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© 2005 Solvay Pharmaceuticals GmbH ® registered trademark Date of preparation: December 2005 Material Code: 201 0241

MOXONIDINE. ®. ®. A review of moxonidine in essential hypertension, with emphasis on metabolic syndrome and other conditions associated with sympathetic overactivity. © 2005 Solvay Pharmaceuticals GmbH ® registered trademark Date of preparation: December 2005 Material Code: 201 0241.

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© 2005 Solvay Pharmaceuticals GmbH ® registered trademark Date of preparation: December 2005 Material Code: 201 0241

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  1. MOXONIDINE ® ® A review of moxonidine in essential hypertension, with emphasis on metabolic syndrome and other conditions associated with sympathetic overactivity © 2005 Solvay Pharmaceuticals GmbH ® registered trademark Date of preparation: December 2005 Material Code: 201 0241

  2. Please see Summary of Product Characteristics before prescribing moxonidine Details of formulations and dosage recommendations may vary between countries Trade names include: Physiotens®, Cynt®, Fisiotens®, Moxon®, Norcynt® and Normatens® References cited in this slide set are numbered to correspond with those in the companion moxonidine e-monograph

  3. Metabolic syndrome • Elevated blood pressure is often associated with obesity, insulin resistance and dyslipidaemia • Clustering of these symptoms has given rise to the concept of the ‘metabolic syndrome’ (with high risk of diabetes and CVD) They may all reflect varying degrees of sympathetic overactivity1 1. Rahn KH et al. J Hypertens 1999;17(suppl 3):S11-S14

  4. Sympathetic overactivity Sympathetic overactivity may be a central feature linking hypertension with other components of the metabolic syndrome

  5. Link with hypertension • In animal models, sympathetic overactivity can initiate and maintain elevated blood pressure2 • In humans, plasma norepinephrine levels in hypertensive patients are significantly higher than in normotensive controls (p<0.05)3 • Sympathetic activation is seen in early phases of hypertension and may precede blood pressure elevation in some patients4 2. Mancia G et al. J Hum Hypertens 1997;11(suppl 1):S3-S8., 3. Goldstein DS. Hypertension 1981;3:48-52., 4. Julius S, Valentini M. Blood Press 1998;7(suppl 3):5-13

  6. Link with hypertension • Sympathetic activity can be high in young subjects with borderline hypertension • This suggests that increased sympathetic activity is the cause, rather than the consequence, of blood pressure elevation1 1. Rahn KH et al. J Hypertens 1999;17(suppl 3):S11-S14

  7. Link with obesity • Raised BMI is associated with an increased rate of sympathetic nerve discharge in skeletal muscle5 • There is a correlation between BMI, body fat distribution and urinary norepinephrine excretion6 5. Scherrer U et al. Circulation 1994;89:2634-2640., 6. Landsberg L. Cardiovasc Risk Factors 1993;3:153-158

  8. Link with insulin resistance and diabetes • Sympathetic activation is a major component of insulin resistance in clinical experiments7 and in humans with type 2 diabetes8 • Cardiac autonomic dysfunction occurs in: • - 30-50% of patients with diabetes • - 40% of obese patients without diabetes9 7. Jamerson KA et al. Hypertension 1993;21:618-623., 8. Huggett RJ et al. Circulation 2003;108:3097-3101., 9. Valensi P et al. ESC 2004 (www.solvaycardio.com)

  9. Link with other risk factors • Sympathetic overactivity is also implicated in: • - renal disease10 • - left ventricular hypertrophy11 • - congestive heart failure12 10. Ritz E et al. Blood Press 1998;7(suppl 3):14-19., 11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65., 12. Lanfranchi A et al. Blood Press 1998;7(suppl 3):40-45

  10. Incidence of metabolic syndrome13 • In a study of 4,483 subjects aged 35-70 years, metabolic syndrome was present in: • 10-15% with normal fasting blood glucose • 42-64% with impaired glucose tolerance/ impaired fasting glucose • 78-84% with type 2 diabetes Risk of CHD, stroke and CV mortality was higher in people with metabolic syndrome (p<0.001) Metabolic syndrome was defined as the presence of at least two of: obesity, hypertension, dyslipidaemia, microalbuminuria 13. Isomaa B et al. Diabetes Care 2001;24:683-689

