Clinical Science (2008) 114, 85–97 - R.C. Tostes and others

Medline/PubMed Citation | Related Articles in PubMed | Download to Citation Manager

Clinical Science (2008) 114, (85–97) (Printed in Great Britain)

Enhanced Full Text

PDF

Legacy HTML

Send to a friend

Add a comment

Review article

Endothelin, sex and hypertension

Rita C. TOSTES*†, Zuleica B. FORTES*, Glaucia E. CALLERA‡, Augusto C. MONTEZANO‡, Rhian M. TOUYZ‡, R. Clinton WEBB† and Maria Helena C. CARVALHO*

*Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, 05508-900 Sao Paulo, Brazil, †Department of Physiology, Medical College of Georgia, Augusta, GA 30912-3000, U.S.A., and ‡Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, Ottawa, Canada K1H 8M5

Key words: arterial hypertension, endothelin, endothelin receptor, end-organ damage, 17β-oestradiol, sex, testosterone.

Abbreviations: ACE, angiotensin-converting enzyme; AngII, angiotensin II; AT₁ receptor, AngII type 1 receptor; BP, blood pressure; CABG, coronary artery bypass graft; COX, cyclo-oxygenase; DAG, diacylglycerol; DOCA, deoxycorticosterone acetate; ERK, extracellular-signal-regulated kinase; ER, oestrogen receptor; ET, endothelin; ECE, ET-converting enzyme; HUVEC, human umbilical vein endothelial cell; IL, interleukin; IP₃, inositol trisphosphate; JAK2, Janus kinase 2; MAPK, mitogen-activated protein kinase; NC-IUPHAR, International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification; NF-κB, nuclear factor κB; NOS, nitric oxide synthase; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLC, phospholipase C; Pyk2, proline-rich tyrosine kinase 2; ROS, reactive oxygen species; SHR, spontaneously hypertensive rat; SHRSP, stroke prone SHR; sl, spotting-lethal; STAT, signal transducer and activator of transcription.

The ETs (endothelins) comprise a family of three 21-amino-acid peptides (ET-1, ET-2 and ET-3) and 31-amino-acid ETs (ET-1^1–31, ET-2^1–31 and ET-3^1–31). ET-1 is synthesized from a biologically inactive precursor, big ET-1, by ECEs (ET-converting enzymes). The actions of ET-1 are mediated through activation of the G-protein-coupled ET_A and ET_B receptors, which are found in a variety of cells in the cardiovascular and renal systems. ET-1 has potent vasoconstrictor, mitogenic, pro-inflammatory and antinatriuretic properties, which have been implicated in the pathophysiology of a number of cardiovascular diseases. Overexpression of ET-1 has been consistently described in salt-sensitive models of hypertension and in models of renal failure, and has been associated with disease progression. Sex differences are observed in many aspects of mammalian cardiovascular function and pathology. Hypertension, as well as other cardiovascular diseases, is more common in men than in women of similar age. In experimental models of hypertension, males develop an earlier and more severe form of hypertension than do females. Although the reasons for these differences are not well established, the effects of gonadal hormones on arterial, neural and renal mechanisms that control blood pressure are considered contributing factors. Sex differences in the ET-1 pathway, with males displaying higher ET-1 levels, greater ET-1-mediated vasoconstrictor and enhanced pressor responses in comparison with females, are addressed in the present review. Sex-associated differences in the number and function of ET_B receptors appear to be particularly important in the specific characteristics of hypertension between females and males. Although the gonadal hormones modulate some of the differences in the ET pathway in the cardiovascular system, a better understanding of the exact mechanisms involved in sex-related differences in this peptidergic system is needed. With further insights into these differences, we may learn that men and women could require different antihypertensive regimens.