Publications

Feb 15, 1995

In an all-genotypes study Bucindolol, metoprolol had similar effects on reverse remodeling, contractility (bucindolol slightly better) and energetics (metoprolol slightly better).

Oct 1, 1994

On exposure to isoproterenol the human β1-AR undergoes less sequestration/internalization compared to the β2-AR, by 25.9% vs. 60.0% respectively. Internalization of the β1-AR can be improved by removing a 24 amino acid proline rich segment from the 3rd intracytoplasmic loop of the β1-AR, which when added to β2-AR reduces internalization.

Jun 3, 1994

The functional consequences of the 2 N-terminus variants of the human β2-AR were investigated by site-directed mutagenesis and stable transfection into Chinese hamster fibroblasts (CHW cells) measuring the receptor protein, mRNA and sequestration/internalization responses to isoproterenol. Since the sequence of both polymorphisms was known the behavior of the various 2-site haplotypes can be determined. On 18 or 24 hour exposure to isoproterenol the Gln27/Arg16 haplotype downregulates without a change in mRNA abundance and internalizes/sequesters at a level of 60% reaching a maximum at 20 minutes. The Glu27Gly16 haplotype also downregulates without a change in mRNA abundance but undergoes less internalization/sequestration.

Apr 1, 1994

Phase 2B trial (N=141), first study to investigate dose response to a β-blocker in HFrEF via a parallel, placebo-controlled design with 3 doses of active drug. Bucindolol was well tolerated (99%) at all doses, produced dose related reverse remodeling (increase in LVEF at 3 mos), and did not increase nighttime heart rate on Holter monitoring (no evidence of ISA). Highest dose (100 mg bid) had greatest increase in LVEF and was only group with no deaths, hence this dose was selected for Phase 3. Maximal exercise is not improved by bucindolol at any dose, but there was a trend for improvement in submaximal exercise at the highest 2 doses. The overall conclusion was that the highest dose is the most effective, but exercise tolerance cannot be used as a Phase 3 trial endpoint.

Dec 11, 1993

Phase 2 placebo controlled randomized trial of metoprolol tartrate in Class II, III IDC LVEF <0.40 subjects (N=383) resulting in a nominal reduction in the primary endpoint of death or listing for heart transplant (by 34%, P=0.058, 63 primary events), no effect on mortality alone (19 deaths placebo, 23 metoprolol, P=0.69), a dose related increase in LVEF, and no increase in maximal exercise tolerance at 6 but an increase at 12 months (P=0.046).

Apr 15, 1993

On exposure to agonist the human β2-AR undergoes phosphorylation, internalization/sequestration and downregulation while the β3-AR does not. When the β2-AR cytoplasmic tail and C-terminus containing multiple Ser and Thr phosphorylation sites were substituted into a β3-AR the chimeric β3/β2 receptor behaved like β2, demonstrating the importance of agonist mediated phosphorylation as a proximal step in receptor internalization.

Sep 10, 1992

Four nonsynonymous SNPs leading to amino acid changes in the coding region of the human β2-AR were identified. Two with relatively high minor allele frequencies (>5%) are in the N-terminus: Arg16Gly (labeled “wild type” based on the structure of the originally cloned β2-AR, although Gly16 is the major allele); and Gln27Glu. The other 2 nonsynonymous SNPS were rare, at the margin between the definition of a mutation and a polymorphism ≈1% minor allele frequency.

Mar 1, 1992

Cloned human β2-ARs identified by radioligand binding (ICYP/CGP12177 or propranolol) undergo internalization and subsequent downregulation in response to isoproterenol to a much greater extent than β1-ARs. (The differential downregulation is in the opposite direction in human hearts).

Feb 1, 1992

Cloned human β2-AR internalization in response to isoproterenol was investigated in HEK293 cells by immunofluorescence microscopy or confocal microscopy, plus radioligand binding with [3H]CGP12177 and 3[H]DHA. Internalization following exposure to Iso was rapid (onset @ 2 min, maximal at 5 min); internalized receptors were identified in intracellular endosomes by colocalization with transferrin receptors, an endosomal marker.

Dec 1, 1991

Phase 2A trial, first placebo-controlled, randomized study (N=51) in HFrEF (with any β-blocker) evaluating both IDC and ischemic cardiomyopathy patients, demonstrating good tolerability (98%), reverse remodeling in both phenotypes with greater effects in IDC. Maximal or submaximal exercise was not improved by bucindolol.

Aug 1, 1990

In an open label, all-genotypes study with no comparator, at 3 months bucindolol reversed remodeling, increased contractility as measured by a load independent index, and improved energetics.

Jun 1, 1990

In human LV or RV preparations bucindolol was a high affinity (low nanomolar Kd) competitive antagonist at both β1- and β2-ARs and was a weak a1-antagonist (≈100 nM Kd), with no sympatholytic activity even in the presence of augmentation of Gs-AC signal transduction by forskolin. Bucindolol (similar to carvedilol) had guanine nucleotide modulatable binding, indicating biased ligand activity for Gs signaling.

Mar 1, 1990

Phase 2A trial (N=23): first double blind, placebo-controlled trial (with any β-blocker) demonstrating that in IDC/HFrEF a nonselective β-blocker with mild vasodilator activity (3rd generation β-blocker) is well tolerated if initiated at low dose; first study to show that compared to placebo a β-blocker improves systolic function at 3 months, likely by increasing contractility, and reverses remodeling; first study to show that bucindolol lowers norepinephrine (NE) in heart failure with reduced ejection fraction (HFrEF). Maximal or submaximal exercise was not improved by bucindolol.

Mar 1, 1989

Both β1-and β2-ARs mediated adenylate cyclase stimulation in membrane preparations from nonfailing and failing human left ventricles. β2-AR activation was greater in both nonfailing and failing LVs, and β1-AR stimulation was more reduced in failing compared to nonfailing.

Sep 1, 1986

β1- but not β2-ARs are selectively downregulated in failing human ventricular myocardium; in failing ventricles β2-ARs were 40% of the total suggesting that a nonselective β-blocker would be preferred over one that is β1-AR selective.

Apr 25, 1986

First evidence that human ventricular myocardium contains β2-adrenergic receptors (β2-ARs) present on cardiac myocytes.

Jul 22, 1982

First evidence that the failing human heart is exposed to excessive adrenergic drive that produces adverse biological effects; authors suggested that β-blockade would be an effective treatment of heart failure.