Fibrotic valvular heart disease (VHD) has been observed in patients with Parkinson's disease treated with dopamine receptor agonists such as pergolide and cabergoline. 5-hydroxytryptamine2B receptor (5-HT2BR) agonism is the most likely cause but other 5-HTRs may also play a role in VHD. We aimed at characterizing the molecular fragment of cabergoline being responsible for agonism at 5-HT2B and 5-HT2ARs. Cabergoline with an allyl substituent at N(6) behaved as a potent 5-HT2BR full agonist in relaxation of porcine pulmonary arteries and as a weaker 5-HT2AR partial agonist in contraction of coronary arteries. The same was true for cabergoline derivatives with cyclopropylmethyl, propyl or ethyl at N(6). However, agonism was converted into antagonism, when the N(6) substituent was methyl. 6-Methylcabergoline retained agonism compared to cabergoline at human hD2L and hD2SRs as determined by [35S]GTPγS binding. In porcine aortic valve cusps, 5-HT-induced contractions were inhibited by ketanserin (5-HT2A/2CR antagonist) but not by SB204741 (5-HT2BR antagonist). In porcine valvular interstitial cells, cabergoline-induced activation of ERK1/2, an initiator of cellular proliferation and activity, was blocked by MDL100907 (5-HT2AR antagonist) and GR127935 (5-HT1BR antagonist), whereas the stimulatory effect on 3H-proline and 3H-glucosamine incorporations (indices of extracellular matrix collagen and glycosaminoglycan) was blocked by MDL100907. We conclude that the bulky N(6) substituent of cabergoline is responsible for 5-HT2A and 5-HT2BR agonism. The increased ERK1/2 phosphorylation and production of extracellular matrix by cabergoline are mediated by 5-HT2ARs. However, the moderate potency of cabergoline at native 5-HT2ARs suggests that these are not the preferential target in VHD in vivo.
- Received March 4, 2011.
- Revision received April 19, 2011.
- Accepted April 19, 2011.
- The American Society for Pharmacology and Experimental Therapeutics