The Role Of Soluble Guanylate Cyclase In Sepsis-Induced Cardiomyopathy In Mice

Background. Soluble guanylate cyclase (sGC) plays multiple, conflicting roles during sepsis (Am.J.Physiol.,2009;297:H654-663). Here we studied the impact of sGC deficiency on cardiac calcium (Ca2+) handling in sepsis-induced cardiomyopathy (SIC). Methods and Results. Cardiomyocyes were isolated from mice deficient in the α1 subunit of sGC (sGCα1-/-) and wild-type (WT), at baseline and 12h after administration of lipopolysacharide (LPS, 25 μg/g, ip). In sGCα1-/- cells (vs. WT), LPS induced a more marked decrease in externally paced Ca2+ transients (ΔCai, fura-2AM, Table), sarcoplasmic reticulum Ca2+ load (CaSR, using caffeine applications), fractional release (FR, ΔCai / CaSR) and trans-sarcolemmal Ca2+ entry (CaE, from the first ΔCai after caffeine removal). Ca2+ transient decay (τCa) was slower in sGCα1-/- vs. WT after LPS, while Ca2+ decay during caffeine (τCaff, measuring Na+/Ca2+ exchange) and L-type Ca2+ currents (ICa,L) were similar (Table; for all, n> 25 cells from >4 mice). Conclusions. LPS induces a decrease in ICa ,L, CaE, FR, CaSR and ΔCai that does not require sGCα1. Moreover, sGC partially protects against Ca2+ handling alteration in SIC, through yet unidentified mechanisms.