Lana J. Dixon

Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure.

Background—Impaired endothelium-mediated vasodilatation (EMVD) in congestive cardiac failure (CCF) has been linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O2·−), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, endothelial nitric oxide synthase (eNOS) produces O2·−. We studied the functional consequences of eNOS uncoupling in relation to EMVD in patients with CCF. Methods and Results—We employed the platelet as a compartmentalized ex-vivo model to examine O2·− and NO production. When eNOS is functioning normally, incorporation of N&ohgr;-Nitro-l-Arginine methyl ester (L-NAME, 1 mmol/L), results in increased O2·− detection, as inhibition of NO production prevents NO scavenging of O2·−. This was observed in controls and 9 of the CCF patients, in whom O2·− detection increased by 63% and 101%, respectively. In the remaining 9 CCF patients, incorporation of L-NAME reduced O2·− production by 39%, indicating O2·− production by eNOS uncoupling. Detection of platelet-derived NO was significantly greater in eNOS-coupled platelets compared with the uncoupled group (2.8±1.4 versus 0.9±0.4 pmol/108 platelets, P =0.04). Endothelium-dependent and -independent vasodilator responses to acetylcholine and sodium nitroprusside recorded using venous occlusion plethysmography were significantly impaired in patients exhibiting eNOS uncoupling. Conclusions—This study provides first evidence that platelet eNOS can become uncoupled in human CCF. Impaired endothelium-dependent and -independent vasodilator responses and diminished platelet-derived NO production occurred in association with enzyme uncoupling.

Platelet nitric oxide and superoxide release during the development of nitrate tolerance: effect of supplemental ascorbate

Background—The therapeutic benefits that accompany the continuous administration of organic nitrates are attenuated by the development of tolerance to the compounds. Altered superoxide production and NO bioavailability have been implicated in contributing to the development of tolerance, an effect that may be ameliorated by the administration of antioxidants. Methods and Results—We studied the effect of 3 days of continuous transdermal administration of nitroglycerin (NTG) (10 mg/24 hours) on platelet free radical (NO and superoxide anion [O2·−] activity) with and without coadministration of supplemental ascorbate (2.4 g/24 hours). NAD(P)H oxidase activity, nitric oxide synthase (NOS) activity, and cyclic guanosine monophosphate (cGMP) content were also assessed. Radial artery pressure pulse waveforms were used to track the hemodynamic actions of NTG. Three days of NTG/placebo was associated with a significant increase in platelet NO and O2·− production from 1.0±1.17 to 2.52±0.88 pmol/108 platelets and 13.2±4.8 to 72.5±34.4 pmol/108 platelets, respectively (P <0.01 for both). These changes were accompanied by increased platelet NADH oxidase activity from 47.9±11.0 to 65.3±13.6 pmol O2·− min/mg protein and cGMP content from 0.60±0.10 to 0.89±0.16 pmol/109 platelets (P <0.05 for both). Administration of NTG/ascorbate attenuated both NO and O2·− release in platelets. Conclusions—Three days of continuous transdermal administration of NTG was accompanied by increased platelet NO and O2·− production and NADH oxidase activity that was suppressed by coadministration of oral ascorbate. Although a significant degree of tolerance would be expected during continuous nitrate administration, a residual hemodynamic action could be identified by arterial pulse contour analysis.

Early vascular abnormalities and de novo nitrate tolerance in diabetes mellitus.

Objective: The haemodynamic consequence of altered mechanical wall properties in diabetes can impair the compliance characteristics or pulsatile function of arteries before changes in calibre or peripheral resistance become evident. We studied the sensitivity of pulsatile and steady‐state haemodynamic variables in identifying vascular abnormalities and assessing arterial responsiveness to glyceryl trinitrate (GTN) in patients with diabetes, free from clinical complications of the disease.

Takotsubo Cardiomyopathy in Two Preoperative Patients with Pain

Reversible stress-induced cardiomyopathy, i.e., Takotsubo cardiomyopathy, rarely presents in preoperative patients. We provide the case reports of two patients who presented with Takotsubo cardiomyopathy, which we surmise was due to excess endogenous catecholamine production in response to acute pain. Electrocardiogram revealed T-wave inversion, with peak Troponin-T elevation in each case, i.e., 0.66 microg/L and 0.14 microg/L (normal range <0.03 microg/L). Despite these findings consistent with acute myocardial infarction, neither patient had obstructive coronary disease at angiography. Left ventriculography showed apical ballooning, a typical feature of the Takotsubo syndrome. Ventricular dysfunction had resolved completely at repeat echocardiography 2 wk later, after adequate analgesia and surgery.

Production of 8-epi prostaglandin F2α in human platelets during administration of organic nitrates

OBJECTIVES The objective of this study was, using isolated platelets as a surrogate for vascular cells, to examine the effect of nonintermittent organic nitrate administration on 8-epi prostaglandin F(2alpha) (8-epi PGF(2alpha)) content and the effect of concurrent oral ascorbate administration. BACKGROUND The long-term efficacy of organic nitrates is hampered by hemodynamic tolerance, which develops during continuous administration. This has been associated with altered production of superoxide and nitric oxide, as well as oxidative stress. This effect may be ameliorated by the co-administration of antioxidants. METHODS Ten healthy male subjects received nitroglycerin (NTG) transdermally at a dosage of 0.4 mg/h for 3 days with ascorbate or lactose (1.2 g/day). After two weeks washout, the treatment was repeated with reversed ascorbate/lactose. Platelets were prepared by centrifugation and esterified 8-epi PGF(2alpha) measured at the start and finish of each treatment by immunoassay. RESULTS Nitroglycerin, in the absence of supplemental ascorbate, was associated with a significant increase in platelet-esterified 8-epi PGF(2alpha), from 32.9 (95% confidence interval [CI] 11.8 to 54.0) to 51.0 (95% CI 16.3 to 85.7) pg/mg protein (p < 0.05). Co-administration of ascorbate with NTG resulted in a significant decrease in 8-epi PGF(2alpha) production, from 38.8 (95% CI 24.9 to 52.7) to 19.0 (95% CI 13.5 to 24.5) pg/mg protein (p < 0.05). CONCLUSIONS Continuous NTG administration results in an increase in platelet-esterified 8-epi PGF(2alpha), a free radical and cyclooxygenase-dependent compound. This is reversed by co-administration of the free radical scavenger ascorbate. Whether this increase is merely a marker for increased oxidative stress or a mediator of oxidative injury contributing to the hemodynamic changes observed in nonintermittent organic nitrate treatment has yet to be resolved.

Arterial Stiffness and Pulse Wave Velocity: Problems with Terminology

To the Editor: It was with interest that we read the recent article by Safar et al.1 We fully agree with the authors’ emphasis on the importance of studying the mechanical properties of arteries and the potential for risk factor stratification provided by the derived information. A number of points require clarification. The authors state, “arterial stiffness [is] usually expressed in the quantitative terms of compliance and distensibility.”1 (p 2864) Compliance (a change in volume or cross-sectional area for a given change in pressure) and distensibility (a fractional change in volume or cross-sectional area for a given change in pressure)2 are parameters that can be quantified and have units of measurement. Arterial stiffness, on the other hand, is a purely …