Synergism of myocardial β-adrenoceptor blockade and I 1 -imidazoline receptor-driven signaling: Kinase-phosphatase switching.

Recently identified imidazoline receptors of the first type (I ₁ Rs) on the cardiomyocyte's sarcolemma open a new field in calcium signaling research. In particular, it is interesting to investigate their functional interaction with other well-known systems, such as β-adrenergic receptors. Here we investigated the effects of I ₁ Rs activation on L-type voltage-gated Ca ²⁺ -currents under catecholaminergic stress induced by the application of β-agonist, isoproterenol. Pharmacological agonist of I ₁ Rs (I ₁ -agonist), rilmenidine, and the putative endogenous I ₁ -ligand, agmatine, have been shown to effectively reduce Ca ²⁺ -currents potentiated by isoproterenol. Inhibitory analysis shows that the ability to suppress voltage-gated Ca ²⁺ -currents by rilmenidine and agmatine is fully preserved in the presence of the protein kinase A blocker (PKA), which indicates a PKA-independent mechanism of their action. The blockade of NO synthase isoforms with 7NI does not affect the intrinsic effects of agmatine and rilmenidine, which suggests NO-independent signaling pathways triggered by I ₁ Rs. A nonspecific serine/threonine protein phosphatase (STPP) inhibitor, calyculin A, abrogates effects of rilmenidine or agmatine on the isoproterenol-induced Ca ²⁺ -currents. Direct measurements of phosphatase activity in the myocardial tissues showed that activation of the I ₁ Rs leads to stimulation of STPP, which could be responsible for the I ₁ -agonist influences. Obtained data clarify peripheral effects that occur during activation of the I ₁ Rs under endogenous catecholaminergic stress, and can be used in clinical practice for more precise control of heart contractility in some cardiovascular pathologies.
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