Patti Larrabee

Age-related changes in beta-adrenergic neuroeffector systems in the human heart.

BackgroundAging decreases cardiac β–adrenergic responsiveness in model systems and in humans in vivo. The purpose of this study was to comprehensively evaluate the age-related changes in the β-receptor-G protein-adenylyl cyclase complex in nonfailing human hearts. Methods and ResultsTwenty-six nonfailing explanted human hearts aged 1 to 71 years were obtained from organ donors and subjected to pharmacological investigation of β-adrenergic neuroeffector systems. When the population was subdivided into the 13 youngest and 13 oldest subjects, total β-receptor density assessed by maximum [125I]ICYP binding (βmax) was reduced in older hearts by 37% in left ventricles and 31 % in right ventricles (both P<.05), and the downregulation was confined to the β1 subtype (r= −.78 left ventricle β1 density versus donor age). Older donor hearts exhibited a 3- to 4-fold rightward shift of ICYP-isoproterenol (ISO) competition curves and demonstrated 43% fewer receptors in a high-affinity agonist binding state (P<.05). Older hearts exhibited decreased adenylyl cyclase stimulation by ISO, by zinterol (β2-agonist), and by the G protein–sensitive probes forskolin, Gpp(NH)p, and NaF. In contrast, there was no change in response to manganese, a specific activator of the adenylyl cyclase catalytic subunit. Toxin-catalyzed ADP ribosylation in membranes prepared from older versus younger hearts revealed a 29% to 30% reduction (P<.05) with cholera toxin (Gβs) but no difference with pertussis toxin (Gβi). The systolic contractile response of isolated right ventricular trabeculae to ISO was decreased by 46%, with a 10-fold increase in ISO EC50 in older relative to younger donor hearts. ConclusionsThere is a profound decrease in cardiac β-adrenergic responsiveness with aging. This occurs by multiple mechanisms including downregulation and decreased agonist binding of β1-receptors, uncoupling of β2-receptors, and abnormal G protein-mediated signal transduction.

Lisinopril lowers cardiac adrenergic drive and increases beta-receptor density in the failing human heart.

BackgroundIn subjects with heart failure, angiotensin converting enzyme inhibitors exhibit mild systemic antiadrenergic effects, as deduced from treatment-related lowering of systemic venous norepinephrine levels. The effects of angiotensin converting enzyme inhibitors on cardiac adrenergic drive in subjects with heart failure has not previously been investigated. Methods and Resuls. In a placebo-controlled, double-blind crossover study of 14 patients, we measured cardiac and systemic adrenergic drive, myocardial and lymphocyte 1-adrenergic receptors, and hemodynamic changes at baseline and after 12 weeks of therapy. Relative to placebo, lisinopril therapy was associated with only minimal, statistically insignificant changes in hemodynamics, a significant increase in myocardial P-receptor density, no significant (P<.05) changes in cardiac or systemic adrenergic drive, and no detectable change in lymphocyte P-receptor density. When subjects were rank ordered into groups with the highest and lowest coronary sinus norepinephrine levels, those with the highest norepinephrine levels exhibited significant decreases in central venous norepinephrine, coronary sinus norepinephrine, and an increase in myocardial 1receptor density relative to changes in placebo or relative to baseline values. Subjects with lower cardiac adrenergic drive exhibited no significant changes in coronary sinus or systemic norepinephrine levels or in myocardial 1-receptor density. ConclusionThe angiotensin converting enzyme inhibitor lisinopril lowered cardiac adrenergic drive and increased 1-receptor density in subjects with increased cardiac adrenergic drive but had no effects on these parameters in subjects with normal cardiac adrenergic drive. These data suggest that cardiac antiadrenergic properties contribute to the efficacy of angiotensin converting enzyme inhibitor in subjects with heart failure.

Myocardial catecholamine and neuropeptide Y depletion in failing ventricles of patients with idiopathic dilated cardiomyopathy. Correlation with beta-adrenergic receptor downregulation.

BackgroundMyocardial adrenergic neurotransmitters and β-adrenergic receptor levels were measured in left and right ventricular myocardial specimens obtained from 30 patients with biventricular failure resulting from idiopathic dilated cardiomyopathy. Methods and ResultsNonfailing myocardium obtained from 12 organ donors provided control data. Norepinephrine, dopamine, and neuropeptide Y concentrations were significantly decreased in failing compared with nonfailing control hearts. The mean ratio of dopamine to norepinephrine and of dopamine to neuropeptide Y in failing hearts was also significantly decreased compared with nonfailing control hearts. Compared with nonfailing control hearts, Bmax and β-receptor density were significantly decreased in failing hearts and there were weak but significantly positive correlations of Bmax and β-adrenergic receptors with norepinephrine, dopamine, and neuropeptide Y ConclusionsNorepinephrine and its cotransmitter neuropeptide Y are depleted in failing human ventricular myocardium. Decreased norepinephrine stores correlate weakly with β-adrenergic receptor downregulation consistent with the hypothesis that norepinephrine depletion occurs in response to increased adrenergic drive. Decreased dopamine relative to norepinephrine implies that an abnormality of dopamine conversion to norepinephrine is not present in failing human heart.

Second- and third-generation beta-blocking drugs in chronic heart failure

The left-ventricular (LV) functional, hemodynamic, and antiadrenergic effects of metoprolol, bucindolol, and carvedilol have been compared in three concurrent placebo-controlled clinical trials in patients with symptomatic idiopathic dilated cardiomyopathy. All three drugs were well tolerated, all produced at least moderate degrees of β-blockade as assessed by reduction in exercise heart rate, and all increased the left-ventricular ejection fraction. Compared with the β_1-selective, second-generation compound metoprolol, the third-generation compounds bucindolol and carvedilol lowered indices of adrenergic activity and tended to improve LV function to a greater extent. In patients with chronic heart failure there may be important therapeutic response differences between second- and third-generation beta-blocking agents.

Nerve growth factor released from a novel PLGA nerve conduit can improve axon growth

Nerve injury can occur due to penetrating wounds, compression, traumatic stretch, and cold exposure. Despite prompt repair, outcomes are dismal. In an attempt to help resolve this challenge, in this work, a poly-lactic-co-glycolic acid (PLGA) nerve conduit with associated biodegradable drug reservoir was designed, fabricated, and tested. Unlike current nerve conduits, this device is capable of fitting various clinical scenarios by delivering different drugs without reengineering the whole system. To demonstrate the potential of this device for nerve repair, a series of experiments were performed using nerve growth factor (NGF). First, an NGF dosage curve was developed to determine the minimum NGF concentration for optimal axonal outgrowth on chick dorsal root ganglia (DRG) cells. Next, PLGA devices loaded with NGF were evaluated for sustained drug release and axon growth enhancement with the released drug. A 20 d in vitro release test was conducted and the nerve conduit showed the ability to meet and maintain the minimum NGF requirement determined previously. Bioactivity assays of the released NGF showed that drug released from the device between the 15th and 20th day could still promote axon growth (76.6–95.7 μm) in chick DRG cells, which is in the range of maximum growth. These novel drug delivery conduits show the ability to deliver NGF at a dosage that efficiently promotes ex vivo axon growth and have the potential for in vivo application to help bridge peripheral nerve gaps.