Characterization of alpha 1-adrenoceptors mediating vasoconstriction to noradrenaline and nerve stimulation in the isolated perfused mesentery of rat.
1. The objective of this study was to investigate the alpha 1-adrenoceptor subtype(s) mediating vasoconstrictor responses to perfused and neuronally-released noradrenaline (NA) in the isolated perfused mesentery preparation of rat. 2. Isolated mesenteric preparations (with gut attached) from male Sprague Dawley rats (250-300g) were perfused via the superior mesenteric artery with oxygenated Krebs solution at approximately 6 ml min-1. The effects of antagonists on vasoconstrictor responses to either perfused (+/-)-NA or periarterial nerve stimulation (70 V, 2 ms pulse width, 10 s train) were determined. 3. Vasoconstrictor responses to perfused NA were antagonized by prazosin (pA2 = 9.3 +/- 0.1), WB4101 (pA2 = 9.6 +/- 0.1), 5-methyl urapidil (5-MU: pA2 = 9.0 +/- 0.1), (+)-niguldipine (insurmountable) and spiperone (pA2 = 7.7 +/- 0.1). The insurmountable nature of the antagonism by (+)-niguldipine (0.1 nM) was greatly reduced by co-perfusion with prazosin (10 nM). Chloroethylclonidine (CEC: 100 microM for 20 min, followed by 40 min washout) caused an approximate twofold increase in the EC50 for (+/-)-NA and reduced the maximum response by approximately 25%. Pre-treatment of tissues with CEC (100 microM as above) did not significantly alter affinity estimates for prazosin (pA2 = 9.2 +/- 0.1), WB4101 (pA2 = 9.3 +/- 0.1) or 5-MU (pA2 = 8.7 +/- 0.2). Vasoconstrictor responses to periarterial nerve stimulation were antagonized by WB4101 > 5-MU > prazosin >> spiperone. CEC (100 microM as above) reduced nerve-stimulated responses by approximately 50%. 4. The affinity estimates for the various antagonists studied suggest that vasoconstrictor responses to both exogenous and neuronally-released NA are mediated via the same a,-adrenoceptor subtype. The pharmacological profile most resembles the 'classical' alpha l A-adrenoceptor, which, in turn, appears to be a rat homologue of the cloned bovine alpha lc-adrenoceptor.
Williams
T J
TJ
Syntex Research, Palo Alto, CA 94303.
Clarke
D E
DE
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects*
D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D009638:Norepinephrine