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Linkage studies in essential hypertension
18A ASH ABSTFACTS
AIH-APRIL 1995-VQL.8, NO.4, PART 2
Friday, 5/19, Mercury Ballroom, 1:30 pm-3:30 pm Theme I: Emerging Impactof Genetics on Hypertension Research
Friday, 5/19, Mercury Ballroom, 1:30 pm-3:30 pm ThemeI: Emerging Impactof Genetics on Hypertension Research
GENETICS OF THE RENIN·ANGIOTENSIN SYSTEM INHUMAN HYPERTENSION Jean-Marc Lalouel, MD, D.Sc., University of Utah. HSC. Salt Lake City, Utah
Linkage Studies In Essential Hypertension. Alain Bonnardeauxl, Xavier leunemaitre2, Toro Nabika2, Pierre Corvol2, Plorent Soubrier2•
Most of human hypertension is deemed 'essential'. an euphemism reflecting lack ofknowledge about itsetiology. Difficult to define, and of unclear clinical specificity, hypertension admits a genetic component and is commonly labeled a polygenic disease. As such, it could qualify as a geneticist's nightmare to the same extent as diabetes mellitus. because a variety of observations support etiological heterogeneity, however. it is reasonable to assume that some genetic determinants may exert predominant effects in the development of at least some forms ofessential hypertension. Given the critical role ofthe renin-angiotensin system in vascular tone and plasma volume control, every component of this system has the potential of being involved in the development of hypertension. While there is little evidence for an involvement of other components of the system, we will review data on angiotensinogen, the substrate of renin, which suggest that molecular variants at this locus may predispose to some forms of hypertension, either in pregnancy orlater inlife.
Universit6 de MontnSal, Montreal, Canada], and Coll~ge de France, Paris, France2. Essential hypertension is a multifactorial and polygenic disease. The absence of hypotheses concerning inheritance imposes critical limits on strategies to define its genetic determinants, Genetic linkage studies in multiple affected hypertensive sibships areusually performed with an affected sib-pair method, and rely on theuse of highly polymorphic markers located near potential candidate genes. Such markers are frequently found In thegenome and canbe identified by cloning methods. Candidate genes to be studied in human hypertensive pedigrees aredeiemlned from human oranimal physiological studies or from animal genetic studies employing experimental models. Linkage and case-control studies of candidate genes have been done recently with a unique sample of 200French hypertensive pedigrees. Using highly informative genetic markers in hypertensive sibships, the anglotenslnogen, angiotensin II type I (AT!) receptor, endothelial nitric oxide synthase, and SAloci have all been studied. It was shown that the anglotenslnogen locus, and possibly the ATt receptor, areimplicated inhypertension. No linkage of the endothelial NO synthase or SA genes was noted. A gene common to human and experimental animal models of hypertension has yet to be found. Such studies demonstrate the usefulness of this approach to unravel the genetic determinants of essential hypertension. Future linkage studies will combine candidate gene and "total genome" approaches, although the effect of a major gene on blood pressure variability is unlikely. Key Words:
Genetics: Essential hypertension: Angiotensin receptors; SA gene; Nitric oxide
Friday, 5/19, West Ballroom, 1:30 pm-3:30 pm Theme II: Endothelin and Hypertension: Pathology and Receptor and Antagonism ENDOTHELIN AND CARDIOVASCULAR REGULATION DJ. Webb, University Department of Medicine. Western General Hospital, Edinburgh EH4 2XU, Scotland. U.K. Endothelin- I is a potent vasoconstrictor, pressor and growth promoting peptide produced by vascular endothelial cells by theaction ofa unique metelloprotease, endothelin converting enzyme (ECE), onitsprecursor big endothelin-I, In humans, local infusion studies in the forearm and hand veins have shown that endothelin-I can act 0,' ETA and ETn receptors in vascular smooth muscle to cause vasoconstriction and venoconstriction, and onETn receptors inendothelial cells to modulate constriction through generation of endothelial dilators. including prostacyclin and nitric oxide. Studies with the ETA receptor antagonist, BQ-123, and the ECE inhibitor, phosphoramidon, show that ECE is present in forearm but not hand veins. and that endothelin-I plays a crucial role in regulation of basal tone in resistance vessels. Systemic studies with endothelin receptor antagonists in healthy subjects confirm these findings, showing that endothelin-I acts tomaintain peripheral vascular resistance and blood pressure. Endothelin-I mediated venoconstriction isgreater in patients with essential hypertension than in matched controls, and sympathetically mediated venoconstriction is enhanced by endothelin-I in hypertensive but notcontrol subjects. Recent studies with ETA receptor antagonists show that they are effective vasodilators in patients with untreated hypertension, and diuretic and ACE inhibitor treated heart failure. However, antagonists at both ETA and ETn receptors may beneeded to fully block the vasoconstriction toendothelin-I. These novel drugs show much promise inthe treatment of hypertension.
