Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by beta-adrenergic receptor stimulation and blockade.

BACKGROUND: Impaired myocardial beta-adrenergic receptor (betaAR) signaling, including desensitization and functional uncoupling, is a characteristic of congestive heart failure. A contributing mechanism for this impairment may involve enhanced myocardial beta-adrenergic receptor kinase (betaARK1) activity because levels of this betaAR-desensitizing G protein-coupled receptor kinase (GRK) are increased in heart failure. An hypothesis has emerged that increased sympathetic nervous system activity associated with heart failure might be the initial stimulus for betaAR signaling alterations, including desensitization. We have chronically treated mice with drugs that either activate or antagonize betaARs to study the dynamic relationship between betaAR activation and myocardial levels of betaARK1. METHODS AND RESULTS: Long-term in vivo stimulation of betaARs results in the impairment of cardiac +betaAR signaling and increases the level of expression (mRNA and protein) and activity of +betaARK1 but not that of GRK5, a second GRK abundantly expressed in the myocardium. Long-term beta-blocker treatment, including the use of carvedilol, improves myocardial betaAR signaling and reduces betaARK1 levels in a specific and dose-dependent manner. Identical results were obtained in vitro in cultured cells, demonstrating that the regulation of GRK expression is directly linked to betaAR signaling. CONCLUSIONS: This report demonstrates, for the first time, that betaAR stimulation can significantly increase the expression of betaARK1 , whereas beta-blockade decreases expression. This reciprocal regulation of betaARK1 documents a novel mechanism of ligand-induced betaAR regulation and provides important insights into the potential mechanisms responsible for the effectiveness of beta-blockers, such as carvedilol, in the treatment of heart failure.

Dust in the wind: How climate variables and volcanic dust affect rates of tooth wear in Central American howling monkeys.

OBJECTIVES: Two factors have been considered important contributors to tooth wear: dietary abrasives in plant foods themselves and mineral particles adhering to ingested food. Each factor limits the functional life of teeth. Cross-population studies of wear rates in a single species living in different habitats may point to the relative contributions of each factor. MATERIALS AND METHODS: We examine macroscopic dental wear in populations of Alouatta palliata (Gray, 1849) from Costa Rica (115 specimens), Panama (19), and Nicaragua (56). The sites differ in mean annual precipitation, with the Panamanian sites receiving more than twice the precipitation of those in Costa Rica or Nicaragua (∼3,500 mm vs. ∼1,500 mm). Additionally, many of the Nicaraguan specimens were collected downwind of active plinian volcanoes. Molar wear is expressed as the ratio of exposed dentin area to tooth area; premolar wear was scored using a ranking system. RESULTS: Despite substantial variation in environmental variables and the added presence of ash in some environments, molar wear rates do not differ significantly among the populations. Premolar wear, however, is greater in individuals collected downwind from active volcanoes compared with those living in environments that did not experience ash-fall. DISCUSSION: Volcanic ash seems to be an important contributor to anterior tooth wear but less so in molar wear. That wear is not found uniformly across the tooth row may be related to malformation in the premolars due to fluorosis. A surge of fluoride accompanying the volcanic ash may differentially affect the premolars as the molars fully mineralize early in the life of Alouatta.