Subtypes and excitation-contraction coupling mechanisms for neurokinin receptors in smooth muscle of the guinea-pig Taenia caeci.
This study investigated the subtype and coupling mechanisms mediating the direct contractile response to tachykinins in the guinea-pig Taenia caeci preparation in vitro. Coupling of neurokinin receptors was compared throughout with coupling of muscarinic receptors. The smooth muscle neurokinin receptors seem to be predominantly of the NK-1 subtype. Thus, the relative activities of the common naturally-occurring tachykinins fell within one order of magnitude, and the selective NK-1 receptor agonist substance P methyl ester was high in activity (0.38 relative to substance P). Some contribution from NK-3 receptors is, however, possible in view of the appreciable activity of the selective NK-3 agonist succ-[Asp6, N-MePhe8]-SP(6-11) (senktide; activity 0.004 relative to substance P), and NK-2 or NK-3 receptors in view of the higher activity of the D-isomer of [Glp6, *Pro9]-SP(6-11) as compared to its NK-1 selective L-isomer (D/L-activity ratio 1.53). Contractile actions of tachykinins were compared with carbachol for reliance on membrane-potential dependent (electromechanical) and membrane-potential independent (pharmacomechanical) coupling mechanisms. Log concentration-response curves to carbachol and substance P in normal Krebs' medium were compared with curves obtained in a high-K+ solution where processes dependent on changes in membrane potential could play no part in excitation. In the high-K+ depolarizing solution, a concentration-related relationship was maintained, though with some diminution in the maximal additional tension generated: the maximum tension with carbachol was under both conditions greater than that with substance P. The relative effects of several tachykinins and carbachol in producing receptor-mediated changes in membrane permeability through presumed receptor-operated ion channel opening, was estimated in terms of the ability to increase 86Rb-efflux, as a marker for K+, in a high-K+ depolarizing solution. Carbachol (10 microM) consistently increased 86Rb-efflux. In contrast, no permeability increase could be detected with any tachykinin tested (substance P, eledoisin, substance P methyl ester, neurokinin A, neurokinin B, 1 or 10 microM). Tachykinins and carbachol were compared in terms of ability to increase phosphatidylinositol hydrolysis. Both substance P and carbachol showed a concentration-related increase in accumulation of total inositol phosphates; though the maximal response to carbachol was considerably greater than that to any tachykinin (substance P, eledoisin, substance P methyl ester, senktide, neurokinin A, neurokinin B), or combination of two tachykinins (substance P and eledoisin, senktide and substance P methyl ester).(ABSTRACT TRUNCATED AT 400 WORDS)
Hall
J M
JM
Biomedical Sciences Divisions, King's College London, UK.
Morton
I K
IK
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007422:Intestines / Q000187:drug effects* / Q000502:physiology; D007473:Ion Channels / Q000502:physiology; D008094:Lithium / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D010716:Phosphatidylinositols / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000032:analysis* / Q000502:physiology; D012414:Rubidium Radioisotopes / Q000378:metabolism; D015320:Tachykinins / Q000494:pharmacology*
D007473:Ion Channels; D010716:Phosphatidylinositols; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; D012414:Rubidium Radioisotopes; D015320:Tachykinins; D002217:Carbachol; D008094:Lithium; D011188:Potassium; D002118:Calcium