KeyWords:
Endothelin, receptors, blood vessels, human, pharmacology.
Friday, 5/19, West Ballroom, 1:30 pm-3:30 pm ThemeII: Endothelin and Hypertension: Pathology and Receptor and Antagonism Endothalln Receptors: Form and Function. Ellis R Levin. Departs. of Medicine and Pharmacology, Univ. of California, Irvine, and Long Beach VAMC. The endothelin peptides actas a result of binding seven transmembrane spanning, G-protein coupled receptors. The first described receptor, ETA, exhibits greater affinity forET·1 compared to ET-3, and is expressed on various cells inclUding vascular smooth muscle and cardiomyocytes. This receptor triggers the cardiac hypertrophic response to ET·1, and the pressor and vasoconstricting effects of this ligand. ETA signals through Cai++ mobilization follOWing PLC hydrolysis and IP3 generation. This underlies cyolosporlne-lnduced hypertension and nephrotoxicity. Activation of protein kinase C and MAP kinase contribute to ET·1 induced vascular smooth muscle proliferation. Hydrolysis of phospholipases A and D lead to pulmonary prostanoid formation and bronchoconstriction. In contrast, this receptor can inhibit cardiac chloride, L·type Ca++, and some K+ channels, projecting against catecholamine-induced arrhythmia. A second receptor, ETB, is expressed on endothelial and vascular smooth muscle cells, and binds ET·1 and ET·3 comparably. This receptor links the EST to the generation of nitric oxide, prostacyclin formation, and vasodil&tation. In human coronaries, ETB may contribute to vasoconstriction. This protein appears to becritical for neural crest development. A third receptor, ETC, has been cloned from frog melonephores, and is highly responsive to ET·3. No compKey Words: arable mammalian receptor has yet been identified. endothelin receptors. calcium . blood pressure.
AIH-APRIL 1995-VQL.8, NO.4, PART 2
Friday, 5/19, Mercury Ballroom, 1:30 pm-3:30 pm Theme I: Emerging Impactof Genetics on Hypertension Research
Friday, 5/19, Mercury Ballroom, 1:30 pm-3:30 pm ThemeI: Emerging Impactof Genetics on Hypertension Research
GENETICS OF THE RENIN·ANGIOTENSIN SYSTEM INHUMAN HYPERTENSION Jean-Marc Lalouel, MD, D.Sc., University of Utah. HSC. Salt Lake City, Utah
Linkage Studies In Essential Hypertension. Alain Bonnardeauxl, Xavier leunemaitre2, Toro Nabika2, Pierre Corvol2, Plorent Soubrier2•
Most of human hypertension is deemed 'essential'. an euphemism reflecting lack ofknowledge about itsetiology. Difficult to define, and of unclear clinical specificity, hypertension admits a genetic component and is commonly labeled a polygenic disease. As such, it could qualify as a geneticist's nightmare to the same extent as diabetes mellitus. because a variety of observations support etiological heterogeneity, however. it is reasonable to assume that some genetic determinants may exert predominant effects in the development of at least some forms ofessential hypertension. Given the critical role ofthe renin-angiotensin system in vascular tone and plasma volume control, every component of this system has the potential of being involved in the development of hypertension. While there is little evidence for an involvement of other components of the system, we will review data on angiotensinogen, the substrate of renin, which suggest that molecular variants at this locus may predispose to some forms of hypertension, either in pregnancy orlater inlife.
