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NO-dependent vasodilation induced by nebivolol in coronary circulation is not mediated by beta-adrenoceptors or by 5 HT 1A-receptors

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Chlopicki S., Kozlovski V. I., Gryglewski R. J.

Journal of Physiology and Pharmacology

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2002

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tom 53

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nr 4,1

Nebivolol is a unique ß1-adrenoceptor antagonist which possesses peripheral vasodilator properties dependent on endothelial NO. Nebivolol-induced release of NO was attributed to its L stereoisomer and to its ability to stimulate endothelial ß2, ß3 adrenoceptors or 5-HT1A receptors. Here, in the isolated guinea pig heart we analysed coronary vasodilator potency of L- and D-nebivolol and a possible role of ß2, ß3 adrenoceptors and 5-HT1A receptors in nebivolol-induced vasodilation. Surprisingly, we found that not only L-nebivolol (3-30x10-6 M) but also D-nebivolol (3-30x10-6 M) induced coronary vasodilation, and both responses were inhibited by L-NAME (10-4 M). In contrast with the stereoisomers of nebivolol, atenolol at the equimolar concentrations did induce slight vasoconstriction. The nonselective ß1/ß2- adrenoceptor antagonist - nadolol (10-5 M), the selective ß3-adrenoceptor antagonist - L 748337 (10-6 M) and the 5 HT1A receptor antagonist - NAN 190 (5 x 10-6 M), none of them inhibited coronary vasodilation induced by D- and L-nebivolol. In summary, in the isolated guinea pig heart both D- and L-nebivolol act as coronary vasodilators. Coronary vasodilation induced by stereoisomers of nebivolol is mediated by endothelium-derived NO and does not depend on ß2, ß3 adrenoceptors or 5 HT1A receptors.

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Clonidine-induced coronary vasodilatation in isolated guinea pig heart is not mediated by endothelial alpha2 adrenoceptors

100%

Chlopicki S., Kozlovski V. I., Gryglewski R. J.

Journal of Physiology and Pharmacology

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2003

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tom 54

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nr 4

Functional role of endothelial alpha2-adrenoceptor in coronary circulation remains unclear. Clonidine, an agonist of alpha2-adrenoceptors, was reported to induce coronary vasodilatation via stimulation of endothelial alpha2-adrenoceptors or coronary vasoconstriction involving vascular smooth muscle alpha2-adrenoceptors. Moreover, H2 receptor-dependent responses to clonidine were described. Here, we reassess the contribution of endothelial alpha2-adrenoceptor and H2 receptors to coronary flow and contractility responses induced by clonidine in the isolated guinea pig heart. We found that clonidine (10-9 - 10-6 M) produced concentration-dependent coronary vasoconstriction without a significant change in contractility. This response was inhibited by the alpha1/alpha2-adrenoceptor antagonist - phentolamine (10-5 M) and the selective alpha2-adrenoceptor antagonist yohimbine (10-6 M), but it was not changed by the selective alpha1-adrenoceptor antagonist prazosin (10-6 M). In the presence of nitric oxide synthase inhibitor, L-NAME (10-4 M) the clonidine-induced vasoconstriction was potentiated. Clonidine at high concentrations of 10-5 – 3 x 10-5 M produced coronary vasodilatation, and an increase in myocardial contractility. These responses were abolished by a selective H2-receptor antagonist, ranitidine (10-5 M), but not by phentolamine (10-5 M). We conclude that in the isolated guinea pig heart, clonidine-induced vasoconstriction is mediated by activation of smooth muscle alpha2-adrenoceptors whereas clonidine-induced coronary vasodilatation is mediated by activation of vascular H2 histaminergic receptors. Accordingly, endothelial alpha2-adrenoceptors does not seem to play a major role in coronary flow response induced by clonidine.

3

Paradoxical augmentation of bradykinin-induced vasodilatation by xanthine-xanthine oxidase-derived free radicals in isolated guinea pig heart

100%

Olszanecki R., Kozlovski V. I., Chlopicki S., Gryglewski R. J.

