Kj Evans

Activation and Functional Significance of the Renin-Angiotensin System in Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor

Background—The functional significance of cross-regulation between the renin-angiotensin system (RAS) and tumor necrosis factor (TNF) has been established in nonmyocyte cell types; however, the degree and functional significance of the interaction between RAS and TNF has not been characterized in the heart. Methods and Results—We examined the expression of components of the RAS in a line of transgenic mice (MHCsTNF) with cardiac restricted overexpression of TNF. When examined at 4, 8, and 12 weeks of age, the MHCsTNF mice had increased activation of myocardial RAS, as shown by an increase in ACE mRNA level and ACE activity and increased angiotensin II peptide levels. Furthermore, myocardial angiotensin receptor mRNA and protein levels were reduced in the MHCsTNF mice, consistent with homologous desensitization of the receptors. However, expression of renin and angiotensinogen was not increased in MHCsTNF mice compared with littermate controls. To determine the functional significance of RAS activation in the MHCsTNF mice, we treated the mice with an angiotensin type I receptor antagonist, losartan (30 mg/kg), or diluent from 4 to 8 weeks of age. Analysis of cardiac structure with MRI showed that treatment with losartan normalized left ventricular mass and wall thickness. Furthermore, treatment with losartan reduced myocardial collagen content and reduced the incidence of myocyte apoptosis. Conclusions—Taken together, these results show that there are functionally significant interactions between RAS and TNF in the heart and that these interactions play an important role in the development and progression of left ventricular remodeling.

Effects of different beta adrenoceptor ligands in mice with permanent occlusion of the left anterior descending coronary artery

We have studied the effects of three βAR ligands (carvedilol, alprenolol, and ICI‐118,551) with different pharmacological profiles and negative efficacy at the β2AR on cardiac in vivo, in vitro, biochemical and gene expression parameters in mice with permanent occlusion of the left anterior descending coronary artery. Cardiac in vivo parameters were determined using Doppler studies. Mitral‐wave E peak velocity (EPV) and aortic peak velocity (AoPV) decreased in the first 2 weeks postocclusion. After 3 weeks of drug treatment, EPV was improved in the carvedilol group to preocclusion values; however, a further reduction in EPV in the alprenolol and control permanent occlusion group was measured and there was no change after ICI‐118,551 treatment. AoPV was unchanged between weeks 2 and 5 in all groups. The left atria were isolated to record isometric tension responses to isoprenaline. Permanent occlusion significantly reduced the maximum isoprenaline response to 30% of control and carvedilol increased the maximum response to isoprenaline significantly to 60%. The biochemical and gene expression studies revealed different effects of the three βAR ligands. Most notably, carvedilol reduced gene expression of myosin heavy chain β. These results indicate that chronic treatment with carvedilol is beneficial in a mouse model of myocardial damage resulting from ischaemia. We hypothesise that these beneficial effects of the drug may be because of the negative efficacy at the β2AR, combined with β1AR antagonism.

From inverse agonism to 'Paradoxical Pharmacology'

Abstract The constitutive or spontaneous activity of G protein-coupled receptors (GPCRs) and compounds acting as inverse agonists is a recent but well-established phenomenon. Dozens of receptor subtypes for numerous neurotransmitters and hormones have been shown to posses this property. However, do to the apparently low percentage of receptors in the spontaneously active state, the physiologic relevance of these findings remains questionable. The possibility that the reciprocal nature of the effects of agonists and inverse agonists may extend to cellular signaling is discussed, and that this may account for the beneficial effects of certain β-adrenoceptor inverse agonists in the treatment of heart failure.