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PubMed1998

A possible role of S-nitrosothiols at the nitrergic relaxations in the mouse corpus cavernosum.

Relaxations induced by electrical field stimulation and acetylcholine were compared with those induced by acidified sodium nitrite, sodium nitroprusside, S-nitrosoglutathione and S-nitroso-N-acetyl-D,L-penicillamine in the mouse corpus cavernosum precontracted with phenylephrine. NG-nitro-L-arginine inhibited electrical field stimulation- or acetylcholine-induced relaxation, but was ineffective on relaxations caused by the other stimuli. Hydroquinone and pyrogallol had no inhibitory action on the relaxations caused by any stimulus except acidified sodium nitrite. Incubation of the tissue with diethyldithiocarbamic acid significantly inhibited the relaxations induced by all stimuli except papaverine. In the tissues pre-treated with diethyldithiocarbamic acid, superoxide dismutase, hydroquinone and pyrogallol failed to yield restore or further inhibit the relaxations in response to electrical field stimulation or acetylcholine. LY 83583 (6-anilino-5,8-quinolinedione) and hydroxocobalamin clearly inhibited the relaxant responses to electrical field stimulation, acetylcholine, S-nitrosoglutathione and acidified sodium nitrite whereas there was significant enhancement of the relaxation produced by S-nitroso-N-acetyl-D,L-penicillamine. These findings suggest that the relaxant factor released from non-adrenergic non-cholinergic nerves or endothelial cells in mouse cavernosal tissue may be a superoxide anion-resistant nitric oxide-containing molecule and that S-nitrosoglutathione rather than S-nitroso-N-acetyl-D,L-penicillamine could be a suitable candidate for this.

Acetylcholine↗

PubMed1988

Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria.

The use of hydroxocobalamin (OH-B12), betaine, carnitine, and folinic acid were studied in two children with the cobalamin C form of methylmalonic acidemia and homocystinuria. When daily injections of 1 mg OH-B12 were discontinued for 3 weeks, there was no significant change in total plasma homocysteine or methionine levels and only a modest increase in methylmalonate. Orally administered OH-B12 1 mg/d in one patient was associated with an increase in plasma homocystine and a decrease in methionine within 1 month. Withdrawal of betaine 250 mg/kg/d was also associated with a rise in plasma homocystine and a fall in methionine levels. Carnitine 100 mg/kg/d lead to an increase in urinary excretion of propionylcarnitine, but did not affect plasma methylmalonate levels. No beneficial biochemical effect of folinic acid could be documented at a dose of 25 mg/d. Our results suggest that daily injections of OH-B12 are not necessary to maintain metabolic control and that orally administered OH-B12 is unlikely to be effective. Betaine appears to act synergistically with OH-B12 and should be part of the treatment regimen. Although there are theoretical reasons for using L-carnitine and folinic acid, we could not document their effectiveness in these two patients.

Administration, Oral↗

PubMed2000

An incident of hydrogen cyanide poisoning.

Seven cases of hydrogen cyanide gas poisoning which occurred in an industrial building in Hong Kong are presented here. Two of them were more severely injured and required specific antidotal treatment. The other five were mild and responded to supportive treatment alone. All except one patient recovered completely. Cyanide poisoning is relatively uncommon in urbanized area, so high index of suspicion is important for early diagnosis and treatment. We believe that prevention of cyanide poisoning can be achieved by proper storage of chemicals, and by enforcing rescuers to wear special chemical protective clothing to avoid systemic poisoning because of dermal absorption of hydrogen cyanide gas. As there are newer and safer cyanide antidotes available, each emergency department should have a stock of updated products such as hydroxocobalamin.

Adult↗

PubMed2001

Three-dimensional structure of ATP:corrinoid adenosyltransferase from Salmonella typhimurium in its free state, complexed with MgATP, or complexed with hydroxycobalamin and MgATP.

