Getting to the heart of the matter
The control of hypertension has been realised mainly through the modulation of the renin-angiotensin system (RAS) which involves the decrease of unfavourable stimulation of angiotensin type 1 receptors (AT1Rs). Previous research by Come-In-Care scientists has suggested that many of the undesirable effects of AT1R are as a result of the increase in activity of type 2 receptors (AT2Rs). The discovery of a new AT2 receptor agonist, compound 21, which stimulates the angiotensin AT2 receptor, has opened up the opportunity to study the upregulation of this receptor even though it does not in itself regulate blood pressure. The 'Compound 21 and melatonin in cardiovascular remodeling' (Come-In-Care) project investigated the effects of melatonin, in conjunction with compound 21. Melatonin, a pineal hormone and antioxidant is well known for its beneficial effects on fibrosis and therefore an ideal candidate for testing in conjunction with a RAS modulator. Rats chemically induced to have hypertension were treated over five weeks with compound 21, melatonin and a combination of the two. A range of state-of-the-art techniques was used to assess risk factors and cardiac function.Echocardiography and cathetirisation measured left ventricular function and pulse wave velocity (PWV), an important risk parameter. Fibrosis was evaluated by hydroxyproline concentration and histomorphology. Relevant genomic indicators, measured by RNA expression, were determined by polymerase chain reaction (PCR). Nitrogen oxide (NO) concentration, a significant indicator of the initiation and progression of CV disease was also monitored. Melatonin successfully improved systolic and diastolic function of the left ventricle and compound 21 prevented the increase of PWV. Anti-inflammatory and anti-fibrotic effects were seen with both compound 21 and melatonin. However, there was no significant blood pressure reduction or nitrogen monoxide (NO) production modulation. Project results look very promising for the development of pharmaceutical products to reduce risks associated with cardiovascular disease. In particular, the research is relevant for patients who require prevention of fibrosis and where inflammatory mechanisms are evident but do not require lowering of blood pressure.
