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- Lopez-Aparicio, Pilar, et al.
(författare)
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Insulin induced phosphorylation and activation of the cGMP-inhibited cAMP phosphodiesterase in human platelets
- 1992
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Ingår i: Biochemical and Biophysical Research Communications. - 1090-2104. ; 186:1, s. 517-523
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Tidskriftsartikel (refereegranskat)abstract
- Insulin induced phosphorylation and activation of the cGMP inhibited cAMP phosphodiesterase (cGI-PDE) in human platelets were demonstrated after isolation of the enzyme with specific polyclonal cGI-PDE antibodies. The demonstration of this insulin effect required suppression of basal cGI-PDE phosphorylation, through the use of the protein kinase inhibitor H-7 (1-(5-isoquinolinylsulfonyl)-2-methylpiperazine). The human platelet insulin receptor beta-subunit, previously identified as a 97 kDa polypeptide, was detected with the use of wheat germ agglutinin chromatography and anti-phosphotyrosine antibodies. These results suggest that insulin, through phosphorylation/activation of cGI-PDE, could decrease cAMP/cAMP dependent protein kinase (cAMP-PK) activity and thereby make the platelets more sensitive towards aggregating agents.
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- Rascon, Ana, et al.
(författare)
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Purification and properties of the cGMP-inhibited cAMP phosphodiesterase from bovine aortic smooth muscle
- 1992
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Ingår i: Biochimica et Biophysica Acta. - 0006-3002. ; 1134:2, s. 149-156
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Tidskriftsartikel (refereegranskat)abstract
- Pure cGMP-inhibited cAMP phosphodiesterase (cGI-PDE) in micrograms quantities was isolated from bovine aortic smooth muscle after more than 5000-fold purification using DEAE ion-exchange and affinity chromatography with a derivative of the specific cGI-PDE inhibitor cilostamide conjugated as a ligand to aminoethyl agarose (CIT-agarose). The cGI-PDE, which constituted about half of the high affinity cAMP-PDE activity of a tissue homogenate, was identified with a 105-kDa protein on SDS-PAGE through use of antibodies towards the human platelet, bovine cardiac and bovine adipose tissue cGI-PDE in Western blot and immunoprecipitation/immunoinactivation analysis. As observed during purification of the enzyme from other tissues the enzyme protein was exquisitely sensitive to proteolytic nicking during purification, resulting in several 30-77-kDa polypeptide fragments. Rapid immunoprecipitation from fresh tissue extracts was the only was found to partially prevent the proteolysis. The native enzyme had apparent molecular sizes of approx. 100,000 or, mainly approx. 220,000 by gel chromatography, presumably indicating the presence of monomeric and dimeric forms. The enzyme hydrolyzed cAMP and cGMP with normal Michaelis-Menten kinetics with Km of 0.16 and 0.09 microM, respectively, with Vmax for hydrolysis of cAMP of 0.3 compared to 3.1 mumol/min per mg protein for cAMP. The enzyme was potently and selectively inhibited by cGMP (IC50 approximately 0.25 microM) and the cardiotonic/vasodilatory drugs OPC-3911 (a cilostamide derivative), milrinone and CI-930 (IC50 approximately 0.05, 0.40 and 0.25 microM, respectively). The cGI-PDE was phosphorylated by cAMP-dependent protein kinase as has been reported for the analogous enzymes in heart, adipose tissue and platelets. The identification of a cGI-PDE in the aortic smooth muscle and its inhibitor specificity is consistent with the hypothesis that inhibition of this enzyme is important in the mechanism through which these drugs produce vasorelaxation.
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- Vagianos, C, et al.
(författare)
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Effects of alpha-adrenoceptor active drugs, prostaglandin F2 alpha and vasopressin on cystic and hepatic arteries of pig and man
- 1990
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Ingår i: Pharmacology and Toxicology. - 1600-0773. ; 66:2, s. 77-82
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Tidskriftsartikel (refereegranskat)abstract
- Human and pig cystic and pig hepatic arteries were suspended in tissue baths and the effect of alpha-adrenoceptor selective drugs, prostaglandin F2 alpha (PGF2 alpha) and vasopressin were investigated. Prazosin fulfilled the criteria for competitive antagonism in concentrations 10(-9)-10(-7) M. The pA2-values were 9.53 in human cystic, 9.74 in pig cystic, and 9.57 in pig hepatic artery. Rauwolscine had no significant effect in the different arteries. In human cystic artery noradrenaline had significantly (P less than 0.05) higher Emax and pEC50-values (135% of the preceding K(+)-induced contraction and 6.4, respectively) compared with pig cystic (106% and 5.7, respectively) and pig hepatic artery (116% and 5.9, respectively). Vasopressin had no effect in the cystic arteries, whereas it had a high potency (pEC50 was 8.5) but low intrinsic activity (Emax was 14%) in pig hepatic artery. Prostaglandin F2 alpha had a significantly higher Emax in human than in pig arteries. No differences were found in pEC50-values. This study indicates a similarity in pharmacological characteristics of some vasoactive drugs especially between pig cystic and hepatic arteries. If this is also true in man, the easily obtainable cystic artery can be used for screening the effect of drugs on the hepatic artery.
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- Wide-Swensson, Dag, et al.
(författare)
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Effects of isradipine, a new calcium antagonist, on maternal cardiovascular system and uterine activity in labour
- 1990
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Ingår i: British Journal of Obstetrics and Gynaecology. - : Wiley. - 1365-215X .- 1470-0328 .- 1471-0528. ; 97:10, s. 945-949
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Tidskriftsartikel (refereegranskat)abstract
- The effects of isradipine (a new calcium antagonist of the dihydropyridine type) on maternal blood pressure and heart rate, fetal heart rate, and uterine activity in labour were measured. Uterine activity was recorded by an intrauterine microtip transducer catheter connected to a fetal monitor. Isradipine was given as a slow injection in doses of 0.5 mg (10 women), 1 mg (11 women), and 1.5 mg (6 women). A reduction of systolic (6-16%) and diastolic (19-22%) blood pressure was seen, and concomitantly there was an increase in maternal (29-34%) and fetal (3-10%) heart rates. Reduction in uterine activity was not dose-related (maximum reduction 17%). Side effects (headache, palpitations) were minor and well tolerated. One women in the high-dose group had a shortlasting episode of hypotension. The results suggest that isradipine given as a bolus dose decreases blood pressure in pregnant women with little effects on uterine activity and fetal heart rate.
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