Interaction of selected vasodilating beta-blockers with adrenergic receptors in human cardiovascular tissues.
beta- And alpha 1-adrenoceptor antagonist properties of bufuralol, carvedilol, celiprolol, dilevalol, labetalol, and pindolol were investigated in human myocardium and mammary artery using binding techniques and functional studies. In myocardial membranes, beta-adrenoceptor antagonists showed monophasic competition isotherms for [125I]pindolol binding with high affinity (Ki from 1-100 nM), except for celiprolol which displayed a biphasic competition isotherm (pKi = 6.4 +/- 0.06 for beta 1- and 4.8 +/- 0.07 for beta 2-adrenoceptors). Drug interactions with alpha 1-adrenoceptors were evaluated in human mammary artery by [3H]prazosin binding and by measuring contractile responses to norepinephrine (NE). Labetalol and carvedilol showed a moderate affinity for alpha 1-adrenoceptors (pKi = 6.2 +/- 0.01 and 6.1 +/- 0.06, respectively), and inhibited NE-induced contractions (pA2 = 6.93 +/- 0.23 and 8.64 +/- 0.24, respectively). Dilevalol, bufuralol, and pindolol displayed weak effect both in binding (Ki in micromolar range) and functional experiments (pA2 = 5.98, 5.54, and 6.23, respectively). Celiprolol did not show antagonist properties up to 100 microM in functional studies, but displayed a slight affinity for alpha 1-adrenoceptors in binding studies. The data indicate that the vasodilating activity of these beta-adrenoceptor antagonists is caused in some instances by an alpha 1-adrenoceptor antagonism (labetalol, carvedilol), whereas for the others alternative mechanisms should be considered.
Monopoli
A
A
Research Laboratories, Essex Italia, Subsidiary of Schering-Plough, Milan.
Forlani
A
A
Bevilacqua
M
M
Vago
T
T
Norbiato
G
G
Bertora
P
P
Biglioli
P
P
Alamanni
F
F
Ongini
E
E
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D002319:Cardiovascular System / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008323:Mammary Arteries / Q000187:drug effects; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010869:Pindolol / Q000378:metabolism; D011224:Prazosin / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011941:Receptors, Adrenergic / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D007457:Iodine Radioisotopes; D011506:Proteins; D011941:Receptors, Adrenergic; D014665:Vasodilator Agents; D010869:Pindolol; D009638:Norepinephrine; D011224:Prazosin