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Unmet needs in the treatment of hypertension
226A
AJH-APRIL 1999-VOL. 12, NO. 4, P A R T 2
ASH XIV ABSTRACTS
Saturday, 8:00 A M
M a y 22, Astor Ballroom, 6:30 A M t o
Selective Aldosterone Receptor A n t a g o n i s m and t h e R e n i n - A n g i o t e n s i n - A l d o s t e r o n e System
Aldosterone: New Concepts in Mechanismof Action, Gordon H. Williams, ~D., Harvard Medical School and Brigham & Women's Hospital Boston Massachusetts, USA. Aldosterone is a major regulator of volume and potassium homeostasis, and its primary target tissue is the epithelial cell of the renal collecting duet. In a series of steps involving a genomic mechanism, sodium is reabsorbed and potassium is secreted into the tubule lumen. Importantly, under normal conditions, there is a prospective mechanism (mineralocorticoid escape) which prevents continued sodium reabsorption, even in the presence of aldosterone. In certain conditions where volume homeostasis is disturbed, i.e. congestive heart failure, this escape mechanism is inoperative. Even minimal amounts of aldosterone can produce continued sodium reabsorption and volume expansion. Recently, aldosterone has been shown to have other effects. Two of the most intriguing are its impact on fibrosis and activity associated with interaction with a cell surface receptor in certain target tissues, including endothelial cells. The traditional concept that aldosterone is synthesized only in the adrenal glomerulosa cell and acts almost exclusively on the kidney to modify sodium and potassium homeostasis needs to be expanded. There is increasing evidence that other tissues, particularly the heart, may be capable of synthesizing aldosterone de novo, and there is also increasing evidence that aldosterone can have an effect on vascular remodeling and collagen formation and a non-genomic action to modify endothelial function. This new information has increased the interest in the development of an antagonist to block aldosterone's effect, not just because of its diuretic effect but also because of its potential cardiovascular protective effect. The current agent available, spironolactone, has significant side effects associated with the non-specificity of its blockade of the mineralocorticoid receptor. It also blocks progesterone and androgen receptors. The development of a selective aldosterone receptor antagonist (SARA) provides entree into a broader use of ~ati-aldostcrone agents in modifying cardiovascular risk. Eplerenone is the first representative of this class of agents. W e d n e s d a y , M a y 19, B r o a d w a y S o u t h , 10:00 A M t o 12:30 P M
Ballroom
Intensive BP Control: Treatment G o a l s , Strategies, and Outcomes
Importance of Blood Pressure for Cardio-Renal Event Reduction:Is the Level or the Agent Used More Important? George L. Bakris, M.D, Rush University Hypertension Center, Chicago, IL Numerous clinical trials have assessed the efficacy of vadous classes of anti-hypertensive medications to slow progression of renal disease and reduce cardiovascular events. These studies have been in people with renal insufficiency resulting from causes related to either diabetic or non-diabetic etiologies. These studies were all designed to control blood pressure to levels of approximately 140190 mmHg. At this level of blood pressure control, it is clear that ACE inhibitors provide unique protective benefits on progression of Type I diabetic nephropathy and while the data is somewhat less convincing probably also Type 2 nephropathy. Additionally, they slow progression of renal disease from non-diabetic causes as exemplified by the results of the AIPRI and REIN trials. This may not be true, however, if blood pressure is lowered to levels below 130185 mmHg. Evidence from post hoc analyses of MDRD trial, the HOT trial and the UKPDS demonstrate that persons whose blood pressure was reduced to a diastolic pressure of < 85 mmHg had fewer cardiovascular events and renal disease progression than those at higher levels. These results were independent of the antihypertensive agents used. Therefore, the recommendation from the JNC Vl are that ACE Inhibitors should be part of the antihypertensive "cocktail" for people with diabetes andlor renal insufficiency. Moreover, blood pressure should be reduced to levels of <130/85 mmHg to optimize renal protection. In short, the JNC VI guidelines focus attention on blood pressure control and potentially lower levels of achieved blood pressure i.e. < 130185 mmHg in order to achieve maximal renal protection and reduction of cardiovascular events.
