Mechanism of resistance to α-adrenergic receptor antagonists of renal nerve stimulation-induced vasoconstriction at low frequencies

E. Sehic, Y. Ruan, Kafait Malik

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Abstract

To determine why renal vasoconstriction elicited by periarterial nerve stimulation (RNS) at lower frequencies (<4 Hz) is resistant to α-adrenergic receptor blockade in the rat kidney, we reevaluated the effect of α-receptor antagonists on the vasoconstrictor response to norepinephrine (NE) and to RNS and on the release of adrenergic transmitter. The α-receptor antagonist prazosin (PZ) at 0.2 and 7 nM reduced the vasoconstrictor response to NE, and 2.4 μM PZ abolished it. PZ (0.2 or 7 nM) reduced RNS-induced vasoconstriction without altering the fractional tritium overflow. PZ (2.4 μM) enhanced fractional tritium overflow and reduced the vasoconstrictor response to RNS at 2-10 Hz, but not at 0.5 or 1 Hz. The effect of 0.2 nM PZ to reduce RNS-induced vasoconstriction was reversed by increasing the concentration to 2.4 μM. Corynanthine (COR; 2.6 μM), a preferential α- receptor blocker, or phenoxybenzamine (PBZ; 30 nM) abolished the vasoconstrictor response to NE but only partially reduced response to RNS and enhanced the fractional tritium overflow. Rauwolscine (RW; 2.5 nM), a preferential α2-receptor antagonist, did not alter the vasoconstrictor response to NE but potentiated RNS-induced vasoconstriction and fractional tritium overflow. RW (7.7 μM) inhibited NE-induced vasoconstriction but potentiated the vasoconstrictor response to RNS and fractional tritium overflow. PZ (7 nM) abolished the potentiation by RW and reduced the vasoconstrictor response to RNS. These data suggest that a component of RNS- induced vasoconstriction in the rat kidney is attributable to co-release of a nonadrenergic transmitter with NE. The diminished effect of α-receptor antagonists at higher concentrations (e.g., PZ 2, 4 μM) to reduce RNS- induced vasoconstriction is caused by their prejunctional action to enhance co-release of the nonadrenergic transmitter.

Original languageEnglish (US)
Pages (from-to)97-108
Number of pages12
JournalJournal of Cardiovascular Pharmacology
Volume29
Issue number1
DOIs
StatePublished - Jan 1 1997

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Adrenergic Antagonists
Prazosin
Vasoconstrictor Agents
Vasoconstriction
Tritium
Norepinephrine
Kidney
Yohimbine
Phenoxybenzamine
Adrenergic Agents
Adrenergic Receptors

