RESEARCH INTERESTS
Research focuses on understanding the role of opioid (mu- and kappa-) and opioid-like peptides (nociceptin/orphanin FQ) in the regulation of cardiovascular and renal function. A major focus is to determine how opioid/nociceptin systems interact with other hormones, neurotransmitters and the renal nerves in the central nervous system (CNS) regulation of renal tubular sodium and water handling during normal and pathological conditions (e.g. hypertension, congestive heart failure, cirrhosis with ascites). These investigations employ techniques for measurement of brain G-protein receptor expression, and changes in cardiovascular and renal function and direct recording of renal nerve activity. From the knowledge obtained from these investigations, we are attempting to develop novel antihypertensive agents and water diuretics for the clinical management of fluid retaining states.

PUBLICATIONS
Meariman JK, Sutphen JC, Gao J, Mercante DE, Kapusta DR. Difelikefalin, a peripherally restricted KOR (kappa opioid receptor) agonist, produces diuresis through a central KOR pathway. Pharmacol Res. 2022 Nov;185:106470. doi: 10.1016/j.phrs.2022.106470. PMID: 36202183.6424.

Meariman JK, Sutphen JC, Gao J, Kapusta DR. Nalfurafine, a G-Protein-Biased KOR (Kappa Opioid Receptor) Agonist, Enhances the Diuretic Response and Limits Electrolyte Losses to Standard-of-Care Diuretics. Hypertension. 2022 Feb; 79(2):379-390. doi: 10.1161/HYPERTENSIONAHA.121.18503. PMID: 34852633; PMCID: PMC8755620.

Denys IB, Gao J, Sutphen JC, Zaveri NT, Kapusta DR. Cardiovascular and renal effects of novel nonpeptide nociceptin opioid peptide receptor agonists. Br J Pharmacol. 2022 Jan; 179(2):287-300. doi: 10.1111/bph.15717. PMID: 34705263; PMCID: PMC871

Erwin LL, Nilges MR, Denys IB, Sutphen JC, Friend AJ, Kapusta DR, Winsauer PJ. Interactive effects of (±)-trans-U50488 and its stereoisomers with cannabinoids. Pharmacol Biochem Behav. 2021 Aug; 207:173218. doi: 10.1016/j.pbb.2021.173218. PMID: 34118232.

Gao J, Denys I, Shahien A, Sutphen J, Kapusta DR. Downregulation of Brain Gα12 Attenuates Angiotensin II-Dependent Hypertension. Am J Hypertens. 2020 Feb 22; 33(2):198-204. doi: 10.1093/ajh/hpz176. PMID: 31677381; PMCID: PMC8205611.

Sharp TE 3rd, Polhemus DJ, Li Z, Spaletra P, Jenkins JS, Reilly JP, White CJ, Kapusta DR, Lefer DJ, Goodchild TT. Renal Denervation Prevents Heart Failure Progression Via Inhibition of the Renin-Angiotensin System. J Am Coll Cardiol. 2018 Nov 27; 72(21):2609-2621. doi: 10.1016/j.jacc.2018.08.2186. PMID: 30466519.

Polhemus DJ, Trivedi RK, Gao J, Li Z, Scarborough AL, Goodchild TT, Varner KJ, Xia H, Smart FW, Kapusta DR, Lefer DJ. Renal Sympathetic Denervation Protects the Failing Heart Via Inhibition of Neprilysin Activity in the Kidney. J Am Coll Cardiol. 2017 Oct 24; 70(17):2139-2153. doi: 10.1016/j.jacc.2017.08.056. PMID: 29050562.

Gao J, Kerut EK, Smart F, Katsurada A, Seth D, Navar LG, Kapusta DR. Sympathoinhibitory Effect of Radiofrequency Renal Denervation in Spontaneously Hypertensive Rats With Established Hypertension. Am J Hypertens. 2016 Dec 1;29(12):1394-1401. doi: 10.1093/ajh/hpw089. PMID: 27538721

Kapusta DR, Pascale CL, Kuwabara JT, Wainford RD. Central nervous system Gαi2-subunit proteins maintain salt resistance via a renal nerve-dependent sympathoinhibitory pathway. Hypertension. 2013 Feb;61(2):368-75. doi: 10.1161/HYPERTENSIONAHA.111.00014. PMID: 23213191

Kapusta DR, Pascale CL, Wainford RD. Brain heterotrimeric Gαi₂-subunit protein-gated pathways mediate central sympathoinhibition to maintain fluid and electrolyte homeostasis during stress. FASEB J. 2012 Jul;26(7):2776-87. doi: 10.1096/fj.11-196550. PMID: 22459149

Wainford RD, Kapusta DR. Hypothalamic paraventricular nucleus G alpha q subunit protein pathways mediate vasopressin dysregulation and fluid retention in salt-sensitive rats. Endocrinology. 2010 Nov;151(11):5403-14. doi: 10.1210/en.2010-0345. PMID: 20861238

Krowicki ZK, Kapusta DR. Microinjection of glycine into the hypothalamic paraventricular nucleus produces diuresis, natriuresis, and inhibition of central sympathetic outflow. J Pharmacol Exp Ther. 2011 Apr;337(1):247-55. doi: 10.1124/jpet.110.175398. PMID: 21233196

Wainford RD, Kurtz K, Kapusta DR. Central G-alpha subunit protein-mediated control of cardiovascular function, urine output, and vasopressin secretion in conscious Sprague-Dawley rats. Am J Physiol Regul Integr Comp Physiol. 2008 Aug;295(2):R535-42. doi: 10.1152/ajpregu.00043.2008. PMID: 18525017

Kapusta DR, Burmeister MA, Calo' G, Guerrini R, Gottlieb HB, Kenigs VA. Functional selectivity of nociceptin/orphanin FQ peptide receptor partial agonists on cardiovascular and renal function. J Pharmacol Exp Ther. 2005 Aug;314(2):643-51. doi: 10.1124/jpet.104.082768. PMID: 15855356.

Kapusta DR, Thorkildsen C, Kenigs VA, Meier E, Vinge MM, Quist C, Petersen JS. Pharmacodynamic characterization of ZP120 (Ac-RYYRWKKKKKKK-NH2), a novel, functionally selective nociceptin/orphanin FQ peptide receptor partial agonist with sodium-potassium-sparing aquaretic activity. J Pharmacol Exp Ther. 2005 Aug; 314(2):652-60. doi: 10.1124/jpet.105.083436. PMID: 15855355.

Larsen, B.D., Petersen, J.S., Harlow, K., Kapusta, D.R.: A diuretic nociceptin derivative. US patent # 09/882,291.

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