ABSTRACT
In vivo microdialysis was used to assess the central serotonergic effects and extracellular brain levels of the 5-HT(1B/1D) receptor agonists eletriptan, zolmitriptan and sumatriptan in rats after intravenous and intracerebral administration, while their binding affinities and functional potencies were determined at 5-HT(1B), 5-HT(1D) and 5-HT(1A) receptors. In vitro studies showed that all three triptans are high affinity, full agonists at 5-HT(1B/1D) receptors, but that sumatriptan is functionally less potent as a 5-HT(1B/1D) agonist than zolmitriptan and eletriptan. Local intracortical perfusion with the compounds via the dialysis probe decreased cortical 5-HT (5-hydroxytryptamine, serotonin) release with ED(50) values of approximately 0.1 microM for eletriptan and zolmitriptan and 0.5 microM for sumatriptan. At 3.2 mg/kg i.v., both eletriptan and zolmitriptan decreased 5-HT levels by about 35%, while sumatriptan had no effect, despite the fact that maximal sumatriptan concentrations in cortical dialysates were higher (8.8 nM at 20 min) than those of zolmitriptan (5.9 nM at 20 min) and eletriptan (2.6 nM at 40 min). The observation that eletriptan and zolmitriptan produce almost identical central serotonergic effects, after intracerebral as well as after systemic administration, is in agreement with their comparable functional 5-HT(1B/1D) receptor agonist potencies and their free levels in cortical dialysates after 3.2 mg/kg i.v. On the other hand, the lack of central serotonergic effects of 3.2 mg/kg i.v. sumatriptan is likely due to its weaker functional 5-HT(1B/1D) receptor agonist potency than eletriptan and zolmitriptan, rather than lower brain levels, consistent with sumatriptan's fivefold lower potency after intracerebral administration.
Subject(s)
Brain/drug effects , Serotonin Receptor Agonists/pharmacology , Animals , Binding, Competitive , Brain/metabolism , Cattle , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Dose-Response Relationship, Drug , Extracellular Space/metabolism , Indoles/metabolism , Indoles/pharmacology , Injections, Intravenous , Membranes/drug effects , Membranes/metabolism , Microdialysis , Oxazolidinones/metabolism , Oxazolidinones/pharmacology , Pyridines/pharmacology , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Rats , Receptors, Serotonin/metabolism , Serotonin/metabolism , Serotonin Receptor Agonists/metabolism , Sumatriptan/metabolism , Sumatriptan/pharmacology , Time Factors , TryptaminesABSTRACT
This study shows that cromakalim (0.4-10 microM) can concentration-dependently hyperpolarize the smooth muscle cell membrane and increase 86Rb efflux from rabbit mesenteric small arteries at concentrations which inhibit noradrenaline-induced increases in perfusion pressure in this preparation. Hyperpolarisation of the cell membrane by cromakalim was inhibited by prior exposure of the tissue to glibenclamide (1 microM). Noradrenaline (greater than 1 microM) depolarized the smooth muscle cell membrane and this effect was reduced in the presence of cromakalim. Experiments involving repetitive stimulation of the perivascular nerves in this tissue showed that cromakalim (2-10 microM) reduced excitatory junction potential amplitude and fall time without affecting the facilitation process. The results of this study suggest that in rabbit small mesenteric arteries the vasodilator action of cromakalim is a consequence of the opening of 86Rb-permeable potassium channels. It is unlikely that any component of the vasorelaxant effects of cromakalim is due to a direct effect on voltage-operated calcium channels or a prejunctional effect on neuroeffector transmission.
