Study of the stimulus-response relationship in a multi-cellular system by use of stretch-induced contractile activation of vascular tissue.

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The contractile reaction of the vascular smooth muscle in response to mechanical stretch, first observed in isolated segments of canine carotid artery by Bayless in 1902 is often postulated to be a mechanism of myogenic control of blood flow. Studies on stretch-induced tone in vascular tissue touch the core of problems with respect to 1) the mechanisms of transmembrane or cell to cell signal transduction; 2) the interaction between blood and/or endothelium with medial smooth muscle or other vascular components; and 3) the specific role of Ca, i.e., extra- and intracellular Ca components or stretch- sensitive Ca channels. The present experiments were undertaken to elucidate the mechanisms of stretch-induced contraction, with particular reference to the role of Ca and endothelium.Quick stretching of cerebral artery obtained from dog, guinea-pig, rat and cat at a rate of 10 cm/sec to 140% of the slack length of the muscle evoked a delayed contraction, which was always preceded by an incre … More asing cytosolic Ca signals measured by using fura-2. The contraction produced by quick stretch was myogenic in nature, because the response was not affected by autonomic blockers such as phentolamine, propranolol, atropine, or by tetrodotoxin. Furthermore, the contractile response to quick stretch occurred almost equally irrespective of the presence or absence of endothelium, while the endothelium- dependent relaxation produced either by A 23187 in dog or by acetylcholine in cat was abolished when the endothelium was mechanically rubbed from the artery. Hemoglobin (0.01- 0.2 mg/ml), which increased the basal tone by 10-15% of the maximum contracture produced by 80 mM K, potentiated the stretch-induced contraction 2- to 3-fold over the control. The enhanced response to stretch was attenuated by removal of the endothelium and was readily suppressed by Ca antagonists such as nisoldipine as well as diltiazem, indicating that hemoglobin potentiates the contraction upon stretch by promoting transmembrane supply of Ca. The presence of endothelium seems to amplify the vasoconstrictor action of hemoglobin.As to the ionic mechanisms of the stretch-induced tone with special reference to Ca, we also studied whether dual Ca components or stretch-sensitive Ca channel could be dominant in the genesis of the stretch-induced tone. Unlike the contraction produced by high K, which is totally dependent on extracellular Ca, the stretch-induced tone was much more resistant to Ca antagonists and Ca withdrawal. it was necessary to stretch the artery repeatedly in Ca-free medium or in a Ca antagonist-containing medium in order to suppress the stretch-induced tone. Furthermore procaine, dantrolene and ryanodine partially inhibited the tone. Ultramicroscopic studies revealed that in the cerebral artery smooth muscle cells at rest, the pyroantimonate precipitate, an measure of ca was localized along the inner surface of the plasma membrane, while in muscle cells fixed during the stretch- induced contraction the precipitate was diffusely distributed in the myoplasm, indicating that the stretch-induced tone is associated with not only influx of Ca through dihydropyridine-sensitive Ca channel but also Ca release from the inner surface of the plasma membrane.The present results strongly suggest that the genesis of the stretch-induced tone is myogenic in nature. Endothelium seems to modulate the tone, dependent upon the agonistic stimuli applied to the artery. Our studies also suggest that the low susceptibility of the stretch-induced contraction to Ca antagonists is attributable to dual Ca supplies. It is unlikely that a new type of Ca channel, i.e., one which is stretch-sensitive but resistant to Ca antagonist, truly exists in the cerebral artery. Less