  11. Origin of cardiovascular symptoms9 Lifestyle Adiposity inflammation INSULIN RESISTANCE /METABOLIC SYNDROME - free fatty acids- oxidative stress Relative sympathetic overactivity Endothelial dysfunction Arterial rigidity hypertension ArrhythmiasLVH Atherothrombosis Cardiovascular complications 9. Valensi P et al. Presented at a satellite symposium at the ESC Congress 2004, Munich, Germany.

  12. Treatment strategy Autonomic dysfunction appears to have an important role in many patients with metabolic syndrome Treatment of patients with hypertension should take account of associated metabolic conditions14 14. Hansson L. Blood Press 1998;7(suppl 3):20-22

  13. Rationale for moxonidine • Sympathetic tone is regulated centrally in the rostral ventrolateral medulla (RVLM)15 • This region contains imidazoline I1-receptors and a2-adrenoceptors which regulate sympathetic activity Moxonidine binds selectively and with high affinity to I1-receptors in the RVLM16 thus reducing peripheral sympathetic activity 15. Hamilton CA. In: van Zwieten PA et al (eds). The I1­ Imidazoline Receptor Agonist Moxonidine. 2nd Ed, London: Roy Soc Med,1996:7-30., 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10

  14. Overview of moxonidine - 1 • Lowers peripheral arterial resistance without significant effects on cardiac output17 • Relatively little affinity for a2-receptors in the brainstem16 (adverse events such as sedation and dry mouth are infrequently reported during prolonged therapy)28 • Low potential for drug interactions 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10., 17. Mitrovic V et al. Cardiovasc Drugs Ther 1991;5:967-972., 28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620

  15. Overview of moxonidine - 2 • Effective when used as monotherapy • An effective adjunct to other first-line therapies such as diuretics and ACE-inhibitors • Linear dose-response effect allows dose titration • Improves glucose metabolism / insulin resistance • Neutral effect on the lipid profile • Renal protective effect The above studies are described in later slides

  16. Efficacy studies reviewed in this slide set • Monotherapy versus active comparators • Dose response • Long-term efficacy • Combination with other antihypertensives • Diabetic / prediabetic hypertensive patients • Obese hypertensive patients • Postmenopausal hypertensive women • Hypertensive patients with LVH • Role in renal protection

  17. Moxonidine versus active comparators • Moxonidine has been found to be similarly effective to other first-line antihypertensive agents in reducing blood pressure including: • Diuretics (hydrochlorothiazide - HCTZ) • Beta-blockers (atenolol) • ACE inhibitors (captopril and enalapril) • Calcium-channel blockers (nifedipine)

  18. Moxonidine versus hydrochlorothiazide19 • Double-blind, placebo-controlled parallel group, randomised study in general practice (n=160) • Moxonidine (0.4mg/day) compared with HCTZ (25mg /day) in mild-to-moderate hypertension • After 8 weeks of monotherapy, moxonidine and HCTZ both gave significant reductions in BP compared with placebo (p<0.05) • No significant differences between the drugs 19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28 Results using the two active agents in combination are described on a later slide

  19. Moxonidine versus atenolol20 Response after 8 weeks of moxonidine or atenolol in a randomised, double-blind study in mild-moderate hypertension N.S. % responders 100 - 80 - 60 - 40 - 20 - 0 - 68% (17/25) 71% (20/28) moxonidine 0.2-0.4mg/day atenolol 50-100mg/day 20. Prichard BNC et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S45-S49 Response was defined as DBP <90 mmHg

  20. Moxonidine versus captopril21 Mean sitSBP and sitDBP during 4 weeks of treatment with moxonidine (0.2-0.4mg/day) or captopril (25-50mg/day) in a randomised, double-blind study moxonidine (n=25) 200 - 160 - 120 - 80 - Mean blood pressure (mmHg) captopril (n=25) systolic diastolic 0 week 1 week 2 week 3 week 4 21. Lotti G, Gianrossi R. Fortschr Med 1993;111(27):429-432

