α₁-adrenergic receptor responses in α_1AB-AR knockout mouse hearts suggest the presence of α_1D-AR

Two functional α₁-adrenergic receptor (AR) subtypes (α_1A and α_1B) have been identified in the mouse heart. However, it is unclear whether the third known subtype, α_1D-AR, is also present. To investigate this, we determined whether there were α₁-AR responses in hearts from a novel mouse model lacking α_1A- and α_1B-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 α_1D-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 α_1A- and α_1B-ARs retain functional α₁-AR responses involving decreases of coronary flow and ventricular pressure that reflect α_1D-AR-mediated vasoconstriction. Furthermore, α₁-AR inotropic responses depend critically on the experimental conditions.