Mechanism of resistance to alpha-adrenergic receptor antagonists of renal nerve stimulation-induced vasoconstriction at low frequencies.
To determine why renal vasoconstriction elicited by periarterial nerve stimulation (RNS) at lower frequencies (< 4 Hz) is resistant to alpha-adrenergic receptor blockade in the rat kidney, we reevaluated the effect of alpha-receptor antagonists on the vasoconstrictor response to norepinephrine (NE) and to RNS and on the release of adrenergic transmitter. The alpha-receptor antagonist prazosin (PZ) at 0.2 and 7 nM reduced the vasoconstrictor response to NE, and 2.4 microM PZ abolished it. PZ (0.2 or 7 nM) reduced RNS-induced vasoconstriction without altering the fractional tritium overflow. PZ (2.4 microM) 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 microM. Corynanthine (COR; 2.6 microM), a preferential alpha-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 alpha 2-receptor antagonist, did not alter the vasoconstrictor response to NE but potentiated RNS-induced vasoconstriction and fractional tritium overflow. RW (7.7 microM) 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 alpha-receptor antagonists at higher concentrations (e.g., PZ 2.4 microM) to reduce RNS-induced vasoconstriction is caused by their prejunctional action to enhance co-release of the nonadrenergic transmitter.
Sehic
E
E
Department of Physiology and Biophysics, College of Medicine, University of Tennessee, Memphis, USA.
Ruan
Y
Y
Malik
K U
KU
D018674:Adrenergic Antagonists / Q000494:pharmacology*; D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D004558:Electric Stimulation; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology*; D010643:Phenoxybenzamine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000187:drug effects* / Q000294:innervation; D014316:Tritium; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D015016:Yohimbine / Q000494:pharmacology
D018674:Adrenergic Antagonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D014662:Vasoconstrictor Agents; D010643:Phenoxybenzamine; D014316:Tritium; D015016:Yohimbine; D009638:Norepinephrine; D011224:Prazosin