Evidence for the presence of regional differences in the calcium antagonist receptors in lower urinary tract smooth muscle.
(+)-[3H]PN 200-100 (a dihydropyridine calcium channel antagonist) was utilized to characterize calcium channel binding sites in rabbit bladder dome, bladder base, and urethra. Specific binding of (+)-[3H]PN 200-110 to membrane particulates was saturable, reversible, linear to protein concentration, and of high affinity. The density of (+)-[3H]PN 200-110 binding sites (Bmax values in fmol/mg of protein) and the affinity constants for (+)-[3H]PN 200-110 (KD value in pM) in urethra, bladder dome and bladder base were 64.1 +/- 7.8 and 179 +/- 31; 21.9 +/- 3.0 and 213 +/- 36; and 18.8 +/- 4.2 and 140 +/- 28, respectively. Agonists and antagonists inhibited (+)-[3H]PN 200-110 binding with Ki values in the following rank order: nitrendipine less than nifedipine less than niguldipine much less than Bay K 8644 much less than verapamil. Although carbachol-induced contractile responses were 20-30 times smaller in muscle strips from urethra than from bladder base or bladder dome, KCl-induced contractions were only 3-4 times smaller in urethra than in bladder tissues. Nifedipine inhibited carbachol-induced contractions in urethra, bladder dome, and bladder base by 76%, 64%, and 60%, respectively, and completely inhibited KCl-induced contractions in all three tissues. IC50 values for nifedipine inhibition of both carbachol- and KCl-induced contractions were significantly smaller in urethra than in bladder base or bladder dome. Nitrendipine, niguldipine and verapamil inhibited urethral contractions induced by carbachol and KCl to the same degree as did nifedipine. The IC50 values, obtained from functional studies, for calcium channel antagonists were in good agreement with Ki values obtained from binding studies.(ABSTRACT TRUNCATED AT 250 WORDS)
Latifpour
J
J
Section of Urology, Yale University School of Medicine, New Haven, CT 06510.
Yoshida
M
M
Weiss
R M
RM
D000818:Animals; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D004095:Dihydropyridines / Q000378:metabolism* / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D017275:Isradipine; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D011817:Rabbits; D014551:Urinary Tract / Q000187:drug effects / Q000378:metabolism
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C038806:1,4-dihydropyridine; D002217:Carbachol; D009543:Nifedipine; D017275:Isradipine