  21. Moxonidine versus captopril22 • A randomised, double-blind, 4-week study compared moxonidine (0.2mg bd) versus captopril (25mg bd) • 26 patients with mild-to-moderate hypertension (over 80% also had evidence of endocrine or metabolic diseases) • Both drugs reduced BP by similar amounts • No evidence of rebound hypertension with moxonidine on withdrawal of therapy 22. Kraft K, Vetter H. J Cardiovasc Pharmacol 1994;24(suppl 1):S29-S33

  22. Moxonidine versus enalapril23 • 8-week, double-blind, placebo-controlled study of moxonidine (0.2-0.4mg/day, n=47) versus enalapril (5-10mg/day, n=47) in outpatients with mild-to-moderate hypertension • Both drugs were significantly superior to placebo at week 8 for sitBP (p<0.001), 24hr SBP (p=0.002) and 24hr DBP (p<0.001) • Response rates were comparable between moxonidine and enalapril (66% vs 60%) 23. Küppers HE et al. J Hypertens 1997;15:93-97 Response was defined asDBP <90 mmHg or >10 mmHg reduction

  23. Moxonidine versus enalapril24 – high dose Change in DBP at week 8 with moxonidine (n=51) and enalapril (n=53) in a randomised, double-blind, placebo-controlled study in mild-to-moderate hypertension moxonidine 0.6mg/day enalapril 20mg/day placebo - 0 - - 4 - - 8 - - 12 - - 16 - Mean change in DBP from baseline (mmHg) - 2.3 -11.9 - 13.2 p<0.001 p<0.001 24. Prichard BNC et al. Blood Press 2002;11:166-172

  24. Moxonidine versus enalapril25 – low dose • 8-week, double-blind, randomised, placebo-controlled study in mild-to-moderate hypertension • Moxonidine 0.2mg/day (n=54) versus enalapril 5mg/day (n=59) • Both gave significant reductions in DBP versus placebo (p<0.001) • No significant difference between moxonidine and enalapril in their effects on blood pressure 25. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51

  25. Moxonidine versus nifedipine26 Mean SBP and DBP after 0.2-4mg/day moxonidine (n=116) and 20-40mg/day nifedipine (n=113) in a double-blind study moxonidine 180 - 160 - 140 - 120 - 100 - 80 - Mean blood pressure (mmHg) systolic nifedipine diastolic 0 4 8 12 19 week 26 26. Wolf R. J Cardiovasc Pharmacol 1992;20(suppl 4):S42-S44

  26. Moxonidine versus nifedipine27 • 4-week, randomised, double-blind study in 60 patients aged 45-71 years • Compared moxonidine (0.2-0.4mg/day) versus sustained-release nifedipine (20-40mg/day) • Mean BP reductions after 4 weeks: • - moxonidine ... from 167/100 to 132/83 mmHg • - nifedipine ... from 167/99 to 134/83 mmHg 27. Mangiameli S et al. Z Allg Med 1992;68:862­866

  27. Dose-response with moxonidine Percentage of patients requiring a moxonidine dose increase from 0.2mg to 0.4mg daily after two weeks of treatment in four clinical trials 20,21,26,27 100 - 80 - 60 - 40 - 20 - 0 - % patients requiring dose doubling 56% (14/25) 42% (49/116) 28% (8/29) 10% (3/30) Prichard 1992 Lotti 1993 Wolf 1992 Mangiameli 1992 20. Prichard BNC et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S45-S49., 21. Lotti G, Gianrossi R. Fortschr Med 1993;111(27):429-432., 26. Wolf R. J Cardiovasc Pharmacol 1992;20(suppl 4):S42-S44., 27. Mangiameli S et al. Z Allg Med 1992;68:862-866

