Mechanisms of action of cicletanine in human and guinea pig resistance arteries.
Human subcutaneous (s.c.) arteries and guinea pig mesenteric vessels (internal diameter 150-570 microns) were isolated and mounted on a microvascular myograph. Cicletanine-induced relaxation curves were constructed after preconstriction with either depolarising potassium (KPSS) or norepinephrine (NE) and in the presence and absence of indomethacin, glibenclamide, or tetraethylammonium chloride (TEA). Using only guinea pig vessels, cicletanine relaxation curves were constructed with and without charybdotoxin. In human vessels, there was no significant difference between cicletanine-induced relaxation in vessels preconstricted with either NE or KPSS, and neither ATP-sensitive or Ca(2+)-activated K channels were involved. However, with indomethacin added, in human vessels the maximal response to cicletanine (30 microM) was reduced by 51% (p less than 0.05). In guinea pig mesenteric arteries, cicletanine (30 microM) produced a 95% relaxation of the NE-constricted vessel and only 30% relaxation of the KPSS-constricted vessel (p less than 0.001). There was no evidence for any involvement of the ATP-sensitive K channel or the eicosanoid system. The relaxation to cicletanine (less than 3 microM) in with TEA added was greatly reduced (p less than 0.001) and with charybdotoxin added the concentration response curve to cicletanine was shifted approximately 3 log units to the right (p less than 0.001), suggesting an involvement of Ca(2+)-activated K channels. The acute vasodilator action of cicletanine is complex, with multiple mechanisms of action, and the relative importance of these varies in different species or at least in different vascular beds.
Calder
J A
JA
Department of Clinical Pharmacology, St. Mary's Hospital, London, England.
Schachter
M
M
Sever
P S
PS
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D018999:Charybdotoxin; D004232:Diuretics / Q000494:pharmacology*; D004347:Drug Interactions; D015777:Eicosanoids / Q000502:physiology; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011725:Pyridines; D012604:Scorpion Venoms / Q000494:pharmacology; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects*
D000959:Antihypertensive Agents; D004232:Diuretics; D015777:Eicosanoids; D015221:Potassium Channels; D011725:Pyridines; D012604:Scorpion Venoms; D013757:Tetraethylammonium Compounds; D018999:Charybdotoxin; D019789:Tetraethylammonium; C038068:cicletanine; D011188:Potassium; D005905:Glyburide; D009638:Norepinephrine; D007213:Indomethacin