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PubMed1983

Influence of vitamin B-12 status on hepatic propionic acid uptake in sheep.

Pregnant ewes were fed a depletion diet low in cobalt (0.06 ppm) for 3 1/2 months. Chronic catheters were implanted 8 weeks postpartum and 7 experiments were performed on these nonlactating vitamin B-12-depleted sheep (de-B12: 340 +/- 30 ng vitamin B-12 per gram wet liver) prior to repletion by intramuscular injection of hydroxocobalamin. Six experiments were then repeated after vitamin B-12 repletion (re-B12: 2220 +/- 50 ng vitamin B-12 per gram wet liver). The hepatic extraction ratios (HER) in continuously fed sheep were 0.81 and 0.77 for de-B12 and re-B12 corresponding to net hepatic uptakes of 460 +/- 50 and 440 +/- 40 mumol propionate per minute, respectively. Continuous infusion of unlabeled propionate into a mesenteric vein at 1 mmol/minute reduced the HER, yet this depression was greatest for re-B12 (0.74 vs. 0.63 for de-B12 and re-B12, respectively). Net hepatic uptake of propionate was increased (1145 +/- 100 vs. 985 +/- 95 mumol/minute, respectively), although vitamin B-12 status was without effect. It is concluded that the ability of liver to extract propionate is not affected at vitamin B-12 concentrations greater than 250 ng/g wet liver. However, when propionate entry rate was enhanced by intramesenteric infusion, the livers of de-B12 sheep had a greater capacity to remove propionate suggesting that alternate routes of metabolism may occur.

Animals↗

PubMed1983

Changes of glucose, insulin and glucagon associated with propionate infusion and vitamin B-12 status in sheep.

The effect of propionate on hormonal and metabolic events was studied in ewes that were vitamin B-12 depleted (de-B12) and repleted (re-B12). Experiments were conducted before and after hydroxocobalamin resupplementation. De-B12 sheep had greater blood concentrations and total hepatic influx and efflux of glucose. However, rates of net hepatic release of glucose were similar. Comparable glucagon concentrations and fluxes were reduced in de-B12, but insulin values were unaffected by vitamin B-12 status. Intramesenteric infusion of propionate elevated concentrations of glucose, insulin and glucagon at nearly all samplings. Secretion of insulin was elevated at the first sampling only (15 minutes), while glucagon appeared elevated until 30 minutes. Rates of hepatic removal of hormones were not altered during infusion. Net hepatic release of glucose was increased at nearly all samplings, but de-B12 ewes had a greater increment of total hepatic influx and efflux. De-B12 ewes exhibited a diminished glucagon response to propionate infusion, whereas insulin concentrations and hepatic uptakes tended to be greater. Vitamin B-12 status, within the range usually considered normal, thus influences metabolic and hormonal responses to increased rates of propionate entry in the sheep, independent of feed intake.

Animals↗

PubMed1998

Cyanide poisoning: pathophysiology and treatment recommendations.

This paper aims to assess and compare currently available antidotes for cyanide poisoning. Such evaluation, however, is difficult. Thus, extrapolation from the results of animal studies has potential pitfalls, as significant inter-species differences in response may exist, and these experiments often involve administration of toxin and antidote almost simultaneously, rather than incorporating a more realistic time delay before initiation of treatment. Direct inference from human case reports is also problematic; either because of uncertainties over the exposure levels involved (and hence the likely outcome without treatment), or because of difficulties in identifying the specific contribution of a particular antidote within the overall treatment regimen. Certainly an effort to compare the relative efficacy of cyanide antidotes produces equivocal findings, with no single regimen clearly standing out. Indeed, factors such as the risks of antidote toxicity to various individuals and other practical issues, may be more important considerations. There is therefore no single treatment regimen which is best for all situations. Besides individual risk factors for antidote toxicity, the nature of the exposure and hence its likely severity, the evolving clinical features and the number of persons involved and their proximity to hospital facilities, all need to be considered. Clinically mild poisoning may be treated by rest, oxygen and amyl nitrite. Intravenous antidotes are indicated for moderate poisoning. Where the diagnosis is uncertain, sodium thiosulphate may be the first choice. With severe poisoning, an additional agent is required. Given the various risks with methaemoglobin formers or with unselective use of kelocyanor, hydroxocobalamin may be preferred from a purely risk-benefit perspective. However the former alternatives will likely remain important.

Antidotes↗

PubMed2002

Cobalamin C disease presenting as hemolytic-uremic syndrome in the neonatal period.

