Nitric oxide effects depend on different mechanisms in different regions of the rat heart

Abstract

The important role of nitric oxide (NO) in regulating cardiac functions has been investigated in prior research. However, NO-induced signaling mechanisms in the different regions of the heart have not been explored until now. In this study, the mechanism of NO effects on the spontaneously beating right atrium and left papillary muscle isolated from the rat heart was examined. The NO donor diethylamine NONOate (DEA/NO) (0.1-100 μM) depressed the resting and developed tensions, as well as the sinus rate, of the right atrium. The effect of DEA/NO on contractions of the right atrium was blocked by the soluble guanylate cyclase (sGC) inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one) (10 μM). The ATP-sensitive potassium channel (K(ATP)) blocker glyburide (3 μM) reversed DEA/NO-induced decreases in the resting tension. The suppressor effect of DEA/NO on the sinus rate was inhibited only by the superoxide radical scavenger superoxide dismutase (25 U/ml). Neither the cGMP-dependent protein kinase (PKG) inhibitor KT5823 (0.1 μM) nor the cAMP-dependent protein kinase (PKA) inhibitor KT5720 (1 μM) changed DEA/NO responses in the right atrium. While the resting tension of the right atrium was decreased by the NO precursor L-arginine (1-100 μM), it was increased by the nitric oxide synthase inhibitor L-NMMA (0.1-100 μM). The sinus rate was not affected by L-arginine or L-NMMA. The left papillary muscle contraction was not influenced by any of these NO-related agents. These results show that high concentration NO-induced depression of the contraction of the right atrium is due to sGC and K(ATP) channel activation, but suppression of the sinus rate depends on redox regulation. Our results may have important implications for the region-dependent functional disability of cardiac myocytes, as well as the regulation of heart performance in high NO-induced pathological conditions.

The concomitant coronary vasodilator and positive inotropic actions of the nitroxyl donor Angeli's salt in the intact rat heart: contribution of soluble guanylyl cyclase‐dependent and ‐independent mechanisms

“…Although the effects of both NO and sGC on cardiac contractile function have been previously examined in a broad range of scenarios, no consensus has yet been reached, with negative inotropic (Balligand et al ., ; Brady et al ., ; Grocott‐Mason et al ., ; Weyrich et al ., ; Mohan et al ., ; Kojda et al ., ; Sandirasegarane and Diamond, ; Muller‐Strahl et al ., ; Gonzalez et al ., ; Cawley et al ., ; Derici et al ., ), positive inotropic (Klabunde and Ritger, ; Smith et al ., ; Kojda et al ., 1995; 1996; 1997; Sarkar et al ., ; Layland et al ., ; Langer et al ., ) or no change observed (Ritchie et al ., 2006; 2009). Indeed, the relationship between NO/sGC and myocardial force may be differentially modulated by concentration, whereby smaller increases in NO/sGC levels elicit positive inotropic effects either secondary to phosphodiesterase‐3 inhibition (elevating cAMP), while high concentrations elicit a cGMP‐mediated negative inotropic effect, perhaps secondary to formation of S‐nitrosothiols on key cardiomyocyte Ca 2+ ‐handling proteins such as RyR, SERCA and phospholamban (Smith et al ., ; Kojda et al ., 1996; 1997; Zahradnikova et al ., ; Paolocci et al ., ; Layland et al ., ; Langer et al ., ; Gonzalez et al ., 2007; 2008; Rastaldo et al ., ; Wang et al ., ; Ziolo, ).…”

High K+-Induced Relaxation by Nitric Oxide in Human Gastric Fundus

“…Thus, we suggest that NO/cGMP-mediated the high K + -induced relaxation of longitudinal muscle in the human proximal stomach. Direct NO/cGMP-dependent and PKG-independent pathways for regulation of K channels are also present [17]. Interestingly, high K + -induced contraction of some circular muscle was followed by small transient relaxation, which was blocked by L-NNA (Fig.…”

“…3D and 3E). In fact, K + channels such as the K V channel [17,30] and K Ca channel [31] are directly regulated by the NO/sGC pathway in smooth muscle [13]. In addition, nNOS neurons are found in the myenteric region of the human stomach [32].…”

Effect of Nitric Oxide on Cardiac Functions: Review

“…Fakat farklı ajanlarla cGMP seviyesi değiştirildiğinde ortaya çıkan yanıtlar her zaman gevşeme yönünde olmamaktadır. 28 62 Öyle gözük-mektedir ki NO, kalbin farklı bölgelerinde farklı mekanizmalar aracılığıyla farklı etkiler göster-mekte ve NO'nun kalp üzerindeki etkilerini genellemek yanıltıcı olabilmektedir. Ayrıca, farklı tür ve dokularda hücrelerin PDE izoform profili farklı olmaktadır.…”

“…Bu nedenle NO'nun kalp hızı üzerine olan etkisinin redoks düzenleme ile süperoksit aracılıyla olduğu düşünülmüştür. 62 İzole sıçan sağ atriyumunda DEA/NO ile ortaya çıkan negatif kronotropi, PDE1 ve PDE4 inhibitörleri ile engellenebilir iken; PDE2, PDE3 ve PDE5 inhibisyonundan etkilenmemiştir. PDE'ye dirençli cGMP analoğu 8-Br-cGMP'nin, sinüs hızı üzerine herhangi bir etkisi gözlenmemiştir.…”