In Salmonella typhimurium, formation of the cobalt-carbon bond in the biosynthetic pathway for adenosylcobalamin is catalyzed by the product of the cobA gene which encodes a protein of 196 amino acid residues. This enzyme is an ATP:co(I)rrinoid adenosyltransferase which transfers an adenosyl moiety from MgATP to a broad range of co(I)rrinoid substrates that are believed to include cobinamide, its precursor cobyric acid and probably others as yet unidentified, and hydroxocobalamin. Three X-ray structures of CobA are reported here: its substrate-free form, a complex of CobA with MgATP, and a ternary complex of CobA with MgATP and hydroxycobalamin to 2.1, 1.8, and 2.1 A resolution, respectively. These structures show that the enzyme is a homodimer. In the apo structure, the polypeptide chain extends from Arg(28) to Lys(181) and consists of an alpha/beta structure built from a six-stranded parallel beta-sheet with strand order 324516. The topology of this fold is very similar to that seen in RecA protein, helicase domain, F(1)ATPase, and adenosylcobinamide kinase/adenosylcobinamide guanylyltransferase where a P-loop is located at the end of the first strand. Strikingly, the nucleotide in the MgATP.CobA complex binds to the P-loop of CobA in the opposite orientation compared to all the other nucleotide hydrolases. That is, the gamma-phosphate binds at the location normally occupied by the alpha-phosphate. The unusual orientation of the nucleotide arises because this enzyme transfers an adenosyl group rather than the gamma-phosphate. In the ternary complex, the binding site for hydroxycobalamin is located in a shallow bowl-shaped depression at the C-terminal end of the beta-sheet of one subunit; however, the active site is capped by the N-terminal helix from the symmetry-related subunit that now extends from Gln(7) to Ala(24). The lower ligand of cobalamin is well-ordered and interacts mostly with the N-terminal helix of the symmetry-related subunit. Interestingly, there are few interactions between the protein and the polar side chains of the corrin ring which accounts for the broad specificity of this enzyme. The corrin ring is oriented such that the cobalt atom is located approximately 6.1 A from C5' of the ribose and is beyond the range of nucleophilic attack. This suggests that a conformational change occurs in the ternary complex when Co(III) is reduced to Co(I).

Adenosine Triphosphate↗

PubMed2003

Oxidative stress in HEp-2 human laryngeal carcinoma cells induced by combination of vitamins B12b and C.

Incubation of human laryngeal epidermoid carcinoma HEp-2 cells with hydroxocobalamin (vitamin B12b) and ascorbic acid (vitamin C) for 1 h initiated oxidative stress accompanied by damage to mitochondria and increase in intracellular oxidative activity. Studies of the kinetics of these processes showed that the increase in intracellular H2O2 activity and mitochondrial damage are more likely a result, but not the cause of cell apoptosis during the first hour of their incubation with vitamins B12b and C.

Ascorbic Acid↗

PubMed1999

Comparison of the redox forms of nitrogen monoxide with the nitrergic transmitter in the rat anococcygeus muscle.

1. A sustained tone was produced in rat isolated anococcygeus muscles with guanethidine and clonidine and relaxant responses were elicited by electrical stimulation of its nitrergic nerves and by the three redox forms of nitrogen monoxide. 2. The nitroxyl anion (NO ) was donated by dissociation of Angeli's salt; the free radical (NO*) was from an aqueous solution of nitric oxide gas; the nitrosonium cation (NO+) was donated by dissociation of nitrosonium tetrafluoroborate. 3. The concentrations producing approximately 50% relaxations of the anococcygeus muscle were 0.3 microM for Angeli's salt (nitroxyl), 0.5 microM for NO* and 100 microM for nitrosonium tetrafluoroborate. Nitrergic nerve stimulation at 1 Hz for 10 s produced equivalent relaxant responses. 4. The superoxide generator pyrogallol (100 microM) had no effect on responses to nitrergic nerve stimulation or Angeli's salt but significantly reduced responses to NO* and nitrosonium tetrafluoroborate. 5. The NO* scavenger carboxy-PTIO (100 microM) had no effect on responses to nitrergic nerve stimulation or Angeli's salt but significantly reduced responses to NO* and nitrosonium tetrafluoroborate. 6. Hydroxocobalamin (30 microM) had no significant effect on responses to the nitrergic transmitter, enhanced the response to Angeli's salt, and significantly reduced responses to NO* and nitrosonium tetrafluoroborate. 7. The findings suggest that the nitroxyl anion donated by Angeli's salt is a better candidate than NO* to serve as the nitrergic transmitter in the rat anococcygeus muscle, although it still does not behave exactly like the transmitter.

Animals↗

PubMed2000

Influence of bilirubin and other antioxidants on nitrergic relaxation in the pig gastric fundus.

