Abstract 18092: Nitroxyl (HNO) Improves Ventricular Relaxation and Ca2+-Handling in Rats with Induced Chronic Diastolic Dysfunction
| Autor: | Steve R Roof, Craig Hartman, John Reardon, Carlos del Rio, Mark Ziolo, Robert Hamlin |
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| Rok vydání: | 2014 |
| Předmět: | |
| Zdroj: | Circulation. 130 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circ.130.suppl_2.18092 |
| Popis: | Despite the morbidity and clinical burden of primary diastolic cardiac dysfunction, effective therapies for patients presenting with heart failure with preserved ejection fraction (HFpEF) are limited. Nitroxyl (HNO) produces cAMP-independent functional support, in part by improving myocardial calcium-handling. We hypothesize that HNO can rescue lusitropic function when acutely administered to rats with chronic diastolic dysfunction, mimicking HFpEF. Diastolic dysfunction, as demonstrated by decreased E/A ratios via echocardiography, was induced by either 4 weeks of chronic isoproterenol administration (via a mini-osmotic pump; ISO) or by renoprival hypertension (secondary to renal wrapping; RW) for 5 weeks. In vivo left-ventricular hemodynamics/pressure-volume relationships were assessed before/during a 30 minute IV administration of a HNO pro-drug (CXL-1020, 100 μg/kg/min). Ca2+ handling in isolated cardiomyocytes was also studied (CXL-1020, at 50 μM). In both cases, milrinone (mil) was used as a cAMP-dependent positive control (at a matched-efficacy in healthy rats, i.e., 10 μg/kg/min and 0.5 μM) In the setting of chronic diastolic dysfunction, HNO lowered the LV filling pressures in both models by a combined average of 46 ± 8% versus baseline, accelerated the time-constant (tau) of relaxation (-26 ± 3%) and improved compliance (flattened the end-diastolic PV relationship) (-61 ±3%). In myocytes isolated from dysfunctional hearts, HNO accelerated the time for Ca2+ to decline to 50% of its max amplitude (RT50) by -10 ± 2% and myocyte relengthening by -12 ± 3% in ISO rats. Despite eliciting comparable responses in healthy animals/myocytes, the HNO-mediated effects on both tau (in vivo) (-33 ± 3% vs mil -25 ± 2%) and Ca2+ decline (myocyte) (-10 ± 2% vs mil -6 ± 1%) were greater than those of milrinone in the ISO rats, which had greater impairment at baseline compared to RW rats. In conclusion, acute-therapy with HNO improved ventricular relaxation, compliance and Ca2+ handling, in the setting of chronic diastolic dysfunction. Moreover, these effects were greater than observed with the cAMP-dependent agent milrinone. |
| Databáze: | OpenAIRE |
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