Hypoxic pulmonary vasoconstriction (HPV), a unique response of pulmonary circulation, is critical to prevent hypoxemia under local hypoventilation. Hypoxic inhibition of K+ channel is known as an important O2-sensing mechanism in HPV. Carbon monoxide (CO) is suggested as a positive regulator of Ca2+-activated K+ channel (BK(Ca)), a stimulator of guanylate cyclase, and an O2-mimetic agent in heme moiety-dependent O2 sensing mechanisms. Here we compared the effects of CO on the HPV (Po2, 3%) in isolated pulmonary artery (HPV(PA)) and in blood-perfused/ventilated lungs (HPV(lung)) of rats. A pretreatment with CO (3%) abolished the HPV(PA) in a reversible manner. The inhibition of HPV(PA) was completely reversed by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor. In contrast, the HPV(lung) was only partly decreased by CO. Moreover, the partial inhibition of HPV(lung) by CO was affected neither by the pretreatment with ODQ nor by NO synthase inhibitor (L-NAME). The CO-induced inhibitions of HPV(PA) and HPV(lung) were commonly unaffected by tetraethylammonium (TEA, 2 mM), a blocker of BK(Ca). As a whole, CO inhibits HPV(PA) via activating guanylate cyclase. The inconsistent effects of ODQ on HPV(PA) and HPV(lung) suggest that ODQ may lose its sGC inhibitory action when applied to the blood-containing perfusate.
Animals ; Anoxia/*physiopathology ; Carbon Monoxide/*pharmacology ; Guanylate Cyclase/antagonists & inhibitors/metabolism ; NG-Nitroarginine Methyl Ester/chemistry/pharmacology ; Nitric Oxide Synthase/antagonists & inhibitors/metabolism ; Oxadiazoles/chemistry/pharmacology ; Pulmonary Artery/*physiopathology ; Quinoxalines/chemistry/pharmacology ; Rats ; Tetraethylammonium/chemistry/pharmacology ; Vasoconstriction/*drug effects/physiology

OBJECTIVETo determine whether matrine, a kind of traditional Chinese medicinal alkaloid, can relax the aortic smooth muscles isolated from guinea pigs and to investigate the mechanism of its relaxant effects.

METHODSPhenylephrine or potassium chloride concentration-dependent relaxation response of aortic smooth muscles to matrine was studied in the precontracted guinea pigs.

RESULTSMatrine (1 x 10(-4) mol/L -3.3 x 10(3) mol/L) relaxed the endothelium-denuded aortic rings pre-contracted sub-maximally with phenylephrine, in a concentration-dependent manner, and its pre-incubation (3.3 x 10(-3) mol/L) produced a significant rightward shift in the phenylephrine dose-response curve, but had no effects on the potassium chloride-induced contraction. The anti-contractile effect of matrine was not reduced by the highly selective ATP-dependent K+ channel blocker glibenclamide (10(-5) mol/L), either by the non-selective K+ channel blocker tetraethylammonium (10(-3) mol/L), or by the beta-antagonist propranolol (10(-5) mol/L). In either "normal" or "Ca(2+)-free" bathing medium, the phenylephrine-induced contraction was attenuated by matrine (3.3 x 10(-3) mol/L), indicating that the vasorelaxation was due to inhibition of intracellular and extracellular Ca2+ mobilization.

CONCLUSIONMatrine inhibits phenylephrine-induced contractions by inhibiting activation of alpha-adrenoceptor and interfering with the release of intracellular Ca2+ and the influx of extracellular Ca2+.

Alkaloids ; chemistry ; pharmacology ; Animals ; Aorta ; drug effects ; physiology ; Calcium ; pharmacology ; Culture Media ; pharmacology ; Dose-Response Relationship, Drug ; Glyburide ; pharmacology ; Guinea Pigs ; In Vitro Techniques ; Male ; Muscle Contraction ; drug effects ; Muscle Relaxation ; drug effects ; Muscle, Smooth, Vascular ; drug effects ; physiology ; Phenylephrine ; pharmacology ; Potassium Chloride ; pharmacology ; Propranolol ; pharmacology ; Quinolizines ; chemistry ; pharmacology ; Tetraethylammonium ; pharmacology

OBJECTIVETo investigate the vasorelaxant effect of puerarin in rat aortic rings and the mechanism.

METHODThe isolated thoracic aortic rings of male Sprague-Dawley rats were mounted on the organ bath and the contractile responses of the vessel were recorded.

RESULTPuerarin completely relaxed the contractions induced by phenylephrine in a concentration-dependent manner in endothelium-intact and endothelium-denuded rat aorta, but it had no effect on those preconstricted by a high concentration of potassium chloride (KCl, 60 mmol x L(-1)). The relaxant effect of puerarin was significantly inhibited by pretreatment of endothelium-denuded aorta with potassium channel antagonists tetraethylammonium, 4-aminopyridine but not glibenclamide.