1. The influence of several antioxidants (bilirubin, urate, ascorbate, alpha-tocopherol, glutathione (GSH), Cu/Zn superoxide dismutase (SOD) and the manganese SOD mimic EUK-8) on nitrergic relaxations induced by either exogenous nitric oxide (NO; 10(-5) M) or electrical field stimulation (4 Hz; 10 s and 3 min) was studied in the pig gastric fundus. 2. Ascorbate (5x10(-4) M), alpha-tocopherol (4x10(-4) M), SOD (300 - 1000 u ml(-1)) and EUK-8 (3x10(-4) M) did not influence the relaxations to exogenous NO. In the presence of GSH (5x10(-4) M), the short-lasting relaxation to NO became biphasic, potentiated and prolonged. Urate (4x10(-4) M) and bilirubin (2x10(-4) M) also potentiated the relaxant effect of NO. None of the antioxidants influenced the electrically evoked relaxations. 3. 6-Anilino-5,8-quinolinedione (LY83583; 10(-5) M) had no influence on nitrergic nerve stimulation but nearly abolished the relaxant response to exogenous NO. Urate and GSH completely prevented this inhibitory effect, while it was partially reversed by SOD and bilirubin. Ascorbate, alpha-tocopherol and EUK-8 were without effect. 4. Hydroquinone (10(-4) M) did not affect the electrically induced nitrergic relaxations, but markedly reduced NO-induced relaxations. The inhibition of exogenous NO by hydroquinone was completely prevented by urate and GSH. SOD and ascorbate afforded partial protection, while bilirubin, EUK-8 and alpha-tocopherol were ineffective. 5. Hydroxocobalamin (10(-4) M) inhibited relaxations to NO by 50%, but not the electrically induced responses. Full protection versus this inhibitory effect was obtained with urate, GSH and alpha-tocopherol. 6. These results strengthen the hypothesis that several endogenous antioxidant defense mechanisms, enzymatic as well as non-enzymatic, might play a role in the nitrergic neurotransmission process.

Aminoquinolines↗

PubMed2002

Influence of antioxidant depletion on nitrergic relaxation in the pig gastric fundus.

1. The hypothesis that endogenous tissue antioxidants might explain the inability of the superoxide generators 6-anilino-5,8-quinolinedione (LY83583) and hydroquinone (HQ) and of the NO-scavengers hydroxocobalamin (HC) and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO) to affect nitrergic neurotransmission in the porcine gastric fundus was tested by selective pharmacological depletion of respectively Cu/Zn superoxide dismutase (Cu/Zn SOD) and reduced glutathione (GSH) in circular smooth muscle preparations. 2. Diethyldithiocarbamate (DETCA; 3x10(-3) M), which almost completely abolished tissue Cu/Zn SOD activity, had no effect per se on nitrergic relaxations induced by either electrical field stimulation (EFS; 4 Hz, 10 s) or exogenous nitric oxide (NO; 10(-5) M). In these DETCA-treated tissues however, electrically-induced nitrergic relaxations became sensitive to inhibition by LY83583 (10(-5) M) or HC (10(-4) M), but not by HQ (10(-4) M) or c-PTIO (10(-4) M); only for the combination of DETCA plus LY83583, this inhibition was partially reversed by exogenous Cu/Zn SOD (1000 u ml(-1)). 3. Immunohistochemical analysis of porcine gastric fundus revealed a 100% colocalization of Cu/Zn SOD and neuronal nitric oxide synthase (nNOS) in the intrinsic neurons of the myenteric plexus. 4. Buthionine sulphoximine (BSO; 10(-3) M) in the absence or presence of LY83583 (10(-5) M) or HC (10(-4) M) did not alter nitrergic relaxations, although it reduced per se the tissue GSH content to 62% of control. 5. Pharmacological depletion studies, corroborated by immunohistochemical data, thus suggest a role for Cu/Zn SOD but not for GSH in nitrergic neurotransmission in the porcine gastric fundus.

Aminoquinolines↗

PubMed2004

Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT).

