(-)-CGP 12177 increases contractile force and hastens relaxation of human myocardial preparations through a propranolol-resistant state of the beta1-adrenoceptor

Two forms of the activated beta(1)-adrenoceptor exist, one that is stabilized by (-)-noradrenaline and is sensitive to blockade by (-)-propranolol and another which is stabilized by partial agonists such as (-)-pindolol and (-)-CGP 12177 but is relatively insensitive to (-)-propranolol. We investigated the effects of stimulation of the propranolol-resistant PI-adrenoceptor in the human heart. Myocardium from non-failing and failing human hearts were set up to contract at 1 Hz. In right atrium from non-ailing hearts in the presence of 200 nM (-)-propranolol, (-)-CGP 12177 caused concentration-dependent increases in contractile force (-logEC(50)[M] 7.3+/-0.1, E-max 23+/-1% relative to maximal (-)-isoprenaline stimulation of beta(1)- and beta(2)-adrenoceptors, n=86 patients), shortening of the time to reach peak force (-logEC(50)[M] 7.4+/-0.1, E-max 37+/-5%, n=61 patients) and shortening of the time to reach 50% relaxation (t(50%), -logEC(50)[M] 7.3+/-0.1, E-max 33+/-2%, n=61 patients). The potency and maxima of the positive inotropic effects were independent of Ser49Gly- and Gly389Arg-beta(1)-adrenoceptor polymorphisms but were potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (-logEC(50)[M] 7.7+/-0.1, E-max 68+/-6%, n=6 patients, P

Genetic and environmental risk factors and their interactions for Parkinson's disease in a Chinese population

The interaction between genetic and environmental factors for PD was examined in a Chinese population. It was found that although the intron 2 MAOB (GT)(n) repeat polymorphism was not associated with PID in the population, a relationship might have been masked by the protective effect of tea drinking. In individuals who did not drink tea (<1 cup/day), the possession of short length less than or equal to 178 bp (GT), alleles conferred a borderline significant increased risk for PD (adjusted OR = 1.47; C.l. = 1.03-2. 1). As the extent of tea consumption increased, the association between the less than or equal to178 bp allele and PD disappeared. This result suggests that the MAOB gene may be associated with PD in Chinese if the putative protective effect of tea drinking is taken into account. The significance of this finding is unclear as the study may be limited because of its marginal significance and limited numbers. However, it does demonstrate the importance of considering putative positive and negative environmental risk factors in any examination of genetic risk factors for PD. (C) 2003 Elsevier Science Ltd. All rights reserved.