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“I1, imidazoline receptors: clinical relevance in hypertensive patients”
220A
ASH XIV ABSTRACTS
AJH-APRIL 1999-VOL. 12, NO. 4, PART 2
Wednesday, M a y 19, B r o a d w a y B a l l r o o m North, 10:00 AM to 12:30 PM "I1, I m i d a z o l i n e Receptors: Clinical Relevance in Hypertensive Patients"
Wednesday, M a y 19, B r o a d w a y B a l l r o o m North, 10:00 AM to 12:30 PM "I1, I m i d a z o l i n e Receptors: Clinical Relevance in Hypertensive Patients"
Rilmenidine: a clinical overview John L Reid, Department of Medicine and Therapeutics, University of Glasgow, Scotland, UK.
EFFICACY OF RILMENID1NE, SELECTIVE I, IMIDAZOLINE RECEPTOR AGENT IN HYPERTENSIVE DIABETICS.
Rilmenidine is an antihypertensive agent with selectivity for 11 imidazoline binding sites in the bulbar lateral reticular nucleus and renal proximal convoluted tubule. Pharmacologically, binding of rilmenidine to Ii receptors reduces .sympathetic activity whilst maintaining physiological responses to posture and exercise. Inhibition of renal sympathetic tone and a direct renal Ii receptor effect may also be implicated in long-term blood pressure control. Efficacy of rilmenidine at 1 mg per day compares favorably with other drugs including atenolol, hydrochlorothiazide, nifedipine, amlodipine and captopril, and with older agents such as clonidine and methyldopa. Tolerance of rilmenidine (notably incidence of dry mouth/sedation) is not different from that of placebo at the usual 1 mg daily dose. Pharmacokinetic studies and clinical experience indicate safety in the elderly and patients with hepatic failure and renal failure (CrCI>I5 mL/min) in whom dose adjustment is not required. Rilmenidine can be given safely with other antihypcrtensive agents, and sudden cessation of rilmenidiue treatment produces no clinical withdrawal syndrome. There are no changes in electrolytes or glucose, lipid, and uric acid metabolism in clinical studies involving both uncomplicated and at-risk hypertensive populations for up to 2 years' treatment. Lipid profiles (total cholesterol, triglycerides) were improved in some populations (elderly, diabetic, and dyslipidemic patients). Clinical studies with rilmenidine show a reduction in left ventricular hypertrophy by 14% over 1 year, a finding confirmed by a comparative controlled study vs nifedipine. New studies also show reduction of microalbuminuria in the type 2 diabetic to a degree similar to a reference ACE inhibitor, and improved glucose tolerance in patients with the metabolic syndrome (Syndrome X) by rilmenidine treatment. Experience of rilmenidine in essential hypertension, its lack of adverse effects on associated cardiovascular risk factors, and its good tolerability support its role as a first-line antihypertensive for all populations of hypertensive patients.
O. Dupuy, B. Baodueeau, H. Mayandon. H6pital d'Instruction des Armtes Btgin, 94160 Salnt-Mand¢~(France).
Key Words: Rilmenidine, Essential Hypertension, Efficacy, Tolerance
The UKPDS results clearly show that normalization of blood pressure (BP) in the type 2 diabetics brings benefits in terms of morbi-mortality at least as important as good glycemic control. Rilraenidine is an innovative antihypertensive agent which binds selectively to I I Imidazoline receptors. At the bulbar level this leads to a reduction in sympathetic overactivity. At the renal level, excessive sodium and water reabsorption by the proximal convoluted tubule is reduced. Clinical studies confirmed rilmenidine's value in the treatment of hypertension in the type 1 and type 2 diabetic. Its very good tolerance facilitates the compliance of these often polymedicated patients. Neither diabetic control, nor other laboratory parameters, notably lipids, are affected by rilmenidine treatment. A 6 month clinical study compared the effects of rilmenidine (R) and captopril (C) on the progress of mioroalbuminuria in hypertensive type 2 diabetics. There was no statistically significant difference between R and C on the main outcome criteria. Between M0 and M6, the mean supine BP reduced in a similar manner on R (SBP from 159 to 140 mmHg and DBP from 98 to 84 mmHg) and on C (SBP from 157 to 144 mmHg and DBP from 101 to 82 mmHg). The median value for. micmalbuminuria was reduced from 160 [90-260] to 56 [27-87] mg per. 24h on R and from 144 [51-200] to 54 [41-123] mg per 24h on C.. Creatinine clearance was not changed during the study by either treatment (R: 95.2 to 95.6 ml/min; C: 86.2 to 90.4 mVmin). There was: no statistical difference in the change in glycosylated hemoglobin in thel R and C groups. Clinical and laboratory aeeeptability was good and comparable between the 2 groups. I Used first line or in combination, rilmenidine is an effective and well~ tolerated antihypertensive agent. Rilmanidine's mode of action is, specifically suited to the treament of hypertensive diabetics, for whom it has possible renal benefits. Key Words: rilmenidine, hypertension, diabetes mellitus, mieroalbuminuria
