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Royal College of Physicians. Obesity report. J R Coll Physicians Lond 1983; 17: 5-65. 2. World Health Organisation. Diet, nutrition and the prevention of chronic diseases. WHO Tech Rep Ser 1990; 797: 29-31. 3. Sobal J, Stunkard AJ. Socioeconomic status and obesity: a review of the literature. Psychol Bull 1989; 105: 260-75. 4. Rona RJ, Morris RW. National Study of Health and Growth: social and family factors and overweight in English and Scottish parents. Ann Human Biol 1982; 9: 147-56. 5. Chinn S, Rona RJ, Gulliford MC, Hammond J. Weight for height in children aged 4 to 12 years: a new index compared with the normalised body mass index. Eur J Clin Nutr 1992; 46: 489-500. 6. Rolland-Cachera MF, Cole TJ, Sempe M, Tichet J, Rossignol C, Charraud A. Body mass index variations: centiles from birth to 87 years. Eur J Clin Nutr 1991; 45: 13-21. 7. Rona RJ, Chinn S. National Study of Health and Growth: social and biological factors associated with weight for height and triceps skinfold of children from ethnic groups in England. Ann Human Biol 1987; 14: 1.
231-48. 8. Brook CGD, Huntley RMC, Slack J. Influence of heredity and environment in determination of skinfold thickness in children. BMJ 1975: ii: 719-21.
9. Bodurtha JN, Mosteller M, Hewitt JK, et al. Genetic analysis of anthropometric measures in 11 year old twins: The Medical College of Virginia Twin Study. Pediatr Res 1990; 28: 1-4. 10. Bouchard C, Tremblay A, Despres JP, et al. The response to long term overfeeding in identical twins. N Engl J Med 1990; 322: 1477-82. 11. Bouchard C, Perusse L. Heredity and body fat. Annu Rev Nutr 1988; 8: 259-77. 12. Sorensen TIA, Holst C, Stunkard AJ. Childhood body mass index: genetic and familial environmental influence assessed in a longitudinal adoption study. Int J Obesity 1992; 16: 705-14. 13. Poskitt EME, Cole TJ. Nature, nurture, and childhood overweight. BMJ 1978; i: 603-05. 14. Stunkard AJ, Sorensen TIA, Hanis C, et al. An adoption study of human obesity. N Engl J Med 1986; 314: 193-98. 15. Sorensen TIA, Price RA, Stunkard AJ, Schulsinger. Genetics of obesity in adult adoptees and their biological siblings. BMJ 1989; 298: 87-90. 16. Teasdale TW, Sorensen TIA, Stunkard AJ. Genetic and early environmental components of sociodemographic influences on adult body fatness. BMJ 1990; 300: 1615-18. 17. Braddon FEM, Rodgers B, Wadsworth MEJ, Davies JMC. Onset of obesity in a 36 year birth cohort study. BMJ 1986; 293: 299-303. 18. Anon. Influences of intrauterine nutritional status on the development of obesity in later life. Nutr Rev 1977; 35: 100-02. 19. Ravelli GP, Stein ZA, Susser MV. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 1976; 295: 349-53. 20. Law CM, Barker DJP, Osmond C, Fall CHD, Simmonds SJ. Early growth and abdominal fatness in adult life. J Epidemiol Community Health 1992; 46: 184-86.
