α1-Adrenoceptor subtypes mediate negative inotropy in myocardium from α1A/C-knockout and wild type mice

alpha(1)-Adrenoceptor Subtypes Mediate Negative Inotropy in Myocardium from alpha1(A/C)-Knockout and Wild Type Mice. Journal of Molecular and Cellular Cardiology (2002) 34,1007-1017. Cardiac alpha(1)-adrenoceptors (AR) have two predominant subtypes (alpha(1A)-AR and alpha(1B)-AR) however, their roles in regulating contraction are unclear. We determined the effects of stimulating alpha(1A)-AR (using the subtype-selective agonist A61603) and alpha(1B)-AR (using a gene knockout mouse lacking aIA-AR) separately, and together (using phenylephrine) on Ca2+ transients, intracellular pH, and contraction of mouse cardiac trabeculae. Stimulation of alpha(1)-AR subtypes separately or together caused a triphasic contractile response. After a transient (approximate to3%) force rise (phase 1), force declined markedly (phase 2), then partially recovered (phase 3). In phase 2, the force decline (% of initial) with combined alpha(1A)-AR Plus alpha(1B)-AR stimulation (50+/-3%) was more than with separate subtype stimulation. (P < 0.01), suggesting alpha(1A)-AR and alpha(1B)-AR mediate additive effects during phase 2. Force decline in phase 2 paralleled decreases of Ca2+ transients that were reduced more with combined vs. separate subtype stimulation. During phase 3 the final force reduction was similar with stimulation of alpha(1A)-AR (20+/-5%), or alpha(1B)-AR (20+/-3%), or both (26+/-4%) suggesting alpha(1A)-AR and alpha(1B)-AR mediate non-additive effects during phase 3. In contrast, Ca2+ transients recovered fully in phase 3 suggesting reduced force in phase 3 involved decreased myofilament Ca2+-sensitivity. Decreased Ca2+-sensitivity was not mediated by changes of intracellular pH since this was not affected by alpha(1)-AR stimulation. In contrast to mouse trabeculae, rat trabeculae demonstrated a positive inotropic response to alpha(1)-AR stimulation. In conclusion, for mouse myocardium in vitro both alpha(1)-adrenoceptor subtypes mediate negative inotropy involving decreased Ca2+ transients and a decreased Ca2+ sensitivity that does not involve altered intracellular pH. (C) 2002 Elsevier Science Ltd. All rights reserved.