Mechanical Transduction of Nitric Oxide Synthesis in the Beating Heart

Abstract

NO alters contractile and relaxant properties of the heart. However, it is not known whether changes in ventricular loading conditions affect cardiac NO synthesis. To understand this potential contractile-relaxant autoregulatory mechanism, production of cardiac NO in response to mechanical stimuli was measured in vivo using a porphyrinic sensor placed in the left ventricular myocardium. The beating rabbit heart exhibited cyclic changes in [NO], peaking at 2.7+/-0.1 micromol/L near the endocardium and 0.93+/-0.20 micromol/L in the midventricular myocardium (concentrations were 15+/-4% lower in the rat heart). In the present study, we demonstrate for the first time that increasing or decreasing ventricular preload in vivo is followed by parallel changes in [NO], which may represent a novel autoregulatory mechanism to adjust cardiac performance or perfusion on a beat-to-beat basis. To quantify the relationship between applied force and NO synthesis, intermittent compressive or distending forces applied to ex vivo nonbeating hearts were shown to cause bursts of NO synthesis, with peak [NO] linearly related to ventricular transmural pressure. Experiments in which denuding cardiac endothelial and endocardial cells abrogated the NO signal indicate that these cells transduce mechanical stimulation into NO production in the heart. Taken together, these studies may help explain load-dependent relaxation, cardiac memory for mechanical events of preceding beats, diseases associated with myocardial distension, autoregulation of myocardial perfusion, and protection from thrombosis in the turbulent flow environment within the beating heart.

Phospholamban S-nitrosylation modulates Starling response in fish heart

“…In mammals, myocardial stretch increases cardiac nitric oxide (NO) release from both vascular endothelium and cardiomyocytes (Pinsky et al 1997;Petroff et al 2001;Balligand et al 2009) facilitating myocardial relaxation, ventricular diastolic distensibility and hence the Starling response . In the past, the effect of NO on preload-induced increases in CO has been attributed to a paracrine effect of endothelialderived NO on myofilament Ca 2þ sensitivity secondary to troponin I phosphorylation by the cGMP-dependent protein kinase G (PKG) (Prendergast et al 1997).…”

A novel method of measuring nitric-oxide-dependent fluorescence using 4,5-diaminofluorescein (DAF-2) in the isolated Langendorff-perfused rabbit heart

“…Attempts to measure NO levels in the whole heart have been made using electron paramagnetic resonance (Zweier et al, 1995), direct assessment of total NO release in coronary effluent using chemiluminescence (Tsukada et al, 2003) and with a NO sensitive probe (Kupatt et al, 1997) but these techniques cannot be used in conjunction with studies on electrophysiological and mechanical events during the cardiac cycle and only total NO activity is reflected. Direct beatto-beat quantification in the whole heart has been performed using a porphyrinic microsensor (Pinsky et al, 1997) but this method is technically challenging and could cause local damage limiting interpretation of data. A more practical method that allows NO to be measured in the beating heart together with simultaneous electrophysiological and mechanical events is lacking.…”

Mechanical compression elicits NO-dependent increases in coronary flow

“…It has also been shown that systolic IMP exhibits a transmural gradient oriented from endocardium toward the epicardium (16). Accordingly, NO release was found to be higher in the endocardium than in the myocardium (19). These results clearly indicate a close relationship between the synthesis of NO and mechanical stimulation of cardiac contraction in coronary vessels.…”

“…Early studies (14), by comparing the cGMP content of platelets passing through a working or arrested heart, have demonstrated that mechanical stimulation potentiates the release of an endothelium-derived relaxing factor. More recent studies (19), by using a porphyrinic sensor placed in the left ventricular myocardium, have further demonstrated the existence of cyclic and preload-dependent changes in NO release in beating rabbit hearts. Cardiac contraction increases intramyocardial pressure (IMP), which decreases transmural pressure of coronary vessels and hence decreases the diameter of the vessels, causing enhanced shear stress and vascular deformation.…”

“…6), it is likely that each factor activates eNOS in a distinct fashion. Cardiac synthesis of NO is regulated on a beat-to-beat basis in response to ventricular contraction or applied mechanical force (19). There are two phases of increase in NO release during each cardiac cycle: a slow, less potent one in systole and a burst and more potent increase in diastole.…”