α1-Adrenergic receptor responses in α1AB-AR knockout mouse hearts suggest the presence of α1D-AR

Abstract

Two functional α1-adrenergic receptor (AR) subtypes (α1Aand α1B) have been identified in the mouse heart. However, it is unclear whether the third known subtype, α1D-AR, is also present. To investigate this, we determined whether there were α1-AR responses in hearts from a novel mouse model lacking α1A- and α1B-ARs (double knockout) (ABKO). In Langendorff-perfused hearts, α1-ARs were stimulated with phenylephrine. For ABKO hearts, phenylephrine reduced left ventricular pressure and coronary flow (to 87 ± 2% and 86 ± 4% of initial, respectively, n = 11, P < 0.01). These effects were blocked by prazosin and 8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-8-azaspirol[4,5]decane-7,9-dione} dihydrochloride, suggesting that α1D-AR-mediated responses were present. In contrast, right ventricular trabeculae from ABKO hearts did not respond to phenylephrine, suggesting that in ABKO perfused hearts, the effects of phenylephrine were not mediated by direct actions on cardiomyocytes. A novel finding was that α1-AR stimulation caused positive inotropy in the wild-type mouse heart, in contrast to negative inotropy observed in mouse cardiac muscle strips. We conclude that mouse hearts lacking α1A- and α1B-ARs retain functional α1-AR responses involving decreases of coronary flow and ventricular pressure that reflect α1D-AR-mediated vasoconstriction. Furthermore, α1-AR inotropic responses depend critically on the experimental conditions.