Time course and extent of α1‐adrenoceptor density changes in rat heart after β‐adrenoceptor blockade

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Abstract
1 It has been suggested that impaired β-adrenoceptor stimulation is a condition under which the functional role of cardiac α1-adrenoceptors is enhanced. We therefore investigated the extent and time course of changes in α1-adrenoceptor characteristics after chronic treatment with the β-adrenoceptor blocker propranolol in rat heart. For comparison β-adrenoceptors were also studied. The mechanism of the changes in adrenoceptor density was investigated with cycloheximide, an inhibitor of protein synthesis. The functional significance of an increased α1-adrenoceptor density was tested by measuring isometric force of contraction in the presence of phenylephrine or isoprenaline in right ventricular papillary muscles. 2 Rats were treated with propranolol (9.9 mg kg−1 daily) or 0.9% NaCl, applied with osmotic minipumps for 1, 2, 3 or 7 days. Propranolol treatment resulted in a maximally 28% increase of α1-adrenoceptor density after 3 days (NaCl 95.9 ± 3.5 vs. propranolol 123.0 ± 1.6 fmol mg−1 protein, n = 6, P < 0.01). This up regulation reached significant levels after 2 days of treatment and was reversible after cessation of treatment within two days. KD-values were the same for NaCl- and propranolol-treated rats. Changes of Bmax and KD in β-adrenoceptor binding assays did not reach significant levels. 3 Cycloheximide (1.5 mg kg−1 i.p. daily for 3 days) inhibited the propranolol-induced increase in Bmax of α1-adrenoceptors completely. In addition, cycloheximide also decreased the density of α1- and β-adrenoceptors also under control conditions. 4 pD2-values for the positive inotropic effect of phenylephrine and isoprenaline in isolated electrically driven papillary muscle were similar in NaCl- and propranolol-treated rats (phenylephrine: 5.41 ± 0.11 vs. 5.41 ± 0.19, n = 7; isoprenaline: 6.31 ± 0.18 vs. 6.65 ± 0.19, n = 7). The observed increase in α1-adrenoceptor density in healthy rat heart may therefore not be high enough to enhance the phenylephrine-induced increase in force of contraction. 5 In conclusion, time course and effects of cycloheximide indicate that the increase in Bmax of myocardial α1-adrenoceptors is due to de novo synthesis of receptors. However, at least for the rat heart model, a functional significance of this increase could not be demonstrated.
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