CONCLUSIONPuerarin induces an endothelium-independent relaxation in rat aortic rings. The mechanisms may involve the reduction in Ca2+ influx through the calcium channels operated by alpha-adrenergic receptor and the activation of the potassium channels (Kv and BKca, but not KATP).

4-Aminopyridine ; pharmacology ; Animals ; Aorta, Thoracic ; drug effects ; physiology ; Endothelium, Vascular ; physiology ; In Vitro Techniques ; Isoflavones ; isolation & purification ; pharmacology ; Male ; Phenylephrine ; antagonists & inhibitors ; Plants, Medicinal ; chemistry ; Potassium Channel Blockers ; pharmacology ; Potassium Channels ; drug effects ; Pueraria ; chemistry ; Rats ; Rats, Sprague-Dawley ; Tetraethylammonium ; pharmacology ; Vasoconstriction ; drug effects ; Vasodilation ; drug effects ; Vasodilator Agents ; pharmacology

OBJECTIVETo study the effects of resvaratrol derivatives on spontaneous HR and CF of isolated guinea pig atrium.

METHODThe dose-effect curve of resvaratrol was observed. The possible mechanism of potassium channels responsible for changes of CF and HR after administering with resvaratrol was measured.

RESULTResvaratrol reduced the spontaneous HR and weakened the CF in a dose-dependent manner ranging from 10(-6) to 3 x 10(-4) mol x L(-1) (P < 0.05). As compared with Res group, the effects were partly blocked by Gli (P < 0.05) and TEA (P < 0.01), but not blocked by 4-AP, BaCl2, Atropine.

CONCLUSIONResvaratrol can induce negative chronotropic action and negative (inotropic action. The mechanism(s) may relate to the opening of K(ATP) and Kc(Ca).

Animals ; Barium Compounds ; pharmacology ; Cardiotonic Agents ; administration & dosage ; isolation & purification ; pharmacology ; Chlorides ; pharmacology ; Dose-Response Relationship, Drug ; Female ; Glyburide ; pharmacology ; Guinea Pigs ; Heart Rate ; drug effects ; In Vitro Techniques ; KATP Channels ; antagonists & inhibitors ; Male ; Myocardial Contraction ; drug effects ; Plants, Medicinal ; chemistry ; Potassium Channel Blockers ; pharmacology ; Potassium Channels, Calcium-Activated ; antagonists & inhibitors ; Potassium Channels, Inwardly Rectifying ; antagonists & inhibitors ; Stilbenes ; administration & dosage ; isolation & purification ; pharmacology ; Tetraethylammonium ; pharmacology

We present accidental findings that potassium channel blockers, such as tetraethyl-ammonium (TEA) or 4-aminopyridine (4-AP), inhibit the sustained tonic contraction induced by carbachol in rat detrusor muscle strips. The relatively lower concentrations (<2 mM) of TEA and 4-AP inhibited phasic and tonic contractions induced by 5 micrometer carbachol, whilst the relatively higher concentrations of TEA and 4-AP (>5 mM) potentiated phasic contractions. The potentiation of phasic contraction was not observed in nicardipine pretreated condition. In nicardipine pretreated condition, the concentration-response curves for the negative inotropic effect of potassium channel blockers were shifted to the right by the increasing concentration of carbachol from 0.5 micrometer to 5 micrometer. IC50 was changed significantly from 0.19 to 0.64 mM (TEA) and from 0.21 to 0.96 (4-AP). Such inhibitory effects were also observed in Ca2+ depleted condition, where 0.1 mM EGTA and 1 micrometer thapsigargin were added into Ca2+ free solution. In conclusion, inhibitory effects of potasssium channel blockers on carbachol-induced contraction may be ascribed to the direct inhibition of receptor-agonist binding.
4-Aminopyridine/pharmacology ; Animals ; Bladder/metabolism ; Calcium/chemistry/metabolism ; Calcium Channel Blockers/pharmacology ; Carbachol/*pharmacology ; Dose-Response Relationship, Drug ; Female ; Guinea Pigs ; Inhibitory Concentration 50 ; Male ; Mice ; Muscle Contraction/*drug effects ; Muscles/drug effects/metabolism/*pathology ; Nicardipine/pharmacology ; Potassium Channel Blockers/*pharmacology ; Protein Binding ; Rabbits ; Rats ; Rats, Sprague-Dawley ; Support, Non-U.S. Gov't ; Tetraethylammonium/pharmacology ; Vasodilator Agents/pharmacology