Key result
Infusion of the selective ETB agonist IRL 1620 (0.4-4.0 nmol/kg) in an open-chest rat model caused a biphasic blood pressure response and a significant positive inotropic effect.
Why the study?
Does the ETB agonist IRL 1620 alter hemodynamics and inotropy in an open-chest rat model?
Does the ETB agonist IRL 1620 alter hemodynamics and inotropy in an open-chest rat model?
Selective activation of ETB receptors by IRL 1620 demonstrates a positive inotropic effect in vivo, independent of its biphasic vascular effects.
Warrants caution against clinical use; extends ETB receptor research in cardiac inotropy but remains hypothesis-generating.
The endothelinB (ETB) receptor is involved in endothelin-induced vasoconstriction and appears to play a role in ET-induced positive inotropy. Our previous study could not detect a positive inotropic effect of ET-1 in vivo. To evaluate specifically the effects of the ETB receptor on hemodynamics and inotropy of ET-1 in the intact circulation, we examined in the open-chest rat model the dose-dependent hemodynamic and inotropic effects of the highly specific ETB agonist IRL 1620 (0.4, 1.0, 2.0, and 4.0 nmol/kg vs. NaCl controls) during and after a 7-min infusion. In addition to measurements in the intact circulation, isovolumic recordings (peak LVSP, peak dP/dtmax) were performed for quantification of myocardial contractility independently of peripheral vascular changes. IRL 1620 caused a significant biphasic blood pressure response with an initial fall and a sustained increase, reflecting the vasoactive effects of IRL 1620, with a transient vasorelaxation followed by dose-dependent and long-lasting vasoconstriction. Although IRL 1620 has a positive chronotropic effect the reduction in stroke volume (probably due to the elevated afterload) causes a decrease in cardiac output. Nevertheless, the isovolumic measurements indicate a significant positive inotropic effect of IRL 1620. Therefore, the selective activation of ETB receptors causes a positive inotropic effect, which is also detectable in vivo, as the vasoconstrictor and coronary constrictor effects are less pronounced compared to activation of both ETA and ETB receptors by ET-1.
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Beyer et al. (1995) studied this question. IRL 1620 vs. NaCl controls was evaluated on Hemodynamic and inotropic effects (blood pressure, stroke volume, cardiac output, peak LVSP, peak dP/dtmax). Infusion of the selective ETB agonist IRL 1620 (0.4-4.0 nmol/kg) in an open-chest rat model caused a biphasic blood pressure response and a significant positive inotropic effect.
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