Different Ca2+ influx pathways mediate tachykinin receptor-induced contraction in circular muscle of guinea-pig colon.

We used an electrophysiological approach (single sucrose gap) to compare the mechanism of action of selective tachykinin NK1 and NK2 receptor agonists ([Sar9]substance P sulfone and [beta ala8]neurokinin A-(4-10), respectively) in producing contraction of the circular muscle of the guinea-pig proximal colon. [Sar9]Substance P sulfone produced a marked depolarization, action potentials and increase in membrane conductance. On the other hand, [beta Ala8]neurokinin A-(4-10) produced less depolarization of the cell membrane and did not change membrane resistance. Nifedipine (1 microM) greatly reduced (80% inhibition) the contraction due to [Sar9]substance P sulfone while that due to [beta Ala8]neurokinin A-(4-10) was slightly affected (13% inhibition). Action potentials induced by either agonist were suppressed by nifedipine, while depolarization was reduced only to a minor extent. When tested in a Ca(2+)-free medium, the contraction produced by either agonist was greatly reduced (84-89%) as compared to the control. In organ bath experiments [Sar9]substance P sulfone and [beta Ala8]neurokinin A-(4-10) produced concentration-dependent contraction of the circular muscle of the colon (EC50 8 and 12 nM, respectively). Nifedipine (1 microM) markedly suppressed the response to [Sar9]substance P sulfone while that to [beta Ala8]neurokinin A-(4-10) was only slightly depressed. These findings demonstrate that NK1 receptor-mediated contraction is strictly linked to membrane depolarization and action potentials generation through nifedipine-sensitive Ca2+ channels (electromechanical coupling) while the NK2 receptor-mediated contraction is substantially unrelated to depolarization and, while being largely dependent upon extracellular Ca2+, is nifedipine-resistant, possibly linked to the opening of non-selective (Ca(2+)-permeable) receptor-gated cation channels (pharmacomechanical coupling).