Saturday, 8:00 A M
M a y 22, Astor Ballroom, 6:30 A M t o
Selective Aldosterone Receptor A n t a g o n i s m and the R e n i n - A n g i o t e n s i n - A l d o s t e r o n e System EPITHELIALAND NON-EPITHELIALEFFECTSON MINERALOCORTICOIDS John W. Funder, Baker Medical Research Melbourne, Australia
Institute,
The classical effect of aldosterone is to activate mineralocorticoid receptors MR to increase unidirectional, transepifhelial sodium transport. MR have high affinity for aldosterone, but bind corfisol {which circulates at much higher concentrations) equally well. In epithelial tissues preferential aldosterone occupancy of MR is achieved by the enzyme l l~ hydroxysteroid dehydrogenase type 2, which converts cortisol to the inactive cortisone, and for which aldosterone is not a substrate. Pathophysiologic effects of oldosterone are largely mediated by activating MR in non-epithelial rather than epithelial target tissues. Mineralocorticoid hypertension, for example, requires aldosterone occupancy of MR in the AV3V region of the brain: aldosterone-infused rats retain salt and water, and become hypertensive, with the latter (but not the former} reversed by intracerebroventricular infusion of MR antagonist, at a dose without effect infused so. Rats infused sc with aldosterone similarly show cardiac hypertrophy and cardiac fibrosis reflecting direct actions of aldosterone via cardiac MR and blocked by concurrent peripheral MR antagonist, but not by intracerebroventricular administration of antagonist fo reverse the hypertension. These effects of aldasterone (hypertension, cardiac fibrosis, cardiac hypertrophy) thus in large part reflect direct, previously unrecognised, non-epithelial effects via MR in brain and heart. Such studies open the way for a radical reconsideration of the therapeutic indications for anti-aldosterone therapy, particularly in the context of congestive cardiac failure. Key Words: Aldosterone; extra-epithelial effects; cardiac fibrosis
W e d n e s d a y , M a y 19, B r o a d w a y S o u t h , 4:30 P M t o 6:30 P M
Ballroom
Unmet Needs in the Treatment Hypertension
of
CLINICAL SIGNIFICANCE OF BORDERLINE HYPERTENSION. Julius S. Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI. The term borderline hypertension includes patients with high normal blood pressure, white coat hypertension, and subjects whose blood pressure oscillates between normal and elevated values. The mild blood pressure elevation in these subjects is associated with only a moderately increased relative risk of cardiovascular events. However, because of its wide prevalence, borderline hypertension has a large impact on public health. About 30% of all strokes and heart attacks occur in patients with borderline hypertension. In addition to mild blood pressure elevation, subjects with borderline hypertension also have tachycardia, dyslipidemia, higher hematocrits, and elevated "plasma insulin values. All these abnormalities are conducive to a poor cardiovascular prognosis. Whereas nonpharmacologic therapy and periodic reexaminations are suggested, in reality, patients with borderline hypertension receive very little attention. We need better strategies and new clinical trials to affect this large segment of subjects at high risk of cardiovascular complications. Key Words:
White coat hypertension, High normal blood pressure
AJH-APRIL 1999-VOL. 12, NO. 4, P A R T 2
ASH XIV ABSTRACTS
Saturday, 8:00 A M
M a y 22, Astor Ballroom, 6:30 A M t o
Selective Aldosterone Receptor A n t a g o n i s m and t h e R e n i n - A n g i o t e n s i n - A l d o s t e r o n e System
Aldosterone: New Concepts in Mechanismof Action, Gordon H. Williams, ~D., Harvard Medical School and Brigham & Women's Hospital Boston Massachusetts, USA. Aldosterone is a major regulator of volume and potassium homeostasis, and its primary target tissue is the epithelial cell of the renal collecting duet. In a series of steps involving a genomic mechanism, sodium is reabsorbed and potassium is secreted into the tubule lumen. Importantly, under normal conditions, there is a prospective mechanism (mineralocorticoid escape) which prevents continued sodium reabsorption, even in the presence of aldosterone. In certain conditions where volume homeostasis is disturbed, i.e. congestive heart failure, this escape mechanism is inoperative. Even minimal amounts of aldosterone can produce continued sodium reabsorption and volume expansion. Recently, aldosterone has been shown to have other effects. Two of the most intriguing are its impact on fibrosis and activity associated with interaction with a cell surface receptor in certain target tissues, including endothelial cells. The traditional concept that aldosterone is synthesized only in the adrenal glomerulosa cell and acts almost exclusively on the kidney to modify sodium and potassium homeostasis needs to be expanded. There is increasing evidence that other tissues, particularly the heart, may be capable of synthesizing aldosterone de novo, and there is also increasing evidence that aldosterone can have an effect on vascular remodeling and collagen formation and a non-genomic action to modify endothelial function. This new information has increased the interest in the development of an antagonist to block aldosterone's effect, not just because of its diuretic effect but also because of its potential cardiovascular protective effect. The current agent available, spironolactone, has significant side effects associated with the non-specificity of its blockade of the mineralocorticoid receptor. It also blocks progesterone and androgen receptors. The development of a selective aldosterone receptor antagonist (SARA) provides entree into a broader use of ~ati-aldostcrone agents in modifying cardiovascular risk. Eplerenone is the first representative of this class of agents. W e d n e s d a y , M a y 19, B r o a d w a y S o u t h , 10:00 A M t o 12:30 P M
