Atypical beta-adrenoceptors, different from beta 3-adrenoceptors and probably from the low-affinity state of beta 1-adrenoceptors, relax the rat isolated mesenteric artery

Abstract

(1) We examined whether beta3- and/or atypical beta-adrenoceptors relax the rat isolated mesenteric artery. (2) Mesenteric arteries precontracted with phenylephrine were relaxed by beta-agonists with the following potencies (pD2): nonselective agonist isoprenaline (6.00)>nonconventional partial agonist cyanopindolol (5.45)>beta2-agonist fenoterol (4.98)>nonconventional partial agonist CGP 12177 (4.19)>beta3-agonist ZD 2079 (3.72). The beta3-agonist CL 316243 1 mm relaxed the vessel only marginally. (3) The concentration-response curves (CRCs) for cyanopindolol, CGP 12177 and ZD 2079 were not affected by the nonselective beta-antagonist propranolol 0.3 microm, the beta2-antagonist ICI 118551 1 microm and by CL 316243 60 microm, but shifted to the right by bupranolol (pA2 5.3-5.7), CGP 20712 (5.4) and SR 59230A (6.5-6.7) (the latter three drugs block atypical and/or beta3-adrenoceptors at high concentrations). (4) The CRC for isoprenaline was shifted to the right by propranolol (pA2 7.0) but, in the presence of propranolol 0.3 microm, not affected by SR 59230A 1 microm. The CRC for fenoterol was shifted to the right by propranolol (pA2 6.9) and ICI 118551 (6.8). (5) Removal of endothelium diminished the vasorelaxant effects of cyanopindolol, CGP 12177 and ZD 2079. (6) Fenoterol and cyanopindolol also relaxed (endothelium-intact) mesenteric arteries precontracted with serotonin. The relaxant effect of cyanopindolol was antagonized by bupranolol to about the same degree as in phenylephrine-contracted vessels. (7) In conclusion, beta2- and atypical beta-adrenoceptors (but not beta3-adrenoceptors) relax the rat mesenteric artery. The atypical beta-adrenoceptor, which is partially located endothelially, may differ from the low-affinity state of the beta1-adrenoceptor.

Figure 1

Effects of β-adrenoceptor agonists in rat mesenteric artery. Results are expressed as percentage relaxation of tone induced by phenylephrine. Means±s.e.m. of four to 25 tissues for each curve. For many points s.e.m. is contained within the symbols.

Figure 2

Influence of β-adrenoceptor antagonists on relaxation induced by isoprenaline and fenoterol in the rat mesenteric artery preconstricted with phenylephrine. Results are expressed as percentage relaxation of tone induced by phenylephrine. PRO − propranolol 0.3 μM. Means±s.e.m. of four to 13 tissues for each curve. For many points s.e.m. is contained within the symbols.

Figure 3

Influence of propranolol 0.3 μM (PRO) and CL 316243 60 μM (CL) on relaxation induced by cyanopindolol (CYP), CGP 12177 (CGP) and ZD 2079 (ZD) in the rat mesenteric artery preconstricted with phenylephrine. Results are expressed as percentage relaxation of tone induced by phenylephrine. Means±s.e.m. of three to 25 tissues for each curve. For many points s.e.m. is contained within the symbols.

Figure 4

Influence of β-adrenoceptor antagonists on relaxation induced by cyanopindolol (a, b), CGP 12177 (c, d) and ZD 2079 (e, f) in rat mesenteric artery preconstricted with phenylephrine. Results are expressed as percentage relaxation of tone induced by phenylephrine. Note that for SR 59230A, which was dissolved in DMSO, a separate control curve was determined. Means±s.e.m. of three to 25 tissues for each curve. For many points s.e.m. is contained within the symbols.

Figure 5

Effects of cyanopindolol ((a) – 100 μM; (b) −10 and 100 μM) and fenoterol ((a) −1 mM) in rat mesenteric artery preconstricted with phenylephrine ((a, b); PHE; 1 μM), serotonin ((a, b); 5-HT; 2 μM), PGF_2α ((a); PGF; 10 μM) and U 44069 ((a); 0.1 μM). Some experiments were performed in the presence of bupranolol (b). Results are expressed as percentage relaxation of tone induced by respective compound. Means±s.e.m. of three to 15 tissues. ^*P<0.05; ^**P<0.01 and ^***P<0.001 compared to the corresponding control.

Figure 6

Influence of endothelium removal on relaxation induced by cyanopindolol, CGP 12177 and ZD 2079 in rat mesenteric artery preconstricted with phenylephrine. Results are expressed as percentage relaxation of tone induced by phenylephrine. Means±s.e.m. of five to 25 tissues for each curve. For many points s.e.m. is contained within the symbols.