The offset of β‐adrenoceptor antagonism of the responses of the rat right ventricle to isoprenaline

Abstract

1. The aim of the study was to test the hypothesis that the offset of action of beta-adrenoceptor antagonists on the heart is related to their lipophilicity, with low and highly lipophilic drugs having a rapid and slow offset, respectively. The effects of beta-blockers with low (atenolol), moderate (celiprolol), high (propranolol) and very high (bopindolol) lipophilicity on the contractile responses of the rat right ventricle to isoprenaline were determined. 2. Atenolol at 10(-6) and 10(-5) M, celiprolol at 10(-7), 10(-6) and 10(-5) M, propranolol at 10(-8), 10(-7) and 10(-6) M and bopindolol at 2 x 10(-9) and 10(-8) M caused parallel rightward shifts of the isoprenaline response curves with no effect on maximum responses. The Schild plots for atenolol, celiprolol and propranolol had slopes that were not significantly different from 1, which is indicative of competitive reversible antagonism. The pKB values were 7.33, 7.78, and 8.79 for atenolol, celiprolol, and propranolol, respectively. The Schild plot for bopindolol had a slope that was significantly greater than 1. 3. Our hypothesis is supported as the effects of propranolol and bopindolol were more slowly offset than those of atenolol and celiprolol. Thus, the concentration-ratio of 141 in the presence of atenolol at 10(-5) M was reduced to 4 after the first wash, whereas the ratio of 100 in the presence of propranolol at 10(-7) M was only reduced to 45 after a similar wash. The ratio of 54 with celiprolol at 10(-6) M was reduced to 5, whereas the ratio of 70 with bopindolol at 10(-8) M was only reduced to 28 by the first wash. 4. The effects of bopindolol were very slowly or not reversible over two washes in the absence or presence of atenolol at 10(-6) M. It is suggested that bopindolol is a very slowly reversible beta-blocker, and that this contributes to its slow offset of action.

Direct demonstration of β1‐ and evidence against β2‐ and β3‐adrenoceptors, in smooth muscle cells of rat small mesenteric arteries

“…In summary, the presence of β 1 ‐ rather than β 2 ‐ARs is based on several experimental observations: (i) the potency ratio between isoprenaline and salbutamol is more than 10 times greater than the usual potency ratio observed in tissues that express mainly β 2 ‐ARs ( Arch et al ., 1984 ; Priest et al ., 1997 ); (ii) the estimated p K B values obtained for propranolol (8.17) and atenolol (6.6), a β 1 ‐AR selective antagonist, versus isoprenaline CRCs were similar to those previously reported in the rat MRA ( White et al ., 2001 ) and aorta ( Doggrell & Henderson, 1998 ) and agree with the recently reported ( Baker, 2005 ) p K D for both agonists at β 1 ‐ARs; (iii) ICI 118551, a highly selective β 2 ‐AR antagonist ( Baker, 2005 ) did not modify the CRC to isoprenaline and (iv) no relaxation to salbutamol was found when the precontractile agent was U 46619 or 5‐HT instead of phenylephrine.…”

β-Adrenergic Receptor and Insulin Resistance in the Heart

“…Previous studies have investigated the K i values by βAR binding assay and showed that various β-blockers have different Ki values for human β 2 AR: propranolol (0.8 nM), metoprolol (2,960 nM), and atenolol (8,140 nM) (Hoffmann et al ., 2004). Moreover, the offset in activity induced by β-blockers in the heart is related to their lipophilicity (Doggrell and Henderson, 1998). The βAR blocking activity of atenolol, which exhibits low lipophilicity, was offset more quickly than that of propranolol, which exhibits high lipophilicity on contractile responses to ISO (Doggrell and Henderson, 1998).…”

“…Moreover, the offset in activity induced by β-blockers in the heart is related to their lipophilicity (Doggrell and Henderson, 1998). The βAR blocking activity of atenolol, which exhibits low lipophilicity, was offset more quickly than that of propranolol, which exhibits high lipophilicity on contractile responses to ISO (Doggrell and Henderson, 1998). Collectively, propranolol showed a more superior effect than atenolol and metoprolol in suppressing β 2 AR-mediated insulin resistance.…”

Bopindolol: Pharmacological Basis and Clinical Implications

“…b-ARA effects of bopindolol were examined by Doggrell (15) and Doggrell and by Henderson (16). Using rat right ventricular specimens, they found that at a low concentration bopindolol competitively shifted the isoproterenol (Iso) concentration-activity curve to the right, while at a high concentration (5´10 -7 M) it inhibited the maximal response to Iso.…”