Predicting in vivo cardiovascular properties of β-blockers from cellular assays: a quantitative comparison of cellular and cardiovascular pharmacological responses

β-Adrenoceptor antagonists differ in their degree of partial agonism. In vitro assays have provided information on ligand affinity, selectivity, and intrinsic efficacy. However, the extent to which these properties are manifest in vivo is less clear. Conscious freely moving rats, instrumented for measurement of heart rate (β1; HR) and hindquarters vascular conductance (β2; HVC) were used to measure receptor selectivity and ligand efficacy in vivo. CGP 20712A caused a dose-dependent decrease in basal HR (P<0.05, ANOVA) at 5 doses between 6.7 and 670 μg/kg (i.v.) and shifted the dose-response curve for isoprenaline to higher agonist concentrations without altering HVC responses. In contrast, at doses of 67 μg/kg (i.v.) and above, ICI 118551 substantially reduced the HVC response to isoprenaline without affecting HR responses. ZD 7114, xamoterol, and bucindolol significantly increased basal HR (ΔHR: +122±12, +129±11, and +59±11 beats/min, respectively; n=6), whereas other β-blockers caused significant reductions (all at 2 mg/kg i.v.). The agonist effects of xamoterol and ZD 7114 were equivalent to that of the highest dose of isoprenaline. Bucindolol, however, significantly antagonized the response to the highest doses isoprenaline. An excellent correlation was obtained between in vivo and in vitro measures of β1-adrenoceptor efficacy (R2=0.93; P<0.0001).—Baker, J. G., Kemp, P., March, J., Fretwell, L., Hill, S. J., Gardiner, S. M. Predicting in vivo cardiovascular properties of β-blockers from cellular assays: a quantitative comparison of cellular and cardiovascular pharmacological responses

Improved survival with bisoprolol in patients with heart failure and renal impairment: an analysis of the cardiac insufficiency bisoprolol study II (CIBIS-II) trial

Information on the effectiveness of beta-blockade in patients with heart failure (HF) and concomitant renal impairment is scarce and beta-blockers are underutilized in these patients. The Cockcroft-Gault formula normalized for body surface-area was used to estimate renal function (eGFR(BSA)) in 2622 patients with HF, left ventricular ejection fraction &lt; 35%, New York Heart Association class III/IV and serum creatinine &lt; 300 mu mol/L (3.4 mg/dL) in the second Cardiac Insufficiency Bisoprolol Study II. Patients were divided into four sub-groups according to baseline eGFR(BSA) (&lt; 45, 45-60, 60-75 and &gt;= 75 mL/min per 1.73 m(2)). Cox proportional-hazards models adjusted for pre-specified confounders were used to assess the effect of bisoprolol and potential heterogeneity of effect across the eGFR(BSA) sub-groups. Older age, female-sex, diabetes and ischaemic-aetiology were more common in those with reduced eGFR(BSA). The hazard associated with bisoprolol use for all-cause mortality, the composite of all-cause mortality or HF-hospitalization and HF-hospitalization alone was consistently &lt; 1.0 across eGFR(BSA) categories with no treatment by renal-function interaction (P = 0.81, P = 0.66, P = 0.71, respectively). The rate of bisoprolol discontinuation was higher in patients with eGFR(BSA) &lt; 45 mL/min per 1.73 m(2). Nevertheless the absolute benefit of bisoprolol was greater for patients with chronic kidney disease compared with those without. The beneficial effects of bisoprolol on mortality and hospitalization for worsening heart-failure were not modified by baseline eGFR(BSA). Renal impairment should not prevent the use of bisoprolol in patients with H