1. The aim was to test the hypothesis that nitric oxide (NO) donor drugs can inhibit the 5-hydroxytryptamine (5-HT) transporter, SERT. 2. The NO donors, MAHMA/NO (a NONOate; (Z)-1-[N-methyl-N-[6-(N-methylammoniohexyl)-amino]]diazen-1-ium-1,2-diolate), SIN-1 (a sydnonimine; 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride), FK409 (an oxime; (+/-)-(4-ethyl-2E-(hydroxyimino)-5-nitro-3E-hexenamide)) and peroxynitrite, but not Angeli's salt (source of nitroxyl anion) or sodium nitrite, caused concentration-dependent inhibition of the specific uptake of [3H]-5-HT in COS-7 cells expressing human SERT. 3. Superoxide dismutase (150 U ml(-1)) plus catalase (1200 U ml(-1)), used to remove superoxide and hence prevent peroxynitrite formation, prevented the inhibitory effect of SIN-1 (which generates superoxide) but not of MAHMA/NO or FK409. 4 The inhibitory effects of the NO donors were not affected by the free radical scavenger, hydroxocobalamin (1 mM) or the guanylate cyclase inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 3 microM). 5. L-Cysteine (1 mM; source of excess thiol residues) abolished or markedly reduced the inhibitory effects of MAHMA/NO, SIN-1, FK409 and peroxynitrite. 6. It is concluded that inhibition of SERT by the NO donors cannot be attributed exclusively to NO free radical nor to nitroxyl anion. It does not involve guanosine-3',5'-cyclic monophosphate, but may involve nitrosation of cysteine residues on the SERT protein. Peroxynitrite mediates the effect of SIN-1, but not the other drugs. 7. Data in mice with hypoxic pulmonary hypertension suggest that SERT inhibitors may attenuate pulmonary vascular remodelling. Thus, NO donors may be useful in pulmonary hypertension, not only as vasodilators, but also because they inhibit SERT, provided they display this effect in vivo at appropriate doses.

Animals↗

PubMed1970

Gluconeogenesis from propionate in kidney and liver of the vitamin B12-deficient rat.

1. Kidney-cortex slices and the perfused livers of vitamin B(12)-deficient rats removed propionate from the incubation and perfusion media at 33 and 17% respectively of the rates found with tissues from rats receiving either a normal or a vitamin B(12)-supplemented diet. There was a corresponding fall in the rates of glucose synthesis from propionate in both tissues. 2. The addition of hydroxocobalamin or dimethylbenzimidazolylcobamide coenzyme to kidney-cortex slices from vitamin B(12)-deficient rats in vitro failed to restore the normal capacity for propionate metabolism. 3. Although the vitamin B(12)-deficient rat excretes measurable amounts of methylmalonate, no methylmalonate production could be detected (probably because of the low sensitivity of the method) when kidney-cortex slices or livers from deficient rats were incubated or perfused with propionate. 4. The addition of methylmalonate (5mm) to kidney-cortex slices from rats fed on a normal diet inhibited gluconeogenesis from propionate by 25%. 5. Methylmalonate formation is normally only a small fraction of the flux through methylmalonyl-CoA. This fraction increases in vitamin B(12)-deficient tissues (as shown by the urinary excretion of methylmalonate) presumably because the concentration of methylmalonyl-CoA rises as a result of low activity of methylmalonyl-CoA mutase (EC 5.4.99.2). Slow removal of methylmalonyl-CoA might depress propionate uptake owing to the reversibility of the steps leading to methylmalonyl-CoA formation.

Animals↗

PubMed2005

Late-onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation.

BACKGROUND: cblC disease is a cause of hemolytic uremic syndrome (HUS), which has been primarily described in neonates and infants with severe renal and neurological lesions. PATIENTS: Two sisters aged 6 and 8.5 years presented with a latent hemolytic process characterized by undetectable or low plasma haptoglobin, respectively, associated with renal failure and gross proteinuria. Renal biopsies performed in both patients found typical findings of thrombotic microangiopathy suggesting the diagnosis of HUS. Both patients were free of neurologic signs. RESULTS: Biochemical investigations found a cobalamin processing deficiency of the cblC type. Search for additional factors susceptible to worsen endothelial damage revealed homozygosity 677C--> T mutation in the methylenetetrahydrofolate reductase gene as well as heterozygosity for a 3254T--> C mutation in factor H in the patient with the most severe clinical presentation. Long-term subcutaneous administration of hydroxocobalamin in combination with oral betaine and folic acid resulted in clinical and biological improvement in both patients. CONCLUSION: cblC disease may be a cause of chronic HUS with delayed onset in childhood. Superimposed mutation of factor H gene might influence clinical severity.

Anemia↗

PubMed1984

Homocystinuria and megaloblastic anemia responsive to vitamin B12 therapy. An inborn error of metabolism due to a defect in cobalamin metabolism.

