Rickets, Vitamin D, and Ca/P Metabolism.

Rickets was a major public health problem dating from Roman times, and medical descriptions of rickets date from the 17th century. Sniadecki first advocated treatment by exposure to sunshine in 1822; contemporaneously, several British physicians advocated use of cod liver oil. Both approaches were successful. Work in 1924 showed that exposure to UV light endowed fats and other foods with antirachitic properties. Vitamins D2 and D3, the antirachitic agent in cod liver oil, were, respectively, produced by UV radiation of ergosterol and 7-dehydrocholesterol. Calcitriol (1,25[OH]2D3) was identified as the biologically active form of vitamin D in the early 1970s. The vitamin D 25-hydroxylase, 24-hydroxylase, and 1α-hydroxylase were cloned in the 1990s and their genetic defects were soon delineated. The vitamin D receptor was also cloned and its mutations identified in vitamin D-resistant rickets. Work with parathyroid hormone (PTH) began much later, as the parathyroids were not identified until the late 19th century. In 1925, James B. Collip (of insulin fame) identified PTH by its ability to correct tetany in parathyroidectomized dogs, but only in the 1970s was it clear that only a small fragment of PTH conveyed its activity. Congenital hypoparathyroidism with immune defects was described in 1968, eventually linked to microdeletions in chromosome 22q11.2. X-linked hypophosphatemic rickets was reported in 1957, and genetic linkage analysis identified the causative PHEX gene in 1997. Autosomal dominant hypophosphatemic rickets similarly led to the discovery of FGF23, a phosphate-wasting humoral factor made in bone, in 2000, revolutionizing our understanding of phosphorus metabolism.

Prevention of covid-19 and other acute respiratory infections with cod liver oil supplementation, a low dose vitamin D supplement: quadruple blinded, randomised placebo controlled trial.

OBJECTIVE: To determine if daily supplementation with cod liver oil, a low dose vitamin D supplement, in winter, prevents SARS-CoV-2 infection, serious covid-19, or other acute respiratory infections in adults in Norway. DESIGN: Quadruple blinded, randomised placebo controlled trial. SETTING: Norway, 10 November 2020 to 2 June 2021. PARTICIPANTS: 34 601 adults (aged 18-75 years), not taking daily vitamin D supplements. INTERVENTION: 5 mL/day of cod liver oil (10 µg of vitamin D, n=17 278) or placebo (n=17 323) for up to six months. MAIN OUTCOME MEASURES: Four co-primary endpoints were predefined: the first was a positive SARS-CoV-2 test result determined by reverse transcriptase-quantitative polymerase chain reaction and the second was serious covid-19, defined as self-reported dyspnoea, admission to hospital, or death. Other acute respiratory infections were indicated by the third and fourth co-primary endpoints: a negative SARS-CoV-2 test result and self-reported symptoms. Side effects related to the supplementation were self-reported. The fallback method was used to handle multiple comparisons. RESULTS: Supplementation with cod liver oil was not associated with a reduced risk of any of the co-primary endpoints. Participants took the supplement (cod liver oil or placebo) for a median of 164 days, and 227 (1.31%) participants in the cod liver oil group and 228 (1.32%) participants in the placebo group had a positive SARS-CoV-2 test result (relative risk 1.00, multiple comparison adjusted confidence interval 0.82 to 1.22). Serious covid-19 was identified in 121 (0.70%) participants in the cod liver oil group and in 101 (0.58%) participants in the placebo group (1.20, 0.87 to 1.65). 8546 (49.46%) and 8565 (49.44%) participants in the cod liver oil and placebo groups, respectively, had ≥1 negative SARS-CoV-2 test results (1.00, 0.97 to 1.04). 3964 (22.94%) and 3834 (22.13%) participants in the cod liver oil and placebo groups, respectively, reported ≥1 acute respiratory infections (1.04, 0.97 to 1.11). Only low grade side effects were reported in the cod liver oil and placebo groups. CONCLUSION: Supplementation with cod liver oil in the winter did not reduce the incidence of SARS-CoV-2 infection, serious covid-19, or other acute respiratory infections compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov NCT04609423.

Vitamin D: part II; cod liver oil, ultraviolet radiation, and eradication of rickets.

