Coronary vasomotor responses to isometric handgrip exercise are primarily mediated by nitric oxide: a noninvasive MRI test of coronary endothelial function

Abstract

Hays AG, Iantorno M, Soleimanifard S, Steinberg A, Schär M, Gerstenblith G, Stuber M, Weiss RG. Coronary vasomotor responses to isometric handgrip exercise are primarily mediated by nitric oxide: a noninvasive MRI test of coronary endothelial function. Am J Physiol Heart Circ Physiol 308: H1343-H1350, 2015. First published March 27, 2015 doi:10.1152/ajpheart.00023.2015.-Endothelial cell release of nitric oxide (NO) is a defining characteristic of nondiseased arteries, and abnormal endothelial NO release is both a marker of early atherosclerosis and a predictor of its progression and future events. Healthy coronaries respond to endothelial-dependent stressors with vasodilatation and increased coronary blood flow (CBF), but those with endothelial dysfunction respond with paradoxical vasoconstriction and reduced CBF. Recently, coronary MRI and isometric handgrip exercise (IHE) were reported to noninvasively quantify coronary endothelial function (CEF). However, it is not known whether the coronary response to IHE is actually mediated by NO and/or whether it is reproducible over weeks. To determine the contribution of NO, we studied the coronary response to IHE before and during infusion of N G -monomethyl-L-arginine (L-NMMA, 0.3 mg·kg Ϫ1 ·min Ϫ1 ), a NO-synthase inhibitor, in healthy volunteers. For reproducibility, we performed two MRI-IHE studies ϳ8 wk apart in healthy subjects and patients with coronary artery disease (CAD). Changes from rest to IHE in coronary cross-sectional area (%CSA) and diastolic CBF (%CBF) were quantified. L-NMMA completely blocked normal coronary vasodilation during IHE [%CSA, 12.9 Ϯ 2.5 (mean Ϯ SE, placebo) vs. Ϫ0.3 Ϯ 1.6% (L-NMMA); P Ͻ 0.001] and significantly blunted the increase in flow [%CBF, 47.7 Ϯ 6.4 (placebo) vs. 10.6 Ϯ 4.6% (L-NMMA); P Ͻ 0.001]. MRI-IHE measures obtained weeks apart strongly correlated for CSA (P Ͻ 0.0001) and CBF (P Ͻ 0.01). In conclusion, the normal human coronary vasoactive response to IHE is primarily mediated by NO. This noninvasive, reproducible MRI-IHE exam of NO-mediated CEF promises to be useful for studying CAD pathogenesis in low-risk populations and for evaluating translational strategies designed to alter CAD in patients. endothelial function; coronary artery disease; magnetic resonance imaging ENDOTHELIAL CELL RELEASE of nitric oxide (NO) is a defining characteristic of nondiseased vascular tissue; it inhibits platelet aggregation, attenuates inflammation, decreases cellular proliferation, and induces local vascular smooth muscle vasodilation (4). Most classic and novel cardiovascular risk factors converge to impair endothelial function, including dyslipidemia, insulin resistance, inflammation, tobacco abuse, and oxidative stress, as well as hemodynamic and genetic factors (4, 33). Critically, endothelial dysfunction is a marker for subclinical disease, an independent predictor of adverse cardiovascular events, and a potential target for medical interventions (21,24,28).Traditionally, coronary endothelial function (CEF) is assessed by the directi...

Local coronary wall eccentricity and endothelial function are closely related in patients with atherosclerotic coronary artery disease

“…The values for CEF are similar to those obtained in our prior CMR studies, demonstrating a coronary vasodilatory response to IHE in the healthy subjects, and no vasodilatory response or a vasoconstrictor response in many CAD patients [16, 17, 22]. We previously showed that the administration of nitroglycerin, an endothelial independent stressor, caused normal vasodilatation in coronary segments with mild to severe CAD that exhibited abnormal responses to IHE.…”

“…Recent studies demonstrate that CMR measures of CEF performed during isometric handgrip exercise (IHE) quantify nitric-oxide mediated coronary endothelial vasoreactivity [16] with excellent short- and longer-term reproducibility [17, 18]. …”

Simultaneous Noninvasive Assessment of Systemic and Coronary Endothelial Function

“…We recently reported that the coronary response to IHE is measurable with MRI 11,15,16 and mediated by NO in healthy individuals 17 . Because it was not previously known whether the IMA response to IHE is NO-mediated 27 , we report here that the NOS inhibitor L-NMMA abolishes the normal IMA vasodilatory and blood flow IHE responses in healthy subjects (Fig 2).…”

“…Furthermore, we recently demonstrated in vivo that the coronary artery response to IHE is reproducible and primarily NO-mediated because it is blocked by the nitric oxide synthase (NOS) inhibitor monomethyl-L-arginine (L-NMMA) in healthy subjects 17 .…”

Regulation of exercise blood flow: Role of free radicals

“…The lack of information on this topic stems from the difficulty in attaining such measures during exercise, especially in healthy humans. However, a recent investigation by Hays et al [112] reported that coronary vasodilation during ischemic handgrip exercise in healthy humans is primarily NO-mediated (Figure 6). Although not directly examined in this study, factors that attenuate NO-bioavailability and alter redox balance, including free radicals, would be expected to impair coronary vasodilation, mimicking the attenuated vasodilation exhibited by patients with coronary artery disease during ischemic handgrip exercise.…”