Pharmacology zyxwvutsrqpo & Toxicology zyxwvutsr 1992, 70, zyxwvutsrq Suppl. zyxwvutsrq 11, sl-sl0. a- and P-Adrenoceptors in Hypertension:Molecular Biology and Pharmacological Studies Martin C. Michel, Thomas Philipp and Otto-Erich Brodde Department of Internal Medicine, University of Essen, Hufelandstrasse 55, D-4300 Essen 1, Germany Abstract: Recent years have witnessed astonishing progress in our understanding of the molecular basis of adrenoceptor structure, function and regulation and revealed an unexpected heterogeneity of adrenoceptors demonstrating the existence of at least 11 subtypes. This paper discusses the implications of these advances on studies regarding a specific role of adrenoceptors in the development of genetic hypertension. The available data indicate that among the a-adrenoceptor subtypes the a,,-adrenoceptor is the most likely candidate for an alteration specifically linked to genetic hypertension in the animal model of the spontaneously hypertensive rat and possibly in some patients. Alterations of other a-adrenoceptor subtypes may be specific for some forms of genetic hypertension but are unlikely to play an important role for blood pressure regulation. Most P-adrenoceptor alterations appear to occur secondary to blood pressure elevation independently of whether hypertension has occured on a genetic basis or not. Moreover, the mechanisms regulating a- and P-adrenoceptor responsiveness upon prolonged agonist exposure may be altered in hypertension and thereby contribute to the pathophysio- logy of this disease. Abbreviations: Chemicals referred to in this paper by code name only: ARC 239,2-(2,4-[0-methoxyphenyl]-piperazin) 1 -yl; CGP 20,712A, 2-hydroxy-5-(2-[(2-hydroxy-3-(4-[1-methyl-4-trifluoromethyl-2-imidazolyl]phenoxy)propyl{amino]ethoxy)-benzamide; ICI 1 zyxwvutsrqponm 18,55 1, erythro-DL-l-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol; SK&F 104,078, 6-chloro-9-(3-methyl-2-but- enyl)oxyl-3-methyl-'H-2,3,4,5-tetrahydro-3-benzazepine maleate; SZL-49, 1 -(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[2- bicyclo(2,2,2)octa-2,5-diene-2-carbonyl]piperazine; WB 4101, N-[2-(2,6-dimethoxyphenoxy)ethyl]-2,3-dihydro- 1,4-benzod- ioxan-2-methanamine. Multiplicity of adrenoceptor subtypes. Adrenoceptors were first subdivided into the subtypes zyxwvut a and P by Ahlquist in 1948 (Ahlquist 1948). In 1967, Lands et al. proposed a further subdivision of P-adrenoceptors into the subtypes PI and P2 based on the differences in the order of potency of the endogenous agonists adrenaline and noradrenaline (Lands et al. 1967). In the 1970's evidence accumulated from various laboratories that further sub- division was also necessary for the a-adrenoceptors yielding the zyxwvutsrq a,- and the a,-subtype (Berthelsen & Pettinger 1977; Starke 1981). This concept has stood for two decades and still appears to explain sufficiently heterogeneity observed among most functional responses (Wilson et al. 1991). Molecular biological techniques, however, have clearly demonstrated the existence of distinct genes coding for more than the above adrenoceptor subtypes. Thus, current con- cepts distinguish three groups of adrenoceptors, a,, a, and P, which have to be considered subfamilies in the overall super gene family of heptahelical G-protein-linked recep- tors. The assignment of their gene products to the pharma- cologically defined adrenoceptor subtypes, however, is not completely understood. a/-Adrenoceptors. To date four distinct a,-adrenoceptor genes have been cloned (fig. 1). The first was an a,-adrenoceptor isolated from the hamster smooth muscle-derived DDTl MF-2 cell line (Cotecchia et al. 1988). The product of this gene when expressed in COS-7 cells has low affinity for WB 4101 and is sensitive to alkylation by chloroethylclonidine and has been designated an a,,-adrenoceptor (Cotecchia et zyx al. 1988). A homologue of this receptor has also been cloned from the rat (Lomasney et al. I991 b). Further studies have revealed three additional genes cod- ing for a,-adrenoceptor subtypes. One of these genes en- codes a rat receptor which has high afinity for WB 4101 and is insensitive to chloroethylclonidine and has been classified as alA (Lomasney et al. 199lb). A third gene isolated from bovine brain encodes a receptor which has high affinity for WB 4101 and is simultaneously sensitive to chloroethylclonidine and which has been designated as alc (Schwinn et al. 1990). Finally, a fourth a,-adrenoceptor subtype has been cloned from rat (Perez et al. 1991); this subtype has the greatest homology with the a,,-adrenocep- tor but following expression in COS-7 cells its gene product has pharmacological characteristics which are distinct from the aIA- and the a,,-subtype and include high sensitivity to the alkylating agent SZL-49. The genes for the aIA- and a,,-adrenoceptor are lo- cated on the human chromosome zyx 5 (regions 5q32-34 and 5q23-3 I, respectively) whereas the u,,adrenoceptor gene has been mapped to chromosome 8 (Lomasney et al. 1991 a); the chromosomal localization of the a,,-adrenoceptor has not yet been determined. In contrast to most other members of the family of heptahelical receptors in particular to the P- and a,-adrenoceptors, the genes for the a,,- and the ale- adrenoceptor subtypes have introns; whether the same is also true for the aIA- and a,,-adrenoceptor has not been determined yet. This opens the possibility that splicing vari-