Bay K 8644 and Acetylcholine: Different Interaction with Calcium Ions in the Rat Duodenal Muscle

Abstract

The contractile effect of the dihydropyridine analogue Bay K 8644, recently described as a Ca²⁺-agonist, has been evaluated in the rat isolated duodenal muscle in comparison with that of acetylcholine. Bay K 8644 (3 x 10^–10–10^–6 mol/l) increased the duodenal motility, whereas it behaved as an inhibitor when tested at high concentrations (>10^–6 mol/l). Bay K 8644 was more potent than acetylcholine (threshold concentration 3 x 10^–10 vs. 10^–8 mol/l) but less efficient. The contractile responses to Bay K 8644 and acetylcholine were reduced in calcium-free medium and abolished by addition of 1 mmol/l EGTA. In some K⁺-depolarized tissues, however, a contractile response to Bay K 8644 was still observed. The effects of Bay K 8644 and acetylcholine were antagonized by nifedipine and verapamil; however, a competitive antagonism was observed only for the interaction Bay K 8644-nifedipine (pA₂ = 9.86). The contraction induced by Bay K 8644 was noncompetitively antagonized by low concentrations of atropine (10^–7 mol/l); Bay K 8644 (10^–7 mol/l) did not modify the response to acetylcholine, while inhibiting it at higher concentration (10^–5 mol/l); in addition, it was able to enhance the response to endogenous acetylcholine, released by field stimulation. The above results indicated that Bay K 8644 and chohnergic stimuli are strong activators of the duodenal motility in vitro. The interference of Bay K 8644 with the chohnergic system, observed in both unstimulated and electrically stimulated strips, suggested a novel site of action of this compound in the gastrointestinal muscle.

Dihydropyridine Receptors in the Pregnant Human Uterus in vitro

“…Experiments performed in Ca2+-free EGTA medium point out that the stimula tory action of Bay K 8644 is dependent on the extracellular calcium, as already sug gested [5,20], Furthermore, the persistence of stimulatory activity after simple removal of calcium from the nutrient fluid indicates an effect involving calcium pools not readily exchangeable with the extracellular fluids (tightly bound calcium) [3]. However, the residual tonic activity observed in the pres ence of EGTA does not exclude a parallel intracellular action [5].…”

“…The marked decrease of the amplitude of spontaneous contractions observed at high concentrations of Bay K 8644 might be pos sibly related to the calcium antagonistic properties of the (+)-enantiomer already de scribed in other tissues [5,10]. However, an effect on inhibitory 'low-affinity' dihydropy ridine receptors cannot be excluded [7,20].…”

The effects of Bay K 8644 and nifedipine on the responses of rat urinary bladder to electrical field stimulation, β,γ‐methylene ATP and acetylcholine

“…The nifedipine-resistant contractions were still cholinergic because they were abolished by atropine. In gastrointestinal systems, such as the mouse isolated distal colon, contractile activity induced by ACh is barely enhanced by Bay K 8644 and partially inhibited by nifedipine (Fontaine & Lebrun, 1988), and in rat duodenal smooth muscle the response induced by ACh is not modified by Bay K 8644 but can be significantly decreased by nifedipine (Coruzzi et al, 1986 1 fM its effect became negative. This characteristic of Bay K 8644 has been observed in many experiments (Bechem & Schramm, 1987).…”

Geranylgeranylacetone Protects the Human Gastric Mucosa from Diclofenac-Induced Injury via Induction of Heat Shock Protein 70

“…Earlier, it was reported [25] that GGA stimulates the mucus production by gastric mucosal cells, other studies [16, 17], however, have shown that the protective effect of GGA on the gastric mucosa is not abolished by NSAIDs which are known to inhibit the mucus production. Therefore, we believe that the most important mechanism by which GGA protects the gastric mucosa against NSAIDs is its potent induction of HSP70, based on the very recent findings by Tanaka et al [26] who clearly demonstrated that GGA does not protect the gastric mucosa against NSAIDs in heat shock factor 1-null mice.…”