Agonist-dependent modulation of Ca2+ sensitivity in rabbit pulmonary artery smooth muscle.
The effects of the stable thromboxane analogue U46619, the alpha 1-adrenergic agent phenylephrine and depolarization with high K+ on cytoplasmic Ca2+ ([Ca2+]i) and force development were determined in rabbit pulmonary artery smooth muscle. Following stimulation with each of the excitatory agents, the time course of the [Ca2+]i/force relationship described counter-clockwise hysteresis loops with the rise and fall in [Ca2+]i leading, respectively, contraction and relaxation. The rank order of the force/[Ca2+]i ratios evoked by the different methods of stimulation was: U46619 greater than phenylephrine high K+. The difference between the actions of U46619 and phenylephrine was due to the lesser Ca2(+)-releasing and greater Ca2(+)-sensitizing action of U46619. Both U46619 and phenylephrine also released intracellular Ca2+ in intact (non-permeabilized) preparations. The effects of the two agonists on force, at constant free cytoplasmic [Ca2+] maintained with EGTA, were also determined in preparations permeabilized with staphylococcal alpha-toxin, in which intracellularly stored Ca2+ was eliminated with A23187. Sensitization of the contractile response to Ca2+ by agonists was indicated by the contractile responses of permeabilized muscles to U46619 and to phenylephrine, in the presence of constant, highly buffered [Ca2+]i. These contractions were inhibited by GDP [beta S] and could also be elicited by GTP. We conclude that, in addition to changing [Ca2+]i, pharmacomechanical coupling can also modulate contraction by altering the sensitivity of the regulatory/contractile apparatus of smooth muscle to [Ca2+]i, through a G-protein-coupled mechanism.
Himpens
B
B
Department of Physiology, University of Virginia, School of Medicine, Charlottesville 22908.
Kitazawa
T
T
Somlyo
A P
AP
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D004533:Egtazic Acid; D005260:Female; D016257:Fura-2; D019204:GTP-Binding Proteins / Q000494:pharmacology; D006460:Hemolysin Proteins / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D012433:Ryanodine / Q000494:pharmacology; D013997:Time Factors
D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D011450:Prostaglandin Endoperoxides, Synthetic; C021091:staphylococcal alpha-toxin; D012433:Ryanodine; D010656:Phenylephrine; D000001:Calcimycin; D004533:Egtazic Acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019204:GTP-Binding Proteins; D011188:Potassium; D002118:Calcium; D016257:Fura-2