Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D1‐, β1‐ and β2‐receptor‐mediated responses

Rats received intravenous infusions of dopexamine, an agonist with selectivity for D1‐dopamine receptors and β2‐adrenoceptors (240 μg kg−1 h−1), isoprenaline, a β1‐ and β2‐adrenoceptor agonist (40 μg kg−1 h−1) or vehicle (isotonic saline at pH 2.5) for 7 days via subcutaneously implanted osmotic minipumps. Tissues were then removed for determination of functional responsivenss to β1‐adrenoceptor, β2‐adrenoceptor and dopamine D1‐receptor stimulation. The β1‐adrenoceptor‐mediated responses of the spontaneously beating right atrium (increase in rate) and paced left atrium (increase in tension) showed significant reductions in sensitivity to isoprenaline following isoprenaline infusion. The EC50 values were significantly increased from 5.6 to 17.7 nm in right atria and from 7.4 to 27.1 nm in left atria. The maximum rate increase of right atria was also significantly less after isoprenaline infusion compared with controls (164.0 and 251.9 beats min−1, respectively) but the maximum tension responses of left atria were not significantly different. After infusion with dopexamine, however, there was no change in sensitivity of the left or right atria to β1‐adrenoceptor stimulation by isoprenaline. β2‐Adrenoceptor‐mediated relaxation responses to isoprenaline of the pulmonary artery, constricted with noradrenaline (6 × 10−8 m), showed no significant difference in maximum response or EC50 in tissue from isoprenaline‐ or dopexamine‐infused rats compared with vehicle‐infused controls. β2‐Adrenoceptor‐mediated vasodilator responses were also examined in the kidney perfused with the thromboxane A2 analogue, U46619 (7.1 × 10−8 m) to raise perfusion pressure. As with the pulmonary artery, there was no significant difference in ED50 or maximum response to isoprenaline in kidneys from isoprenaline‐infused animals compared with vehicle controls. The D1‐receptor‐mediated vasodilator responses to dopamine of the kidney perfused with U46619 were reduced after infusion of rats with dopexamine. The maximum fall in perfusion pressure (16.0 mmHg) and ED50 value (5.2 μg) were significantly different from those after vehicle infusion (31.5 mmHg; 1.5 μg). These results show that functional responses mediated via β1‐adrenoceptors and D1‐receptors are reduced by intravenous infusions of isoprenaline and dopexamine, respectively. In contrast, the β2‐adrenoceptor‐mediated vasodilator responses of the pulmonary artery and kidney are not reduced by these agonists. Thus, under identical conditions, there appears to be selective down‐regulation of peripheral β1‐ and D1‐receptors, but not of β2‐adrenoceptors.