PURPOSE: After Glisson's description of rickets, it took two centuries to realize that rickets was due to the absence of antirachitic nutrients in the diet or lack exposure of the skin to ultraviolet rays. This bone disease caused by vitamin D deficiency was one of the most common diseases of children 100 years ago. This paper explores how the definition, diagnosis, and treatment of rickets shifted in the first decades of the twentieth century. MATERIAL AND METHODS: Although benefits of cod liver oil as food were known as early as the seventh century, cod liver oil was only proposed as medicinal for rickets in Northern Europe at the end of the eighteenth century. The relationship between rickets and nutritional deficiency was suspected and demonstrated between 1880 and 1915, at the same time of the discovery of other vital substances (vitamins) needed to prevent beriberi, scurvy, and pellagra. Understanding that the lack of photosynthesized vitamin D or the lack of dietary vitamin D was a similar risk of rickets was an important turn in the comprehension of the disease. We look at the sequence and turn of events related to the discovery of vitamin D. RESULTS: Rickets has been recognized first as a disease of urban living people. Cod liver oil had been used since 1700 as a nonspecific treatment for a range of diseases. Generations of children in cities of the north of Europe had learned to hate the taste and smell of the black oily liquid and then grown up to be parents who, in turn, hated to force it down their children's throats. Occasional papers before 1900 pointed to its efficacy for rickets, and most textbooks of the early 1900s mentioned it only as a treatment option. The discovery in the early 1900s that artificial and natural ultraviolet rays had both antirachitic activity allowed to produce antirachitic foods just by food irradiation with artificial ultraviolet irradiation. Clinical guidelines were adopted to propose exposure to sunlight or to artificial ultraviolet radiation to prevent rickets in children. By the mid-1920s, rickets was promoted as universal, at times invisible to non-experts, but present to some degree in nearly every young child regardless of race or class. It was thus used to promote the young disciplines of preventive medicine, pediatrics, and public health. Innovative advances were made in the understanding of vitamin D synthesis from 1915 to 1935. A public health campaign of the 1930s was a success to eradicate rickets, using irradiated ergosterol from yeast to enrich milk and other foods with vitamin D, ensuring that the general population was consuming sufficient vitamin D. CONCLUSION: Rickets therefore provides an excellent window into the early politics of preventive health and the promotion of targeted interventions in the world. It is also a relevant historical counterpoint for current debates over the role of risk factors (absence of light or sun) for disease (today's so-called "lifestyle" diseases).

Vitamin D, cod liver oil, sunshine, and phototherapy: Safe, effective and forgotten tools for treating and curing tuberculosis infections - A comprehensive review.

Tuberculosis remains an epidemic throughout the world, with over 2 billion people, or more than one third of the world's population, infected with TB. In 2015, there were an estimated 10.4 million new cases of tuberculosis, and 1.8 million deaths, making TB one of the top ten causes of death worldwide. Approximately 95% of new TB cases occur in developing countries, where the costs of treatment force many patients and their families into poverty. The United Nations and the World Health Organization are working to end this global epidemic. Historically, cod liver oil in the 1840's, phototherapy in the 1890's, sunshine in the 1890's and 1930's, oral vitamin D in doses of 100,000-150,000 international units a day the 1940's, and injectable vitamin D in the 1940's were all shown to be able to safely treat tuberculosis. However, for reasons that are unclear, these treatments are no longer being used to treat tuberculosis. We will review several reports that documented the clinical efficacy of these seemingly disparate treatments in treating tuberculosis. Taken together, however, these reports show the consistent efficacy of vitamin D in treating tuberculosis infections, regardless of whether the vitamin D was produced in the skin from the effects of phototherapy or sunshine, taken orally as a pill or in cod-liver oil, or put into solution and injected directly into the body. We will discuss how vitamin D, through its action as a steroid hormone that regulates gene transcription in cells and tissues throughout the body, enables the body to eradicate TB by stimulating the formation of a natural antibiotic in white blood cells, the mechanism of which was discovered in 2006. We will speculate as to why vitamin D, cod liver oil, sunshine, and phototherapy are no longer being used to treat tuberculosis, in spite of their proven efficacy in safely treating this disease dating back to the early 1800's. In fact, in 1903 the Nobel Prize in Medicine or Physiology was awarded to a physician who was able to cure hundreds of cases of long-standing lupus vulgaris (cutaneous TB) with refracted light rays from an electric arc lamp. Vitamin D, cod liver oil, sunshine, and phototherapy have never been shown to lose their ability to safely eradicate tuberculosis infections, and deserve consideration to be re-examined as first-line treatments for tuberculosis. These treatments have the potential to help cost-effectively and safely end the global TB epidemic.

Timing of use of cod liver oil, a vitamin D source, and multiple sclerosis risk: The EnvIMS study.

