The systolic response to myocardial stretch in the normal and ischemic myocardium: the role of PKG and related pathways

Abstract

Purpose: Myocardial ischemia is frequently associated with acute hemodynamic overload. The effects of ischemia on the Frank-Starling Mechanism (FSM) and the Slow Force Response (SFR) are largely unknown. We aimed to characterize the systolic response to acute stretch and its modulation by PKG and related pathways. Methods: Rabbit papillary muscles (0.2 Hz, 30°C) were acutely stretched from 92% to 100% Lmax (muscle length at which maximal force is developed) in a modified Krebs-Ringer solution under normal conditions (A) in the absence (n=9) and in the presence of (B) Rp-8-Br-PET-cGMPS (an inhibitor of PKG, 10-6M, n=7). The other protocols were performed in ischemic conditions (C) in the absence (n=7) and in the presence of (D) 8-Bromo-cGMP (an agonist of PKG, 10-5M, n=7), (E) S-nitroso-N-acetyl-penicillamine (a NO donor, 10-5M, n=9), (F) BNP (B-type natriuretic peptide, 10-6M, n=9) and (G) sildenafil (a PDE5 inhibitor, 10-6M, n=7). Immediate and delayed contractile responses to muscle stretch were evaluated. Results are presented as mean±standard error of mean (P < 0.05). Results: Under normal conditions, acute myocardial stretch elicited an immediate increase in contractility (FSM) of 35.6±5.3% and a further increase over the next 15 minutes (SFR) of 25.2±4.3%. PKG inhibition was associated with a significant attenuation of FSM (13.7%±6.0, P=0.016) and SFR (11.5%±5.9, P=0.016). Ischemia induced a significant decrease of the FSM (20.0%±4.2, P=0.044). After the FSM, ischemic muscles exhibited a progressive decrease of contractility over the following 15 minutes (-59.1%±4.9). The NO donor and the BNP addition did not significantly modify the response under ischemic conditions. FSM was further inhibited, under ischemia, by the addition of 8-Bromo-cGMP (-2.8%±7.9, P=0.026) and sildenafil (0.1%±7.8, P=0.045). While 8-Bromo-cGMP did not influence the progressive force decline, sildenafil significantly attenuated the contractility decrease after acute stretch (-8.6%±17.6, P=0.007) thereby compensating the FSM abolishment (active tension variation vs pre-stretch: -2.4±20.9 vs -50.5±6.7 in the ischemic control group, P=0.049). Conclusions: Systolic response to acute myocardial stretch is dependent on PKG activity. This response is markedly impaired in the ischemic myocardium. We also demonstrated that, contrarily to the activation of NO and BNP pathways, sildenafil exerts a previously unknown protective effect on the contractile function following stretch in the ischemic myocardium highlighting its potential therapeutic role in this setting.