Role of calcium channel in postvagal potentiation of contraction as evident from the effects of Mn2+, La3+, D-600, and deoxycholate on isolated guinea pig atria-vagus nerve preparation.

The role of the calcium channel in the first large contraction (postvagal potentiation, PVP) of the atria at the end of the inhibitory phase of its response (IPR) to vagal stimulation has been investigated by studying the effects of agents acting on the calcium channel (e.g., Ca2+, Mn2+, La3+, and D-600) or sarcoplasmic reticulum (SR) (e.g., deoxycholate (DOC)). IPR was potentiated by high [Ca2+]o (3-16 mM) and also by the calcium channel blockers, Mn2+ (1 microM-0.5 mM), La3+ (0.1 microM-0.5 mM), D-600 (1.0-10 microM), and DOC (1 microM-0.5 mM). PVP was also potentiated by enhanced [Ca2+]o, but the PVP ratio, which employs a correction for the simultaneous changes in the force of spontaneous contraction was inhibited. This indicated greater potentiation of contractility during spontaneous activity by Ca2+ than during PVP. Mn2+, La3+, and D-600 and even DOC in the above concentrations inhibited PVP but increased the PVP ratio. High concentrations of DOC (greater than 1 mM), which disrupt SR, strongly inhibited PVP. It is concluded that the calcium channel plays a more prominent role in spontaneous contractions than in PVP in guinea pig atria. PVP is suggested to be generated by excessive triggered release of Ca2+ from SR leading to a marked increase in [Ca2+]i. The calcium channel and the calcium trapped in the glycocalyx also play significant roles in PVP.

Mechanism of inhibitory effect of calcium on negative inotropic activity of acetylcholine in guinea pig atria.

The mechanism of inhibition of negative inotropic effect (NIE) of acetylcholine (ACh) by high extracellular calcium concentration ([Ca2+]0) has been studied in isolated guinea pig atria. Atropine (10(-10) - 10(-7) M) as well as enhanced [Ca2+]0 (3.26 - 13.6 X 10(-3) M) caused a concentration dependent inhibition of NIE indicating a competitive antimuscarinic effect of these agents. The observed dose ratio of ACh in the presence of atropine and high [Ca2+]0 together was greater than the theoretically expected value. D600 (10(-7) - 10(-6) M), a calcium channel blocker, potentiated NIE of ACh, reduced its dose ratio and antagonised the antimuscarinic effect of excess [Ca2+]0. It is concluded that the present observations support the suggestion that NIE of ACh is primarily due to inhibition of calcium channel by muscarinic receptor activation. In addition, high [Ca2+]0 inhibits the NIE of ACh by acting on multiple sites, e.g. muscarinic receptors, calcium channel and other sites, sensitive to variations in [Ca2+]0.

Studies on the cholinergic receptors in sinoauricular node and adjacent auricular tissues of cat.

Cholinergic receptors in pacemaker and contractile tissue of heart were studied in an isolated sinoauricular (s.a.) node preparation of cat containing crista terminalis. Acetylcholine (ACh), 10(-9) - 10(-5), caused concentration dependent negative inotropic and negative chronotropic effects, the former being more prominent than the latter. Atropine (10(-10) - 10(-4)M) prevented these inhibitory effects of ACh in a competitive manner. No cardioexcitatory effect of ACh was seen in these preparations treated with up to 10(-4)M atropine. It is concluded that the pacemaker cells of s.a. node and contractile atrial cells in cat contain inhibitory muscarinic receptors but no ACh sensitive excitatory nicotinic receptors. The contractile cells of atrium are more sensitive than the pacemaker cells of s.a. node of cat to the inhibitory effects of ACh.

Arecoline induced nicotinic and muscarinic stimulation of the superior cervical ganglion of cat.

Arecoline (10-500 micrograms) stimulated the superior cervical ganglion (s.c.g.) of cat following intra-arterial injection into the ganglion. The ganglion stimulating effect of arecoline was weaker than that of dimethylphenylpiperizinium (DMPP) but stronger than that of pilocarpine. Similarly, the time course of response to arecoline was slower than that of DMPP but faster than that of pilocarpine. The gangliomimetic effects of arecoline, nicotine and DMPP are prevented by hexamethonium, tetraethylammonium and high doses of nicotine and arecoline. Eserine potentiated the response to arecoline but not that to DMPP and nicotine. Response to submaximal preganglionic stimulation and KCl were potentiated by arecoline and pilocarpine but not by DMPP and nicotine. The responses to arecoline and pilocarpine were also prevented by atropine which did not alter the responses to DMPP and nicotine. It is suggested that arecoline stimulated the muscarinic as well as nicotinic receptors in the s.c.g. of cat and that acetylcholine is likely to be involved partially in the gangliomimetic effects of arecoline.

Adrenoceptor blocking agents. 2. 2-(alpha-Hydroxyarylmethyl)-3,3-dimethylaziridines, a new class of selective beta2-adrenoceptor antagonists.

Threo- and erythro-2-(alpha-hydroxybenzyl)-3,3-dimethylaziridines (1a and 1b) and threo-2-[alpha-hydroxy(2-naphthyl)methyl]- and 2-[alpha-hydroxy(3,4-dichlorobenzyl)]-3,3-dimethylaziridines (1d and 1c) have been prepared as conformationally restricted analogues of beta-adrenoceptor blocking agents like dichloroisoproterenol (DCI) and pronethalol. The aziridine analogues 1 except possibly 1c are competitive antagonists of isoproterenol-induced response on a guinea pig tracheal chain preparation and the order of potency is 1d greater than 1a greater than or equal to 1b greater than propranolol greater than 1c. Unlike propranolol, these compounds have no effect on the isoproterenol-induced response on guinea pig auricles and no significant local anesthetic and antiarrhythmic activity. The aziridine analogues 1 represent the first of a new class of selective beta2-adrenoceptor blocking agents.

Studies on the action of acetylcholine on the sino-auricular node of the dog.

1. The response of the sino-auricular node to direct injection of acetylcholine in the artery supplying the node has been studied in the dog.2. Acetylcholine in graded doses (2, 5, 10 mug) caused acceleration of the sinus rhythm.3. The time course of the positive chronotropic action of acetylcholine resembled that produced by adrenaline or noradrenaline.4. The positive chronotropic action produced by acetylcholine was blocked by dichloro-isopropylnoradrenaline and pronethalol and potentiated by cocaine.5. In reserpinized dogs, acetylcholine in similar doses produced sinus bradycardia. The positive chronotropic response could be temporarily restored by infusion of adrenaline or noradrenaline.6. Atropine blocked both the positive and negative chronotropic actions of acetylcholine.