Published Online
on September 7, 2004

A more recent version of this article appeared on September 14, 2004

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Submitted on August 5, 2003
Revised on April 15, 2004
Accepted on April 19, 2004

Systemic Inhibition of Nitric Oxide Synthase Unmasks Neural Constraint of Maximal Myocardial Blood Flow in Humans

Philipp A. Kaufmann MD, Ornella Rimoldi MD, Tomaso Gnecchi-Ruscone MD, Robert S. Bonser MD, FRCS, FRCP, Thomas F. Lüscher MD, FESC, FRCP, and Paolo G. Camici MD, FESC, FRCP^*

From the MRC Clinical Sciences Centre (P.A.K., O.R., T.G.-R., P.G.C.), Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, and Department of Cardiopulmonary Transplantation (R.S.B.), Queen Elizabeth Medical Centre, Birmingham, United Kingdom; and the Cardiovascular Center (P.A.K., T.F.L.), Division of Cardiology and Nuclear Cardiology Section, University Hospital, Zurich, Switzerland.

^* To whom correspondence should be addressed. E-mail: paolo.camici{at}csc.mrc.ac.uk.

Background--Nitric oxide (NO) is an endothelial mediator that regulates vascular smooth muscle tone, but it may exert its cardiovascular action also by modulating the autonomic control of vasomotor tone. We assessed the effect of simultaneous inhibition of both endothelial (eNOS) and neuronal (nNOS) NO synthase isoforms on myocardial blood flow (MBF) and coronary flow reserve (CFR) in volunteers and in (denervated) transplant recipients.

Methods and Results--MBF (mL · min^-1 · g^-1) was measured at rest and during adenosine-induced hyperemia with positron emission tomography and ¹⁵O-labeled water. CFR was calculated as adenosine/resting MBF. Measurements were repeated during one of the following intravenous infusions: group 1 (n=12), saline; group 2 (n=9), 3 mg/kg N^G-monomethyl-L-arginine (L-NMMA), which crosses the blood-brain barrier and inhibits both eNOS and nNOS; group 3 (n=13), 10 mg/kg L-NMMA; group 4 (n=8), phenylephrine titrated to simulate the hemodynamic changes in group 3; and group 5 (n=6), 10 mg/kg L-NMMA infused into the heart transplant recipients. After intervention, hyperemic MBF and CFR were unchanged in groups 1, 2, and 4. By contrast, both hyperemic MBF (+53%, P<0.0001 versus baseline) and CFR (+52%, P<0.0001 versus baseline) increased in group 3, whereas they remained unchanged in group 5, which suggests that an intact cardiac innervation was required for the increase in MBF and CFR observed in group 3.

Conclusions--The results of the present study suggest that maximal adenosine-induced hyperemia and CFR in humans are constrained by neurally mediated vasoconstriction, which can be relieved by systemic NOS inhibition with L-NMMA.

Key words: nitric oxide • nitric oxide synthase • blood flow • imaging

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