BACKGROUND: Low vitamin D levels have been associated with an increased risk of multiple sclerosis (MS), although it remains unknown whether this relationship varies by age. OBJECTIVE: The objective of this paper is to investigate the association between vitamin D3 supplementation through cod liver oil at different postnatal ages and MS risk. METHODS: In the Norwegian component of the multinational case-control study Environmental Factors In Multiple Sclerosis (EnvIMS), a total of 953 MS patients with maximum disease duration of 10 years and 1717 controls reported their cod liver oil use from childhood to adulthood. RESULTS: Self-reported supplement use at ages 13-18 was associated with a reduced risk of MS (OR 0.67, 95% CI 0.52-0.86), whereas supplementation during childhood was not found to alter MS risk (OR 1.01, 95% CI 0.81-1.26), each compared to non-use during the respective period. An inverse association was found between MS risk and the dose of cod liver oil during adolescence, suggesting a dose-response relationship (p trend = 0.001) with the strongest effect for an estimated vitamin D3 intake of 600-800 IU/d (OR 0.46, 95% CI 0.31-0.70). CONCLUSIONS: These findings not only support the hypothesis relating to low vitamin D as a risk factor for MS, but further point to adolescence as an important susceptibility period for adult-onset MS.

Effect of cod liver oil supplementation on the stearoyl-CoA desaturase index in obese children: a pilot study.

To investigate the effects of n-3 polyunsaturated fatty acids on stearoyl-CoA desaturase (SCD) activity, we treated 10 obese children (mean age: 12.9 years) with cod liver oil once daily for 12 weeks. The effects of cod liver oil supplementation on SCD activity, as estimated by the palmitoleate/palmitate ratio, depended on the docosahexaenoic acid (DHA) contents at baseline. Baseline DHA contents were negatively correlated with baseline SCD activity. After the treatment, baseline DHA contents were found to be significantly associated with the reduction of SCD activity. Cod liver oil supplementation may be a complementary treatment for obese children with low baseline contents of DHA.

[Radiated drugs, the way of health]. / Médicaments irradiés, sources de santé.

During the inter-war years, the word "radiated" did not only suggest radioactivity, but it was also used to indicate exposure to others radiations, such as ultraviolets. The actinotherapy, a new therapy in vogue, was applied to many pathologies and tried on many substances. "Radiated drugs" result of those experimentations. Their therapeutical characteristics were found during searches on rickets. Our study relates the story of fight against rickets in France, from the use of cod liver oil to the synthesis of Vitamine D.

[Interventional effect of vitamin A supplementation on re-vaccination to hepatitis B virus among rural infants and young children in China].

OBJECTIVE: The objective of this study was to observe the interventional effect of cod liver oil supplementation on re-vaccination to hepatitis B virus (HBV) among infants and young children. METHODS: All 7-36 months old infants and young children, who had been vaccinated with obligatory HBV vaccines routinely by the national technical and administrative procedures for HBV vaccination on children of China, were convened among villages in Linyi, Shandong province, from October 2008 to March 2009. After detection of serum anti-HBV, one hundred children with lower serum anti-HBV were picked out for the randomized, double blinded, placebo controlled vitamin A supplementation study. The children in the intervention group (50 subjects) took 0.5 g condensed cod liver oil (containing 25 000 IU vitamin A and 2500 IU vitamin D(2)) every 15 days for six times. The children in the control group (50 subjects) were given corn oil with same volume. All children were re-vaccinated at the 30th and the 60th day of the experiment. The serum samples were collected from each child at the 90th day of the experiment. Retinol concentration in serum samples was analyzed with HPLC method before and after the intervention. The levels of serum anti-HBs were detected by the electro-chemi-luminescence immunoassay (ECLIA). RESULTS: Total 74 children finished the supplemental experiment and blood collection, 37 subjects in each group, respectively. After intervention, the serum retinol level in the experimental and control group were (404.1 ± 123.1) and (240.8 ± 92.8) µg/L (t = 6.441, P < 0.01), respectively. The serum anti-HBs levels in the experimental and control group were (2737.2 ± 2492.6) and (1199.7 ± 2141.6) U/L (t = 2.846, P < 0.01), respectively. The rate of weak or no-answer case in experimental and control groups was 0.00% (0/37) and 10.81% (4/37) (χ(2) = 4.229, P = 0.040), respectively. CONCLUSION: The results showed that vitamin A supplementation might enhance the re-vaccination reaction against HB vaccine in infants and young children.

