Phenylephrine contracts porcine pulmonary veins via alpha(1B)-, alpha(1D)-, and alpha(2)-adrenoceptors.
We have recently shown that the postjunctional alpha(2)-adrenoceptor mediating contraction of porcine pulmonary veins is of the alpha(2C)-subtype. We could also demonstrate that alpha(1)-adrenoceptors might contribute to the contraction in that blood vessel. In the present study, we aimed at characterising the alpha(1)-adrenoceptor subtype(s) involved using pharmacological and molecular biological methods. In isolated rings of porcine pulmonary veins the typical alpha(1)-adrenoceptor agonist phenylephrine caused a concentration-dependent contraction that was inhibited by the alpha(1B)-adrenoceptor selective antagonists 1-[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-2-[2-(isopropyl)-6-methoxyphenoxy]ethan-1-one (Rec15/2615; pA(2) 8.96+/-0.13) and 4-amino-2-[4-[1-(benzyloxycarbonyl)-2(S)-[[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6,7-dimethoxyquinazoline (L-765,314; pA(2) 7.22+/-0.05), as well as the alpha(1D)-adrenoceptor selective antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY7378; pA(2) 8.29+/-0.15, slope of the Schild plot 0.75+/-0.09, significantly different from unity, P<0.05), but not by the alpha(1A)-adrenoceptor selective antagonists (+/-)-1,3,5-trimethyl-6-[[3-[4-((2,3-dihydro-2-hydroxymethyl)-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl]amino]-2,4(1H,3H)-pyrimidinedione (B8805-033) and N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha,alpha-dimethyl-1H-indole-3-ethanamine (RS-17053). These findings suggest that phenylephrine activates both alpha(1B)- and alpha(1D)-adrenoceptors. The observation was confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR) in porcine pulmonary veins, where mRNA signals for alpha(1B)- and alpha(1D)-adrenoceptors could be detected. However, the antagonist properties of rauwolscine and yohimbine (non-subtype selective alpha(2)-adrenoceptor antagonists) against phenylephrine showed that this agonist also activates alpha(2)-adrenoceptors in pulmonary veins. This was strengthened in experiments using tissues that were stimulated with forskolin (cell permeable activator of adenylyl cyclase). Phenylephrine mimicked the effect of the selective alpha(2)-adrenoceptor agonist UK14304 by causing an inhibition of forskolin-stimulated cAMP accumulation that was blocked by rauwolscine. It is concluded that, in addition to alpha(1B)- and alpha(1D)-adrenoceptors, phenylephrine can stimulate alpha(2)-adrenoceptors in porcine pulmonary veins.
Freie Universität Berlin, Institut für Pharmazie, Berlin (Dahlem), Germany.
Tilo
T
Görnemann
Carlos M
CM
Villalón
David
D
Centurión
Heinz H
HH
Pertz
D000262:Adenylyl Cyclases / Q000378:metabolism; D000322:Adrenergic Agonists / Q000494:pharmacology*; D018674:Adrenergic Antagonists / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D066298:In Vitro Techniques; D010656:Phenylephrine / Q000494:pharmacology*; D011667:Pulmonary Veins / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011941:Receptors, Adrenergic / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
D000322:Adrenergic Agonists; D018674:Adrenergic Antagonists; D012333:RNA, Messenger; D011941:Receptors, Adrenergic; D010656:Phenylephrine; D015016:Yohimbine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases