Endothelin-1-induced phosphoinositide hydrolysis and contraction in isolated rabbit detrusor and urethral smooth muscle.
1. Endothelin-1 (ET-1) caused a concentration-dependent increase in the formation of inositol phosphates (IPs) in isolated rabbit detrusor and urethral smooth muscle preparations prelabelled with myo-[3H]inositol. 2. The increase in accumulation of IPs was slow in onset in both detrusor and urethra, with no significant accumulation demonstrable during the first 30 min. The increase in IPs accumulation found after exposure of detrusor tissue to ET-1 (10(-7) M) for 2 hr (250 +/- 38%, n = 7) was not significantly different from that found in the urethra (279 +/- 40%, n = 6), when expressed as per cent of corresponding control values. 3. Pretreatment with nifedipine (10(-6) M) did not reduce IPs formation. In contrast, no increase in IPs formation was demonstrated in Ca(2+)-free medium. 4. ET-1 (10(-11)-10(-7) M) produced concentration-dependent, slowly developing contractions in both detrusor and urethral preparations. Pretreatment with H-7 (3 x 10(-5) M) for 30 min before ET-1 application resulted in a non-parallel shift of the ET-1 concentration-response curve with significant reductions in maximal responses in both tissues. 5. ET-1-induced contractions in urethral preparations were markedly inhibited by Ni2+ (3 x 10(-4) M), whereas the effect of Ni2+ in the detrusor was less pronounced. 6. The results suggest that ET-1 stimulates phosphoinositide hydrolysis in the rabbit detrusor and urethra. Both IPs formation and contractile activation evoked by ET-1 are dependent on extracellular Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Clinical Pharmacology, Lund University Hospital, Sweden.
A
A
Garcia-Pascual
K
K
Persson
F
F
Holmquist
K E
KE
Andersson
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D005260:Female; D006868:Hydrolysis; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D009532:Nickel / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011817:Rabbits; D014521:Urethra / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects
D002121:Calcium Channel Blockers; D016232:Endothelins; D007546:Isoquinolines; D010716:Phosphatidylinositols; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D009532:Nickel; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D009543:Nifedipine; D002118:Calcium