Vasospastic persons exhibit differential expression of ABC-transport proteins.

ATP binding cassette (ABC) transporter proteins belong to a large superfamily of transport proteins that are highly conserved across evolution [1]. These transport proteins mediate the translocation of different structurally unrelated molecules across various membranes and are expressed in different tissues. They are located in the plasma membrane or in the membrane of different cellular organelles [2]. Therefore, they control the distribution of endogenous metabolic products and exogenous xenobiotics on a subcellular level as well as in the organism as a whole. Some of these proteins form specific membrane channels [3]. Others facilitate the transport of inorganic ions, or pump various organic compounds [4]. For this transport activity, ABC proteins utilize the energy of ATP hydrolysis [5]. Numerous clinical data, mainly derived from cancer research, have revealed that the multidrug resistance phenotype is often associated with the over-expression of certain ABC transporters, termed multidrug resistance (MDR) proteins. The P-glycoprotein (Pgp, MDR1, ABCB1) mediated multidrug resistance was the first discovered [6-9] and probably still is the most widely observed mechanism in clinical multidrug resistance [10]. Beside Pgp, other efflux-pumps belonging to the group of multidrug resistance-associated proteins with 7 homologues (MRP1-MRP7) were characterized. Over-expression of some of these transport proteins lead to MDR phenotype [11,12]. MDR proteins possess a broad substrate specifity [2]. Therefore, acute inhibition or decreased expression of such MDR proteins may result in an enhanced uptake and systemic accumulation of drugs, which may lead to an increased sensitivity or toxicity. Self-reported observations of vasospastic subjects revealed an enhanced sensitivity to different drugs such as beta blockers and calcium channel blockers (many of them are substrates of MDR transport proteins). All these subjects showed characteristic symptoms for the vasospastic syndrome like an inborn tendency towards cold hands and sometimes cold feet, a low body mass index, and low blood pressure that fluctuates markedly [13]. They also often show a slower sleep onset [14], significantly less feelings of thirst coupled with less daily fluid intake (unpublished data), and a higher plasma level of endothelin [13]. Recently it was shown that Endothelin-1 (ET-1) in subnanomolar to nanomolar concentrations was able to rapidly reduce the activity of MRP2 mediated drug transport in shark rectal gland [15]. This effect of MRP2 function could be confirmed in killifish renal proximal tubules [16] and a similar inhibitory effect was seen for P-glycoprotein. Both effects could be abolished when an ET B receptor antagonist was given but not when an ET A receptor antagonist was given. This prompted us to investigate the expression levels of Pglycoprotein and MRP1 to MRP5 in subjects with vasospastic syndrome and elevated ET-1 plasma levels, and compare it with the expression of these transport proteins in healthy controls. ©2003 Molecular Vision