Resistant hypertension (RHTN) is an emerging etiology and was defined as persistent elevation of blood pressure above goal despite concurrent use of 3 antihypertensive agents, each of unique class with a diuretic included among the treatment regimen, and with all drugs at target dose. It has been estimated that 12.8% of the hypertensive population in the U.S. met the strict definition for RHTN, and 10% of these patients are refractory to treatment even with 5-6 different classes of antihypertensives. RHTN patients have significantly increased risk of all-cause mortality, cardiovascular mortality, nonfatal stroke, and nonfatal myocardial infarction. While the antihypertensive treatment options have increased from just three classes in 1970' to over eleven different classes now, physicians are having difficulties to achieve controlled blood pressure in RHTN patients. In fact, there is scant evidence for beneficial outcomes using additional drug treatment after three antihypertensives have failed to achieve target blood pressure. Because reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischemic heart diseases by 21%, and reduce the likelihood of dementia and heart failure, clearly there is a substantial unmet medical need of novel therapeutics that can actively improve hemodynamics and endothelial function in RHTN patients. Importantly, an endocrine hormoneâadrenomedullin (ADM)âwas shown to be among the most potent hypotensive hormones and regulators of vascular barrier functions. ADM also exhibits neuroprotective, renoprotective, and diuresis effects in a variety of cardiovascular disease models. Despite its promise for treating a variety of cardiovascular diseases, wild-type ADM has short half-life. To overcome this obstacle, we have developed a group of super- agonistic ADM peptidomimetics that exhibit 10- to 100-fold higher potency on receptor activation. By serendipity, we have also discovered that select super-agonists self-assemble and form in situ gel depots. Together, these data suggested that the ADM analogs, which possess unrivaled super-agonistic activity and the novel self-assemble depot-formation capability, could be an ideal drug for sustained activation of ADM signaling in RHTN patients. Accordingly, we propose to investigate the translational potential of the super- agonist gels in an RHTN rat model. Successful development of the nanomedicine has the potential to drastically improve the care of patients with RHTN or other endothelial dysfunction-associated diseases.
Public Health Relevance Statement: Based on human hormones that play critical roles in the regulation of hemodynamics and vascular integrity, we have developed novel therapeutic candidates for the treatment of resistant hypertension. We will identify a lead candidate, and characterize the pharmacokinetics and efficacy of self-assemble gel depots made of the selected analog. Successful development of the proposed therapy has the potential to prevent the progression of resistant hypertension and to reduce mortality resulting from uncontrolled hypertension.
NIH Spending Category: Aging; Biotechnology; Brain Disorders; Cardiovascular; Heart Disease; Heart Disease - Coronary Heart Disease; Hypertension; Kidney Disease; Neurosciences; Women's Health
Project Terms: Acromegaly; adrenomedullin; Aftercare; Agonist; Aldosterone; American; analog; Angiotensins; Animals; Antihypertensive Agents; Award; base; Blood Pressure; blood pressure reduction; Blood Vessels; Cardiac health; Cardiovascular Diseases; Cardiovascular system; Chronic; Clinical Research; Complex; Coronary Arteriosclerosis; Data; Dementia; Development; Disease; Disease model; Diuresis; Diuretics; Dose; drug candidate; Drug Delivery Systems; Drug Kinetics; Endocrine; endothelial dysfunction; Endothelin; Endothelium; Etiology; Exhibits; Extravasation; Formulation; Gel; Goals; Half-Life; Health; Heart failure; hemodynamics; Hormonal; Hormones; Human; Hypertension; improved; In Situ; in vivo; Inbred SHR Rats; Injections; Ischemia; Kinetics; lead candidate; Left Ventricular Hypertrophy; Mammals; Medical; Modeling; mortality; Mus; Myocardial Infarction; Myocardial Ischemia; nanomedicine; Neuroendocrine Tumors; novel; novel therapeutics; nutrition; Organ; Outcome; Patient Care; Patients; peptide drug; Peptides; peptidomimetics; Pharmaceutical Preparations; Pharmacotherapy; Physicians; Play; Population; pregnant; Prevalence; prevent; Process; Pulmonary Hypertension; Rattus; Receptor Activation; Refractory; Regulation; renal damage; Renal function; Renin; Resistance; Resistant Hypertension; Risk; Risk Factors; Role; Self Efficacy; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Somatostatin Receptor; Stroke; stroke risk; System; Therapeutic; therapeutic candidate; Toxicokinetics; Treatment Protocols; Vascular resistance; vasoconstrict
