Mechanisms involved in the regulation of bovine pulmonary vascular tone by the 5‐HT1B receptor

Background and purpose: 5‐HT1B receptors may have a role in pulmonary hypertension. Their relationship with the activity of BKCa, a T‐type voltage‐operated calcium channel (VOCC) and cyclic nucleotide‐mediated relaxation was examined. Experimental approach: Ring segments of bovine pulmonary arteries were mounted in organ baths in modified Krebs–Henseleit buffer (37oC) under a tension of 20 mN and gassed with 95% O2/5% CO2. Isometric recordings were made using Chart 5 software. Key results: Contractile responses to 5‐HT (10 nM–300 µM) were inhibited similarly by the 5‐HT1B receptor antagonist SB216641 (100 nM) and the T‐type VOCC blockers mibefradil (10 µM) and NNC550396 (10 µM) with no additive effect between SB216641 and mibefradil. Inhibition by SB216641 was prevented by the potassium channel blocker, charybdotoxin (100 nM). 5‐HT1B receptor activation and charybdotoxin produced a mibefradil‐sensitive potentiation of responses to U46619. Bradykinin (0.1 nM–30 µM), sodium nitroprusside (0.01 nM–3 µM), zaprinast (1 nM–3 µM), isoprenaline (0.1 nM–10 µM) and rolipram (1 nM–3 µM) produced 50% relaxation of arteries constricted with 5‐HT (1–3 µM) or U46619 (30–50 nM) in the presence of 5‐HT1B receptor activation, but full relaxation of arteries constricted with U46619, the 5‐HT2A receptor agonist 2,5 dimethoxy‐4 iodoamphetamine (1 µM) or 5‐HT in the presence of 5‐HT1B receptor antagonism. Enhanced relaxation of 5‐HT‐constricted arteries by cGMP‐dependent pathways, seen in the presence of the 5‐HT1B receptor antagonist, was reversed by charybdotoxin whereas cAMP‐dependent relaxation was only partly reversed by charybdotoxin. Conclusions and implications: 5‐HT1B receptors couple to inhibition of BKCa, 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 BKCa.