Observations on ‘fade’: a complication of the contractile response of smooth muscle to a large dose of an agonist

Fastier, F. N.; Purves, Robert D.; Taylor, Kenneth M.

doi:10.1111/j.1476-5381.1973.tb17259.x

Cited by 9 publications

(4 citation statements)

References 9 publications

(13 reference statements)

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“…A similar mechanism has been envisaged for the effects of carbachol and catecholamines on intestinal smooth muscle (see Fastier, Purves & Taylor, 1973;Ohashi, Takewaki, Shibata & Okada, 1975;Bulbring & Tomita, 1977;Bolton, 1979;Casteels & Raeymaekers, 1979;Brading & Sneddon, 1980). In this model, fading of the contractile response and desensitization to substance P would be accounted for by depletion of the Ca2+ store.…”

Section: Resultsmentioning

confidence: 99%

On the mechanism of contraction and desensitization induced by substance P in the intestinal muscle of the guinea‐pig.

Holzer¹,

Petsche²

1983

The Journal of Physiology

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SUMMARY1. The contractile effect of substance P on the longitudinal muscle of the isolated guinea-pig small intestine and the desensitization of the muscle which occurs on prolonged exposure to the peptide have been investigated. All experiments were performed in the presence of atropine.2. The response to a substance P concentration which produced a nearly maximal effect was not sustained but faded rapidly. It was found that not elimination of substance P from the bath, but desensitization of the muscle to substance P was the main cause for the fading of contraction.3. Desensitization of the muscle to substance P only developed if the muscle was exposed to the peptide for a certain time. The degree of and the time needed for recovery from desensitization were directly related to concentration of substance P and contact time.4. Tetraethylammonium (3 mM), which reduces the membrane conductance for K+, enhanced the potency of substance P in contracting the muscle and reduced the fading of contraction. Noradrenaline (295 nM), which increases the K+ conductance, produced opposite effects.5. Lowering the extracellular Ca2+ concentration to one-tenth decreased the potency of substance P in contracting the muscle, accelerated the fading of contraction, and reduced the ability of the muscle to respond to a second addition of substance P after the response to the first addition had faded away.6. Concentrations of substance P (22 nM) and tetraethylammonium (30 mM), which produced nearly maximal contractions, slightly enhanced the efflux of 86Rb from pre-loaded muscle strips. Both substances, however, caused a sustained reduction of 86Rb efflux from strips depolarized by high [K+], the effect of substance P being smaller than that of tetraethylammonium. The effect of substance P and tetraethylammonium on 86Rb efflux appeared independent of the extracellular [Ca2+].7. On exposure of the muscle to substance P (22 nM) for 8 min the intracellular uptake of 46Ca was first decreased and then increased while the 45Ca influx was instantly enhanced by tetraethylammonium (30 mM) or K+ (108 mM). The delayed increase in 45Ca influx caused by substance P was also observed in muscle strips depolarized with high [K+].-P. HOLZER AND U. PETSCHE 8. Taken together, the results suggest that there are two mechanisms of action by which substance P causes contraction of intestinal smooth muscle: reduction of a K+ conductance and a mechanism dependent on the extracellular [Ca2+]. Circumstantial evidence indicates that desensitization of the muscle to substance P arises from a block in excitation-contraction coupling and the hypothesis has been put forward that fading of the contractile response and desensitization reflect depletion of a Ca2+ store which is operated by the substance P receptor.

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Section: Resultsmentioning

confidence: 99%

On the mechanism of contraction and desensitization induced by substance P in the intestinal muscle of the guinea‐pig.

Holzer¹,

Petsche²

1983

The Journal of Physiology

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“…Desensitization is not necessarily spedfic in other smooth muscles, however (Bown et al, 1973), implicating a common step intermediate to activation of different receptors and contraction as a cause of desensitization. The decline in contraction of guinea pig ileum to several agonists is lessened by increases in the external caldum concentration (Fastier et al, 1973). KCl produces a sustained contraction in 5-HT-contracted bovine coronary arteries (Ratz and Flaim, 1982), suggesting that a generalized inactivation of caldum channels was not induced in time by 5-HT receptor binding in this artery type.…”

Section: -H T Inducedmentioning

confidence: 99%

Mechanism of 5-HT contraction in isolated bovine ventricular coronary arteries. Evidence for transient receptor-operated calcium influx channels.

