Brain, Vol. 125, No. 2, 437-439,
January 1, 2002
© 2002 Oxford University Press
Book Review |
NITRIC OXIDE AND FREE RADICALS IN PERIPHERAL NEUROTRANMISSION
Institute of Neurology, Queen Square, London, UK
NITRIC OXIDE AND FREE RADICALS IN PERIPHERAL NEUROTRANSMISSION.
By Stanley Kalsner.2000. Basel: Birkhauser Verlag AG.
Price $89.95. Pp. 357. ISBN 3-81764-0070-3..
This book represents the 2nd volume in a series entitled Nitric Oxide in Biology and Medicine. My initial reaction when considering this book was: not another book on nitric oxide (NO)! However, this feeling soon disappeared when I started to read the book.
A major benefit of this book is that each of the 15 chapters are almost stand-alone reviews written by the appropriate experts in the field. Furthermore, there is little overlap and each chapter is self-contained, i.e. a (comprehensive) reference list is included at the end of the chapter. In addition, in the majority of the chapters, actual experimental data is shown in order to support the various concepts and hypotheses being discussed.
The first chapter of the volume considers the origin and evolution of nitric oxide signalling. A wealth of intriguing information is covered, e.g. NO formation in invertebrates and plant tissues. Leonid Moriz has also been very thorough in searching the literature, and references from 1965 and 1973 have been uncovered that consider NO formation by mitochondria, a subject that is very much in vogue today!
Whilst some of the titles of the various chapters my not initially appeal to all, e.g. Chapter 2: ‘the nitrergic transmitter of the anococcygeus’, I found that in many cases a dip into such a chapter was worth it. Often, as in the case of Chapter 2, information can be found that may be relevant to all fields of NO biology and medicine. Of particular interest (to me at least) was the discussion relating to the nature of NO release from non-adrenergic non-cholinergic (NANC) nerves. In view of the unstable/reactive nature of NO, it has been proposed that ‘guardian’ molecules are concomitantly released in order to optimize nitrergic transmission. One candidate molecule is ascorbate, the release of which appears to be increased under depolarizing conditions.
The interaction of NO with other NANC inhibitory neurotransmitters and the proposed roles of NO in penile erection, bladder function, the enteric nervous system and lung tissue are considered in Chapters 3–6. Other putative neurotransmitters originating from the endothelium that mediate smooth muscle hyperpolarization include ATP and possibly K+. However, the mechanism whereby the latter simple ion is released from endothelial cells remains to be elucidated. With regards to penile erection, NO has certainly made an impact, not least for the pharmaceutical industry, in the form of Viagra (sidenafil). The mode of action of this drug is considered in Chapter 4 along with the (patho)physiological roles of NO for penile erection and bladder function. Turning to the gastrointestinal tract, there is now strong evidence to suggest that NO is an inhibitory neurotransmitter. In Chapter 5, Kenton Sanders and Kathleen Keef consider the data to support this and draw analogies with classic neurotransmitters, i.e. methods of release, substrate recycling and inactivation. The airways develop embryologically from the foregut. Thus, the demonstration of NANC neurotransmitters in the respiratory chain was not unexpected. In Chapter 6, the role of NO in the bronchodilator response is considered. Furthermore, experimental data, derived from a range of model systems (guinea pig, cat, rabbit, horse, ferret and human) are reviewed. It is certainly clear after reading this chapter that species differences occur in the neural control of airway relaxation. As NANC bronchodilator nerves represent a major pathway in the human airway, it is not surprising that this system is the subject of attention with regard to the pathogenesis of disorders such as asthma. However, for humans at least, the NANC response appears to be normal in asthmatic patients. In contrast, this response may be impaired in cystic fibrosis due to accelerated degradation of NO.
The resistance blood vessels have a diameter of <400 µm and play a key role in regulating the microcirculation to organs. Chapters 7 and 8 of this book cover the regulation and mode of action of NO in controlling relaxation of this vessel type. These chapters consider the source of NO, i.e. endothelial cells and perivascular nitrergic nerves and the interaction of NO with other neurotransmitter types such as acetylcholine. With regard to the latter, NO and acetylcholine may be produced by the same nerve terminal (choinergic nitric oxidergic nerve). Acetylcholine it appears may modulate NO release via pre-synaptic muscarinic receptors.
NO has been described as being a pluripotent molecule, having both physiological and pathophysiological effects. The majority, but not all of the remaining chapters consider the role of NO in the pathogenesis of various disease states.
Migraine attacks are known to involve alterations in the regulation of tone in intra- and/or extra-cranial blood vessels. Consequently, NO has been proposed to play a role in migraine. The 9th chapter of the book considers the evidence for this suggestion. The data presented certainly suggest that individuals prone to migraine attacks display an increased sensitivity to NO. Furthermore, pharmacological blockade of NO generation, following administration of non-specific NO synthase inhibitors, appears to convey some relief with regards to headache severity, phonophobia and photophobia. However, the use of such an agent was, as predicted, associated with alterations in mean blood pressure and heart rate. Despite this, the authors suggest that the development of drugs targeted to specific isoforms of NO synthase could lead to the development of an effective treatment for migrane. The obvious question here is which isoform? One intriguing possibility is the inducible form of the enzyme which is induced following cytokine exposure. Recent evidence suggests that, following cortical spreading depression, substantial amounts of NO may be generated via this enzyme.
The following chapter (10) covers the possible pre-synaptic modulation of nitrergic transmission and deviates from the theme of the preceding and subsequent chapters, which tend to focus on the potential role of NO in disease states. Despite this, the chapter is worthwhile, and putative pre-synaptic mechanisms whereby NO formation may be regulated are considered, e.g. negative feedback of NO synthase activity by NO itself and alterations in intracellular Ca2+ availability.
With regard to polymorphonuclear neutrophils (PMNs), it has, not unreasonably, been assumed that NO formation is derived solely from the activity of the inducible isoform of NO synthase. However, this assumption has been challenged and in Chapter 11 the evidence for the existence of a functional constitutive NO synthase (neuronal NOS) in PMNs is considered. It is postulated that the recruitment of PMNs into the lung, during infection and inflammation, is regulated by a constitutive NO synthase. Studies with appropriate knockout mice convincingly support this suggestion, i.e. data are presented in this chapter to suggest that, in the absence of NOS, increased recruitment of PMNs occurs following lipopolysaccharide exposure.
Peroxynitrite (ONOO–) formed by the favourable reaction between NO and superoxide is considered by many to be the actual species responsible for the cytotoxicity associated with inappropriate/excessive NO formation. Chapters 12–14 consider the putative pathogenic mechanisms whereby ONOO– may contribute to disorders such as motor neurone disease and diabetes. Certainly, the evidence that is presented is persuasive, and elaborate mechanisms with supporting informative figures are provided. Whether formation of reactive nitrogen species in such conditions is the critical key event or simply a surrogate marker of disease progression remains to be elucidated.
The final chapter considers the potential clinical use of modulators of NO metabolism. Already NO, delivered by inhalation, is yielding promising results in the treatment of acute respiratory distress syndrome and pulmonary hypertension. Arginine supplementation is also discussed. This amino acid is the substrate for all isoforms of NO synthase and was not considered to be rate limiting for NO formation. However, in heart failure, oral arginine is reported to increase peripheral blood flow. As expected, this chapter also considers the use of NOS inhibitors in conditions such as septic shock and the need for specific NO synthase inhibitors is reiterated.
In conclusion, in view of the monumental amount of literature relating to NO, this book will be invaluable to those researchers with an interest in the peripheral nervous system and who have not recently performed a literature search on NO.
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