Kaumann A J, Preitner F, Sarsero D, Molenaar P, Revelli J P, Giacobino J P
The Babraham Institute, Cambridge, UK.
Mol Pharmacol. 1998 Apr;53(4):670-5. doi: 10.1124/mol.53.4.670.
Some blockers of beta1- and beta2-adrenoceptors cause cardiostimulant effects through an atypical beta-adrenoceptor (putative beta4-adrenoceptor) that resembles the beta3-adrenoceptor. It is likely but not proven that the putative beta4-adrenoceptor is genetically distinct from the beta3-adrenoceptor. We therefore investigated whether or not the cardiac atypical beta-adrenoceptor could mediate agonist effects in mice lacking a functional beta3-adrenoceptor gene (beta3 KO). (-)-CGP 12177, a beta1- and beta2-adrenoceptor blocker that causes agonist effects through both beta3-adrenoceptors and cardiac putative beta4-adrenoceptors, caused cardiostimulant effects that were not different in atria from wild-type (WT) mice and beta3 KO mice. The effects of (-)-CGP 12177 were resistant to blockade by (-)-propranolol (200 nM) but were blocked by (-)-bupranolol (1 microM) with an equilibrium dissociation constant of 15 nM in WT and 17 nM in beta3 KO. (-)-[3H]CGP 12177 labeled a similar density of the putative beta4-adrenoceptor in ventricular membranes from the hearts of both WT (Bmax = 52 fmol/mg protein) and beta3 KO (Bmax = 53 fmol/mg protein) mice. The affinity of (-)-[3H]CGP 12177 for the cardiac putative beta4-adrenoceptor was not different between WT (Kd = 46 nM) and beta3 KO (Kd= 40 nM). These results provide definitive evidence that the cardiac putative beta4-adrenoceptor is distinct from the beta3-adrenoceptor.
一些β1和β2肾上腺素能受体阻滞剂通过一种类似于β3肾上腺素能受体的非典型β肾上腺素能受体（假定的β4肾上腺素能受体）产生心脏刺激作用。假定的β4肾上腺素能受体在基因上可能与β3肾上腺素能受体不同，但尚未得到证实。因此，我们研究了心脏非典型β肾上腺素能受体是否能在缺乏功能性β3肾上腺素能受体基因的小鼠（β3基因敲除小鼠）中介导激动剂效应。（-）-CGP 12177是一种β1和β2肾上腺素能受体阻滞剂，可通过β3肾上腺素能受体和心脏假定的β4肾上腺素能受体产生激动剂效应，其在野生型（WT）小鼠和β3基因敲除小鼠心房中引起的心脏刺激效应并无差异。（-）-CGP 12177的效应不受（-）-普萘洛尔（200 nM）的阻断，但可被（-）-布普萘洛尔（1 μM）阻断，在WT小鼠中的平衡解离常数为15 nM，在β3基因敲除小鼠中为17 nM。（-）-[3H]CGP 12177在WT小鼠（Bmax = 52 fmol/mg蛋白质）和β3基因敲除小鼠（Bmax = 53 fmol/mg蛋白质）心脏心室膜中标记的假定β4肾上腺素能受体密度相似。（-）-[3H]CGP 12177对心脏假定β4肾上腺素能受体的亲和力在WT小鼠（Kd = 46 nM）和β3基因敲除小鼠（Kd = 40 nM）之间没有差异。这些结果提供了确凿的证据，证明心脏假定的β4肾上腺素能受体与β3肾上腺素能受体不同。
