Mechanisms of α1-adrenergic vascular desensitization in conscious dogs

K. Kiuchi, Dorothy Vatner, N. Uemura, M. Bigaud, N. Hasebe, D. M. Hempel, R. M. Graham, Stephen Vatner

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1185-1199
Number of pages15
JournalCirculation research
Volume71
Issue number5
DOIs
StatePublished - Jan 1 1992

Fingerprint

Adrenergic Agents
Blood Vessels
Adrenergic Receptors
Dogs
Norepinephrine
Prazosin
Vascular Resistance
Adrenergic Agonists
Arterial Pressure
amidephrine mesylate
Mesenteric Arteries
Mesentery
Atrial Pressure
Membranes
Vasoconstrictor Agents
Endothelium
Neurotransmitter Agents
Reflex
Catheters
Binding Sites

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology

Keywords

  • catecholamine
  • desensitization
  • dogs
  • α-adrenergic receptor

Cite this

Kiuchi, K. ; Vatner, Dorothy ; Uemura, N. ; Bigaud, M. ; Hasebe, N. ; Hempel, D. M. ; Graham, R. M. ; Vatner, Stephen. / Mechanisms of α1-adrenergic vascular desensitization in conscious dogs. In: Circulation research. 1992 ; Vol. 71, No. 5. pp. 1185-1199.
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abstract = "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.",
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Kiuchi, K, Vatner, D, Uemura, N, Bigaud, M, Hasebe, N, Hempel, DM, Graham, RM & Vatner, S 1992, 'Mechanisms of α1-adrenergic vascular desensitization in conscious dogs', Circulation research, vol. 71, no. 5, pp. 1185-1199. https://doi.org/10.1161/01.RES.71.5.1185

Mechanisms of α1-adrenergic vascular desensitization in conscious dogs. / Kiuchi, K.; Vatner, Dorothy; Uemura, N.; Bigaud, M.; Hasebe, N.; Hempel, D. M.; Graham, R. M.; Vatner, Stephen.

In: Circulation research, Vol. 71, No. 5, 01.01.1992, p. 1185-1199.

Research output: Contribution to journalArticle

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T1 - Mechanisms of α1-adrenergic vascular desensitization in conscious dogs

AU - Kiuchi, K.

AU - Vatner, Dorothy

AU - Uemura, N.

AU - Bigaud, M.

AU - Hasebe, N.

AU - Hempel, D. M.

AU - Graham, R. M.

AU - Vatner, Stephen

PY - 1992/1/1

Y1 - 1992/1/1

N2 - 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.

AB - 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.

KW - catecholamine

KW - desensitization

KW - dogs

KW - α-adrenergic receptor

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