Universit6 de MontnSal, Montreal, Canada], and Coll~ge de France, Paris, France2. Essential hypertension is a multifactorial and polygenic disease. The absence of hypotheses concerning inheritance imposes critical limits on strategies to define its genetic determinants, Genetic linkage studies in multiple affected hypertensive sibships areusually performed with an affected sib-pair method, and rely on theuse of highly polymorphic markers located near potential candidate genes. Such markers are frequently found In thegenome and canbe identified by cloning methods. Candidate genes to be studied in human hypertensive pedigrees aredeiemlned from human oranimal physiological studies or from animal genetic studies employing experimental models. Linkage and case-control studies of candidate genes have been done recently with a unique sample of 200French hypertensive pedigrees. Using highly informative genetic markers in hypertensive sibships, the anglotenslnogen, angiotensin II type I (AT!) receptor, endothelial nitric oxide synthase, and SAloci have all been studied. It was shown that the anglotenslnogen locus, and possibly the ATt receptor, areimplicated inhypertension. No linkage of the endothelial NO synthase or SA genes was noted. A gene common to human and experimental animal models of hypertension has yet to be found. Such studies demonstrate the usefulness of this approach to unravel the genetic determinants of essential hypertension. Future linkage studies will combine candidate gene and "total genome" approaches, although the effect of a major gene on blood pressure variability is unlikely. Key Words:
Genetics: Essential hypertension: Angiotensin receptors; SA gene; Nitric oxide
Friday, 5/19, West Ballroom, 1:30 pm-3:30 pm Theme II: Endothelin and Hypertension: Pathology and Receptor and Antagonism ENDOTHELIN AND CARDIOVASCULAR REGULATION DJ. Webb, University Department of Medicine. Western General Hospital, Edinburgh EH4 2XU, Scotland. U.K. Endothelin- I is a potent vasoconstrictor, pressor and growth promoting peptide produced by vascular endothelial cells by theaction ofa unique metelloprotease, endothelin converting enzyme (ECE), onitsprecursor big endothelin-I, In humans, local infusion studies in the forearm and hand veins have shown that endothelin-I can act 0,' ETA and ETn receptors in vascular smooth muscle to cause vasoconstriction and venoconstriction, and onETn receptors inendothelial cells to modulate constriction through generation of endothelial dilators. including prostacyclin and nitric oxide. Studies with the ETA receptor antagonist, BQ-123, and the ECE inhibitor, phosphoramidon, show that ECE is present in forearm but not hand veins. and that endothelin-I plays a crucial role in regulation of basal tone in resistance vessels. Systemic studies with endothelin receptor antagonists in healthy subjects confirm these findings, showing that endothelin-I acts tomaintain peripheral vascular resistance and blood pressure. Endothelin-I mediated venoconstriction isgreater in patients with essential hypertension than in matched controls, and sympathetically mediated venoconstriction is enhanced by endothelin-I in hypertensive but notcontrol subjects. Recent studies with ETA receptor antagonists show that they are effective vasodilators in patients with untreated hypertension, and diuretic and ACE inhibitor treated heart failure. However, antagonists at both ETA and ETn receptors may beneeded to fully block the vasoconstriction toendothelin-I. These novel drugs show much promise inthe treatment of hypertension.
KeyWords:
Endothelin, receptors, blood vessels, human, pharmacology.
Friday, 5/19, West Ballroom, 1:30 pm-3:30 pm ThemeII: Endothelin and Hypertension: Pathology and Receptor and Antagonism Endothalln Receptors: Form and Function. Ellis R Levin. Departs. of Medicine and Pharmacology, Univ. of California, Irvine, and Long Beach VAMC. The endothelin peptides actas a result of binding seven transmembrane spanning, G-protein coupled receptors. The first described receptor, ETA, exhibits greater affinity forET·1 compared to ET-3, and is expressed on various cells inclUding vascular smooth muscle and cardiomyocytes. This receptor triggers the cardiac hypertrophic response to ET·1, and the pressor and vasoconstricting effects of this ligand. ETA signals through Cai++ mobilization follOWing PLC hydrolysis and IP3 generation. This underlies cyolosporlne-lnduced hypertension and nephrotoxicity. Activation of protein kinase C and MAP kinase contribute to ET·1 induced vascular smooth muscle proliferation. Hydrolysis of phospholipases A and D lead to pulmonary prostanoid formation and bronchoconstriction. In contrast, this receptor can inhibit cardiac chloride, L·type Ca++, and some K+ channels, projecting against catecholamine-induced arrhythmia. A second receptor, ETB, is expressed on endothelial and vascular smooth muscle cells, and binds ET·1 and ET·3 comparably. This receptor links the EST to the generation of nitric oxide, prostacyclin formation, and vasodil&tation. In human coronaries, ETB may contribute to vasoconstriction. This protein appears to becritical for neural crest development. A third receptor, ETC, has been cloned from frog melonephores, and is highly responsive to ET·3. No compKey Words: arable mammalian receptor has yet been identified. endothelin receptors. calcium . blood pressure.