Anew case of cobalamin C disease associated with hemolytic-uremic syndrome (HUS) in the neonatal period is described. A 28-day-old boy presented with failure to thrive, hypotonia, pancytopenia, and features of HUS (microangiopathic hemolytic anemia, thrombocytopenia, and renal failure). The possibility of the diagnosis of an underlying vitamin B12 disorder was prompted by evidence of megaloblastic changes on the peripheral smear and by finding in the literature a suggested association of neonatal HUS with this cobalamin-related metabolic disorder. Amino acid analysis showed elevated homocysteine levels in the plasma and increased levels of both homocysteine and methyl malonic acid in the urine. Diagnosis of cobalamin C disease was confirmed by complementation studies using skin fibroblasts. Therapy included parenteral hydroxocobalamin, carnitine, and leucovorin calcium (folinic acid). Cobalamin C disease should be considered in the diagnosis of patients presenting with HUS in infancy who have unexplained megaloblastosis, pancytopenia, neurologic impairment, and failure to thrive. Early diagnosis and institution of therapy may be effective in improving survival and quality of life.

Diagnosis, Differential↗

PubMed1982

Thiamine responsive anaemia: a study of two further cases.

A brother and sister of Pakistani origin suffered from sensorineural deafness, diabetes mellitus and a macrocytic anaemia. Their bone marrows showed megaloblastic erythropoiesis and contained many ringed sideroblasts. Electron microscope studies of the bone marrow revealed (1) iron-laden mitochondria in many erythroblasts, (2) non-specific abnormalities indicative of dyserythropoiesis in some erythroblasts, and (3) evidence of ineffective erythropoiesis. The deoxyuridine suppression test indicated that the megaloblastic changes were not caused by an impairment of the methylation of deoxyuridylate. Studies of nucleic acid synthesis in the bone marrow cells showed that the rate of incorporation of [3H]thymidine into DNA was increased and that the rates of incorporation of [14C]glycine and [14C]adenine into both DNA and RNA were essentially within the normal range. The anaemia did not respond to therapy with hydroxocobalamin, folic acid or pyridoxine but responded to 25 mg thiamine, daily, by mouth. In one of the cases a post-thiamine marrow aspirate showed a considerable improvement in both the megaloblastic and sideroblastic changes.

Anemia, Macrocytic↗

PubMed1990

Reduced serum vitamin B12 levels during oral cyproterone-acetate and ethinyl-oestradiol therapy in women with diffuse androgen-dependent alopecia.

In a group of healthy, non-vegetarian females currently being treated for diffuse androgen-dependent alopecia with 50 or 100 mg of oral cyproterone acetate for 11 days and 30 or 40 micrograms of ethinyl oestradiol for 20 days of the menstrual cycle, significant decreases in mean serum vitamin B12 (P less than 0.0001), haemoglobin (P less than 0.003) and haematocrit (P less than 0.004) values, were observed after 6 months. Serum folic acid, red-cell folate and mean cell volume remained unchanged within the normal range during this time. All patients responded to oral cyanocobalamin, or intramuscular injections of hydroxocobalamin. In patients with baseline serum vitamin B12 levels below 350 ng/l, we would suggest prophylactic cyanocobalamin concurrent with cyproterone-acetate-ethinyl-oestradiol (CPA EE2) therapy. Studies involving other dose regimens of CPA EE2 (Dianette) or cyproterone acetate alone (Androcur, Cyprostat), may require evaluation of the vitamin B12 status if treatment is to be given for periods of longer than 3 months.

Administration, Oral↗

PubMed1996

Sodium ion translocation by N5-methyltetrahydromethanopterin: coenzyme M methyltransferase from Methanosarcina mazei Gö1 reconstituted in ether lipid liposomes.

The N5-methyltetrahydromethanopterin (H,MPT):coenzyme M methyltransferase is a membrane associated, corrinoid-containing protein that uses the methylation of coenzyme M (HS-CoM) by methyl-tetrahydromethanopterin to drive an energy-conserving sodium ion pump. The enzyme was purified from acetate-grown Methanosarcina mazei Gö1 by a two-step solubilization with n-octyl-beta-glucoside, chromatography on hydroxyapatite, and by gel filtration on Superdex 200 or Sepharose CL-6B. The highly purified protein was apparently composed of six different subunits of 34, 28, 20, 13, 12, and 9 kDa. The N-terminal amino acid sequences of these polypeptides were determined. The native enzyme exhibited an apparent molecular mass of about 380 kDa. During purification, the enzyme was stabilized with 10 microM hydroxocobalamin. The highest specific activity reached during purification was 10.4 U/mg. The purified enzyme was reconstituted in monolayer liposomes prepared from ether lipids of M. mazei Gö1. In experiments with radioactive sodium ions, it was shown that the methyltransferase catalyzes the vectorial translocation of sodium ions across the membrane. Methyltransferase activity was stimulated by sodium ions. 1.7 mol Na-/mol methyl groups transferred were translocated. Methyltetrahydrofolate and methyl-cobalamin could substitute for methyl-H,MPT.