  28. Linear dose-response25 Dose-response of moxonidine in reducing office sitDBP at trough from three double-blind, placebo-controlled trials 15 - 10 - 5 - 0 - Mean placebo-adjusted reduction in sitDBP (mmHg) 10.5 7.01 4.65 0.2mg 0.4mg 0.6mg moxonidine dosage (mg/day) 25. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51

  29. Long-term efficacy of moxonidine28 Change in mean sitSBP and sitDBP during up to two years of treatment with moxonidine (week 3 = end of dose titration) 1 year (n=141) Change in mean blood pressure (mmHg) 180 - 160 - 140 - 120 - 100 - 80 - systolic 2 years (n=49) diastolic 0 26 52 78 104 weeks of moxonidine treatment 28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620., 44. Prichard BNC. In: van Zwieten PA et al, editors. The I1Imidazoline Receptor Agonist Moxonidine. 2nd Edition. London: Roy Soc Med, 1996:49-75

  30. Long-term efficacy of moxonidine29 • Open, multicentre study of 223 outpatients with mean sitBP >160/95 to <240/114 mmHg • Moxonidine (0.2-0.6mg/day) was given for 12 months, with a supplementary diuretic if required • Mean sitBP was reduced by 25/15 mmHg at week 12 and by 27/16 mmHg at week 52 • Response was 82% at week 12 and 85% at week 52 29. Trieb G et al. Eur J Clin Res 1995;7:227-240 Response defined as DBP <90 mmHg or a reduction of >10 mmHg

  31. Moxonidine in combination with HCTZ19 Mean reduction in sitDBP after 8 weeks of moxonidine and HCTZ as monotherapy or in combination in a double-blind study moxonidine+ HCTZ(0.4/25mg/day) moxonidine(0.4mg/day) HCTZ25mg/day placebo - 0 - - 10 - - 20 - Mean reduction in diastolic blood pressure from baseline (mmHg) 9mmHg(n=41) 12mmHgn=37* 13mmHg(n=40) * 16mmHg(n=42) ** *p<0.05 vs placebo **p<0.05 vs placebo and monotherapies 19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28

  32. Moxonidine in combination with HCTZ19 Percentage response for all patients after 8 weeks of moxonidine and HCTZ as monotherapy or in combination in a double-blind study 88%(n=42) % patients with response 100 - 80 - 60 - 40 - 20 - 0 - 70%(n=40) 70%(n=37) 44%(n=41) moxonidine+ HCTZ(0.4/25mg/day) placebo moxonidine(0.4mg/day) HCTZ(25mg/day) 19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28 Intent-to-treat analysis. Response defined as DBP <90 mmHg or >10 mmHg decrease

  33. Combination therapy – TOPIC study30 Mean change in SBP and DBP after 4 weeks of combination therapy in patients who had not responded to previous moxonidine monotherapy moxonidine 0.4mg+ amlodipine 5mg(n=81) moxonidine 0.4mg+ enalapril 10mg(n=82) moxonidine 0.4mg+ HCTZ 12.5mg(n=90) 0 - - 4 - - 8 - - 12 - - 16 - - 20 - Change in mean BP from baseline (mmHg) -5.5 -3.2 -4.4 -4.8 -7.3* -7.9 -10.7* sitDBP sitSBP * p<0.05 versus the other combinations 30. Waters J et al. J Clin Basic Cardiol 1999;2:219-224

  34. Diabetic/prediabetic hypertensive patients • Prediabetic conditions include insulin resistance, hyperinsulinaemia and hyperglycaemia • Long-term benefits of antihypertensive therapy may be compromised if the drugs chosen have adverse effects on insulin sensitivity • In hypertensive patients, moxonidine has been shown to reduce plasma glucose levels and increase insulin sensitivity

