Alpha 1-adrenoceptor antagonist activity of novel pyrimidine derivatives (SHI437 and IK29) in rabbit aorta and trigone of the bladder.
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.
Azuma
H
H
Department of Medicinal Chemistry, Tokyo Medical and Dental University, Japan.
Sugimoto-Tokushima
M
M
Tanaka
K
K
Ikenoue
Y
Y
Ito
S
S
Ishikawa
M
M
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
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