Age-dependent differential crosstalk between alpha(1)-adrenergic and angiotensin receptors

Abstract

Previous reports of crosstalk between alpha(1)- adrenergic receptors (alpha(1)-AR) and angiotensin receptors (ATR) have pointed to the existence of physiological regulation between the sympathetic nervous system and the renin-angiotensin system at the receptor level. This regulation may have an important role in the control of blood pressure and may be modified in different cardiovascular pathologies. Aging is considered to be an independent cardiovascular risk factor. Nevertheless, neither the variation in physiological action or interaction of signal transduction between these two receptors as a result of aging has been established. To clarify these aspects, the interaction between alpha(1)-AR and ATR was evaluated. The inotropic response of alpha(1)-AR to agonists was assessed in the presence and absence of angiotensin II using the left atria of 3.5-, 12-, 18- and 24-month-old (young adult, middle aged, elderly and aged, respectively) male Wistar rats. In the four age groups of rat hearts, the activities of tyrosine kinase were measured when just the AT(1)R subtype was activated, or when both alpha(1)-AR and AT(1)R were activated. The activities of cytosolic phospholipase A(2) and the levels of cyclic GMP were investigated when just the AT(2)R subtype was activated, or when both alpha(1)-AR and AT(2)R were activated. No effect was found on the cumulative concentration-response curve for phenylephrine when AT(1)R was activated in 3.5- or 12-month-old rats. However, in 18- and 24-month-old rats, the maximum positive inotropic response and the negative logarithm of the effective 50% concentration increased markedly. No effect was found on the cumulative concentration response curve induced by phenylephrine when AT(2)R was activated. The activities of tyrosine kinase increased significantly in 3.5- and 12-month-old rats, but there was no difference in 18- and 24-month-old rats when alpha(1)-AR and AT(1)R were both activated compared with when just AT(1)R was activated. Cytosolic phospholipase A(2) activity and cyclic GMP levels decreased significantly when both alpha(1)-AR and AT(2)R were activated compared with when just AT(2)R was activated. In the isolated left atria of elderly and aged rats, the activation of AT(1)R enhanced the positive inotropic response induced by the activation of alpha(1)-AR. The activation of AT(2)R had no effect on the positive inotropic response induced by the activation of alpha(1)-AR. The action of alpha(1)-AR increased the signal transduction of AT(1)R in young-adult and middle-aged rat hearts but had no effect in elderly and aged hearts. The action of alpha(1)-AR had no effect on AT(2)R signal transduction.