DIFFERENCES BETWEEN THE 3RD CARDIAC BETA-ADRENOCEPTOR AND THE COLONICBETA(3)-ADRENOCEPTOR IN THE RAT

1 The heart of several species including man contains atypical beta-ad renoceptors, in addition to coexisting beta(1)- and beta(2)-adrenocept ors. We now asked the question whether or not the third cardiac beta-a drenoceptor is identical to the putative beta(3)-adrenoceptor. We comp ared the properties of the third cardiac beta-adrenoceptor with those of beta(3)-adrenoceptors in isolated tissues of the rat. To study the third cardiac beta-adrenoceptor we used spontaneously beating right at ria, paced left atria and paced left ventricular papillary muscles. As a likely model for putative beta(3)-adrenoceptors we studied atypical beta-adrenoceptors of the colonic longitudinal muscle precontracted w ith 30 mM KCl. We used beta(3)-adrenoceptor-selective agonists, antago nists and non-conventional partial agonists (ie high-affinity blockers of both beta(1)- and beta(2)-adrenoceptors known to exert also stimul ant effects through beta(3)- adrenoceptors). 2 The non-conventional pa rtial agonist (-)-CGP 12177 caused positive chronotropic effects in ri ght atria (pD(2)=7.3) and positive inotropic effects in left atria (pD (2)=7.5). The stimulant effects of (-)-CGP 12177 were resistant to blo ckade by 200 nM-2 mu M (-)-propranolol and 3 mu M ICI 118551 (a beta(2 )-selective antagonist) but antagonized by 1 mu M (-)-bupranolol (pK(B )=6.4-6.8), 3 mu M CGP 20712A (a beta(1)-selective antagonist) (pK(B)= 6.3-6.4) and 6.6 mu M SR 59230A (a beta(3)-selective antagonist, pK(B) =5.1-5.4). 3 The non-conventional partial agonist cyanopindolol caused positive chronotropic effects in right atria (pD(2)=7.7) and positive inotropic effects in left atria (pD(2)=7.1). The stimulant effects of cyanopindolol were resistant to blockade by 200 nM (-)-propranolol bu t antagonized by 1 mu M (-)-bupranolol (pK(B)=6.8-7.1). 4 Neither (-)- CGP 12177 nor cyanopindolol caused stimulant effects in papillary musc les at concentrations between 0.2 nM and 20 mu M. 5 In the presence of 200 nM (-)-propranolol the beta(3)-adrenoceptor-selective agonists BR L 37344 (6 mu M), SR 58611A (6 mu M), ZD 2079 (60 mu M) and CL 316243 (60 mu M) did not cause stimulant effects or modify the potency and ef ficacy of the effects of (-)-CGP 12177 in right and left atria. The co mbination of 2 mu M (-)-propranolol and 2 mu M (-)-noradrenaline did n ot modify the chronotropic potency and efficacy of (-)-CGP 12177 compa red to the potency and efficacy in the presence of 2 mu M (-)propranol ol alone. 6 (-)-CGP 12177 relaxed the colon with a pD(2) of 6.9 and a maximum effect of 55% compared to (-)-isoprenaline. The relaxant effec ts of (-)-CGP 12177 were resistant to blockade by 200 nM (-)-propranol ol, 3 mu M CGP 20712A, 3 mu M ICI 118551 but blocked by 2 mu M (-)-pro pranolol (pK(B)=6.0), 1 mu M (-)-bupranolol (pK(B)=6.4) and 3 mu M SR 59230A (pK(B)=6.3). In the presence of 200 nM (-)-propranolol, (-)-CGP 12177 (20 mu M) antagonized surmountably the relaxant effects of BRL 37344 (pK(p)=7.3), (-)-noradrenaline (pK(p)=7.0); and CL 316243 (pK(p) =7.0). 7 Cyanopindolol in the presence of 200 nM (-)-propranolol relax ed the colon with a pD(2) of 7.0 and a maximum effect of 40% compared to (-)-isoprenaline. As expected from a partial agonist, cyanopindolol antagonized the relaxant effects of both BRL 37344 and CL 316243 with a pK(p)=7.6 and (-)-noradrenaline with a pK(p)=7.4. 8 The following b eta(3)-adrenoceptor-selective agonists were potent colonic relaxants ( pD(2) values between parentheses): BRL 37344 (9.1), ZD 2079 (7.0), CL 316243 (9.0) and SR 58611A (8.2). The relaxant effects of these agonis ts were only marginally affected by 200 nM (-)-propranolol, not blocke d by 3 mu M CGP 20712A or 3 mu M ICI 118551, and blocked by SR 59230A 3 mu M (pK(B)=6.9-7.5), 1 mu M (-)-bupranolol (pK(B)=6.2-6.4) and 2 mu M (-)-propranolol (pK(B)=6.3-6.5). 9 The colonic relaxation caused by the nanomolar concentrations of the beta(3)-adrenoceptor-selective ag onists and the non-conventional partial agonists (-)-CGP 12177 and cya nopindolol and their relative resistance to blockade by antagonists wi th high affinity for beta(1)- and beta(2)-adrenoceptors but blockade b y the beta(3)-adrenoceptor selective SR 59230A agree with the hypothes is that the receptors involved are beta(3)-adrenoceptors. On the other hand, the failure of micromolar concentrations of beta(3)-adrenocepto r-selective agonists to produce cardiac stimulation or affect the card iostimulant effects of (-)-CGP 12177 is inconsistent with the hypothes is that the third cardiac beta-adrenoceptor is beta(3). Additionally, the selective blockade of the colonic putative beta(3)-adrenoceptor co mpared to the third cardiac beta-adrenoceptor by SR 59230A, as well as the blockade of cardiac but not colonic receptors by CGP 20712A is al so inconsistent with an identical putative beta(3)-adrenoceptor in col on and heart. We conclude that in the rat the third cardiac beta-adren oceptor is different from the colonic beta(3)-adrenoceptor.