Journal of Physiology and Pharmacology

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2002

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tom 53

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nr 4,1

Increased generation of reactive oxygen species contribute to endothelial dysfunction in atherosclerosis, hypertension and heart failure. Recently, it was suggested that bursts of superoxide anions may inactivate endothelial surface-bound enzymes such as angiotensin converting enzyme (ACE). Here, we tested effects of xanthine/xanthine oxidase-derived superoxide anions on vascular responses and ACE activity in the isolated guinea pig heart. We analysed effects of intracoronary infusion of low concentration of xanthine oxidase (10 mU/ml) in the presence of xanthine (0,5 mM) (X/XO) on bradykinin, other endothelium-dependent and independent vasodilators (acetylcholine, ADP, SNAP), as well as vasoconstrictor responses to angiotensin I and angiotensin II. Surprisingly, X/XO significantly augmented coronary response to bradykinin without an effect on responses to ADP, acetylcholine, SNAP, angiotensin I and angiotensin II. In contrast, inhibition of ACE by perindoprilate (100 nM) resulted in augmentation of bradykinin-induced vasodilatation as well as diminution of angiotensin I-evoked vasoconstriction without an influence on other responses. In summary, in the isolated guinea pig heart, X/XO-derived free radicals selectively augmented coronary vasodilator response to bradykinin, which cannot be explained by X/XO- induced derangement of ACE. The mechanism of this paradoxical phenomenon, which might represent a defensive response of the coronary circulation to oxidative stress requires further investigations.

4

Flavonoids and nitric oxide synthase

100%

Olszanecki R., Gebska A., Kozlovski V. I., Gryglewski R. J.

Journal of Physiology and Pharmacology

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2002

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tom 53

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nr 4,1

Induction of NOS-2 in macrophages and smooth muscles within vascular wall with concomittant suppression of endothelial NOS-3 activity is considered to be a hallmark of vascular inflammation that triggers atherogenesis. Accordingly, drugs designed to reverse these changes should not only support vaning function of NOS-3 but also suppress proinflammatory NO production by NOS-2. It means that using selective inhibitors of induction of NOS-2 (they spare ex definitione constitutive activity of NOS-3) is a more rational approach than using isselectivel. inhibitors of activity of previously induced NOS-2. First of all, those drugs are never sufficiently selective. In our work we tried to identify inhibitors of NOS-2 induction within the group of flavonoids, known stimulators of NOS-3 with putative antiatherogenic effects. Representatives of four main groups of flavonoids: flavonols (kaempferol, quercetin, rutin), flavones (apigenin, primuletin), flavanols (catechine) and flavanones (hesperetin, hesperidin, naringenin) were tried on NOS-2 induction and activity in the in vitro model of LPS-treated macrophages (cell line J774.2). While none of these compounds inhibited activity of NOS-2, all with unexpectedly scattered potencies inhibited induction of NOS-2 protein in LPS-treated J774.2 cells, as evidenced by Western blotting technique. Subsequently, RT-PCR and Northern blotting methods revealed that so far the most potent compounds, kaempferol and apigenin, at micromolar concentrations did inhibit NOS-2 induction at the level of NOS-2 gene transcription. We conclude that some of flavonoids are potent inhibitors of NOS-2 induction. At the same time they may increase endothelial NOS-3 activity. Could these flavonoids become natural parents of future drugs, which will be used for reversal of inflammatory component of atherothrombosis?

Ograniczanie wyników

4 Journal of Physiology and Pharmacology

4 Gryglewski R. J.

4 Kozlovski V. I.

3 Chlopicki S.

2 Olszanecki R.

1 Gebska A.

1 2003

3 2002

NO-dependent vasodilation induced by nebivolol in coronary circulation is not mediated by beta-adrenoceptors or by 5 HT 1A-receptors

Clonidine-induced coronary vasodilatation in isolated guinea pig heart is not mediated by endothelial alpha2 adrenoceptors

Paradoxical augmentation of bradykinin-induced vasodilatation by xanthine-xanthine oxidase-derived free radicals in isolated guinea pig heart

Flavonoids and nitric oxide synthase