Ratz¹,

Flaim²

1984

Circulation Research

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SUMMARY. The effect of serotonin on isometric tension and transmembrane calcium influx was investigated in rings cut from branches of male bovine circumflex and left anterior descending coronary arteries. Responses were compared to those produced by potassium chloride, and to the serotonin contraction produced in rabbit thoracic aorta. Serotonin in bovine ventricular coronary arteries produced a strong, transient contraction, even at a maximum concentration. Contraction did not decline because of serotonin degradation in the bathing medium. The ability of serotonin to contract bovine ventricular coronary arteries was largely preserved when rings were exposed to a calcium-free medium. When calcium was replaced in the medium, both tension (T) and calcium influx (C, 45 Ca) were increased above control only transiently by serotonin (3 minutes post-serotonin: T = 49.0 ± 13.3 mg/mg, C = 27.33 ± 1.8 ^mol/kg, compared with control T = -4.8 ± 1.5, C = 19.7 ± 1.4; 30 minutes post-serotonin: T = -17.3 ± 2.1, C = 19.3 ± 1.1, compared with control T = -19.6 ± 4.1, C = 18.1 ± 1.4). Potassium chloride-stimulated increases in tension and calcium influx in bovine ventricular coronary arteries and a maximum serotonin contraction in rabbit thoracic aorta were not transient, but were sustained 30 minutes via a mechanism that appeared to be dependent on the influx of extracellular calcium. We suggest that the transient nature of the serotonin contraction in bovine ventricular coronary arteries was the result of a time-dependent decline in both calcium release from intracellular stores and calcium influx through serotonin receptor-operated calcium channels. These data suggest that bovine ventricular coronary arteries contain calcium channels that can operate in a transient manner. (CircRes 54:135-143, 1984)

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“…Several studies [23,24] have indicated that relaxation occurs in response to high concentrations of 5-HT, epinephrine or histamine. Although this relaxation has been explained as fading [23], escape [24] or desensitization or tachyphylactic effects, the precise mechanism of relaxation induced by high doses of agonists remains to be clarified.…”

Section: Inhibitory Effects Of Sarpogrelate and Ketanserin On Relaxationmentioning

confidence: 99%

A Novel 5-HT<sub>2</sub> Antagonist, Sarpogrelate Hydrochloride, Shows Inhibitory Effects on Both Contraction and Relaxation Mediated by 5-HT Receptor Subtypes in Porcine Coronary Arteries

Gong¹,

Nakamura²,

Hattori³

et al. 2000

Pharmacology

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In isolated porcine coronary arteries, concentrations of 5-HT (10^–8 to 3 × 10^–5 mol/l), α-methylserotonin (α-Me-5-HT, 10^–8 to 3 × 10^–5 mol/l) and ergonovine (10^–9 to 3 × 10^–4 mol/l) produced contraction, whereas high concentrations (10^–5 to 10^–4 mol/l) of these drugs produced relaxation. Both sarpogrelate and ketanserin produced rightward shifts of contraction concentration-response curves induced by 5-HT and α-Me-5-HT at the concentration from 10^–9 to 3 × 10^–5 mol/l, and only sarpogrelate inhibited the relaxation at high concentrations of 5-HT and displayed 155% of maximal contraction at 10^–4 mol/l 5-HT. On the other hand, sarpogrelate and ketanserin did not show any inhibitory effects on the relaxation induced by high concentrations of ergonovine. These results suggested that sarpogrelate and ketanserin show different inhibitory effects on the relaxation induced by high concentrations of 5-HT, indicating that these two drugs may have different affinities to 5-HT receptor subtypes that may be involved in relaxation.

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Observations on ‘fade’: a complication of the contractile response of smooth muscle to a large dose of an agonist

Cited by 9 publications

References 9 publications

On the mechanism of contraction and desensitization induced by substance P in the intestinal muscle of the guinea‐pig.

On the mechanism of contraction and desensitization induced by substance P in the intestinal muscle of the guinea‐pig.

Mechanism of 5-HT contraction in isolated bovine ventricular coronary arteries. Evidence for transient receptor-operated calcium influx channels.

A Novel 5-HT<sub>2</sub> Antagonist, Sarpogrelate Hydrochloride, Shows Inhibitory Effects on Both Contraction and Relaxation Mediated by 5-HT Receptor Subtypes in Porcine Coronary Arteries

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