Nitric oxide and erection Nitric oxide synthase exists as a constitutive enzyme present under normal physiological conditions in many cell types (cNOS), and as an inducible form which may be expressed following immunological stimulation (iNOS).l It may be either particulate or soluble, and there are multiple isofonns.2,3 Endothelial cNOS has an important role in the regulation of tone vasomotor by synthesising the potent endogenous nitrovasodilator endothelium-derived relaxing factor (EDRF). EDRF is widely believed to be the NO radical at the moment of its formation from L-arginine, and can be detected extracellularly as such near the endothelial cell membrane by use of electrochemical microsensors.4 Non-adrenergic, noncholinergic nerves synthesise and release NO and can thereby modulate the constrictor tone of cerebral and mesenteric arteries.5-7 In a third NO-mediated vasomotor control mechanism, neurotransmitters such as acetylcholine and substance P diffuse from
the endothelium in to adventitial nerves concentrations sufficient to stimulate EDRF/NO release. Thus, vagally induced coronary and pulmonary vasodilatation is blocked not only by atropine, but also by N G-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS.8,9 An analogous mechanism explains why skeletal muscle vasodilatation following nerve stimulation is blocked by the substance P antagonist spantide and by L-NAAiE.10 There is now convincing evidence that penile erection, which is generally thought to be a vascular event dependent on relaxation of the trabecular muscle of the corpora cavemosa, is mediated by NO. During erection, active filling of the sinusoids compresses the peripheral venules of the corpora against the rigid tunica albuginea, causing outflow obstruction. The process is therefore not mediated simply by passive engorgement with blood." Conversely, flaccidity is enhanced by contraction of corporal tissue after activation of adrenergic receptors by noradrenaline released from sympathetic nerve terminals. 12 Thus, intracavemosal injection of a vasodilator such as papaverine, or the ol-blocker phenoxybenzamine, can induce sustained erection for 24 hours or more." Functional studies with isolated human and animal corpus cavemosum tissue have shown that relaxation induced by electrical stimulation of autonomic nerves is abolished by blockade of NOS, and that this inhibition is reversed by excess L-arginine. 14-18 Immunohistochemical staining of both rat and canine tissue has shown that NOS is widely distributed throughout the urogenital tract, high concentrations being found in major pelvic ganglia, the membranous urethra, and the bladder neck, as well as in the penis itself. 18 In many species the smooth muscle of the corpora cavemosa and retractor penis muscle can be regarded as a single functional entity, although in some cases (notably primates) the retractor penis is absent whereas in others the cavernous bodies are virtually devoid of smooth muscle.ll Thus, neurally mediated relaxation of the retractor penis and related anococcygeus muscle is also mediated via the NO/Larginine pathway.19 As in arterial smooth muscle, NO leads to a reduction of cytosolic free Ca2’ in the retractor penis muscle as a result of activation of the soluble form of guanylyl cyclase.’9 In the penis itself, antibody to NOS stains efferent axons from the cavernous nerves that arise from the pelvic plexus and innervate both the trabecular mesh of the corpus cavemosum smooth muscle and their main arterial supply, the deep cavemosal arteries.18 Bilateral cavernous nerve transection thus abolishes staining of NOS-containing penile neurons, but not that of vascular endothelium, which could also participate in the control of erection by N0.18 Staining of NOS can also be shown in the endothelium and adventitial innervation of the dorsal penile artery and the intracorporal network of helicine arteries, which
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elongate during erection, but is less evident in the cavernous sinusoids.18 The high functional NOS activity found in the membranous urethra and its involvement in relaxation of the bladder neck further suggests that NO may be important in the regulation of micturition and urinary continence. 18,20 Although acetylcholine evokes endotheliumdependent relaxation of isolated corpus cavemosal tissue, erection is unlikely to involve release of
acetylcholine from parasympathetic nerves and its subsequent diffusion to the endothelium, since both atropine and neostigmine are without effect when injected intracavernosally.13,18 Furthermore, nonadrenergic, non-cholinergic inhibitory responses mediated through the NO/L-arginine pathway do not require functional endothelium.1s In some vascular beds vasoactive intestinal polypeptide (VIP) may be responsible for atropine-resistant vasodilatation following parasympathetic stimulation, and in addition to a direct smooth muscle action can induce relaxation by stimulating endothelial NO synthesis in some artery types.21 VIP could thus contribute indirectly to NO-mediated erection since concentrations are high in pudendal arteries and the corpora cavemosa and it induces partial erection when injected intracavernosally.22 In certain parts of the parasympathetic system, VIP and NO may function as cotransmitters: VIP and NOS co-localise in the adventitial innervation of cerebral arteries and arise from parasympathetic cell bodies in the sphenopalatine ganglion; in the myenteric plexus NOS-containing neurons also contain VIP.18 Involvement of the NO/L-arginine pathway in penile erection explains pharmacologically the aphrodisiac effect of amyl nitrite,23 which provides a rapidly available source of exogenous NO, unlike commonly used organic nitrates that generate NO only after enzymatic conversion. In impotent diabetic men, there is impairment of both neurogenic and endothelium-mediated relaxation in penile corporal smooth muscle whereas responses to exogenous donors of NO are preserved.14 The enhanced ol-mediated constrictor tone and penile flaccidity found in diabetes may be a direct consequence of impaired NO synthesisY From a clinical perspective, this provides a rationale for the treatment of certain types of impotence by intracavemosal administration of vasodilators, and conversely, it is possible that inhibition of NOS will be beneficial in the treatment of priapism. Another suggestion is that surgical section of NOS innervation should be avoided during correction of conditions such as hypospadias and Peyronie’s disease to diminish the risk of subsequent impotence. 18 1. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 1991; 43: 109-42. 2. Forstermann U, Pollock JK, Schmidt HHHW, Heller M, Murad F.
Calmodulin-dependent endothelium-derived relaxing factor/nitric oxide synthase activity is present in the particulate and cytosolic fractions of bovine aortic endothelial cells. Proc Natl Acad Sci USA 1991; 88: 1788-92.
