Actions of thalidomide in producing vascular relaxations.

We have investigated the cardiovascular actions of thalidomide in vivo and in vitro. Blood pressure was recorded in pentobarbitone anaesthetized rats. Isometric contractions were examined in rings of rat tail artery and aorta. Radioligand binding studies of alpha(1A)- and alpha(1B)-adrenoceptor sites were carried out in membranes of rat submandibular gland and spleen, respectively. In pentobarbitone anaesthetized rats, thalidomide and the T-type calcium channel blocker NNC55-0396 (both 1mg/kg, i.v.) significantly reduced blood pressure. In rat tail artery, thalidomide (10-100 microM) produced relaxations of phenylephrine (1 microM) induced contractions. Also in tail artery, thalidomide (100 microM) significantly reduced the contraction to phenylephrine (1 microM), but not KCl (40mM), produced by calcium restoration, and NNC55-0396 (100 microM) had similar actions to thalidomide. Glibenclamide (10 microM), calphostin C (1 microM) or SB203580 (1 microM) failed to affect the inhibitory actions of thalidomide, and thalidomide did not affect contractions to caffeine (10mM). Ligand binding studies found no evidence for alpha(1A)- or alpha(1B)-adrenoceptor affinity of thalidomide, and functional studies in rat aorta found no evidence for alpha(1D)-adrenoceptor affinity. It is concluded that thalidomide has previously unreported vascular relaxant actions. Relaxant actions in vitro do not seem to involve alpha(1)-adrenoceptors, caffeine sensitive calcium stores, glibenclamide sensitive potassium channels, protein kinase C (PKC) or P38 mitogen activated protein kinase (P38 MAP kinase). However, actions of thalidomide resembled those of the T-type calcium channel blocker NNC 55-0396. Further study is necessary to establish the mode of action of thalidomide in causing relaxations.