Pharmacological and molecular analysis of ATP-sensitive K(+) channels in the pig and human detrusor.
The pharmacological and molecular properties of ATP-sensitive K(+) channels present in pig detrusor smooth muscle were investigated. In isolated pig detrusor strips, ATP-sensitive K(+) channel openers inhibited contractions elicited by low frequency field-stimulation in a concentration-dependent manner. The inhibitory effects of P1075 [N-cyano-N'-(1,1-dimethylpropyl)-N"-3-pyridylguanidine] were attenuated by glyburide with a pA(2) value of 7.38 (slope=1.08). The potency of the inhibitory effects of the K(+) channel openers on the field-stimulated contractions correlated well with those evoked by the muscarinic receptor agonist, carbachol (r=0.93) and furthermore, to relaxation of the pre-contracted (25 mM potassium chloride, KCl) human detrusor (r=0.95). Reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed the presence of mRNA for sulfonylurea receptors SUR1 and SUR2B in both pig and human detrusor. Considering the similarities in the molecular and pharmacological profile of ATP-sensitive K(+) channels between the pig and the human detrusor, it is concluded that the pig detrusor may serve as a suitable in vitro model for the evaluation of novel K(+) channel openers with potential use in urological disorders in humans.
Buckner
S A
SA
Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, D47C, Bldg. AP9, First Floor, 100 Abbott Park Road, Abbott Park, IL 60064-6118, USA. steven.a.buckner@abbott.com
Milicic
I
I
Daza
A
A
Davis-Taber
R
R
Scott
V E
VE
Sullivan
J P
JP
Brioni
J D
JD
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D012313:RNA / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
D015221:Potassium Channels; D012313:RNA; D000255:Adenosine Triphosphate; D002217:Carbachol; D005905:Glyburide