Mechanisms of action of noradrenaline and carbachol on smooth muscle of guinea‐pig anterior mesenteric artery.

Abstract

SUMMARY1. Membrane potential was recorded by micro-electrode in segments of small (200-500 jsm o.d.) mesenteric arteries of guinea-pig. Isotonic shortening was recorded in helical strips cut from these arteries.2. Raising the external potassium concentration, [K+]0, caused shortening and substantial depolarization. The threshold for contraction was about 30 mm which corresponded to a membrane potential of about -45 mV. Since high-potassium contractions were abolished in calcium-free solution it was suggested that they occur due to potential-sensitive calcium channels opening positive to about -45 mV.3. Noradrenaline weakly depolarized the muscle and produced contractions resistant to calcium-free conditions. It was suggested that noradrenaline contractions are mainly caused by mechanisms other than the opening of potential-sensitive calcium channels, namely entry of calcium via other channels and release of stored calcium.4. Carbachol had no effect on basal tension but inhibited shortening by noradrenaline or by raising [K+]0. The inhibitory effect of carbachol on tension under various conditions was associated with hyperpolarization or depolarization in a range negative to -45 mV, or no effect on potential, so that modulation of the number of open potential-sensitive calcium channels could not be evoked to explain its relaxant action.5. Removal or destruction of the endothelium by rubbing or by distilled water perfusion left tension responses to noradrenaline or raised [K+]. essentially unchanged. However, the inhibitory effect of carbachol on tension was attenuated and hyperpolarization of the resting artery was converted to a depolarization. 6. It was concluded that carbachol has both a strong inhibitory and a weak excitatory effect on these vascular smooth muscle cells. Membrane potential changes are not essential to its inhibitory action but may, by closing potential-sensitive calcium channels, sometimes reinforce it. Hyperpolarization by carbachol may be caused by a factor released by the action of carbachol on endothelial cells: in its absence carbachol may weakly depolarize but this alone is normally insufficient to generate tension.

Effect of cromakalim on contractions in rabbit isolated renal artery in the presence and absence of extracellular Ca2+

“…The extent of cell membrane depolarisation associated with the contractile activity of these receptor agonists in vascular smooth muscle remains a matter of controversy (see Johansson & Somylo, 1980;Hermsmeyer, 1983). It is evident, however, that in isolated arteries such as rat small mesenteric (Mulvany et al, 1982), guinea-pig anterior mesenteric (Bolton et al, 1984) and rabbit pulmonary (Haeusler, 1985), the degree of depolarisation associated with a given contraction is considerably smaller for noradrenaline than for KCL This applies to other receptor agonists such as histamine, 5-HT and angiotensin II (see Johansson & Somlyo, 1980). Nevertheless, cromakalim is an effective inhibitor of contractions to all of these agents (Cain & Nicholson, 1988;Cook et al, 1988;Wilson, 1988).…”

“…The efflux of operated Ca2+ channels (VOC). Thus cromakalim K+ ions from the vascular smooth muscle cell hyperinhibits contractions induced by KCl, although high polarises the membrane towards the K+ equilibrium concentrations (>60mM) of KCl, produce contracpotential (Hamilton et al, 1986; tions which are resistant to cromakalim Clapham & Wilson, 1987 Cromakalim also inhibits contractions induced by receptor agonists such as noradrenaline, histamine, 5-hydroxytryptamine (5-HT) and angiotensin II (Clapham & Wilson, 1987;Cain & Nicholson, 1988;Cook et al, 1988;Wilson, 1988), even though contractions to these agents are less dependent on depolarisation than the equivalent contractions to KCI (Mulvany et al, 1982;Bolton et al, 1984;Haeusler, 1985;Neild & Kotecha, 1987). Unlike contractions to KCl, contractions to all concentrations of the receptor agonists are inhibited.…”

Heterogeneous distribution of muscarinic receptors in the rabbit saphenous artery

“…However, ACh-induced dilatation is mediated mainly by substances released from endothelial cells (Furchgott & Zawadzki, 1980;Furchgott, 1983). Also AChinduced hyperpolarization is mainly due to substances released from the endothelial cells, and a direct action of muscarinic agonists on vascular smooth muscle cells results in either depolarization of the membrane (Bolton et al, 1984) or an almost negligible effect (Komori & Suzuki, 1987). However, in the rabbit lingual artery, ACh hyperpolarizes directly the smooth muscle cells and the endothelial cells do not appear to be involved (Brayden & Large, 1986).…”

Evidence that nitric oxide does not mediate the hyperpolarization and relaxation to acetylcholine in the rat small mesenteric artery

“…Acetylcholine and related cholinomimetics cause both vasorelaxation and hyperpolarization in vascular smooth muscle cells by an endothelium-dependent mechanism (Bolton et al, 1984;Chen et al, 1988;Feletou & Vanhoutte, 1988;McPherson & Angus, 1991;Rand & Garland, 1991). Smooth muscle relaxation follows the stimulation of soluble guanylate cyclase by a diffusible factor which is released from endothelial cells (EDRF; see Angus & Cocks, 1989).…”