Amino Acid Sequence↗

PubMed2006

Three novel and six common mutations in 11 patients with methylmalonic acidemia.

BACKGROUND: Patients with a defect in methylmalonyl-coenzyme A mutase (MCM) are classified as having methylmalonic acidemia, which is divided into two subclasses: mut(0) and mut(-). Fifty-five disease-causing mutations have been identified. Although most are private mutations, only three (E117X, G717V, and N219Y) are reportedly common in Japanese, Black, and Caucasian populations, respectively. Here we identified mutations in 11 Japanese patients with MCM deficiency. METHODS: Mutational analysis was performed in 11 unrelated Japanese patients with MCM deficiency using polymerase chain reaction and direct sequencing. RESULTS: Three novel (L494X, R727X, and 449_461del) and six previously reported (R93H, E117X, N219Y, R369H, G648D and IVS2 + 5G>A) mutations were identified. The L494X mutation was found in three unrelated patients, and the R93H, E117X, R369H, G648D, and IVS2 + 5G>A mutations occurred more than once. Two of the patients were classified as mut(-) phenotype because of residual [(14)C]-propionate incorporation in the presence of a high concentration of hydroxocobalamin. The two mut(-) patients were heterozygous for the G648D mutation and presented with lethargy and metabolic acidosis after 2 years of life. Their psychomotor development has been documented as normal. The patients with the R727X or c.374_385del [corrected] mutations clinically exhibited mut(0) phenotype. Two patients with mut(0) phenotype died in infancy. One presented early in the neonatal period; the other was symptomatic in the late infantile period. CONCLUSIONS: The L494X, R93H, E117X, R369H, G648D, and IVS2 + 5G>A mutations are found in more than two unrelated families in the Japanese population. The short-term outcome was generally poor in patients with mut(0), and therefore alternative treatments should be considered.

Child, Preschool↗

PubMed1996

Antioxidant protection of NO-induced relaxations of the mouse anococcygeus against inhibition by superoxide anions, hydroquinone and carboxy-PTIO.

1. The potential protective effect of several antioxidants [Cu/Zn superoxide dismutase (Cu/Zn SOD), ascorbate, reduced glutathione (GSH), and alpha-tocopherol (alpha-TOC)] on relaxations of the mouse anococcygeus muscle to nitric oxide (NO; 15 microM) and, where appropriate, nitrergic field stimulation (10 Hz; 10 s trains) was investigated. 2. The superoxide anion generating drug duroquinone (100 microM) reduced relaxations to exogenous NO by 54 +/- 6%; this inhibition was partially reversed by Cu/Zn SOD (250 u ml-1), and by ascorbate (500 microM). Following inhibition of endogenous Cu/Zn SOD activity with diethyldithiocarbamate (DETCA), duroquinone (50 microM) also reduced relaxations to nitrergic field stimulation (by 53 +/- 6%) and this effect was again reversed by Cu/Zn SOD and by ascorbate. Neither GSH (500 microM) nor alpha-TOC (400 microM) afforded any protection against duroquinone. 3. Xanthine (20 mu ml-1); xanthine oxidase (100 microM) inhibited NO-induced relaxations by 73 +/- 14%, but had no effect on those to nitrergic field stimulation, even after DETCA treatment. The inhibition of exogenous NO was reduced by Cu/Zn SOD (250 u ml-1) and ascorbate (400 microM), but was unaffected by GSH or alpha-TOC (both 400 microM). 4. Hydroquinone (100 microM) also inhibited relaxations to NO (by 52 +/- 10%), but not nitrergic stimulation. In this case, however, the inhibition was reversed by GSH (5-100 microM) and ascorbate (100-400 microM), although Cu/Zn SOD and alpha-TOC were ineffective. 5. 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO, 50 microM) inhibited NO-induced relaxations by 50 +/- 4%, but had no effect on nitrergic responses; the inhibition was reduced by ascorbate (2-200 microM) and alpha-TOC (10-200 microM), but not by Cu/Zn SOD or GSH. 6. Hydroxocobalamin (5-100 microM) inhibited, equally, relaxations to both NO (-logIC40 3.14 +/- 0.33) and nitrergic stimulation (-logIC40 3.17 +/- 0.22). 7. Thus, a number of physiological antioxidants protected NO from superoxide anions, and from direct NO-scavengers. The possibility that the presence of these antioxidants within nitrergically-innervated tissues might explain the lack of effect of the NO inhibitors on nerve-induced relaxation, without the need to invoke a transmitter other than free radical NO, is discussed.

