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

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.