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

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title = "Mechanism of resistance to α-adrenergic receptor antagonists of renal nerve stimulation-induced vasoconstriction at low frequencies",
abstract = "To determine why renal vasoconstriction elicited by periarterial nerve stimulation (RNS) at lower frequencies (<4 Hz) is resistant to α-adrenergic receptor blockade in the rat kidney, we reevaluated the effect of α-receptor antagonists on the vasoconstrictor response to norepinephrine (NE) and to RNS and on the release of adrenergic transmitter. The α-receptor antagonist prazosin (PZ) at 0.2 and 7 nM reduced the vasoconstrictor response to NE, and 2.4 μM PZ abolished it. PZ (0.2 or 7 nM) reduced RNS-induced vasoconstriction without altering the fractional tritium overflow. PZ (2.4 μM) enhanced fractional tritium overflow and reduced the vasoconstrictor response to RNS at 2-10 Hz, but not at 0.5 or 1 Hz. The effect of 0.2 nM PZ to reduce RNS-induced vasoconstriction was reversed by increasing the concentration to 2.4 μM. Corynanthine (COR; 2.6 μM), a preferential α- receptor blocker, or phenoxybenzamine (PBZ; 30 nM) abolished the vasoconstrictor response to NE but only partially reduced response to RNS and enhanced the fractional tritium overflow. Rauwolscine (RW; 2.5 nM), a preferential α2-receptor antagonist, did not alter the vasoconstrictor response to NE but potentiated RNS-induced vasoconstriction and fractional tritium overflow. RW (7.7 μM) inhibited NE-induced vasoconstriction but potentiated the vasoconstrictor response to RNS and fractional tritium overflow. PZ (7 nM) abolished the potentiation by RW and reduced the vasoconstrictor response to RNS. These data suggest that a component of RNS- induced vasoconstriction in the rat kidney is attributable to co-release of a nonadrenergic transmitter with NE. The diminished effect of α-receptor antagonists at higher concentrations (e.g., PZ 2, 4 μM) to reduce RNS- induced vasoconstriction is caused by their prejunctional action to enhance co-release of the nonadrenergic transmitter.",
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N2 - To determine why renal vasoconstriction elicited by periarterial nerve stimulation (RNS) at lower frequencies (<4 Hz) is resistant to α-adrenergic receptor blockade in the rat kidney, we reevaluated the effect of α-receptor antagonists on the vasoconstrictor response to norepinephrine (NE) and to RNS and on the release of adrenergic transmitter. The α-receptor antagonist prazosin (PZ) at 0.2 and 7 nM reduced the vasoconstrictor response to NE, and 2.4 μM PZ abolished it. PZ (0.2 or 7 nM) reduced RNS-induced vasoconstriction without altering the fractional tritium overflow. PZ (2.4 μM) enhanced fractional tritium overflow and reduced the vasoconstrictor response to RNS at 2-10 Hz, but not at 0.5 or 1 Hz. The effect of 0.2 nM PZ to reduce RNS-induced vasoconstriction was reversed by increasing the concentration to 2.4 μM. Corynanthine (COR; 2.6 μM), a preferential α- receptor blocker, or phenoxybenzamine (PBZ; 30 nM) abolished the vasoconstrictor response to NE but only partially reduced response to RNS and enhanced the fractional tritium overflow. Rauwolscine (RW; 2.5 nM), a preferential α2-receptor antagonist, did not alter the vasoconstrictor response to NE but potentiated RNS-induced vasoconstriction and fractional tritium overflow. RW (7.7 μM) inhibited NE-induced vasoconstriction but potentiated the vasoconstrictor response to RNS and fractional tritium overflow. PZ (7 nM) abolished the potentiation by RW and reduced the vasoconstrictor response to RNS. These data suggest that a component of RNS- induced vasoconstriction in the rat kidney is attributable to co-release of a nonadrenergic transmitter with NE. The diminished effect of α-receptor antagonists at higher concentrations (e.g., PZ 2, 4 μM) to reduce RNS- induced vasoconstriction is caused by their prejunctional action to enhance co-release of the nonadrenergic transmitter.

AB - To determine why renal vasoconstriction elicited by periarterial nerve stimulation (RNS) at lower frequencies (<4 Hz) is resistant to α-adrenergic receptor blockade in the rat kidney, we reevaluated the effect of α-receptor antagonists on the vasoconstrictor response to norepinephrine (NE) and to RNS and on the release of adrenergic transmitter. The α-receptor antagonist prazosin (PZ) at 0.2 and 7 nM reduced the vasoconstrictor response to NE, and 2.4 μM PZ abolished it. PZ (0.2 or 7 nM) reduced RNS-induced vasoconstriction without altering the fractional tritium overflow. PZ (2.4 μM) enhanced fractional tritium overflow and reduced the vasoconstrictor response to RNS at 2-10 Hz, but not at 0.5 or 1 Hz. The effect of 0.2 nM PZ to reduce RNS-induced vasoconstriction was reversed by increasing the concentration to 2.4 μM. Corynanthine (COR; 2.6 μM), a preferential α- receptor blocker, or phenoxybenzamine (PBZ; 30 nM) abolished the vasoconstrictor response to NE but only partially reduced response to RNS and enhanced the fractional tritium overflow. Rauwolscine (RW; 2.5 nM), a preferential α2-receptor antagonist, did not alter the vasoconstrictor response to NE but potentiated RNS-induced vasoconstriction and fractional tritium overflow. RW (7.7 μM) inhibited NE-induced vasoconstriction but potentiated the vasoconstrictor response to RNS and fractional tritium overflow. PZ (7 nM) abolished the potentiation by RW and reduced the vasoconstrictor response to RNS. These data suggest that a component of RNS- induced vasoconstriction in the rat kidney is attributable to co-release of a nonadrenergic transmitter with NE. The diminished effect of α-receptor antagonists at higher concentrations (e.g., PZ 2, 4 μM) to reduce RNS- induced vasoconstriction is caused by their prejunctional action to enhance co-release of the nonadrenergic transmitter.

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