Imidazoline receptors in the heart: a new therapeutic target?

• Grant number: 09/08349-7
• Support Opportunities: Scholarships abroad - Research
• Start date: July 01, 2009
• End date: November 30, 2009
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Angelita Maria Stabile
• Grantee: Angelita Maria Stabile
• Host Investigator: Suhayla Mukaddam-Daher
• Host Institution: Escola de Enfermagem de Ribeirão Preto (EERP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Université de Montréal, Canada

Abstract

The objective of this proposal is to pursue the role of imidazoline receptor activation in heart failure. Imidazoline receptors (I1-receptors), implicated in blood pressure regulation through inhibition of sympathetic nervous (SNS) activity have been identified in the heart. Our in vivo studies have shown that moxonidine, an I1-receptor agonist, exerts cardiovascular effects mediated through stimulation of natriuretic peptides, cardiac vasodilatory, natriuretic, and diuretic hormones with anti-hypertrophic, anti-fibrotic, and anti-inflammatory actions. Despite the established beneficial actions of moxonidine in hypertension, its use in heart failure, a condition of activated hormonal systems and inflammatory processes that are influenced by sympathetic overactivity, are less clear, with some studies demonstrating positive outcomes and others demonstrating negative effects. The fact that reduction of sympathetic activity with some sympatholytic agents is beneficial, while other compounds that also inhibit sympathetic activity increase morbidity and mortality clearly demonstrates that we do not properly understand the role of sympathetic activation in the pathophysiology of heart disease progression to failure. Further investigations are needed to delineate downstream signalling pathways that are both unique and common to the SNS/NE and I1-receptors, including natriuretic peptides and inflammatory cytokines, with the intent of better understanding the important homeostatic, as well as the deleterious interactions that occur between these systems. We have preliminary evidence in a genetic model of heart failure, that moxonidine given at an early stage prevents development of LVH and up-regulates mitochondrial anti-apoptotic protein, Bcl-2. In vitro investigation revealed that moxonidine inhibits NE-induced fibroblast proliferation and opposes NE-induced cardiomyocyte apoptosis. Therefore, our hypothesis is that activation of imidazoline receptors may have cardioprotective effects and accordingly, delay the progression of cardiac pathologies into heart failure by inhibition of SNS activity and maladaptive proliferative signalling and downstream apoptotic pathways. These effects are dose- and time-dependent, being most effective when given before and during the transition from compensation into decompensation. Studies on the hemodynamic, biochemical and molecular levels will be performed on hamsters with genetic cardiomyopathy, an animal model for human non-ischemic congestive heart failure, Protocol 1) The effect of various doses of 4-week moxonidine treatment, and 2-weeks-off treatment will be evaluated in 150-day-old normal and myopathic hamsters by weekly measurement of renal parameters and continuous telemetric measurement of blood pressures and heart rate, as well as in vivo cardiac function by echocardiography. Neurohormones, cytokines, interstitial collagen deposit, and cellular markers of cardiac apoptosis/survival will be evaluated in plasma and cardiac tissues. LVH, fibrosis and cardiac lesions will be evaluated histologically and by measurement of collagen deposit. Sympathetic activity will be determined by measurement of urinary, plasma and cardiac catecholamines and tyrosine hydroxylase protein and mRNA. Apoptosis will be detected on heart sections by TUNEL method and DNA fragmentation, and apoptotic proteins. Protocol 2: After establishing the doses, survival/mortality studies on normal and cardiomyopathic hamsters with and without chronic treatment with moxonidine will explore whether longer treatment by moxonidine and the degree of subsequent inhibition of SNS activity may prevent/delay/regress/stimulate heart failure. Measurements will be taken before and during 6 months treatment, with first deaths in the groups recorded. The end point is death of e 50%. These studies will correlate animal survival/mortality to the degree of sympathetic inhibition and hormonal effects and apoptotic markers. (AU)