Prevention by Guanethidine Analogues of Output of Noradrenaline Induced by Sodium Reduction in Rabbit Ventricular Slices

Abstract

The prevention by guanethidine and related agents of the output of noradrenaline induced by low sodium was investigated in rabbit ventricular slices. When external NaCl was reduced, the output of noradrenaline into the medium collected at 30 min intervals, increased and the endogenous levels decreased. These changes induced by replacing sodium with sucrose or choline were not affected either by the omission of calcium and addition of 0.5 mm ethylene glycol‐bis(aminoethyl‐ether)N,N,N′,N′ tetra‐acetic acid (EGTA) or by an increase in the calcium concentration to 10 mm 30 min before sodium deprivation. Guanethidine 4 × 10−6 and 4 × 10−5m and 4–7‐exo‐methylene‐hexahydroisoindoline‐ethyl guanidine (No. 865‐123) 4 × 10−5 to 8 × 10−4m inhibited, in a dose‐dependent manner, increases in output of noradrenaline induced by reduction of sodium to 18 mm, while guanethidine 8 × 10−5m and high doses of bretylium produced no inhibition: the latter two released noradrenaline. The inhibitory actions of guanethidine 4 × 10−5m and No. 865‐123 4 × 10−4m were prevented by tetracaine 3.3 × 10−4m, which per se did not modify the output of noradrenaline induced by 18 mm sodium. Accumulation of guanethidine and No. 865‐123 in ventricular slices was greater than that noted in striated muscle slices and was dose‐, time‐ and temperature‐dependent. Tetracaine 3.3 × 10−4m did not prevent the accumulation of guanethidine 4 × 10−5m and No. 865‐123 1.1 × 10−6 to 4 × 10−4m. The guanidine derivatives appear to increase the permeability of adrenergic nerve endings to sodium ions.

Comparative Studies of (−)‐, (±), (+)‐propranolol, Atenolol, Guanethidine, Bretylium and Tetracaine on Adrenergic Transmission

“…This result is consistent with findings that inhibition by local anaesthetics is usually frequency-dependent in various neuronal systems (Bentley, 1966;Stricharz, 1973;Courtney, 1975;Yeh & Narahashi, 1976). These results suggest that the mode of action of adrenergic neurone blocking agents and local anaesthetics on adrenergic neurones may be different (Kubo & Misu, 1974;Misu, Nishio, Hosotani & Hamano, 1976;Maxwell & Wastila, 1977 Nishio, 1978;Hosotani & Misu, 1978a;Hosotani & Misu, 1978b;Hausler & Haefely, 1979). The action of (±)-propranolol was biphasic with a gradual transition from tetracaine-to bretylium-like transmission failure in the ileum and pulmonary arteries and from a bretylium-to guanethidine-like pattern in the vas deferens.…”

4,7-Dihydro-, 4,5,6,7-tetrahydro-, and octahydroisoindoles (and methanoisoindoles). (Review)

“…Their syntheses are based on reduction of the C=O groups in the imides and imidines of tetraand hexahydrophthalic acids and their "bridged" analogs with lithium aluminum hydride. Guanisoline 59 [83] and preparation "865-123" 60 [9,84,85], which are analogs of guanetidine exhibiting the characteristics of adrenoblockers and hypotensive agents, and also tripamide 61, which is a modern hypotensive drug and an effective diuretic [11][12][13][86][87][88][89][90][91][92], were obtained in this way. Neuropsychotropic agents as analogs of dopamine 64 and 65 [74,76], analgesics 66 [97], antidepressants 67 [98], and medicines for the treatment of diabetes 68 [99][100][101][102][103] A method for the production of analogs of the analgesic profadol 70 was based on the transformations of 2-methyl-7a-phenyl-3a,b-epoxy-2,3,6,7-tetrahydroisoindol-1-one (69) [104].…”

“…Phthalimides and phthalimidines are similar in structure to isoindoles, are easily obtainable, and are therefore often used in the synthesis of isoindoles [2,3,5] and their isologs [7][8][9][10][78][79][80][81][82][83][84][85][86].…”