Subject(s)
Benzopyrans/pharmacology , Muscle, Smooth, Vascular/drug effects , Nifedipine/pharmacology , Pyrroles/pharmacology , Animals , Blood Pressure/drug effects , Cell Membrane/drug effects , Cromakalim , Electric Stimulation , Glyburide/pharmacology , Humans , In Vitro Techniques , Infant, Newborn , Male , Membrane Potentials/drug effects , Mesenteric Arteries/drug effects , Muscle, Smooth, Vascular/cytology , Norepinephrine/pharmacology , Perfusion , Potassium Channels/drug effects , RabbitsABSTRACT
1. The actions of diazoxide and minoxidil sulphate have been compared with those of cromakalim in rat aorta and portal vein. 2. Diazoxide and minoxidil sulphate hyperpolarized the rat portal vein in a similar manner to cromakalim. 3. Cromakalim, diazoxide and minoxidil sulphate increased 42K and 86Rb efflux from rat portal vein, although minoxidil sulphate had only a small effect on 86Rb efflux. 4. Cromakalim, diazoxide and minoxidil sulphate increased 42K efflux from rat aorta but only cromakalim and diazoxide increased 86Rb efflux from this tissue. 5. Glibenclamide inhibited the relaxant actions of cromakalim, diazoxide and minoxidil sulphate on rat aorta and the increase in 42K efflux produced by these agents in this tissue. 6. Diazoxide relaxed an 80 mM KCl-induced contraction of rat aorta, whilst cromakalim and minoxidil sulphate were without effect. 7. Cromakalim, diazoxide and minoxidil sulphate had no effect on cyclic AMP or cyclic GMP concentrations in rat aorta. 8. It is concluded that diazoxide and minoxidil sulphate like cromakalim exhibit K+ channel opening properties in vascular smooth muscle. Diazoxide exerts an additional inhibitory action not related to the production of cyclic AMP or cyclic GMP. The action of minoxidil sulphate may be primarily located at a K+ channel which is relatively impermeable to 86Rb.
Subject(s)
Antihypertensive Agents/pharmacology , Benzopyrans/pharmacology , Diazoxide/pharmacology , Minoxidil/pharmacology , Muscle, Smooth, Vascular/drug effects , Pyrroles/pharmacology , Animals , Aorta, Thoracic/drug effects , Cromakalim , Cyclic AMP/metabolism , Cyclic GMP/metabolism , Glyburide/pharmacology , In Vitro Techniques , Male , Membrane Potentials/drug effects , Microelectrodes , Portal Vein/physiology , Potassium Channels/drug effects , Potassium Radioisotopes , Rabbits , Rats , Rats, Inbred Strains , Rubidium RadioisotopesABSTRACT
(+/-) Pinacidil inhibited noradrenaline-induced contractions in rat aorta and portal vein. The spontaneous tone of guinea-pig bronchial and taenia caeci muscles was relaxed and the spontaneous mechanical activity of rat portal vein was abolished. (+/-) Pinacidil abolished contractions produced by low concentrations of KCl in rat aorta and portal vein, but had relatively little effect on responses to high KCl concentrations. The mechano-inhibitory effects of (+/-) pinacidil were antagonised by tetraethylammonium or procaine. In studies with the purified enantiomers of pinacidil, (-) pinacidil was approximately 20 times more potent that (+) pinacidil. Measurements of electrical activity showed that low concentrations of (+/-) pinacidil selectively inhibited spontaneous electrical discharges in rat portal vein. The duration of multispike electrical complexes was shortened, but spike frequency within a complex and the rate of spike rise and fall were unaffected. At higher concentrations, a dose-dependent hyperpolarisation was observed in both rat aorta and portal vein and the membrane potential approached EK. Using both 86Rb and 42K, (+/-) pinacidil produced a concentration-dependent increase in isotope exchange which correlated with those concentrations at which electrical and mechanical inhibitory effects were observed. Using radioimmunoassay, no pinacidil-induced changes in cyclic AMP or cyclic GMP concentrations were detected in rat aorta. These electrical, ion flux and biochemical measurements suggest that the in vitro mechano-inhibitory effects of pinacidil are associated with the opening of 86Rb-permeable K+ channels in smooth muscle. These effects were observed at concentrations of pinacidil similar to those found in vivo in the plasma of experimental animals and man. It is thus concluded that the hypotensive and antihypertensive effects of pinacidil are the consequence of the cessation of ongoing electrical activity and hyperpolarisation which follows the opening of K+ channels in vascular smooth muscle.