STRESS, NEUROTRANSMITTERS, AND HORMONES Adrenoceptors and Adaptive Mechanisms in the Heart during Stress Regina C. Spadari-Bratfisch a,b and Iraides Nunes dos Santos b a Department of Health Sciences, Federal University of S ˜ ao Paulo (UNIFESP), Santos, S ˜ ao Paulo, Brazil b Department of Physiology and Biophysics, Institute of Biology, State University of Campinas (UNICAMP), Campinas, S ˜ ao Paulo, Brazil Several cardiovascular disorders have been related to alterations in beta-adrenoceptor (β-AR) signaling at or beyond the receptor level. During the stress reaction, the sympathetic-adrenal medullary system and the hypothalamus-pituitary-adrenal cor- tex axis are activated, causing β-AR overstimulation and remodeling of the β 1 /β 2 /β 3 -AR ratio in cardiomyocytes. In a model of foot-shock stress, we described decreased β 1 - AR signaling occurring simultaneously with increased β 2 -AR signaling, whereas the response to the nonconventional agonist, CGP12177, was not altered. These alterations may play an adaptive role to the increased sympathetic drive to the heart, protecting the cardiac tissue from the cardiotoxic effects mediated by β 1 -ARs overstimulation without altering cardiac output, since this would be sustained by the β 2 -AR, which would also protect myocytes from apoptosis. Moreover, the selective enhancement of the β 2 -AR population might help to diminish the risk of overstimulation since this adrenocep- tor subtype couples to both, stimulatory G (Gs) and inhibitory G (Gi) proteins. On the other hand, in the model of neurogenic hypertension, the decrease in β 1 -AR–mediated response is not followed by increase in the β 2 -AR–mediated response. However, the response to CGP12177, which was desensitized 48 h after the surgery, was normalized 7 days after that, when β 1 -AR were downregulated. Therefore, both experimental mod- els provided evidence that the classical isoform of β 1 -AR and the recently described low-affinity isoform of β 1 -AR show independent behavior and provide the heart with adaptive mechanisms to increased sympathetic stimulation during stress. Key words: beta-adrenoceptors; stress; cardiac function; adaptive responses Introduction The term “homeostasis” has been widely used to define the constancy of the internal medium that is essential to maintain life. 1,2 The organic processes aimed to maintain home- ostasis have been called homeostatic 1 or allo- static mechanisms. 3,4 Under this perspective, the stress concept has evolved since its pro- posal by Selye 5 until the recently proposed con- cept of stress as “the body’s multi-system re- Author for correspondence: R.C. Spadari-Bratfisch, Departamento de Ciˆ encias da Sa´ ude, Campus Baixada Santista, Universidade Federal de S˜ ao Paulo (UNIFESP), Rua Ana Costa, 95, 11060-001 Santos, SP, Brazil. Voice/fax: +55-13-3222-2048. regina.spadari@unifesp.br sponse to any challenge that overwhelms, or is judged likely to overwhelm, selective homeo- static mechanisms.” 6 The process of maintain- ing homeostasis involves wear and tear, or allo- static load, which can either lead to adaptation and survival or impact adversely on health. The cardiovascular diseases are responsible for at least 50% of all deaths in the occidental world, with one-third of the adult population suffering from some cardiovascular pathology, mostly hypertension. The action potential ve- locity of propagation and the velocity of con- traction and relaxation and force of contraction in cardiac muscle cells determine cardiac out- put, which is regulated minute-by-minute, to keep blood pressure constant. Blood pressure Stress, Neurotransmitters, and Hormones: Ann. N.Y. Acad. Sci. 1148: 377–383 (2008). doi: 10.1196/annals.1410.075 C  2008 New York Academy of Sciences. 377