title: Alpha 1-adrenoceptor antagonist activity of novel pyrimidine derivatives (SHI437 and IK29) in rabbit aorta and trigone of the bladder.
abstract: 1. In the rabbit isolated aorta and trigone of the bladder, noradrenaline, phenylephrine and clonidine elicited concentration-dependent contractions, which may be caused through activation of postsynaptic alpha 1-adrenoceptors. 2. SHI437, IK29, prazosin and yohimbine competitively antagonized the contractile responses induced by noradrenaline in the aorta and trigone. The pA2 values of SHI437, IK29, prazosin and yohimbine were 7.35 +/- 0.09, 7.47 +/- 0.10, 8.55 +/- 0.02 and 6.28 +/- 0.05 in the aorta, and 8.07 +/- 0.04, 8.30 +/- 0.03, 8.22 +/- 0.04 and 6.46 +/- 0.04 in the trigone, respectively. 3. SHI437, IK29, prazosin and yohimbine also possessed competitive alpha 2-adrenoceptor blocking properties, judging from their antagonism of the clonidine-induced inhibitory effect on the twitch responses in the electrically stimulated vas deferens of the rat. The pA2 values of SHI437, IK29, prazosin and yohimbine were determined to be 4.76 +/- 0.02, 4.74 +/- 0.02, 5.06 +/- 0.03 and 7.86 +/- 0.04, respectively. 4. SHI437, IK29 and prazosin inhibited the contractile responses elicited by transmural electrical stimulation without affecting the evoked 3H-overflow from the [3H]-noradrenaline-preloaded rabbit aorta. Yohimbine augmented the contractile responses and 3H-overflow. 5. SHI437 and IK29 at a concentration sufficient to inhibit noradrenaline-induced contraction failed to attenuate the contractile responses of aorta to KCl, 5-hydroxytryptamine and prostaglandin F2 alpha, and of the trigone to acetylcholine and histamine. 6. The present results suggest that SHI437 and IK29 are highly selective alpha 1-adrenoceptor antagonists, especially in the trigone of the bladder.
authors.affiliation: Department of Medicinal Chemistry, Tokyo Medical and Dental University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Azuma
authors.forename: M
authors.initials: M
authors.lastname: Sugimoto-Tokushima
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Ikenoue
authors.forename: S
authors.initials: S
authors.lastname: Ito
authors.forename: M
authors.initials: M
authors.lastname: Ishikawa
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D004558:Electric Stimulation; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
chemical_list: D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; D011743:Pyrimidines; C060265:IK 29; C060264:SHI 437; D010656:Phenylephrine; D012701:Serotonin; D011189:Potassium Chloride; D006632:Histamine; D015237:Dinoprost; D003000:Clonidine; D009638:Norepinephrine