Title : Alpha1D- adrenoceptor RNAm silencing and its contribution to cardiovascular function in sympathectomized spontaneously hypertensive rats
Abstract:
a1D-adrenoceptor (a1D-AR) is a G-coupled receptor involved in blood pressure regulation, so far, its activity has been determined using BMY 7378, a drug with high affinity for them; but, with some other therapeutic blanks, as 5HT1 receptors, which could contribute indirectly with blood pressure regulation. However, the importance of a1D-AR in cardiac function has been limited to the contraction of coronary arteries. But recently, it has been demonstrated that its antagonism with BMY 7378 produce the reversion of left ventricular hypertrophy and improves the cardiac function in hypertensive cardiac disease. Thus, the main goal of the present work is to downregulate selectively the expression of a1D-AR, to determine its contribution in cardiovascular function of Spontaneously Hypertensive Rats (SHR). To reach the objective and to test the functionality of siRNA we used reserpinized (sympathectomized) SHR in order to exacerbate sympathetic nervous system activity and inhibit central responses, later we administered 3 nM, i.v. of three sequences of siRNAm complementary to endogenous RNAm of a1D-AR; then, we constructed systemic and intraventricular dose-response curves to phenylephrine (Phe; dose 0.1-310 mg/kg, i.v.) in presence and absence of RS-100329, a selective a1A-AR antagonist. Previous and after the administration of siRNAs and RS-100329 we measured the cardiac function by echocardiogram. Results showed that the acute administration of siRNA diminished the maximum contraction of the response to Phe; meanwhile, RS-100329 caused a parallel shift to the right of the curves, which was greater when the mixture of siRNA and RS-100329 were administered. The response to Phe in the intraventricular curves was diminished in a similar way in presence of RS-100329, siRNA and the mixture of both. Additionally, echocardiograms showed anatomical changes in the thickness of myocardial walls and function after the administration of a1D-AR siRNAm, these changes were different of that produced by the antagonism of a1A-AR with RS-100329 and the mixture of both drugs. In conclusion, a1D-AR are important in cardiac structure and functionality of SHR.
Audience Take Away Notes
- The relevance of a1D-AR and a1A-AR in cardiovascular physiology.
- The importance of a1D-AR as a novel therapeutic target in cardiac diseases.
- The use of siRNAm as a selective tool for the downregulation of a1D-AR.