We describe an inborn error of vitamin B12 metabolism in an infant who had severe developmental delay, megaloblastic anemia, and homocystinuria. There was no evidence of methylmalonic aciduria or deficiency of folate or vitamin B12. Treatment with hydroxocobalamin, but not with cyanocobalamin and folic acid, resulted in rapid clinical and biochemical improvement. Cultured fibroblasts showed an absolute growth requirement for methionine, defective incorporation of radioactivity from [14C]5-methyltetrahydrofolate into protein, and normal incorporation of radioactivity from [14C]propionate, thus assigning the intracellular defect to methionine synthesis. The proportion of intracellular methylcobalamin in the fibroblasts was decreased, but that of 5'-deoxyadenosylcobalamin was normal. Methionine synthetase activity in cell extracts was normal, as was cobalamin incorporation into cultured cells. This defect differs from those described previously in being limited to methylcobalamin accumulation and defective use of 5-methyltetrahydrofolate by intact cells with normal activity of methylmalonyl CoA mutase.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed1997

Prevalence and haemopoietic effects of low serum vitamin B12 levels in geriatric medical patients.

The clinical significance of low serum vitamin B12 levels in elderly people is controversial. We aimed to document the prevalence of a low serum vitamin B12 (< 175 pmol/l) in patients referred to a geriatric medical unit, and to determine whether haemopoiesis is commonly affected in elderly patients with low serum vitamin B12. We studied prospectively 472 consecutive referrals to a geriatric medical unit; fifty-six (13%) had a low serum vitamin B12 level, of whom nineteen (34%) of the fifty-six also had evidence of Fe deficiency (serum ferritin < 45 ng/ml). Low vitamin B12 was associated with a raised mean erythrocyte volume (MCV; mean 96.0 (SD 6.7) fl), compared with a control group (91.7 (SD 6.0) fl; P = 0.001). However, only thirteen (23%) of the fifty-six patients with a low vitamin B12 had an MCV > or = 100 fl. Mean haemoglobin (Hb) levels were not significantly reduced in those with a low vitamin B12. In a subsequent study the haematological response to intramuscular hydroxocobalamin was examined in thirty-four patients with a low serum vitamin B12. Treatment resulted in a significant fall in MCV and rise in Hb; these effects could be detected both in those patients with an initially normal full blood count (change in MCV -1.2 (SD 1.2); Hb +0.5 (SD 0.6); P < 0.01) and in those with macrocytosis and/or anaemia (-9.1 (SD 11.8); +0.8 (SD 1.2); P < 0.05). A low serum vitamin B12 is common in geriatric medical patients. This is usually associated with an upset in erythropoiesis, although the abnormalities are often subtle and may not be apparent on inspection of the full blood count. Elderly patients with serum vitamin B12 < 175 pmol/l should be assumed to have vitamin deficiency even if their full blood count is normal.

Aged↗

PubMed2002

Acute cyanide intoxication treated with a combination of hydroxycobalamin, sodium nitrite, and sodium thiosulfate.

An 80-year-old diabetic patient was admitted to the hospital because of sudden unconsciousness and severe metabolic acidosis. His son reported the possibility of cyanide poisoning. Clinical data and the detection of cyanide in blood and gastric material confirmed this possibility. Supportive therapy and the following antidotes--sodium nitrite two doses 300 mg i.v., sodium thiosulfate 3 g i.v., and hydroxocobalamin 4 g in 24 hours--were administered immediately and the patient completely recovered in 48 hours. Our observations suggest that timely and appropriate use of antidotes for cyanide intoxication may prevent death, even in aged diabetic patients.

Acidosis↗

PubMed1975

Interrelationships between the B-vitamins in B12-deficiency neuromyelopathy. A possible malabsorption-malnutrition syndrome.

Five patients presenting clinically with a form B12-deficiency neuromyelopathy, with cord involvement in all and proximal muscle weakness in two of them, were investigated for their neurologic, hematologic and vitamin status. Megaloblastosis and achlorhydria were present in all, and impaired absorption of 57Co vitamin B12 and of D-xylose was detected in four. Total cyanide extracted vitamin B12 (A) was lowered in all cases and noncyanide extractable (B) in four of the five, being zero in three. All five responded to injections of hydroxocobalamin. In two patients sequential estimations showed that both A and B, especially the latter, rose steeply initially, normalizing at 50% of A after some weeks. Moiety B is suggested to be physiologically the more active and dissociable form of vitamin B12. Markedly elevated initial serum folate levels, and their subsequent fall under treatment with B12, indicated the operation of the "methyltetrahydrofolate trap". Blood levels of thiamin, nicotinic acid and pantothenic acid were within normal limits. However, serum riboflavin (B2) total vitamin B6 and pyridoxal were reduced in all where tested. Vitamin B6 deficiency could have resulted from its own malabsorption and have contributed to be B12 deficiency. Vitamin B2 and B6 levels also corrected themselves on B12 therapy. The B-vitamin deficiencies in our patients probably resulted from intestinal malabsorption, with a possible factor of malnutrition consequent to their strictly vegetarian diet.

