn

1873-488X

pii

S1056-8719(16)30128-9

journal_volume

pub_type

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Promising approach for the preclinical assessment of cardiac risks using left ventricular pressure-volume loop analyses in anesthetized monkeys.