Ballroom
Intensive BP Control: Treatment G o a l s , Strategies, and Outcomes
Importance of Blood Pressure for Cardio-Renal Event Reduction:Is the Level or the Agent Used More Important? George L. Bakris, M.D, Rush University Hypertension Center, Chicago, IL Numerous clinical trials have assessed the efficacy of vadous classes of anti-hypertensive medications to slow progression of renal disease and reduce cardiovascular events. These studies have been in people with renal insufficiency resulting from causes related to either diabetic or non-diabetic etiologies. These studies were all designed to control blood pressure to levels of approximately 140190 mmHg. At this level of blood pressure control, it is clear that ACE inhibitors provide unique protective benefits on progression of Type I diabetic nephropathy and while the data is somewhat less convincing probably also Type 2 nephropathy. Additionally, they slow progression of renal disease from non-diabetic causes as exemplified by the results of the AIPRI and REIN trials. This may not be true, however, if blood pressure is lowered to levels below 130185 mmHg. Evidence from post hoc analyses of MDRD trial, the HOT trial and the UKPDS demonstrate that persons whose blood pressure was reduced to a diastolic pressure of < 85 mmHg had fewer cardiovascular events and renal disease progression than those at higher levels. These results were independent of the antihypertensive agents used. Therefore, the recommendation from the JNC Vl are that ACE Inhibitors should be part of the antihypertensive "cocktail" for people with diabetes andlor renal insufficiency. Moreover, blood pressure should be reduced to levels of <130/85 mmHg to optimize renal protection. In short, the JNC VI guidelines focus attention on blood pressure control and potentially lower levels of achieved blood pressure i.e. < 130185 mmHg in order to achieve maximal renal protection and reduction of cardiovascular events.
Saturday, 8:00 A M
M a y 22, Astor Ballroom, 6:30 A M t o
Selective Aldosterone Receptor A n t a g o n i s m and the R e n i n - A n g i o t e n s i n - A l d o s t e r o n e System EPITHELIALAND NON-EPITHELIALEFFECTSON MINERALOCORTICOIDS John W. Funder, Baker Medical Research Melbourne, Australia
Institute,
The classical effect of aldosterone is to activate mineralocorticoid receptors MR to increase unidirectional, transepifhelial sodium transport. MR have high affinity for aldosterone, but bind corfisol {which circulates at much higher concentrations) equally well. In epithelial tissues preferential aldosterone occupancy of MR is achieved by the enzyme l l~ hydroxysteroid dehydrogenase type 2, which converts cortisol to the inactive cortisone, and for which aldosterone is not a substrate. Pathophysiologic effects of oldosterone are largely mediated by activating MR in non-epithelial rather than epithelial target tissues. Mineralocorticoid hypertension, for example, requires aldosterone occupancy of MR in the AV3V region of the brain: aldosterone-infused rats retain salt and water, and become hypertensive, with the latter (but not the former} reversed by intracerebroventricular infusion of MR antagonist, at a dose without effect infused so. Rats infused sc with aldosterone similarly show cardiac hypertrophy and cardiac fibrosis reflecting direct actions of aldosterone via cardiac MR and blocked by concurrent peripheral MR antagonist, but not by intracerebroventricular administration of antagonist fo reverse the hypertension. These effects of aldasterone (hypertension, cardiac fibrosis, cardiac hypertrophy) thus in large part reflect direct, previously unrecognised, non-epithelial effects via MR in brain and heart. Such studies open the way for a radical reconsideration of the therapeutic indications for anti-aldosterone therapy, particularly in the context of congestive cardiac failure. Key Words: Aldosterone; extra-epithelial effects; cardiac fibrosis
W e d n e s d a y , M a y 19, B r o a d w a y S o u t h , 4:30 P M t o 6:30 P M
Ballroom
Unmet Needs in the Treatment Hypertension
of
CLINICAL SIGNIFICANCE OF BORDERLINE HYPERTENSION. Julius S. Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI. The term borderline hypertension includes patients with high normal blood pressure, white coat hypertension, and subjects whose blood pressure oscillates between normal and elevated values. The mild blood pressure elevation in these subjects is associated with only a moderately increased relative risk of cardiovascular events. However, because of its wide prevalence, borderline hypertension has a large impact on public health. About 30% of all strokes and heart attacks occur in patients with borderline hypertension. In addition to mild blood pressure elevation, subjects with borderline hypertension also have tachycardia, dyslipidemia, higher hematocrits, and elevated "plasma insulin values. All these abnormalities are conducive to a poor cardiovascular prognosis. Whereas nonpharmacologic therapy and periodic reexaminations are suggested, in reality, patients with borderline hypertension receive very little attention. We need better strategies and new clinical trials to affect this large segment of subjects at high risk of cardiovascular complications. Key Words:
White coat hypertension, High normal blood pressure