Wednesday, May 19, Broadway Ballroom North, 10:00 AM to 12:30 PM "I1, I m i d a z o l i n e R e c e p t o r s : C l i n i c a l R e l e v a n c e in Hypertensive Patients"
Wednesday, M a y 19, B r o a d w a y B a l l r o o m North, 10:00 AM to 12:30 PM "I1, I m i d a z o l i n e Receptors: Clinical Relevance in Hypertensive Patients"
The Sympathetic System and Hypertension
THE ROLE OF SYMPATHETIC OVERACTIVITY IN THE PATHOPHYSIOLOGY OF CARDIOVASCULAR DISEASES. Julius S, Department of Internal Medicine, University of Michigan, Ann Arbor, MI In hypertension, the sympathetic overactivity is associated with high insulin, cholesterol, and triglycerides combined with decreased HDL levels. Excessive sympathetic tone can cause insulin resistance/dyslipidemia via direct stimulation of skeletal muscle beta-adrenergic receptors or by alpha-adrenergic vasoconstriction, which decreases the delivery of glucose and insulin to the skeletal muscles. Superimposed on the risk of developing premature atherosclerosis is the propensity for higher risk of coronary complications in patients with hypertension. Hypertensives are at a higher risk for coronary thrombosis; their hematocrit is elevated and the turnover of platelets is increased. The high hematocrit is due to alpha-adrenergic venoconstriction and the platelet overactivity is associated with increased adrenaline levels. Tachycardia, which is the hallmark of the hypersympathetic state in hypertension, increase the risk of cardiovascular mortality/morbidity. The increased sympathetic and decreased parasympathetic tone which underlie the tachycardia are conducive to fatal arrhythmias. Furthermore, tachycardia, by increasing the pulsatile stress, favors coronary atherosclerosis. The sympathetic stimulation, through its trophic effect, is conducive to left ventricular and arteriolar hypertrophy. These processes lead to excess cardiac mortality, acceleration of hypertension and a decrease of the coronary reserve. At present the antihypertensive treatment is less efficacious in reducing coronary events in hypertension than would be expected. Understanding the pathophysiologic relationship of coronary risk with sympathetic overactivity in hypertension will likely lead to further improvements in clinical practice. Judicious use of appropriate drugs promises to further improve the efficacy of the antihypertensive treatment.
Murray Esler MBBS Phl) Baker Medical Research Institute, Melbourne, Australia Measurement of regional sympathetic activity in lean essential hypertension patients, using electrophysiological (clinical m i c r o n e u r o g r a p h y ) and n e u r o c h e m i c a l ( r a d i o t r a c e r norepinephrine kinetics) techniques demonstrates activation of sympathetic outflow to the heart, kidneys and skeletal muscle vasculature in younger (<45 years) patients. The increase in sympathetic activity is a m e c h a n i s m for initiating, and sustaining the blood pressure elevation. Cardiac sympathetic stimulation possibly also confers specific cardiovascular risk, promoting LVH and ventricular arrhythmias. Understanding the neural pathophysiology of obesity-related hypertension has been more difficult. In normotensive obesity renal sympathetic tone is doubled, but cardiac norepinephrine s p i l l o v e r is only 50% of normal. In obesity-related hypertension, there is a comparable elevation of renal norepinephrine spillover, but without suppression of cardiac sympathetics, as here cardiac norepinephrine spillover is more than double that of normotensive obese and 25% higher than in healthy volunteers. Increased renal sympathetic activity in obesity may be a necessary cause for the development of hypertension, but apparently not a sufficient cause. The discriminating feature of obesity-related hypertension is absence of the probably adaptive suppression of cardiac sympathetic outflow seen in the normotensive obese. The sympathetic nervous system has moved towards centre stage in cardiovascular medicine. The importance of sympathetic activation in heart failure, ventrieular arrhythmias and hypertension is now established, and therapeutic sympathetic inhibition is under continuing investigation. Through their central inhibition of sympathetic nervous activity, I1 agents such as rilmenidine powerfully reduce sympathetic nervous activity in essential hypertension patients, lowering BP and carrying the potential for specific cardiovascular protection.
