Physalin promotes positive cardiac inotropism by a PKARYR2‐ dependent pathway

Abstract

Long‐term positive cardiac inotropic therapy that increases both life quality and expectancy is still lacking. A phytosteroid isolated from Physalis angulata (Solonacea), and denominated F9, was probed in guinea‐pig cardiac tissues in vitro. Concentration‐response curves (0.2 to 200 μM) were performed in both spontaneous beating right atria and eletrically driven left atria. The effects of F9 in the atria were evaluated either in the absence or presence of propranolol (1 μM), verapamil (0.1 μM), staurosporine (0.1μM ) and H89 (10μM). Saponin‐skinned fibers were studied in order to further study its mechanism of action. F9 increased left atria tension to 377.57±24.73 % without any remarkable arrhythmogenic, chronotropic or tonotropic effect. This positive inotropic effect was not affected by pretreating tissues with propranolol, staurosporine or verapamil. Nevertheless, this effect was blunted by 91.8% by H89 (n=5) a PKA inhibitor. F9 (10μM) evoked a contraction of trabecular skinned fiber that attained 53% of the maximal contraction achieved with 0.25 μM Ca2+. This compound did neither affect calcium loading nor shifted the concentration‐response curve to pCa (7.0– 4.8). The increase in tension promoted by F9 in skinned fibers was not blocked by xestopongin C (3μM) or herbymicin A (1μM) but was blunted by either ruthenium red (30μM) or genistein (100μM). F9 does neither affect NKA enzymatic activity nor cAMP levels. The positive cardiac inotropic effect of F9 seems to be dependent of activation of PKA and RYR2 phosphorylation. This hypothesis is being currently tested.