- Email: [email protected]
20-HETE and Salt-Sensitivity of Blood Pressure
AJH
2006; 19:1181–1182
Reviewer Critique
20-HETE and Salt-Sensitivity of Blood Pressure A Novel Emerging Concept Fernando Elijovich linicians and scientists are familiar with the cyclooxygenase and lipoxygenase products of arachidonic acid metabolism because of the role of these substances in arthritis, asthma, gastrointestinal ulceration by anti-inflammatory agents, and platelet adhesiveness. However, many of us are still unaware of a third metabolic pathway: oxidation of arachidonic acid by cytochrome P450 enzymes. An abundant product of such oxidation in mammals, 20-hydroxyeicosatetraenoic acid (20-HETE), caught the attention of cardiorenal investigators because it has prohypertensive (renal and systemic vasoconstriction) and concomitant antihypertensive effects (blockade of sodium transport, ie, natriuretic potential). It has been established that a deficit of renal medullary 20-HETE is the most likely culprit for salt-sensitivity of blood pressure in Dahl-SS rats, a strain inbred for this phenotype.1 In hypertensive patients, we showed that 20-HETE is responsive to a salt load and to furosemide,2,3 as if its ability to block the mTAL cotransporter were involved in the natriuretic response to these stimuli. We also reported that hyperinsulinemia inhibits 20-HETE excretion in human beings, consistent with data in vitro, and offering a plausible link between obesity and hypertension.4 Our salt-sensitive hypertensive subjects did not have a deficit of 20-HETE as Dahl-SS do,2 but had evidence for another defect instead: an apparent inability of 20HETE to normally drive natriuresis. An article in this issue of the Journal provides support for the existence of a dual defect in rodents also. Sankaralingam et al5 describe that young rats exhibit salt-sensitivity of blood pressure (as opposed to salt-resistant adults) in conjunction with both inability to stimulate 20-HETE in response to salt and impairment in 20-HETE-driven natriuresis (see Fig. 3 in that article). The latter observation explains how a “deficit” in 20-HETE could be responsible for salt sensitivity if 20-HETE levels inyoung animals are higher than those in adults.
C
See related article on page 1174
Received April 28, 2006. First decision May 15, 2006. Accepted May 15, 2006. From the Department of Medicine, Scott and White Clinic, Texas A&M University, Temple, Texas. © 2006 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
Why do I want to bring the 20-HETE story to the attention of the readership, particularly clinicians? The answer is three-pronged. First, it has just been reported that a common polymorphism of CYP4A11, the isoform that synthesizes 20-HETE in human beings, is a risk factor for hypertension in large populations, probably because the variant enzyme has half the catalytic activity of the wild-type one.6 We are in the process of genotyping our patients to shed some light on the possible mechanisms for this observation. Second, it has become clear that salt-sensitivity of blood pressure predicts hypertension and also that it is a cardiovascular risk factor independent of blood pressure. Finally, and most importantly, the CYP isoforms of the 4A family, which synthesize 20-HETE in different species, are inducible by the PPAR-alpha agonists (fibrates) that we clinicians use for the management of hypertriglyceridemia or the metabolic syndrome. As the research in this field evolves, I presume we will develop markers to identify easily those hypertensive individuals who are salt-sensitive (now a cumbersome proposition), and newer, more specific agents for pharmacologic manipulation of CYP450 enzymes. Eventually, diagnosing salt-sensitivity in prehypertension or in stage I hypertension may become part of the rationale for more aggressive management of blood pressure. Also, newly developed therapeutic agents may allow specific targeting of the risk conferred by saltsensitivity of blood pressure.
References 1.
2.
3.
Sarkis A, Lopez B, Roman RJ: Role of 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids in hypertension. Curr Opin Nephrol Hypertens 2004;13:205–214. Laffer CL, Laniado-Schwartzman M, Wang MH, Nasjletti A, Elijovich F: Differential regulation of natriuresis by 20-hydroxyeicosatetraenoic acid in human salt-sensitive versus salt-resistant hypertension. Circulation 2003;107:574 –578. Laffer CL, Laniado-Schwartzman M, Wang MH, Nasjletti A,
Address correspondence and reprint requests to Dr. Fernando Elijovich, Department of Medicine, Scott and White Clinic, Texas A&M University, 2401 31st Street, Temple, TX 76508; e-mail: [email protected] 0895-7061/06/$32.00 doi:10.1016/j.amjhyper.2006.05.013
1182
4.
5.
AJH–November 2006 –VOL. 19, NO. 11
20-HETE AND SALT-SENSITIVITY OF BP
Elijovich F: 20-HETE and furosemide-induced natriuresis in salt-sensitive essential hypertension. Hypertension 2003;41:703–708. Laffer CL, Laniado-Schwartzman M, Nasjletti A, Elijovich F: 20HETE and circulating insulin in essential hypertension with obesity. Hypertension 2004;43:388 –392. Sankaralingam S, Desai KM, Glaeser H, Kim RB, Wilson TW: Inability to upregulate cytochrome P450 4A and 2C causes salt
6.
sensitivity in young Sprague-Dawley rats. Am J Hypertens 2006;19:1174 –1180. Gainer JV, Bellamine A, Dawson EP, Womble KE, Grant SW, Wang Y, Cupples LA, Guo CY, Demissie S, O’Donnell CJ, Brown NJ, Waterman MR, Capdevila JH: Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension. Circulation 2005;111:63– 69.