Key Words:
norepinephrine, obesity-related hypertension, heart, kidneys, cardiovascular risk
Key Words: Coronary risk, Sympathetic overactivity, H~/pertension, Dyslipidemia, Hyperinsulinemia
ASH XIV ABSTRACTS
AJH-APRIL 1999-VOL. 12, NO. 4, PART 2
Wednesday, M a y 19, B r o a d w a y B a l l r o o m North, 10:00 AM to 12:30 PM "I1, I m i d a z o l i n e Receptors: Clinical Relevance in Hypertensive Patients"
Wednesday, M a y 19, B r o a d w a y B a l l r o o m North, 10:00 AM to 12:30 PM "I1, I m i d a z o l i n e Receptors: Clinical Relevance in Hypertensive Patients"
Rilmenidine: a clinical overview John L Reid, Department of Medicine and Therapeutics, University of Glasgow, Scotland, UK.
EFFICACY OF RILMENID1NE, SELECTIVE I, IMIDAZOLINE RECEPTOR AGENT IN HYPERTENSIVE DIABETICS.
Rilmenidine is an antihypertensive agent with selectivity for 11 imidazoline binding sites in the bulbar lateral reticular nucleus and renal proximal convoluted tubule. Pharmacologically, binding of rilmenidine to Ii receptors reduces .sympathetic activity whilst maintaining physiological responses to posture and exercise. Inhibition of renal sympathetic tone and a direct renal Ii receptor effect may also be implicated in long-term blood pressure control. Efficacy of rilmenidine at 1 mg per day compares favorably with other drugs including atenolol, hydrochlorothiazide, nifedipine, amlodipine and captopril, and with older agents such as clonidine and methyldopa. Tolerance of rilmenidine (notably incidence of dry mouth/sedation) is not different from that of placebo at the usual 1 mg daily dose. Pharmacokinetic studies and clinical experience indicate safety in the elderly and patients with hepatic failure and renal failure (CrCI>I5 mL/min) in whom dose adjustment is not required. Rilmenidine can be given safely with other antihypcrtensive agents, and sudden cessation of rilmenidiue treatment produces no clinical withdrawal syndrome. There are no changes in electrolytes or glucose, lipid, and uric acid metabolism in clinical studies involving both uncomplicated and at-risk hypertensive populations for up to 2 years' treatment. Lipid profiles (total cholesterol, triglycerides) were improved in some populations (elderly, diabetic, and dyslipidemic patients). Clinical studies with rilmenidine show a reduction in left ventricular hypertrophy by 14% over 1 year, a finding confirmed by a comparative controlled study vs nifedipine. New studies also show reduction of microalbuminuria in the type 2 diabetic to a degree similar to a reference ACE inhibitor, and improved glucose tolerance in patients with the metabolic syndrome (Syndrome X) by rilmenidine treatment. Experience of rilmenidine in essential hypertension, its lack of adverse effects on associated cardiovascular risk factors, and its good tolerability support its role as a first-line antihypertensive for all populations of hypertensive patients.
O. Dupuy, B. Baodueeau, H. Mayandon. H6pital d'Instruction des Armtes Btgin, 94160 Salnt-Mand¢~(France).
Key Words: Rilmenidine, Essential Hypertension, Efficacy, Tolerance
The UKPDS results clearly show that normalization of blood pressure (BP) in the type 2 diabetics brings benefits in terms of morbi-mortality at least as important as good glycemic control. Rilraenidine is an innovative antihypertensive agent which binds selectively to I I Imidazoline receptors. At the bulbar level this leads to a reduction in sympathetic overactivity. At the renal level, excessive sodium and water reabsorption by the proximal convoluted tubule is reduced. Clinical studies confirmed rilmenidine's value in the treatment of hypertension in the type 1 and type 2 diabetic. Its very good tolerance facilitates the compliance of these often polymedicated patients. Neither diabetic control, nor other laboratory parameters, notably lipids, are affected by rilmenidine treatment. A 6 month clinical study compared the effects of rilmenidine (R) and captopril (C) on the progress of mioroalbuminuria in hypertensive type 2 diabetics. There was no statistically significant difference between R and C on the main outcome criteria. Between M0 and M6, the mean supine BP reduced in a similar manner on R (SBP from 159 to 140 mmHg and DBP from 98 to 84 mmHg) and on C (SBP from 157 to 144 mmHg and DBP from 101 to 82 mmHg). The median value for. micmalbuminuria was reduced from 160 [90-260] to 56 [27-87] mg per. 24h on R and from 144 [51-200] to 54 [41-123] mg per 24h on C.. Creatinine clearance was not changed during the study by either treatment (R: 95.2 to 95.6 ml/min; C: 86.2 to 90.4 mVmin). There was: no statistical difference in the change in glycosylated hemoglobin in thel R and C groups. Clinical and laboratory aeeeptability was good and comparable between the 2 groups. I Used first line or in combination, rilmenidine is an effective and well~ tolerated antihypertensive agent. Rilmanidine's mode of action is, specifically suited to the treament of hypertensive diabetics, for whom it has possible renal benefits. Key Words: rilmenidine, hypertension, diabetes mellitus, mieroalbuminuria
