9-(tetrahydro-2-furyl)-adenine and barium-chloride

Testosterone induces vasorelaxation through non-genomic mechanisms in several isolated blood vessels, but no study has reported its effects on the canine basilar artery, an important artery implicated in cerebral vasospasm. Hence, this study has investigated the mechanisms involved in testosterone-induced relaxation of the canine basilar artery. For this purpose, the vasorelaxant effects of testosterone were evaluated in KCl- and/or PGF(₂α)-precontracted arterial rings in vitro in the absence or presence of several antagonists/inhibitors/blockers; the effect of testosterone on the contractile responses to CaCl₂ was also determined. Testosterone (10-180 μM) produced concentration-dependent relaxations of KCl- or PGF(₂α)-precontracted arterial rings which were: (i) unaffected by flutamide (10 μM), DL-aminoglutethimide (10 μM), actinomycin D (10 μM), cycloheximide (10 μM), SQ 22,536 (100 μM) or ODQ (30 μM); and (ii) significantly attenuated by the blockers 4-aminopyridine (K(V); 1 mM), BaCl₂ (K(IR); 30 μM), iberiotoxin (BK(Ca²+); 20 nM), but not by glybenclamide (K(ATP); 10 μM). In addition, testosterone (31, 56 and 180 μM) and nifedipine (0.01-1 μM) produced a concentration-dependent blockade of the contraction to CaCl₂ (10 μM to 10 mM) in arterial rings depolarized by 60mM KCl. These results, taken together, show that testosterone relaxes the canine basilar artery mainly by blockade of voltage-dependent Ca²+ channels and, to a lesser extent, by activation of K+ channels (K(IR), K(V) and BK(Ca²+)). This effect does not involve genomic mechanisms, production of cAMP/cGMP or the conversion of testosterone to 17β-estradiol.

Topics: 4-Aminopyridine; Adenine; Aminoglutethimide; Androgen Receptor Antagonists; Animals; Aromatase Inhibitors; Barium Compounds; Basilar Artery; Calcium Channel Blockers; Calcium Channels; Chlorides; Cycloheximide; Dactinomycin; Dogs; Enzyme Inhibitors; Flutamide; In Vitro Techniques; Male; Nifedipine; Nucleic Acid Synthesis Inhibitors; Oxadiazoles; Potassium Channel Blockers; Potassium Channels; Protein Synthesis Inhibitors; Quinoxalines; Testosterone; Vasodilation; Vasodilator Agents

We investigated the role of the inward rectifier potassium (KIR) channel and the cyclic AMP-dependent pathway in mediating vasorelaxation induced by the prostacyclin analogue cicaprost.. Small vessel myography was used to assess responses to cicaprost in segments of rat tail artery contracted with phenylephrine. Microelectrode recordings were made from helical strips to assess effects on membrane potential.. Cicaprost caused relaxation and hyperpolarisation that were significantly inhibited by Ba2+ (30-100 microM), a known blocker of KIR channels. Raising extracellular K+ from 5 to 15 mM elicited membrane hyperpolarisation and an endothelium-independent relaxation that was blocked by Ba2+ (30-100 microM), suggesting the existence of functional KIR channels on the smooth muscle. In contrast, neither glibenclamide (10 microM), a blocker of ATP-sensitive K+ channels, nor fluoxetine hydrochloride (100 microM), a blocker of G-protein-gated inward rectifier K+ channels, nor pertussis toxin (PTX; 1 microg/ml), which irreversibly inhibits Gi/Go, reduced relaxation to cicaprost. Indeed, PTX significantly potentiated responses. Relaxation to cicaprost was not mediated by NO but was partially endothelium-dependent, consistent with a similar inhibition by a combination of charybdotoxin (0.1 microM) and apamin (0.5 microM), blockers of endothelium-derived hyperpolarising factor (EDHF). However, relaxation was unaffected by adenylyl cyclase (SQ22536, dideoxyadenosine) or protein kinase A (Rp-2-O-monobutyryl-cAMP) inhibitors, consistent also with Ba2+ only weakly inhibiting relaxation to the adenylyl cyclase activator forskolin.. We conclude that cicaprost relaxes rat tail artery by activating KIR channels with some involvement from EDHF. The mechanism appears to be largely independent of cyclic AMP and Gi/Go, although the latter appears to counteract relaxation through an unknown pathway and/or receptor.

Topics: Adenine; Adenylyl Cyclase Inhibitors; Animals; Apamin; Barium Compounds; Charybdotoxin; Chlorides; Cromakalim; Cyclic AMP; DDT; Dose-Response Relationship, Drug; Epoprostenol; Fluoxetine; Glyburide; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Neurotoxins; Phenylephrine; Potassium Channels, Inwardly Rectifying; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol; Vasodilator Agents