To investigate the mechanisms of α1-adrenergic vascular desensitization, osmotic minipumps containing either saline (n=9) or amidephrine mesylate (AMD) (n=9), a selective α1-adrenergic receptor agonist, were implanted subcutaneously in dogs with chronically implanted arterial and right atrial pressure catheters and aortic flow probes. After chronic α1-adrenergic receptor stimulation, significant physiological desensitization to acute AMD challenges was observed, i.e., pressor and vasoconstrictor responses to the α1-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 μg/kg per minute) in the presence of β-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 β-adrenergic receptor plus ganglionic blockade after AMD pump implantation, physiological desensitization to NE was unmasked since the control responses to NE (0.1 μg/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 β-adrenergic receptor, ganglionic, plus NE-uptake blockade after AMD pump implantation, desensitization was even more apparent, since NE (0.1 μg/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, α1-adrenergic receptor density, as determined by [3H]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 α1-adrenergic receptor density in AMD pump dogs did not differ from saline pump dogs, but the affinity of the aortic receptors for [3H]prazosin binding was decreased (K(d), 0.29±0.07 versus 0.14±0.01 nM, p<0.01), and NE-induced displacement of [3H]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 α1-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.
All Science Journal Classification (ASJC) codes
- Cardiology and Cardiovascular Medicine
- α-adrenergic receptor