Systemic nitric oxide synthase inhibition improves coronary flow reserve to adenosine in patients with significant stenoses

Abstract

Kaufmann PA, Rimoldi OE, Gnecchi-Ruscone T, Luscher TF, Camici PG. Systemic nitric oxide synthase inhibition improves coronary flow reserve to adenosine in patients with significant stenoses. Am J Physiol Heart Circ Physiol 293: H2178-H2182, 2007. First published July 27, 2007; doi:10.1152/ajpheart.01292.2006.-We studied the impact of systemic infusion of the nitric oxide synthase (NOS) inhibitor N G -monomethyl-L-arginine (L-NMMA) on coronary flow reserve (CFR) in patients with coronary artery disease (CAD). We have previously demonstrated that CFR to adenosine was significantly increased after systemic infusion of L-NMMA in normal volunteers but not in recently transplanted denervated hearts. At baseline, myocardial blood flow (MBF; ml ⅐ min Ϫ1 ⅐ g Ϫ1 ) was measured at rest and during intravenous administration of adenosine (140 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) in 10 controls (47 Ϯ 5 yr) and 10 CAD patients (58 Ϯ 8 yr; P Ͻ 0.01 vs. controls) using positron emission tomography and 15 O-labeled water. Both MBF measurements were repeated during intravenous infusion of 10 mg/kg L-NMMA. CFR was calculated as the ratio of MBF during adenosine to MBF at rest. CFR was significantly higher in healthy volunteers than in CAD patients and increased significantly after L-NMMA in controls (4.00 Ϯ 1.10 to 6.15 Ϯ 1.35; P Ͻ 0.0001) and in patients, both in territories subtended by stenotic coronary arteries (Ͼ70% luminal diameter; 2.06 Ϯ 1.13 to 3.21 Ϯ 1.07; P Ͻ 0.01) and in remote segments (3.20 Ϯ 1.23 to 3.92 Ϯ 1.62; P Ͻ 0.05). In conclusion, CFR can be significantly increased in CAD by a systemic infusion of L-NMMA. Similarly to our previous findings in normal volunteers, this suggests that adenosine-induced hyperemia in CAD patients is constrained by a mechanism that can be relieved by systemic NOS inhibition with L-NMMA. coronary circulation; autonomic nervous system; ischemic heart disease; cardiac imaging; positron emission tomography IT IS WELL ESTABLISHED THAT myocardial ischemia is a powerful stimulus for vasodilatation of coronary resistive vessels. The vasodilator response is reported to be near maximal for ischemic times of up to 15-20 s, while no further changes are observed for longer ischemic times (16).Experimental studies in animals have proven that intracoronary or intravenous infusion of adenosine achieves a degree of coronary vasodilatation comparable to that obtained after a period of ischemia of 15-20 s. In normal humans, intravenous infusion of 140 g/kg adenosine produces an increase in myocardial blood flow (MBF) approximately fourfold above the resting value with no further increase at higher adenosine doses (12,29).In a recent study in normal volunteers (15), we demonstrated that hyperemic MBF measured during the combined intravenous infusion of adenosine (140 g/kg) and the nitric oxide synthase (NOS) inhibitor N G -monomethyl-L-arginine (L-NMMA; 10 mg/ kg) was 53% higher than that during infusion of adenosine alone. This effect seems to necessitate an intact cardiac innervation, since no increase in MBF during ...

The Clinical Value of Myocardial Blood Flow Measurement

“…This latter was paradoxically relieved by systemic infusion of the nitric oxide synthase inhibitor L-NMMA, as suggested by the lack of flow increase after L-NMMA observed in transplant recipients whose hearts were denervated for several months after surgery. In a subsequent study using the same methodology, the same authors have shown that the systemic infusion of L-NMMA in patients with CAD significantly increased the MBF response to adenosine in territories subtended by stenotic ($70% luminal diameter) coronary arteries (81). The notion that the flow response to adenosine or dipyridamole does not represent the maximum flow achievable in the coronary system has been previously demonstrated in animals (82,83).…”

L’hémodilution ne modifie pas les effets vasodilatateurs coronariens de l’oxyde nitrique endogène ou exogène

“…Intravenous influsions of NOS inhibitors cause increases in systemic vascular resistance (and concomitant increases in arterial pressure and left ventricular afterload), 3,26 suggesting that tonic release of NO may play a role in modulating basal vascular tone in the peripheral circulation. In the present study, the use of selective intracoronary infusions of L-NAME avoided its systemic effects and, thus, simplified interpretation of the changes in MBF.…”

Platelet Nitric Oxide Signaling System in Patients with Coronary Artery Disease

“…Experiments conducted in hypertensive animals have shown a similar diversity of findings, with NO generation reported to be normal, decreased, or enhanced. [21][22][23][24][25][26][27][28][29] Studies with reduced NO basal production in patients with essential hypertension were reported. 30,31) The data were largely attributed to the reduced bio-activity of NO.…”