Animals↗

PubMed1971

Vitamin B 12.

In spite of the considerable progress made in recent years toward the understanding of the chemistry and biological function of the cobalt-containing B(12) group of compounds, much of the information still is more descriptive than definitive in nature. In general terms, it is known that the free vitamin forms can function as methyl group carriers and that the 5'-deoxyadenosyl or coenzyme forms serve as hydrogen carriers; but the mechanism of these processes is not understood in detail. More systematic studies of the pure chemistry of these complex molecules containing a carbon-cobalt covalent bond are needed before the biochemist can interpret many of his observations on the enzyme-catalyzed reactions. Even in relatively simple solutions it is difficult to ascertain the state of oxidation of several of the vitamin forms, and these problems are compounded when the reactive thiol compounds and complex proteins of the biological systems also are present. For example, both vitamin B(12r) (the Co(2+) form) and corresponding analogs are known to disproportionate in solution to B(12s) (Co(1+)) and B(12a) (Co(3+)) under a variety of mild conditions (12, 57). This means that in the biological systems it is exceedingly difficult to ascertain the chemical nature of many B(12) intermediates and reaction products. The role of the protein moiety of the various B(12)-linked enzymes in the catalytic processes is little known as is, also, the mode of binding of the B(12) derivative to the protein. These types of questions perhaps can be answered eventually by the crystallographers, whose art is becoming increasingly sophisticated. Note added after preparation of manuscript. In contrast to the values given in Table 4 for the molecular weights of the two dissimilar protein moieties of glycerol dehydrase, a recent report (57a), gives a value of 188,000 for the molecular weight of a stable, catalytically inactive complex of 1 mole of hydroxocobalamin and 1 mole of the apoenzyme complex of glycerol dehydrase. The latter is presumed to contain one equivalent of each of the two dissimilar protein subunits. The original estimate of 240,000 as the molecular weight of the unstable sulfhydryl protein moiety (39) was undoubtedly made on partially aggregated material.

Adenosine Triphosphate↗

PubMed1992

Enzymes Involved in Anaerobic Polyethylene Glycol Degradation by Pelobacter venetianus and Bacteroides Strain PG1.

In extracts of polyethylene glycol (PEG)-grown cells of the strictly anaerobically fermenting bacterium Pelobacter venetianus, two different enzyme activities were detected, a diol dehydratase and a PEG-degrading enzyme which was characterized as a PEG acetaldehyde lyase. Both enzymes were oxygen sensitive and depended on a reductant, such as titanium citrate or sulfhydryl compounds, for optimal activity. The diol dehydratase was inhibited by various corrinoids (adenosylcobalamin, cyanocobalamin, hydroxocobalamin, and methylcobalamin) by up to 37% at a concentration of 100 muM. Changes in ionic strength and the K ion concentration had only limited effects on this enzyme activity; glycerol inhibited the enzyme by 95%. The PEG-degrading enzyme activity was stimulated by the same corrinoids by up to 80%, exhibited optimal activity in 0.75 M potassium phosphate buffer or in the presence of 4 M KCI, and was only slightly affected by glycerol. Both enzymes were located in the cytoplasmic space. Also, another PEG-degrading bacterium, Bacteroides strain PG1, contained a PEG acetaldehyde lyase activity analogous to the corresponding enzyme of P. venetianus but no diol dehydratase. Our results confirm that corrinoid-influenced PEG degradation analogous to a diol dehydratase reaction is a common strategy among several different strictly anaerobic PEG-degrading bacteria.

Journal Article↗

PubMed1965

OBSERVATIONS ON VITAMIN B12 IN SERUM AND CEREBROSPINAL FLUID IN MULTIPLE SCLEROSIS.

