Thomas Maack, M.D.

Hormones and Receptors in Cardiovascular and Renal Function

Cardiovascular and renal functions are geared towards the maintenance of the internal environment in the mammalian organism, including the homeostatic regulation of plasma volume and composition, and of blood pressure. Our research has been directed at some of the hormones and receptors involved in these essential homeostatic mechanisms. Particular attention has been devoted in the past decade to the study of atrial natriuretic factor (ANF) and its receptors.

Studies by several laboratories, including our own, revealed that ANF is a 28 amino acid polypeptide hormone secreted by the heart atria when blood volume or pressure increases. ANF leads to an increase in sodium excretion by the kidney, an inhibition of the renin-angiotensin-aldosterone system, vasorelaxation, and an increase in capillary permeability that tend to return plasma volume and pressure to normal levels. These effects are mediated by a specific receptor (GCA-ANF receptor), which generates cGMP, the major second messenger of ANF actions. A second class of receptors, named by us clearance receptors (C-ANF receptors), is involved in the removal of ANF from plasma by a process of receptor-mediated endocytosis. In vivo blockade of C-ANF receptors by small ligands increases plasma levels of ANF, a finding that is of potential therapeutic importance in the treatment of cardiovascular and renal diseases. After having elucidated the overall systemic role and cellular mechanisms of the clearance function of C-ANF receptors, we are presently investigating the molecular mechanisms of this function by using recombinant DNA and mutagenesis techniques. We are also actively investigating the dynamics of ANF interaction with recombinant wild type and mutated GCA-ANF receptor to determine the molecular mechanisms by which ANF exerts its biological actions. In addition, studies of other members of the family of natriuretic peptides (BNP, CNP), and of angiotensin receptors are subjects of interest to the laboratory.

Relevant publications

Vieira MA, Gao M, Nikonova LN, Maack T. Molecular and cellular physiology of the dissociation of atrial natriuretic peptide from guanylyl cyclase a receptors. J Biol Chem. 2001 Sep 28;276(39):36438-45.

Maack T. Cardiovascular receptors as drug targets. Eur omega Conferences’ Cardiovascular receptors as drug targets. Institut Pasteur, Paris, France, 3-4 October 1996. Mol Med Today. 1997 Mar;3(3):101-2.

Maack T, Nikonova LN, Friedman O, Cohen D. Functional properties and dynamics of natriuretic peptide receptors. Proc Soc Exp Biol Med. 1996 Nov;213(2):109-16. Review.

Maack T. Role of atrial natriuretic factor in volume control. Kidney Int. 1996 Jun;49(6):1732-7. Review.

Cohen D, Koh GY, Nikonova LN, Porter JG, Maack T. Molecular determinants of the clearance function of type C receptors of natriuretic peptides.
J Biol Chem. 1996 Apr 19;271(16):9863-9.

Maack T, Okolicany J, Koh GY, Price DA. Functional properties of atrial natriuretic factor receptors. Semin Nephrol. 1993 Jan;13(1):50-60. Review.

Okolicany J, McEnroe GA, Koh GY, Lewicki JA, Maack T. Clearance receptor and neutral endopeptidase-mediated metabolism of atrial natriuretic factor. Am J Physiol. 1992 Sep;263(3 Pt 2):F546-53.

Price DA, Okolicany J, Maack T. Renal receptors and effects of atrial natriuretic factor in compensatory renal hypertrophy. Kidney Int. 1992 Jul;42(1):75-82.

Koh GY, Nussenzveig DR, Okolicany J, Price DA, Maack T. Dynamics of atrial natriuretic factor-guanylate cyclase receptors and receptor-ligand complexes in cultured glomerular mesangial and renomedullary interstitial cells. J Biol Chem. 1992 Jun 15;267(17):11987-94.

Maack T. Receptors of atrial natriuretic factor. Annu Rev Physiol. 1992;54:11-27. Review. No abstract available.

Okolicany J, McEnroe GA, Gregory LC, Lewicki JA, Maack T. Effects of small C-ANF receptor ligands on plasma levels of atrial natriuretic factor, blood pressure, and renal function in the rat. Can J Physiol Pharmacol. 1991 Oct;69(10):1561-6.

Lenz T, Sealey JE, Maack T, James GD, Heinrikson RL, Marion D, Laragh JH. Half-life, hemodynamic, renal, and hormonal effects of prorenin in cynomolgus monkeys. Am J Physiol. 1991 Apr;260(4 Pt 2):R804-10.

Fontoura BM, Nussenzveig DR, Timmermans PB, Maack T. DuP 753 is a potent nonpeptide antagonist of angiotensin II receptors in isolated perfused rat kidney and cultured renal cells. Am J Hypertens. 1991 Apr;4(4 Pt 2):303S-308S.

Almeida FA, Suzuki M, Maack T. High salt intake increases the vasorelaxant effect of ANF on the isolated perfused rat kidney. Braz J Med Biol Res. 1991;24(11):1149-57.

Nussenzveig DR, Lewicki JA, Maack T. Cellular mechanisms of the clearance function of type C receptors of atrial natriuretic factor.
J Biol Chem. 1990 Dec 5;265(34):20952-8.

Fontoura BM, Nussenzveig DR, Pelton KM, Maack T. Atrial natriuretic factor receptors in cultured renomedullary interstitial cells. Am J Physiol. 1990 Apr;258(4 Pt 1):C692-9.