2006; 19:1181–1182
Reviewer Critique
20-HETE and Salt-Sensitivity of Blood Pressure A Novel Emerging Concept Fernando Elijovich linicians and scientists are familiar with the cyclooxygenase and lipoxygenase products of arachidonic acid metabolism because of the role of these substances in arthritis, asthma, gastrointestinal ulceration by anti-inflammatory agents, and platelet adhesiveness. However, many of us are still unaware of a third metabolic pathway: oxidation of arachidonic acid by cytochrome P450 enzymes. An abundant product of such oxidation in mammals, 20-hydroxyeicosatetraenoic acid (20-HETE), caught the attention of cardiorenal investigators because it has prohypertensive (renal and systemic vasoconstriction) and concomitant antihypertensive effects (blockade of sodium transport, ie, natriuretic potential). It has been established that a deficit of renal medullary 20-HETE is the most likely culprit for salt-sensitivity of blood pressure in Dahl-SS rats, a strain inbred for this phenotype.1 In hypertensive patients, we showed that 20-HETE is responsive to a salt load and to furosemide,2,3 as if its ability to block the mTAL cotransporter were involved in the natriuretic response to these stimuli. We also reported that hyperinsulinemia inhibits 20-HETE excretion in human beings, consistent with data in vitro, and offering a plausible link between obesity and hypertension.4 Our salt-sensitive hypertensive subjects did not have a deficit of 20-HETE as Dahl-SS do,2 but had evidence for another defect instead: an apparent inability of 20HETE to normally drive natriuresis. An article in this issue of the Journal provides support for the existence of a dual defect in rodents also. Sankaralingam et al5 describe that young rats exhibit salt-sensitivity of blood pressure (as opposed to salt-resistant adults) in conjunction with both inability to stimulate 20-HETE in response to salt and impairment in 20-HETE-driven natriuresis (see Fig. 3 in that article). The latter observation explains how a “deficit” in 20-HETE could be responsible for salt sensitivity if 20-HETE levels inyoung animals are higher than those in adults.
C
See related article on page 1174
Received April 28, 2006. First decision May 15, 2006. Accepted May 15, 2006. From the Department of Medicine, Scott and White Clinic, Texas A&M University, Temple, Texas. © 2006 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
Why do I want to bring the 20-HETE story to the attention of the readership, particularly clinicians? The answer is three-pronged. First, it has just been reported that a common polymorphism of CYP4A11, the isoform that synthesizes 20-HETE in human beings, is a risk factor for hypertension in large populations, probably because the variant enzyme has half the catalytic activity of the wild-type one.6 We are in the process of genotyping our patients to shed some light on the possible mechanisms for this observation. Second, it has become clear that salt-sensitivity of blood pressure predicts hypertension and also that it is a cardiovascular risk factor independent of blood pressure. Finally, and most importantly, the CYP isoforms of the 4A family, which synthesize 20-HETE in different species, are inducible by the PPAR-alpha agonists (fibrates) that we clinicians use for the management of hypertriglyceridemia or the metabolic syndrome. As the research in this field evolves, I presume we will develop markers to identify easily those hypertensive individuals who are salt-sensitive (now a cumbersome proposition), and newer, more specific agents for pharmacologic manipulation of CYP450 enzymes. Eventually, diagnosing salt-sensitivity in prehypertension or in stage I hypertension may become part of the rationale for more aggressive management of blood pressure. Also, newly developed therapeutic agents may allow specific targeting of the risk conferred by saltsensitivity of blood pressure.
References 1.
2.
3.
Sarkis A, Lopez B, Roman RJ: Role of 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids in hypertension. Curr Opin Nephrol Hypertens 2004;13:205–214. Laffer CL, Laniado-Schwartzman M, Wang MH, Nasjletti A, Elijovich F: Differential regulation of natriuresis by 20-hydroxyeicosatetraenoic acid in human salt-sensitive versus salt-resistant hypertension. Circulation 2003;107:574 –578. Laffer CL, Laniado-Schwartzman M, Wang MH, Nasjletti A,
Address correspondence and reprint requests to Dr. Fernando Elijovich, Department of Medicine, Scott and White Clinic, Texas A&M University, 2401 31st Street, Temple, TX 76508; e-mail: [email protected] 0895-7061/06/$32.00 doi:10.1016/j.amjhyper.2006.05.013
1182
4.
5.
AJH–November 2006 –VOL. 19, NO. 11
20-HETE AND SALT-SENSITIVITY OF BP
Elijovich F: 20-HETE and furosemide-induced natriuresis in salt-sensitive essential hypertension. Hypertension 2003;41:703–708. Laffer CL, Laniado-Schwartzman M, Nasjletti A, Elijovich F: 20HETE and circulating insulin in essential hypertension with obesity. Hypertension 2004;43:388 –392. Sankaralingam S, Desai KM, Glaeser H, Kim RB, Wilson TW: Inability to upregulate cytochrome P450 4A and 2C causes salt
6.
sensitivity in young Sprague-Dawley rats. Am J Hypertens 2006;19:1174 –1180. Gainer JV, Bellamine A, Dawson EP, Womble KE, Grant SW, Wang Y, Cupples LA, Guo CY, Demissie S, O’Donnell CJ, Brown NJ, Waterman MR, Capdevila JH: Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension. Circulation 2005;111:63– 69.