Selective Reserpine‐induced Supersensitivity of the Positive Inotropic and Chronotropic Responses to Isoprenaline and Salbutamol in Guinea‐pig Isolated Atria

Abstract

I Dose-response curves for the positive inotropic and chronotropic responses to isoprenaline were obtained in atria from untreated guinea-pigs and those receiving various reserpine pretreatments. 2 Tension responses were unaffected, whereas rate responses were depressed by the lowest dose of reserpine (0.05 mg/kg i.p. at 24 hours). 3 With larger 24 h doses and a 3 day pretreatment, the rate and tension dose-response curves were progressively displaced to the left, indicating supersensitivity which was greater for tension at each pretreatment.4 No supersensitivity to histamine or Ca2+ could be detected, leading to the conclusion that it was selective for the f-adrenoceptor agonists possibly at the receptor level. 5 As an indication of the adrenergic neurone depleting effectiveness of each reserpine dosage, preparations were exposed to test doses of P-phenylethylamine. 6 Salbutamol was a partial agonist in untreated atria, the maximum rate (63.3%) and tension (10.0%) responses being less than those for isoprenaline. In atria from reserpine pretreated animals the supersensitivity was revealed as an increase of this maximum compared with isoprenaline. 7 The significance of this observation in relation to the possible mechanism of the supersensitivity is discussed.

Reserpine induces vascular α2‐adrenergic supersensitivity and platelet α2‐adrenoceptor up‐regulation in dog

“…Several reports have suggested that the supersensitivity phenomenon is specific, i.e. demonstrable only with fi-adrenoceptor agonists (Broadley & Lumley, 1977;Haw-thorn & Broadley, 1984). Indeed, several studies have demonstrated increased fi-adrenoceptor density after chronic reserpine treatment (Tenner et al, 1982;Latifpour & McNeill, 1984;Chess-Williams et al, 1987).…”

Comparison of Reserpine-Induced Supersensitivity of Newborn and Adult Rabbit Ventricular Muscles to Cardiotonic Agents

“…Some report an increase ( 19) and the others report no change (2,12) in the IT in the atria from reserpinized animals. No significant changes in maximal developed force was reported following reserpinization (6,11,12,20).…”

“…Depletion of norepinephrine from the nerve endings alone is not sufficient to induce supersensitivity since the development of supersensitiv ity and the degree of norepinephrine depletion are not directly related (7,15). Those who observed specificity to catecholamines have suggested a certain change at the adrenergic receptor site, possibly an increase in the number of available receptors (2,9) or an increased efficacy of the receptor (2). Several workers (9,12,24) have suggersted that the mechanism of non selective supersensitivity lies beyond the receptor, such as an alteration in membrane permeability or in the contractile mechanisms.…”

“…This dose and the method were found to be adequate to produce supersen sitivity in vascular smooth muscle and atrial tissues by others (2,3,19,20) and to deplete norepinephrine from the ventricular myocardium to negligible levels in our laboratory (18). For 1-week-old rabbits, reserpine 2.0 mg/kg was given intraperitoneally 24 h prior to the experiment.…”

“…We have shown this dose of reserpine to deplete cardiac norepinephrine stores m 1-week-old animals to negligible levels (18). Although a prolonged treatment with reserpine is known to increase the degree of supersensitivity (2,9) and is perhaps preferred in other tissues, it was not practical to employ a chronic reserpinization schedule when dealing with 1-week-old rabbits. In addition, the cardiovascular system is known to exhibit supersensitivity more rapidly than other systems (7).…”