  35. Effects on insulin resistance31 Effects of moxonidine (0.4mg/day for 8 weeks) in hypertensive patients with reduced insulin sensitivity in a double-blind, placebo-controlled, randomised, parallel group study GLUCOSE INFUSION RATE INSULIN SENSITIVITY INDEX p=0.026 p=0.056 % change from baseline 25 - 20 - 15 - 10 - 5 - 0 - - 5 - -10 - p=0.004 p=0.027 moxonidine (n=25) 21% 21% placebo (n=13) - 6.0% - 6.0% N.S. N.S. Insulin sensitivity evaluated by hyperinsulinaemic euglycaemic clamp test. Insulin sensitivity index = glucose infusion rate/mean insulin concentration at steady-state 31. Haenni A, Lithell H. J Hypertens 1999;17(Suppl 3):S29-S35

  36. Patients with normal glucose tolerance32 • 30 patients with mild-to-moderate hypertension and normal glucose tolerance • Insulin sensitivity was studied after 6 months of treatment with moxonidine (0.2-0.6mg/day) • Following oral GTT, the 2-hour plasma insulin level was statistically significantly reduced by moxonidine compared with pretreatment (18% reduction, p<0.05) 32. Almazov VA et al. J Hypertens 2000;18(suppl 2):12

  37. Insulin-resistanthypertensivepatients33 • Open, randomised study of 202 mildly hypertensive, insulin-resistant, overweight patients • Moxonidine (0.2mg bd) or metformin (500mg bd) for 16 weeks • Insulin AUC after OGTT was 14.7% lower with moxonidine than metformin (p=0.052) • Difference in AUC between treatments was 23.8% in patients with high sympathetic activity at baseline (p<0.05) High sympathetic activity was defined as heart rate of >80 beats per minute 33. Betteridge J. ESC 2004 (www.solvaycardio.com)

  38. Hypertensive diabetic patients34 • 12-week study in hypertensive patients with type 2 diabetes • Moxonidine (0.2-0.6mg/day as an adjunct to stable antihypertensive therapy) versus metoprolol • Moxonidine significantly improved fasting plasma glucose levels compared with metoprolol • No significant differences between treatments in the change in insulin sensitivity from baseline 34. Jacob S et al. Exp Clin Endocrinol Diabetes 2004;112(6):315-322

  39. Obesity and hypertension • Hypertension in obese patients may be related to activation of renal sympathetic nerves and stimulation of the renin-angiotensin system45,46 • Urinary norepinephrine levels increase with rising BMI49 • Most obese subjects and obese hypertensive patients have high circulatory levels of the hormone leptin50,51 45. Hall JE. Am J Hypertens 1997;10: S49-S55., 46. Tuck ML et al. N Engl J Med 1981;304:930-933., 49. Landsberg L. J Cardiovasc Pharmacol 1994;23(suppl 1):S1-S8., 50. Barroso SG et al. Trace Elem Electrolytes 2003;20:134-139., 51. Masuo K et al. Am J Hypertens 2001;14:530-538

  40. Moxonidine in obese hypertensives37 Effects of moxonidine 0.2-0.4mg/day and amlodipine 5mg/day on office sitDBP after 12 and 24 weeks in an open study of 40 obese patients with mild-to-moderate hypertension moxonidine amlodipine week 12 week 24 week 12 week 24 Change in sitDBP from baseline (mmHg) - 0 - - 10 - - 20 - -10.2 * -12.7 * -14.7 * -15.9 * *p<0.05 vs baseline (no significant difference between active treatments) BP was controlled in 58% patients on moxonidine and 52% on amlodipine 37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25

  41. Metabolic effects in obese hypertensives37 Effect of 24 weeks of moxonidine 0.2-0.4mg/day. Subgroup analysis according to blood pressure response (response was defined as achieving office BP <140/90mmHg) reduction of standing norepinephrine (pg/ml) reduction of plasma leptin (pg/ml) reduction of fasting insulin (U/ml) 100 - 50 - 0 - 6 - 3 - 0 - 10 - 5 - 0 - * ** * 9.6 90.7 5.5 4.3 57.3 4.7 responders ** p<0.003 responders vs non-responders* p<0.05 responders vs non-responders non-responders 37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25

