To study of the mechanisms and effects of carvedilol, a drug used for the treatment of heart disease, in the human heart at a molecular level by encompassing the use of pharmacology and molecular biology techniques.
The aim of this project is to determine the mechanisms and effects of a third-generation ▀-blocker called carvedilol in heart disease. ▀-blockers block or prevent the effects of the chemicals noradrenaline and adrenaline in the heart. Activated ▀-adrenoceptors initiate biochemical pathways which may be toxic for hearts with heart disease. In order to understand the mechanisms of carvedilol in the human heart, we will first determine how carvedilol interacts with the different subtypes of ▀-adrenoceptors in the heart and the levels at which these interactions occur. We will then determine whether carvedilol has protective effects for the heart following bypass surgery. Patients with ischaemic heart disease and treated with carvedilol who have undergone bypass surgery will be asked to participate. These patients will be screened for arrhythmias post-surgery. Arrhythmias usually occur in many patients within 2 days following surgery. Results from patients treated with carvedilol will be compared to the presence of arrhythmias in patients who are not being treated with carvedilol. From this, we can establish whether carvedilol is able to protect the heart from post-surgical arrhythmias.
This project will also determine why an important class of ▀-blockers work well in some patients with heart failure, but poorly in others. Overall, the use of ▀-blockers has resulted in a prolongation of life often associated with an improvement in the ability of the heart to pump blood around the body. Unfortunately, some patients do not receive benefit or only obtain a poor result from the administration of ▀-blockers. The reason for the failure of ▀-blockers in some patients is not known. We are investigating possible genetic causes for the variability in ▀-blocker response in patients who have heart failure. It is already known that there are slight differences in the structure of ▀-adrenoceptors in different patients. We can determine the structure of each patientsĺ ▀-adrenoceptor from a blood sample because the same ▀-adrenoceptor that exists in the heart also exists in blood cells. We can then relate the structure of the ▀-adrenoceptor back to the patientsĺ heart condition and response to ▀-blocker. We shall then determine whether it is the structure of the ▀-adrenoceptor which determines the response of the heart failure patient to the ▀-blocker.
Finally we will elucidate the mechanism through which some ▀-blockers such as pindolol cause cardiostimulant effects in human heart using molecular techniques.