Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D1-, beta 1- and beta 2-receptor-mediated responses.
1. Rats received intravenous infusions of dopexamine, an agonist with selectivity for D1-dopamine receptors and beta 2-adrenoceptors (240 micrograms kg-1 h-1), isoprenaline, a beta 1- and beta 2-adrenoceptor agonist (40 micrograms 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 responsiveness to beta 1-adrenoceptor, beta 2-adrenoceptor and dopamine D1-receptor stimulation. 2. The beta 1-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 beta 1-adrenoceptor stimulation by isoprenaline. 3. beta 2-Adrenoceptor-mediated relaxation responses to isoprenaline of the pulmonary artery, constricted with noradrenaline (6 x 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. beta 2-Adrenoceptor-mediated vasodilator responses were also examined in the kidney perfused with the thromboxane A2 analogue, U46619 (7.1 x 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.4. The DI-receptor-mediated vasodilator responses to dopamine of the kidney perfused with U46619were reduced after infusion of rats with dopexamine. The maximum fall in perfusion pressure(16.0 mmHg) and ED50 value (5.2 microg) were significantly different from those after vehicle infusion(31.5 mmHg; 1.5 microg).5. These results show that functional responses mediated via beta1-adrenoceptors and DI-receptors are reduced by intravenous infusions of isoprenaline and dopexamine, respectively. In contrast, the beta2-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 beta 1- and D,-receptors, but not of beta 2-adrenoceptors.
Martin
S W
SW
Department of Pharmacology, Welsh School of Pharmacy, University of Wales, Cardiff.
Broadley
K J
KJ
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004298:Dopamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004343:Drug Implants; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007545:Isoproterenol / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects*; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D012079:Renal Circulation / Q000187:drug effects; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D004343:Drug Implants; D011450:Prostaglandin Endoperoxides, Synthetic; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D017447:Receptors, Dopamine D1; C046318:dopexamine; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D007545:Isoproterenol; D004298:Dopamine