Nancy J. Brown, MD

The renin-angiotensin-aldosterone system (RAAS) is one of the major blood pressure regulating systems in the body. The small peptide angiotensin II, Ang II, raises blood pressure by constricting blood vessels and increasing salt retention, in part by stimulating synthesis of the mineralocorticoid aldosterone. Studies in our laboratory have examined how Ang II and aldosterone cause inflammation and fibrosis, promote clotting and affect the risk of diabetes.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists (MRAs) are classes of drugs that interrupt the RAAS. ACE inhibitors decrease formation of Ang II whereas ARBs block the effect of Ang II at its major receptor and MRAs block the effects of aldosterone. ACE inhibitors also prevent the breakdown of bradykinin, a peptide in the body that lowers blood pressure and causes salt excretion.

We have shown that bradykinin has other beneficial effects, like increasing release of tissue-type plasminogen activator from the vascular endothelium. Bradykinin can also have detrimental effects, promoting inflammation. The net beneficial or detrimental effect of bradykinin may depend on the health of the blood vessels. Neprilysin inhibitors, combined with an ARB in the heart failure drug sacubitril/valsartan, also affect the breakdown of bradykinin and other vasoactive peptides such as substance P. We are currently studying how bradykinin and substance P contribute to the effects of sacubitril/valsartan.

Despite the many beneficial effects of ACE inhibitors, this class of medications can cause swelling of the lips, tongue, or face, a side effect called angioedema. Likely, this side effect results from decreased breakdown of bradykinin and another peptide called substance P. We have determined groups of patients who are at increased risk for angioedema. Studies in our laboratory have identified genetic variants in pathways involved in angioedema, allowing us to better predict risk and prevent the side effect.

Another class of drugs that affects the breakdown of substance P as well as the incretin hormones like glucagon-like peptide-1 (GLP-1) are the dipeptidyl peptidase-4 (DPP4) inhibitors such as sitagliptin (Janvuia).

Over the last several years, we have been studying the differing effects of DPP4 inhibitors and GLP-1 agonists such as liraglutide (Victoza and Saxenda) or semaglutide (brand names Ozempic, Wegovy, and Rybelsus) the cardiovascular function.