There are several claims that B(12) concentrations in serum and cerebrospinal fluid are grossly abnormal in multiple sclerosis, but results are conflicting. This paper reports measurements of these concentrations in 40 serum samples and 23 samples of lumbar cerebrospinal fluid from cases of multiple sclerosis, and in appropriate controls, using Euglena gracilis, z strain. The serum concentrations were found to be normal; the mean concentration in cerebrospinal fluid was slightly reduced, but all values were within the control range. In both control samples and samples from cases of multiple sclerosis, the B(12) concentration in lumbar cerebrospinal fluid was correlated with the concentration in serum. There was no correlation between B(12) concentration and total protein in cerebrospinal fluid.A number of estimations of serum B(12) were also made with Lactobacillus leichmannii, after extraction in the presence and absence of cyanide. These showed a difference between cases of multiple sclerosis and controls, one interpretation of which might be that the serum in multiple sclerosis contains an abnormally low concentration of hydroxocobalamin.

Blood↗

PubMed1971

Cobalamins in human pregnancy and lactation.

Samples of maternal and foetal blood and of human milk, cow's milk, and dried cow's milk have been analysed for cobalamins by chromatography and bioautography. Plasma cobalamins in late pregnancy and after delivery differed quantitatively from those in healthy non-pregnant women. Differences in the proportions of plasma cobalamins were also observed between mothers and their newborn infants. The findings suggest that methylcobalamin may be a more labile plasma form of the vitamin than 5-deoxyadenosyl cobalamin. Breast milk from healthy mothers contained more deoxyadenosylcobalamin and proportionately less methylcobalamin than their plasma. Cyanocobalamin given parenterally to lactating women was detected in the plasma, and high concentrations appeared unchanged in the milk. The B(12) in fresh cow's milk was found to be largely 5-deoxyadenosyl cobalamin whereas dried milk contained only hydroxocobalamin and a little cyanocobalamin. The nutritional implications of the findings, and their bearing on problems of cobalamin transport, are discussed.

Adolescent↗

PubMed1992

Radioimmunoassay that measures serum vitamin B12.

AIMS: To develop a specific radioimmunoassay for the routine determination of serum vitamin B12. METHODS: Antisera were raised in rabbits by immunisation with the monocarboxylic acid derivative of cyanocobalamin coupled to human serum albumin. Antibody titres and affinities were determined and the antiserum giving the highest binding affinity constant, Ka, was used to develop the assay protocol. Donkey-anti-rabbit gamma globulin-coated magnetisable particles were used to separate the bound from free vitamin B12. The considerable cobalamin binding capacity of human serum was destroyed by autoclaving in acetate-cyanide buffer. Sixty samples were assayed by the radioimmunoassay (RIA) and the Lactobacillus leichmannii assay. Recovery and cross-reactivity experiments were performed. RESULTS: Final rabbit antibody titres varied from 1/20,000 to 1/188,000. Scatchard plots did not correlate with the antibody titres. The Ka values varied from 2.6 to 6.7 x 10(10) litres/mol. For maximum sensitivity the highest Ka (titre 1/66,000) was chosen. A tracer concentration of 22 pmol/l, an antiserum dilution of 1/100,000, and a sample volume of 0.1 ml were used. At an antiserum dilution of 1 in 100,000 the cyanocobalamin binding of the rabbit serum was diluted out. The assay showed excellent correlation with the microbiological assay, with 100% recovery of added vitamin B12. Levels of cross-reactivity for dicyanide cobinamide and hydroxocobalamin were 9.8 and 8.1%, respectively. CONCLUSIONS: The development of this immunoassay permits the measurement of serum vitamin B12 without important interference from cobalamin analogues, related corrinoids, and non-specific binders.

Animals↗

PubMed2003

Mitogen-activated protein kinases mediate peroxynitrite-induced cell death in human bronchial epithelial cells.

Peroxynitrite, formed by the reaction of nitric oxide (NO. ) with superoxide anions (O(2)(-).), may play a role in the pathophysiology of inflammation. The effects of 3-morpholinosydnonimine (SIN-1), a peroxynitrite generator, on the human bronchial epithelial cell line BEAS-2B, were examined. SIN-1 exposure resulted in cell death in a time- and dose-dependent manner. Depletion of intracellular glutathione increased the vulnerability of the cells. Pretreatment with Mn(III)tetrakis(N-methyl-4'-pyridyl)porphyrin (MnTMPyP) or hydroxocobalamin (HC), O(2)(-). and NO. scavengers, respectively, reduced significantly SIN-1-induced cell death (18.66 +/- 3.57 vs. 77.01 +/- 14.07 or 82.20 +/- 9.64, % cell viability SIN-1 vs. MnTMPyP or HC). Moreover, the mitogen-activated protein kinases (MAPK) p44/42 (ERK), p38, and p54/46 (JNK) were also activated in a time- and concentration-dependent manner. PD-98059 and SB-239063, specific inhibitors of ERK and p38 MAPK pathways, failed to protect cells against 1 mM SIN-1. However, PD-98059 partially inhibited (60% cell survival) SIN-1 effects at < or =0.25 mM, and this was increased with the inclusion of SB-239063. Therefore, MAPKs may mediate signal transduction pathways induced by peroxynitrite in lung epithelial cells leading to cell death.

