Effects of a topical nitric oxide generator on skin microcirculation in sickle cell disease

Tucker AT, Ekwebelem TC, Heath M, Johnston A, Telfer P. The Ernest D. Cooke Clinical Microvascular Unit, St. Bartholomew’s Hospital, West Smithfield, London. EC1A7BE. Clinical Pharmacology, Barts and The London, Queen Mary’s School of Medicine and Dentistry, Charterhouse Square, London. EC1M6BQ. Department of Haematology, The Royal London Hospital, Whitechapel, London. E11BB.

A novel system of generation and delivery of nitric oxide (NO) and related higher oxides of nitrogen (NOx) is being developed. The system generates exogenous NO/NOX via the chemical reactions of acidified nitrite [1]. The bioavailability of NO is normally modulated by haemoglobin, which limits the ability of free NO to activate soluble guanylyl cyclase. Oxygenated haemoglobin scavenges NO from the circulation by converting NO to nitrate, while deoxygenated haemoglobin binds to NO to form haem-nitrosyl-haemoglobin. Reiter et al [2], demonstrated that in Sickle-Cell (SS) patients, plasma cell-free haemoglobin released from lysed erythrocytes inactivates NO, so abolishing local NO-mediated vascular control. The aim of this study was to determine the safety/tolerability and the effects of the NO/NO X system on the skin microcirculation in the lower limbs of ten patients with SS.

The NO/NO X generation system was applied to the skin of the medial aspect of the calf for 60 minutes and measurements taken prior to and during application of the generation and delivery system. The system composed of 2.5g each of sodium nitrite and ascorbic acid suspended in aqueous gel and contained within the membrane patch covering approximately 200cm2. Pulse oximetery was measured at the great toe of the treated leg. Heart rate and blood pressure were continuously measured during the session. Microcirculatory responses were assessed non-invasively by simultaneous measurements using Laser Doppler fluxmetry (LDF) and a transcutaneous gas probe (PO2/PCO2) in the region of the patch application.

The transmembrane NO/NO X system was effective in enhancing microcirculatory blood flow and tissue oxygen. LDF showed significant increases (mean baseline 37.2 [SEM 3.87] Flux Units to mean maximum response 83.5 Flux Units [11.6]; p=0.01). Enhancement of microcirculatory velocity was associated with elevation of tissue oxygen levels. The increases in Tc-PO2 measurements were significant (p=0.01) and clinically relevant (mean baseline 70mmHg [6.7] to mean maximum response 91mmHg [5.6]). In contrast, Tc-PCO2, pulse oxymetry and blood pressure measurements remained unchanged (p>0.2). The application was well tolerated in all subjects.

These findings, linked with the well-defined anti-microbial activity of nitric oxide, indicate that this system may be advantageous for surgical prophylaxis and wound care management. As such, a cheap, effective and safe wound management system would be particularly suited to the global Sickle cell population

Tucker A, Cooke ED, Pearson RM, Benjamin N (1999).
Effect of a nitric oxide generating system on microcirculatory blood flow in the skin of patients with Raynaud’s Syndrome. Lancet 354(9191):1670-5. Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO, Schechter AN, Gladwin MT. Cell-free haemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nature Medicine. 2002 Vol 8 (12) 1383-9.