  42. Moxonidine in obese hypertensives38 • Moxonidine (0.4mg/day) was added to the current antihypertensive treatment of 112 obese patients with uncontrolled hypertension • Open, multicentre study in primary care, which included 25 patients with type 2 diabetes • After 6 months of treatment, there were mean decreases in SBP and DBP of 23.0 and 12.9 mmHg, respectively • Overall, SBP and DBP were controlled in 63% and 86% of patients, respectively 38. Abellán J et al. Kidney Int 2005;67(suppl 93):S20-S24

  43. Postmenopausal hypertension • SBP tends to increase in women after the menopause • The prevalence of hypertension in women after the menopause is similar to that in men52 • ‘Menopausal metabolic syndrome’ describes comorbidities such as hypertension, abdominal obesity, insulin resistance, type 2 diabetes, and changes in the lipid profile53,54 52. Burt VL et al. Hypertension 1995;25:305-313., 53. Tong PL et al. Atherosclerosis 2002;161(2):409-415., 54. Mercuro G et al. Ital Heart J 2001; 2(10):719-727

  44. Regional fat metabolism Energy expenditure Menopausal metabolic syndrome55 MENOPAUSE Estrogen deficiency Central adiposity Insulin resistance Hypertension and endothelial dysfunction Metabolic syndrome Vascular inflammation Impaired glucose tolerance Type 2 diabetes Atherosclerosis 55. Sjoberg L et al. Int J Clin Pract 2004;suppl 139:4-12

  45. 0.2 - 0 - - 0.2 - - 0.4 - - 0.6 - - 0.8 - - 1.0 - Moxonidine in postmenopausal women35 Change from baseline in plasma glucose during OGTT following treatment with moxonidine (0.6mg/day) and atenolol (50mg/day) (n=109): double-blind study in hypertensive, obese, postmenopausal women Plasma glucose (mmol/L) * * 0hr 1hr 2hr * Hours after oral glucose tolerance test AUC *p<0.01 versus pretreatment moxonidine atenolol 35. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32 Intention to treat analysis

  46. 6 - 4 - 2 - 0 - - 2 - - 4 - - 6 - Moxonidine in postmenopausal women35 Change from baseline in plasma insulin during OGTT following treatment with moxonidine (0.6mg/day) and atenolol (50mg/day) (n=109): double-blind study in hypertensive, obese, postmenopausal women Plasma insulin (mU/L) 0hr 1hr 2hr Hours after oral glucose tolerance test AUC moxonidine atenolol 35. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32

  47. LVH and hypertension • LVH in hypertensive patients is an adaptation response to try and overcome increased peripheral vascular resistance • LVH is a major independent risk factor for cardiovascular morbidity and mortality62,63 • Sympathetic overstimulation may play an important role in the development of myocardial hypertrophy64 62. Levy D et al. N Engl J Med 1990;322:1561-1566., 63. Koren MJ et al. Ann Intern Med 1991;114:345-352., 64. Trimarco B et al. Circulation 1985;72:38-46

  48. Moxonidine in LVH11 Interventricular septum end-diastolic diameter at baseline and after 3, 6 and 9 months of moxonidine monotherapy (0.2-0.6mg/day) in 20 hypertensive patients with LVF p<0.05 Interventricular septum end-diastolic diameter (cm) 1.8 - 1.6 - 1.4 - 1.2 - 1.0 - p<0.05 p<0.05 baseline 3 6 9 months 11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65

  49. Moxonidine in LVH11 Left ventricular mass at baseline and after 3, 6 and 9 months of moxonidine monotherapy (0.2-0.6mg/day) in 20 hypertensive patients with LVF p<0.05 p<0.05 Left ventricular mass (g) 400 - 350 - 300 - 250 - 200 - 150 - baseline 3 6 9 months 11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65

  50. Renal protection in hypertension • Increased sympathetic activity leads to renal vasoconstriction, stimulation of renin release, and stimulation of sodium reabsorption10 • Moxonidine may be renoprotective by: • - reducing sympathetic output centrally • - direct renal effects (independent of blood • pressure lowering) via imidazoline binding • sites in the kidney 10. Ritz E et al. Blood Press 1998;7(suppl 3):14-19

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