Research Opportunities in the Division of Clinical Pharmacology

CARDIOVASCULAR AND RENAL PHARMACOLOGY

MICHAEL H. HUMPHREYS, M.D., Professor of Medicine, Nephrology.

Dr. Humphreys' research laboratory has been interested in the study of factors involved in the regulation of sodium excretion and their role in the maintenance of sodium balance. His group has obtained evidence that a high dietary sodium intake increases the abundance of mRNA of the pituitary prohormone proopiomelanocortin (POMC), as well as the pituitary content and plasma concentration of a natriuretic peptide derived from it, g -melanocyte stimulating hormone (g -MSH). This system could participate in the integrated adjustments to a high sodium diet to achieve sodium balance. Rats with experimental, salt-sensitive hypertension do not regulate this system normally, suggesting that it may be a contributor to the development of salt-sensitive hypertension.

Dr. Humphreys' lab has also obtained evidence that the renal resistance to the natriuretic action of atrial natriuretic peptide (ANP) which occurs in states of pathological sodium retention (e.g., nephrotic syndrome, chronic liver disease) may occur as a result of heightened activity of a cyclic GMP-specific phosphodiesterase. This enzyme rapidly catabolizes cGMP formed when ANP interacts with its biologically active receptors on target cells such as those in the renal inner medullary collecting duct. Pharmacologic inhibitors of this enzyme correct ANP resistance in both in vitro and in vivo settings, and cGMP by dialysis is increased suggesting that this mechanism may be an important component of the sodium retention which occurs in these states. Fellows working in Dr. Humphreys' lab will become familiar with techniques of acute physiological experimentation, radioimmunoassay of peptide hormones, some aspects of enzyme biochemistry, and RNA quantitation, including Northern blots RNAse protection assays and in situ hybridization, and reverse transcription-polymerase chain amplification.

Future goals include an examination of the effect of dietary sodium intake on pituitary enzymes involved in the processing of POMC into g -MSH, investigation of the renal actions of this peptide, and measurement of cGMP phosphodiesterase enzyme protein and mRNA abundance in renal target cells for ANP action. Ultimately, these studies will extend to animal models of hypertension and pathological sodium retention.

SELECTED PUBLICATIONS:

Humphreys, M.H. ?-MSH, sodium metabolism, and salt-sensitive hypertension. Am J Physiol, R417-R430, 2004.
Ni, X-P., M. Safai, R. Rishi, C. Baylis, and M.H. Humphreys. Increased activity of cGMP-specific phosphodiesterase (PDE5) contributes to renal resistance to atrial natriuretic peptide in the pregnant rat. J Am Soc Nephrol, 15:1254-1260, 2004.
Mayan, H., X-P. Ni, S. Almog, and M.H. Humphreys. Suppression of ?-melanocyte stimulating hormone secretion is accompanied by salt-sensitive hypertension in the rat. Hypertension, 42:962-967, 2003.