The anticancer effects of Vitamin D and omega-3 PUFAs in combination via cod-liver oil: one plus one may equal more than two.

In the past number of years, the anticancer activities of omega-3 polyunsaturated fatty acids (ω3-PUFAs) as well as Vitamin D have been intensively studied, but separately. Supplementation of Vitamin D and omega-3 PUFA via cod-liver oil, one of few natural sources of both of these molecules, may have additive and possibly synergistic anticancer effects. Cod-liver oil has been used effectively to treat diseases such as Rheumatism but has not been studied as an anticancer agent. This review examines the prominent, striking and possibly important similarities between the anticancer effects of ω3-PUFAs and Vitamin D metabolites as well as the possible overlapping signaling pathways by which they may operate. The mechanisms that will be examined in this review fall broadly under the categories of being anti-inflammatory, pro-apoptotic, anti-angiogenic and anti-proliferative. Finally, we compare the potential for use of ω3-PUFAs, Vitamin D combinatorial supplementation both in prevention and treatment of disease. Some data also suggests that the timing of supplementation modifies the effects of Vitamin D and ω3 fatty acids.

Long-term administration of cod liver oil ameliorates cognitive impairment induced by chronic stress in rats.

Cod liver oil (CLO) is a rich source of omega-3 fatty acids (FA), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The existing data suggest that EPA and DHA are the active agents of fish oil. In this study, we tested a hypothesis that the active constituents of CLO alleviate the negative impact of prolonged restraint stress on cognitive functions of male Wistar rats. Specifically, we attempted to characterize the preventive action of long-lasting treatment with CLO [0.375 ml/100 g body weight (equivalent to a dose of 300 mg/kg DHA and 225 mg/kg EPA), p.o. for 21 days] against an impairment caused by chronic restraint stress (2 h daily for 21 days) on recall as tested in a passive avoidance situation and on the spatial reference and working memory tested in a Barnes maze as well as on locomotor activity and anxiety behavior tested respectively in an open field and elevated plus-maze. We found that CLO administration statistically significantly (p < 0.01, both) prevented the deleterious effects of chronic restraint stress on recall and the spatial memory.

[Cod liver oil. A natural Vitamin D for preserving health]. / Csukamájolaj. Egy természetes D-vitamin az egészség megorzésére.

Vitamin D deficiency is pandemic in industrialized countries due to life-style changes. Recent studies suggest that besides bone-metabolism, vitamin D plays a central role in basic cell function like multiplication, differentiation and metabolism. This may explain that low vitamin D levels represent a risk factor for several apparently different diseases such as infective, autoimmune, neurodegenerative and cardiovascular diseases, as well as diabetes, osteoporosis and cancer. Accumulating evidences suggest that an adequate intake of vitamin D may significantly decrease prevalence and clinical outcome of these diseases. Estimated reduction of the economic burden might reach about 10 percent through normalizing vitamin D levels for these diseases. However, high doses of vitamin D monotherapy needs precaution for potential adverse effects and it should be substituted with the recommended doses of vitamin D in combination with synergistic vitamin A and omega 3 fatty acids, such as cod liver oil.

Vitamin D: extraskeletal health.

Vitamin D deficiency is the most common nutritional deficiency and likely the most common medical condition in the world. The major cause of vitamin D deficiency has been the lack of appreciation that the body requires 5- to 10-fold higher intakes than is currently recommended by health agencies. There is now overwhelming and compelling scientific and epidemiologic data suggesting that the human body requires a blood level of 25(OH)D above 30 ng/mL for maximum health. To increase the blood level to the minimum 30 ng/mL requires the ingestion of at least 1000 IU of vitamin D per day for adults. In general, there is no downside to increasing either a child's or adult's vitamin D intake.

Do early intake of fish and fish oil protect against eczema and doctor-diagnosed asthma at 2 years of age? A cohort study.

