| 1. |
- Bodelsson, Mikael, et al.
(författare)
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Endothelial relaxing 5-hydroxytryptamine receptors in the rat jugular vein: similarity with the 5-hydroxytryptamine1C receptor
- 1993
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - 1521-0103. ; 264:2, s. 709-716
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Tidskriftsartikel (refereegranskat)abstract
- Serotonin (5-HT) at low concentrations induces an endothelium-dependent relaxation in the rat jugular vein mediated via a 5-HT1-like receptor. The receptor mediating this relaxation was characterized in vitro using agonists and antagonists in segments precontracted with prostaglandin F2 alpha in the presence of the 5-HT2 receptor antagonist ketanserin. The following substances acted as agonists, with the order of potency: 5-HT > dl-alpha-methyl-5-hydroxytryptamine = 5-carboxamidotryptamine > quipazine > 8-hydroxy-2-(dl-n-propylamino) tetralin. dl-Propranolol, mesulergine and mianserin acted as competitive, methysergide, 6-methyl-1-(1-methylethyl)-ergoline-8 beta-carboxylic acid 2-hydroxy-1-methylpropyl ester and sumatriptan as non-competitive, and ritanserin acted as both a competitive and non-competitive antagonist of the 5-HT-induced relaxation. Neither the 5-HT2 antagonists ketanserin and spiperone nor the 5-HT3 antagonist 1 alpha-H,3 alpha,5 alpha-H-tropan-3-yl,3,5-dichlorbenzoate affected the 5-HT-induced relaxation. The pEC50 values of the agonists and the pA2 and pAh values of the antagonists correlated strongly with pKD values at the 5-HT1C binding site. These results are consistent with a peripheral vascular 5-HT1C receptor in the rat jugular vein.
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| 2. |
- Grundemar, L, et al.
(författare)
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Neuropeptide Y acts at an atypical receptor to evoke cardiovascular depression and to inhibit glutamate responsiveness in the brainstem
- 1991
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - 0022-3565. ; 258:2, s. 633-638
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Tidskriftsartikel (refereegranskat)abstract
- Microinjection of neuropeptide Y (NPY) into the nucleus tractus solitarius (NTS) induces an initial and reversible fall in arterial pressure (AP) and heart rate (HR), along with a delayed and long-lasting blockade of cardiovascular responses to L-glutamate (L-Glu) injected into the same site and an inhibition of the baroreflex arc. By injecting NPY-receptor subtype selective agonists and NPY-related peptides into NTS we have sought to characterize the receptors that mediate these responses. Unilateral injections into NTS (9-90 pmol) of NPY as well as the Y1 receptor selective agonist [34Pro]NPY and the Y2 receptor selective fragment NPY 13-36 evoked comparable dose-dependent falls of AP and HR in the anesthetized and paralyzed rat. Injections into NTS of peptide YY or pancreatic polypeptide had no effect. Preinjection of NPY, [34Pro]NPY, NPY 13-36 (all at 90 pmol) as well as norepinephrine (6.7 nmol) virtually abolished the fall in AP and HR evoked by subsequent injections of L-Glu into NTS. Injection of peptide YY or pancreatic polypeptide (both at 90 pmol) did not affect the cardiovascular responses evoked by L-Glu in NTS. Injection of NPY (90 pmol) into the caudal ventrolateral medulla induced a slight fall in AP of -17 +/- 5 mm Hg (P less than .05) and a sustained fall in HR of -44 +/- 8 beats per min (P less than .01). Injection of NPY also abolished the fall in HR and AP evoked by L-Glu in the caudal ventrolateral medulla. The profile of the cardiovascular effects elicited by the NPY-related peptides in NTS does not correspond to either of the Y1 or the Y2 receptor subtypes. The findings suggest that NPY acts on an atypical receptor in NTS to lower AP and HR. Moreover, this receptor may also interfere with the L-Glu-evoked neurotransmission in the NTS. Finally, norepinephrine shared with NPY the ability to inhibit L-Glu-evoked responses in NTS; however, a much higher dose of norepinephrine (than NPY) was required.
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| 3. |
- Lundin, Stefan, et al.
(författare)
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Pharmacokinetic and pharmacologic properties of antiuterotonic oxytocin analogs in the rat
- 1993
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - 1521-0103. ; 264:2, s. 783-788
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Tidskriftsartikel (refereegranskat)abstract
- The pharmacologic and pharmacokinetic properties were evaluated in a series of antiuterotonic oxytocin analogs, modified at positions 1, 2, 4, 8 and, in one case, position 9 of the oxytocin (OT) molecule. [Mpa1,D-Tyr2(Et),Val4,Orn8,desGly9]-OT, [Mpa1,Tyr2(Et),Val4,Orn8]-OT and [Mpa1,D-Tyr2,Val4,Orn8]-OT displayed similar plasma clearance rates (Clps) using the constant infusion method in rats. Two analogs, [Mpa1,D-Tyr2(Et),Val4,Orn8]-OT and, particularly, [Mpa1,D-Tyr2(Et),Thr4,Orn8]-OT, were cleared at significantly higher rates compared with the others. [Mpa1, D-Tyr2(Et), Val4, Orn8]-OT and [Mpa1, D-Tyr2(Et), Thr4, Orn8, desGly9]-OT were most potent in eliciting a short-term in vivo antiuterotonic effect, whereas the duration of effect was longest for [Mpa1, D-Tyr2, Val4, Orn8]-OT and [Mpa1, D-Tyr2(Et), Thr4, Orn8, desGly9]-OT. The Clp of [Mpa1, D-Tyr2, Val4, Orn8]-OT was similar regardless of the infusion rate. No relationship between antiuterotonic effect and Clp of the five peptides could be demonstrated, and no significant linear correlation between Clp and effect duration was found. The apparent volumes of distribution for the present analogs were 10-fold larger than the blood volume, a finding to be considered when measuring in vivo antagonistic activity. The 24-h urinary excretion ranged from 14.3 to 25.6% of the i.v. dose and was negatively correlated with peptide lipophilicity. It is concluded that, in addition to diverging pharmacologic properties, peptide analogs may differ markedly in kinetic parameters like Clp, volumes of distribution and urinary excretion despite minor molecular modifications.
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