3. Forstermann U, Schmidt HHHW, Pollock JS, et al. Isoforms of nitric oxide synthase. Biochem Pharmacol 1991; 42: 1849-57. 4. Malinski T, Taha Z. Nitric oxide release from a single cell measured in situ by a porphyrin-based microsensor. Nature 1992; 358: 676-78. 5. Toda N, Minami Y, Okamura T. Inhibitory effects of L-N4-nitroarginine on the synthesis of EDRF and the cerebroarterial response to vasodilator nerve stimulation. Life Sci 1990; 47: 345-51. 6. Lee TJ-F, Sarwinski SJ. Nitric oxidergic neurogenic vasodilation in the porcine basilar artery. Blood Vessels 1991; 28: 407-12. 7. Ahlner J, Ljusegren ME, Grundstrom N, Axelsson KL. Role of nitric oxide and cyclic GMP as mediators of endothelium-independent neurogenic relaxation in bovine mesenteric artery. Circ Res 1991; 68: 756-62. 8. Broten TP, Miyashiro JK, Moncada S, Feigl EO. Role of endotheliumderived relaxing factor in parasympathetic coronary vasodilation. Am J Physiol 1992; 262: H1579-84. 9. McMahon TJ, Wood JS, Kadowitz PJ. Pulmonary vasodilator response to vagal stimulation is blocked by Nw-nitro-L-arginine methyl ester in the cat. Circ Res 1992; 70: 364-69. 10. Persson MG, Hedqvist P, Gustafsson LE. Nerve-induced tachykininmediated vasodilation in skeletal muscle is dependent on nitric oxide formation. Eur J Pharmacol 1991; 205: 295-301. 11. Klinge E, Sjostrand NO. Comparative study of some isolated mammalian smooth muscle effectors of penile erection. Acta Physiol Scand 1974; 100: 354-67. 12. Christ GJ, Schwartz CB, Stone BA, et al. Kinetic characteristics of &agr;1-adrenergic contractions in human corpus cavernosum smooth muscle. Am J Physiol 1992; 263: H15-19. 13. Brindley GS. Pilot experiments on the action of drugs injected into the human corpus cavernosum penis. Br J Pharmacol 1986; 87: 495-500. 14. De Tejeda IS, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989; 320: 1025-30. 15. Kim N, Azadzoi KM, Goldstein I, De Tejeda IS. A nitric oxide-like factor mediates non-adrenergic non-cholingergic neurogenic relaxation of penile corpus cavemosum smooth muscle. J Clin Invest 1991; 88: 112-18. 16. Homlquist F, Hedlund H, Andersson KE. L-GG-nitro arginine inhibits non-adrenergic, non-cholinergic relaxation of human isolated corpus cavernosum. Acta Physiol Scand 1991; 141: 441-42. 17. Raifer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ. Nitric oxide as a mediator of relaxation of the corpus cavemosum in response to nonadrenergic, non-cholinergic neurotransmission. N Engl J Med
1992; 326: 90-94. CJ, Bredt DS, Chang TCK, Snyder SH. Nitric physiologic mediator of penile erection. Science 1992; 257:
18. Burnett AL, Lowenstein
oxide: a 401-03. 19.
Ramagopal MV, Leighton HJ. Effects of NG-monomethyl-L-arginine on field stimulation-induced decreases in cytosolic Ca2+ levels and relaxation in the rat anococcygeus muscle. Eur J Pharmacol 1989; 174: 297-99.
Thornbury KD, Hollywood MA, McHale NG. Mediation by nitric oxide of neurogenic relaxation of the urinary bladder neck muscle in sheep. J Physiol 1992; 451: 133-44. 21. Ignarro LJ, Byrns RE, Buga GM, Wood KS. Mechanisms of endothelium-dependent vascular smooth muscle relaxation elicited by bradykinin and VIP. Am J Physiol 1987; 253: H1074-82. 22. Polak JM, Gu J, Mina S, Bloom SR. Vipergic nerves in the penis. Lancet 20.
1981; ii: 217-19. 23. Haverkos HW, Dougherty J. Health hazards of nitrite inhalants. Am J Med 1987; 84: 479-82. 24. Feelish M. The biochemical pathways of nitric oxide formation from nitrovasodilators: appropriate choice of exogenous NO donors and aspects of preparation and handling of aqueous NO solutions. J Cardiovasc Pharmacol 1991; 17 (suppl 3): S25-33.
Preventing
cataract
Cataract is a cause of visual disablement that affects millions world wide and causes incalculable hardship. Good vision and independence are readily restored by extracapsular cataract surgery with intraocular lens implant, but this curative option is unavailable to most people outside the developed world. Effective nonsurgical treatment is likely to remain an elusive goal for the forseeable future, although some approaches under investigation may have an application in certain