Achlorhydria↗

PubMed1984

Effects of cobalt or hydroxycobalamin supplementation on vitamin B-12 content and (S)-methylmalonyl-CoA mutase activity of tissue from cobalt-depleted sheep.

Lambs (3 months of age) and ewes were fed ad libitum a depletion diet low in cobalt (0.06 ppm) for 7 months. Five sheep were then assigned to each of the following treatments: 330 micrograms hydroxocobalamin (OH-B-12) intramuscularly, 2.7 mg cobalt (Co) orally, and no supplementation (no suppl). Treatments were given on alternate days for 9 weeks. Both forms of resupplementation increased the animal's body weight at slaughter compared to nonsupplementation, while absolute weights and protein concentrations of brain, liver, heart, rumen and kidney were not affected. Supplementation increased concentrations of vitamin B-12 in all tissues; Co and OH-B-12 being equally effective in brain and ruminal mucosa, whereas OH-B-12 had a greater effect in heart, liver and kidney. The greatest concentrations of vitamin B-12 were observed in liver (2630 +/- 160, 1500 +/- 230 and 60 +/- 20 ng/g wet liver for OH-B-12, Co and no suppl groups, respectively) and kidney, although liver contained the greatest absolute amount of vitamin B-12. Activity of (S)-methylmalonyl-CoA mutase, assayed in the presence of added coenzyme B-12, was not increased with resupplementation except in kidney. The activity of mutase without coenzyme added in vitro was correlated with tissue content of vitamin B-12. Through this study we demonstrate that in sheep tissue the activity of (S)-methylmalonyl-CoA mutase is limited by coenzyme rather than enzyme per se. Liver possesses the greatest quantitative activity of mutase and is most responsive to alterations of vitamin B-12 status.

Administration, Oral↗

PubMed1982

Cobalamin forms in plasma and tissue during treatment of vitamin B12 deficiency.

Thin-layer chromatography and bioautography were used to study the cobalamin pattern of plasma, erythrocytes, and hepatic tissue from patients with cobalamin deficiency on maintenance therapy with hydroxocobalamin (Vibeden), a cyanocobalamin depot preparation (Betolvex), or cyanocobalamin tablets (Behepan). The cobalamin pattern in plasma is dominated by the form in which it is administered. The results of assaying the erythrocytes and liver biopsies show that the cobalamins administered are converted to the coenzyme forms in vivo, irrespective of the type of cobalamin preparation.

Administration, Oral↗

PubMed2004

Developmental changes in myoendothelial gap junction mediated vasodilator activity in the rat saphenous artery.

A role for myoendothelial gap junctions (MEGJs) has been proposed in the action of the vasodilator endothelium-derived hyperpolarizing factor (EDHF). EDHF activity varies in disease and during ageing, but little is known of the role of EDHF during development when, in many organ systems, gap junctions are up-regulated. The aims of the present study were therefore to determine whether an up-regulation of heterocellular gap junctional coupling occurs during arterial development and whether this change is reflected functionally through an increased action of EDHF. Results demonstrated that in the saphenous artery of juvenile WKY rats, MEGJs were abundant and application of acetylcholine (ACh) evoked EDHF-mediated hyperpolarization and relaxation in the presence of N(omega)-nitro-l-arginine methyl ester (L-NAME) and indomethacin to inhibit nitric oxide and prostaglandins, respectively. Responses were blocked by a combination of charybdotoxin plus apamin, or 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34) plus apamin, or by blockade of gap junctions with the connexin (Cx)-mimetic peptides, (43)Gap26, (40)Gap27 and (37,43)Gap27. On the other hand, we found no evidence for the involvement of the putative chemical mediators of EDHF, eicosanoids, L-NAME-insensitive nitric oxide, hydrogen peroxide or potassium ions, since 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE), hydroxocobalamin, catalase or barium and ouabain were without effect. In contrast, in the adult saphenous artery, MEGJs were rare, EDHF-mediated relaxation was absent and hyperpolarizations were small and unstable. The present study demonstrates that MEGJs and EDHF are up-regulated during arterial development. Furthermore, the data show for the first time that this developmentally regulated EDHF is dependent on direct electrotonic coupling via MEGJs.

8,11,14-Eicosatrienoic Acid↗