BACKGROUND: There are ambiguous results regarding the role n-3 polyunsaturated fatty acids and fish might play in primary prevention of allergic diseases. The aim was to investigate the association between cod liver oil and fish consumption during pregnancy and in the first year of life and asthma and eczema at 2 years of age. METHODS: From the Prevention of Allergy among Children in Trondheim study, a prospective birth cohort study in primary healthcare in Trondheim, Norway, 3086 children were followed prospectively from 1 year to approximately 2 years of age. The primary outcome variable was parental reported asthma and eczema at 2 years. RESULTS: The mean age for introducing fish in the diet was 9.1 months. Excluding children with incident eczema before 1 year, a reduced risk of developing eczema was found if the child was eating fish once a week or more, adjusted OR (aOR) for any kind of fish 0.62 (95% CI 0.42 to 0.91 p=0.02), for oily fish aOR 0.21 (95% CI 0.05 to 0.86 p=0.03) and for lean fish aOR 0.67 (95% CI 0.41 to 1.08 p=0.10). The associations between maternal diet and eczema at 2 years and between the dietary factors and doctor-diagnosed asthma were all insignificant. CONCLUSIONS: Fish consumption in infancy was more important than maternal fish intake during pregnancy in preventing eczema in childhood. The intake of fish per se, not specifically n-3 polyunsaturated fatty acids, was most important in preventing eczema.

The role of complementary and alternative therapies in pediatric diabetes.

Complementary and alternative medicine (CAM), also referred to as holistic, or integrative, medicine, are terms that describe a heterogeneous collection of nontraditional therapies, from chemical substances, to biofeedback, to prayer. This review focuses on CAM in pediatric patients with type 1 and type 2 diabetes. CAM prevalence in this population and the specific modalities that have been studied in children are described. Randomized, placebo-controlled, prospective studies in young adults are evaluated for their applicability to pediatric patients. CAM's "complementary" role is emphasized, as there is evidence of significant morbidity when CAM replaces standard-of-care therapy.

Rickets in lion cubs at the London Zoo in 1889: some new insights.

In 1889, when Dr John Bland-Sutton, a prominent surgeon in London, England, was consulted concerning fatal rickets in more than 20 successive litters of lion cubs at the London Zoo, he evaluated the role of diet relative to the development of rickets. He prescribed goat meat and bones and cod-liver oil to be added to the lean horse-meat diet of the cubs and their mothers. Rickets reversed, the cubs survived, and litters were reared successfully. In classic controlled studies conducted in puppies and young rats 3 decades later, the crucial role of calcium, phosphate, and vitamin D in both prevention and therapy of rickets was elucidated. Later studies led to the identification of the structural features of vitamin D. Although the Bland-Sutton interventional diet obviously provides calcium and phosphate from bones and vitamin D from cod-liver oil, other benefits of this diet were not initially recognized. Chewing bones promotes tooth and gum health and removes bacteria-laden tartar. Cod-liver oil also contains vitamin A, which is essential for the prevention of infection and for epithelial cell health. Taurine-conjugated bile salts are also necessary for the intestinal absorption of fat-soluble vitamins, including A and D. Moreover, unlike dogs and rats, all feline species are unable to synthesize taurine yet can only conjugate bile acids with taurine. This sulfur-containing beta-amino acid must be provided in the carnivorous diet of a large cat. Taurine-conjugated bile salts were provided in the oil cold-pressed from cod liver. The now famous Bland-Sutton "experiment of nature," namely, fatal rickets in lion cubs, was cured by the addition of minerals and vitamin D. However, gum health and the presence of taurine-conjugated bile salts undoubtedly permitted absorption of vitamin A and D, the latter promoting the cure of rickets.

[Omega-3: from cod-liver oil to nutrigenomics]. / Omega-3: dall'olio di fegato di merluzzo alla nutrigenomica.

The leading role of cod-liver oil on rickets was a relevant factor in the knowledge of this disease. In 1922 the preventive and therapeutic value of cod-liver oil and sunlight against rickets in young infants was confirmed. The seasonal variation in the incidence of rickets, the role of skin pigmentation, of diet and the fact that breast milk was not an adequate source of vitamin D were understood. The discovery of essential fatty acids omega-6 and omega-3 have shown that deficiencies, mainly of omega-3 long chain polyunsaturated fatty acids, result in visual and cognitive impairment and disturbances in mental functions in infants and also in cognitive function in adults, as fatty acids are beneficial to vascular health and may forestall cerebrovascular disease and thus dementia. An adequate ratio of n-6 and n-3 fatty acids may promote a healthier balance of eicosanoids, which would protect membrane function with a nutraceutical function. Dietary lipids not only influence the biophysical state of the cell membranes but, via direct and indirect routes, they also act on multiple pathways including signalling, gene and protein activities, protein modifications and they probably play important role in modulating protein aggregation. Significant advances have been made in understanding the relation between dietary factors and inflammation, which is a central component of many chronic diseases, including coronary artery disease, rheumatoid arthritis, cancer prevention. However, the identification of those who will or will not benefit from dietary intervention strategies remains a major obstacle. Adequate knowledge about how the responses depend on an individual's genetic background (nutrigenetic effects), the cumulative effects of food components on genetic expression profiles through nutrigenomics mechanism, may assist in identifying responders and non-responders. Thus, fish and fish oil consumption might encourage brain development and gene expression to brain maintenance during aging through nutrigenomic mechanism.

Peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism, cod liver oil and risk of type 1 diabetes.

OBJECTIVE: We have previously described an association between use of cod liver oil (a dietary n-3 fatty acid supplement) and reduced risk of type 1 diabetes. n-3 fatty acids are ligands for the peroxisome proliferator-activated receptor-gamma (PPARG), which has recently been implicated in the control of inflammation and possibly autoimmunity. We aimed to estimate the association between the common Pro12Ala polymorphism of PPARG2 and risk of type 1 diabetes, and to test whether there is gene-environment interaction with use of cod liver oil in the first year of life or gene-gene interaction with the established insulin gene (INS) and human leukocyte antigen DQ (HLA-DQ) genetic susceptibility loci. METHODS: We designed a population-based case-control study of childhood-onset type 1 diabetes in Norway with information on use of cod liver oil in the first year of life from questionnaires and PPARG2 genotype data for 483 cases and 1520 control subjects. We used logistic regression for analysis. RESULTS: The odds ratio for the PPARG2 Ala/Ala or Pro/Ala vs. Pro/Pro genotype and type 1 diabetes was 0.89 (95% CI: 0.69-1.13, p = 0.33). There was no significant interaction with cod liver oil in the first year of life [P (interaction) = 0.35] or with the INS polymorphism [P(interaction) = 0.42]. CONCLUSIONS: Although the association between PPARG2 and type 1 diabetes was not significant, the observed odds ratio was almost identical to that observed in two previous studies and can contribute to meta-analysis indicating a weak but significant association. Our hypothesized interaction between cod liver oil and PPARG2 in reducing type 1 diabetes risk was not supported.

Cod liver oil supplementation improves cardiovascular and metabolic abnormalities in streptozotocin diabetic rats.

Abnormalities in the metabolism of essential fatty acids and the results of increased oxidative stress have been implicated in cardiovascular disorders observed in diabetes mellitus. This study, therefore, aimed to investigate the effects of cod liver oil (CLO, Lysi Ltd, Iceland), which comprises mainly an antioxidant vitamin A, n:3 polyunsaturated fatty acids (n:3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on cardiovascular abnormalities in streptozotocin (STZ)-diabetic rats. Two days after single STZ (55 mg kg(-1), i.p.) or vehicle injection, diabetes was verified by increased blood glucose, and non-diabetic and diabetic rats were left untreated or treated with CLO (0.5 mL kg(-1) daily, by intragastric probing) for 12 weeks. Plasma glucose, triacylglycerol and cholesterol concentrations were significantly elevated in 12-week untreated-diabetic rats; CLO provided better weight gain, entirely prevented the plasma lipid abnormalities, but partially controlled the glycaemia in diabetic rats. In isolated aorta rings, diabetes resulted in increased phenylephrine-induced vasoconstriction and isoprenaline-induced vasorelaxation, impaired endothelium-dependent vasodilatation and unchanged responsiveness to sodium nitroprusside. CLO treatment completely prevented endothelial deficiency, partly corrected the phenylephrine-induced vasoconstriction and did not affect the responses to isoprenaline and sodium nitroprusside in diabetic aorta. Diabetes also produced a marked decrease in the rate of spontaneously beating right atria and a significant increase in basal contractile force of left ventricular papillary muscle. The responsiveness of right atria to the positive chronotropic effect of isoprenaline was significantly decreased in diabetic rats, and was increased in CLO-treated diabetic rats. The positive chronotropic effect of noradrenaline was markedly increased in diabetic atria, but prevented by CLO treatment. Diabetes also resulted in an increased positive inotropic response of papillary muscle to both noradrenaline and isoprenaline, which were prevented by CLO treatment. CLO treatment also resulted in lower tissue sensitivity (pD(2)) to these agonists in diabetic papillary muscle. Ventricular hydroxyproline content was found to be unchanged among the experimental groups. The ultrastructure of diabetic myocardium displayed various degenerations (i.e. intracellular oedema, myofibrillar fragmentation, condensed pleomorphic mitochondria, thick capillary irregular basement membrane, swollen endothelial cells), which were partially prevented by CLO treatment. We conclude that the supplementation with CLO is effective in preventing cardiovascular disorders observed in experimental diabetes.