To investigate the mechanisms of alpha1-adrenergic vascular desensitization, osmotic minipumps containing either saline (n=9) or amidephrine mesylate (AMD) (n=9), a selective alpha1-adrenergic receptor agonist, were implanted subcutaneously in dogs with chronically implanted arterial and right atrial pressure catheters and aortic flow probes. After chronic alpha1-adrenergic receptor stimulation, significant physiological desensitization to acute AMD challenges was observed, i.e., pressor and vasoconstrictor responses to the alpha1-adrenergic agonist were significantly depressed (p<0.01) compared with responses in the same dogs studied in the conscious state before pump implantation. However, physiological desensitization to acute challenges of the neurotransmitter norepinephrine (NE) (0.1 mug/kg per minute) in the presence of beta-adrenergic receptor blockade was not observed for either mean arterial pressure (MAP) (30+/-7 versus 28+/-5 mm Hg) or total peripheral resistance (TPR) (29.8+/-4.9 versus 28.9+/-7.3 mm Hg/l per minute). In the presence of beta-adrenergic receptor plus ganglionic blockade after AMD pump implantation, physiological desensitization to NE was unmasked since the control responses to NE (0.1 mug/kg per minute) before the AMD pumps were now greater (p<0.01) than after chronic AMD administration for both MAP (66+/-5 versus 32+/-2 mm Hg) and TPR (42.6+/-10.3 versus 23.9+/-4.4 mm Hg/l per minute). In the presence of beta-adrenergic receptor, ganglionic, plus NE-uptake blockade after AMD pump implantation, desensitization was even more apparent, since NE (0.1 mug/kg per minute) induced even greater differences in MAP (33+/-5 versus 109+/-6 mm Hg) and TPR (28.1+/-1.8 versus 111.8+/-14.7 mm Hg/l per minute). The maximal force of contraction induced by NE in the presence or absence of endothelium was significantly decreased (p<0.05) in vitro in mesenteric artery rings from AMD pump dogs compared with saline control dogs. Furthermore, alpha1-adrenergic receptor density, as determined by [H-3]prazosin binding in membrane preparations from vessels in the mesentery, was decreased (8.2-1.0 versus 18.4+/-1.4 fmol/mg protein, p<0.001) without any change in K(d) in the AMD pump dogs compared with the saline pump dogs. In aortic membranes alpha1-adrenergic receptor density in AMD pump dogs did not differ from saline pump dogs, but the affinity of the aortic receptors for [H-3]prazosin binding was decreased (K(d), 0.29+/-0.07 versus 0.14+/-0.01 nM, p<0.01), and NE-induced displacement of [H-3]prazosin binding demonstrated a loss of high-affinity binding sites (12+/-9 versus 82+/-2 percent, p<0.05). Thus, although endothelial mechanisms do not appear important, both autonomic reflex and biochemical mechanisms are altered by chronic alpha1-adrenergic receptor stimulation in the conscious dog; the altered autonomic mechanisms affect the physiological expression of desensitization, whereas separate biochemical mechanisms observed in vessels of different caliber mediate the desensitization.
