Mechanisms involved in the regulation of bovine pulmonary vascular tone by the 5-HT1B receptor.
OBJECTIVE
5-HT(1B) receptors may have a role in pulmonary hypertension. Their relationship with the activity of BK(Ca,) a T-type voltage-operated calcium channel (VOCC) and cyclic nucleotide-mediated relaxation was examined.


METHODS
Ring segments of bovine pulmonary arteries were mounted in organ baths in modified Krebs-Henseleit buffer (37 degrees C) under a tension of 20 mN and gassed with 95% O(2)/5% CO(2). Isometric recordings were made using Chart 5 software.


RESULTS
Contractile responses to 5-HT (10 nM-300 microM) were inhibited similarly by the 5-HT(1B) receptor antagonist SB216641 (100 nM) and the T-type VOCC blockers mibefradil (10 microM) and NNC550396 (10 microM) with no additive effect between SB216641 and mibefradil. Inhibition by SB216641 was prevented by the potassium channel blocker, charybdotoxin (100 nM). 5-HT(1B) receptor activation and charybdotoxin produced a mibefradil-sensitive potentiation of responses to U46619. Bradykinin (0.1 nM-30 microM), sodium nitroprusside (0.01 nM-3 microM), zaprinast (1 nM-3 microM), isoprenaline (0.1 nM-10 microM) and rolipram (1 nM-3 microM) produced 50% relaxation of arteries constricted with 5-HT (1-3 microM) or U46619 (30-50 nM) in the presence of 5-HT(1B) receptor activation, but full relaxation of arteries constricted with U46619, the 5-HT(2A) receptor agonist 2,5 dimethoxy-4 iodoamphetamine (1 microM) or 5-HT in the presence of 5-HT(1B) receptor antagonism. Enhanced relaxation of 5-HT-constricted arteries by cGMP-dependent pathways, seen in the presence of the 5-HT(1B) receptor antagonist, was reversed by charybdotoxin whereas cAMP-dependent relaxation was only partly reversed by charybdotoxin.


CONCLUSIONS
5-HT(1B) receptors couple to inhibition of BK(Ca), thus increasing tissue sensitivity to contractile agonists by activating a T-type VOCC and impairing cGMP-mediated relaxation. Impaired cAMP-mediated relaxation was only partly mediated by inhibition of BK(Ca).
McKenzie
C
C
Department of Biological & Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK.
Alapati
V R
VR
MacDonald
A
A
Shaw
A M
AM
D000818:Animals; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000378:metabolism*; D002417:Cattle; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism*; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000008:administration & dosage / Q000494:pharmacology
D020747:Calcium Channels, T-Type; D051036:Large-Conductance Calcium-Activated Potassium Channels; D044302:Receptor, Serotonin, 5-HT1B; D012701:Serotonin; D000242:Cyclic AMP; D006152:Cyclic GMP