Wednesday, May 19, Broadway Ballroom North, 10:00 AM to 12:30 PM "I1, I m i d a z o l i n e R e c e p t o r s : C l i n i c a l R e l e v a n c e in Hypertensive Patients"
Wednesday, M a y 19, B r o a d w a y B a l l r o o m North, 10:00 AM to 12:30 PM "I1, I m i d a z o l i n e Receptors: Clinical Relevance in Hypertensive Patients"
The Sympathetic System and Hypertension
THE ROLE OF SYMPATHETIC OVERACTIVITY IN THE PATHOPHYSIOLOGY OF CARDIOVASCULAR DISEASES. Julius S, Department of Internal Medicine, University of Michigan, Ann Arbor, MI In hypertension, the sympathetic overactivity is associated with high insulin, cholesterol, and triglycerides combined with decreased HDL levels. Excessive sympathetic tone can cause insulin resistance/dyslipidemia via direct stimulation of skeletal muscle beta-adrenergic receptors or by alpha-adrenergic vasoconstriction, which decreases the delivery of glucose and insulin to the skeletal muscles. Superimposed on the risk of developing premature atherosclerosis is the propensity for higher risk of coronary complications in patients with hypertension. Hypertensives are at a higher risk for coronary thrombosis; their hematocrit is elevated and the turnover of platelets is increased. The high hematocrit is due to alpha-adrenergic venoconstriction and the platelet overactivity is associated with increased adrenaline levels. Tachycardia, which is the hallmark of the hypersympathetic state in hypertension, increase the risk of cardiovascular mortality/morbidity. The increased sympathetic and decreased parasympathetic tone which underlie the tachycardia are conducive to fatal arrhythmias. Furthermore, tachycardia, by increasing the pulsatile stress, favors coronary atherosclerosis. The sympathetic stimulation, through its trophic effect, is conducive to left ventricular and arteriolar hypertrophy. These processes lead to excess cardiac mortality, acceleration of hypertension and a decrease of the coronary reserve. At present the antihypertensive treatment is less efficacious in reducing coronary events in hypertension than would be expected. Understanding the pathophysiologic relationship of coronary risk with sympathetic overactivity in hypertension will likely lead to further improvements in clinical practice. Judicious use of appropriate drugs promises to further improve the efficacy of the antihypertensive treatment.
Murray Esler MBBS Phl) Baker Medical Research Institute, Melbourne, Australia Measurement of regional sympathetic activity in lean essential hypertension patients, using electrophysiological (clinical m i c r o n e u r o g r a p h y ) and n e u r o c h e m i c a l ( r a d i o t r a c e r norepinephrine kinetics) techniques demonstrates activation of sympathetic outflow to the heart, kidneys and skeletal muscle vasculature in younger (<45 years) patients. The increase in sympathetic activity is a m e c h a n i s m for initiating, and sustaining the blood pressure elevation. Cardiac sympathetic stimulation possibly also confers specific cardiovascular risk, promoting LVH and ventricular arrhythmias. Understanding the neural pathophysiology of obesity-related hypertension has been more difficult. In normotensive obesity renal sympathetic tone is doubled, but cardiac norepinephrine s p i l l o v e r is only 50% of normal. In obesity-related hypertension, there is a comparable elevation of renal norepinephrine spillover, but without suppression of cardiac sympathetics, as here cardiac norepinephrine spillover is more than double that of normotensive obese and 25% higher than in healthy volunteers. Increased renal sympathetic activity in obesity may be a necessary cause for the development of hypertension, but apparently not a sufficient cause. The discriminating feature of obesity-related hypertension is absence of the probably adaptive suppression of cardiac sympathetic outflow seen in the normotensive obese. The sympathetic nervous system has moved towards centre stage in cardiovascular medicine. The importance of sympathetic activation in heart failure, ventrieular arrhythmias and hypertension is now established, and therapeutic sympathetic inhibition is under continuing investigation. Through their central inhibition of sympathetic nervous activity, I1 agents such as rilmenidine powerfully reduce sympathetic nervous activity in essential hypertension patients, lowering BP and carrying the potential for specific cardiovascular protection.
Key Words:
norepinephrine, obesity-related hypertension, heart, kidneys, cardiovascular risk
Key Words: Coronary risk, Sympathetic overactivity, H~/pertension, Dyslipidemia, Hyperinsulinemia