Bronchi↗

PubMed2006

[Antidotes availability in health services of Catalonia, Spain].

BACKGROUND AND OBJECTIVE: Acute poisoning can be treated in different hospital and extrahospital health services. Thus, availability of antidotes in hospital pharmacies, emergency departments and health centres play an important role in poisoning treatment. MATERIAL AND METHOD: This is a descriptive and transversal study of antidotes availability in different health services of Catalonia (Spain). From April to May 2005, a proper questionnaire was sent to 50 different health centres: 28 basic health centres (including medical ambulances) and 22 hospitals with a distinct medical complexity level, to assess the qualitative (QLA) and quantitative availability (QTA) of antidotes. RESULTS: QLA resulted to be 82% in extrahospital health centres and 50% in medical ambulances. QTA was 94% for ambulances, whereas, in health centres, differences were observed between rural (55%) and urban (33%) areas. Regarding basic general hospitals (level 1), reference hospitals (level II) and high technology hospitals (level III) the QLA showed values of 39, 54 and 55%, respectively, and the QTA came about 70, 54 y 54.5%, in that order. Furthermore, lack of adequate stocking was observed for compounded formulations, such as albumin, starch, ipecacuanha syrup or IV ethanol, and for essential antidotes as snake antivenin, digoxin immune Fab or hydroxocobalamine. CONCLUSIONS: There is understocking of poisoning antidotes throughout the health services of Catalonia. Heterogeneity was observed between services with a medical complexity level. The main deficiencies are found in antidotes that, to date, are available as compounded formulations or imported from other countries.

Acute Disease↗

PubMed1990

Cytotoxic activity of cobalamin in cultured malignant and nonmalignant cells.

The cytotoxic effect of cobalamin (vitamin B12) on the growth of malignant and nonmalignant cell lines in culture has been examined. Among the four cobalamins studied, 5'-deoxyadenosylcobalamin, an enzymatically active derivative, was an effective cytotoxic agent. The data indicated that adenosylcobalamin seemed to act selectively on fast-growing malignant cells. Methylcobalamin was also effective at elevated concentrations. Cyanocobalamin was not toxic to all cell lines studied. Hydroxocobalamin at very high concentrations was able to slightly decrease growth of certain cell lines. The results support the hypothesis that the cytotoxic effect of cobalamin was associated with the metabolic activities of this vitamin at the cellular level. Also, cobalamin may be a potential antitumor agent.

Animals↗

PubMed2003

Structure, function, and endothelium-derived hyperpolarizing factor in the caudal artery of the SHR and WKY rat.

OBJECTIVE: To quantify structural and functional characteristics of the caudal artery from spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats with particular reference to endothelium-derived hyperpolarizing factor (EDHF). METHODS AND RESULTS: Ultrastructural studies showed that the number of myoendothelial gap junctions, smooth muscle cell (SMC) layers, and medial cross-sectional area were significantly greater in SHR than WKY. Intracellular dye labeling demonstrated hyperplasia of SMCs in SHR. Analysis of nerve-mediated excitatory junction potentials recorded in SMCs at the adventitial and luminal borders demonstrated decreased radial coupling of SMCs in SHR. In both SHR and WKY, in the presence of NG-nitro-L-arginine methyl ester and indomethacin, acetylcholine-elicited EDHF was abolished by charybdotoxin and apamin, while iberiotoxin had no effect, implicating the involvement of small and intermediate, but not large, calcium-activated potassium channels. EDHF was abolished by Gap-mimetic peptides, 18beta-glycyrrhetinic acid, and endothelial removal but not affected by the NO scavengers hydroxocobalamin and carboxy-PTIO. CONCLUSIONS: Significant differences in SMC morphology and homocellular and heterocellular coupling exist between the caudal artery of SHR and WKY rats. In the caudal artery of SHR, significantly greater heterocellular coupling compensates for other structural changes in the media to maintain a functional role for EDHF.

Acetylcholine↗