- Email: [email protected]
Renal effects of angiotensin II (ANGII): Physiology and Pathology
AIR 1996; 9:195A-207B
SPECIAL SYMPOSIA Wednesday, May 15, West Ballroom, 8:30 am II: A New Target for Intervention in Hypertension RENAL EFFECTS OF ANGIOTENSIN II (ANGII): PHYSIOLOGY AND PATHOLOGY. Dick de Zeeuw, Div of Nephrology, Univ Hospital, Groningen, The Netherlands Experimental in-vitro and in-vivo data suggest several renal Angll actions: glomerular capillary constriction, proximal tubular sodium reabsorption, and cell proliferation. In addition Angll may induce proteinuria. Oinical data for such effects has been gathered through two different approaches: exogenous Angll infusion and inhibition of endogenous AngII formation. Indeed. AngIl subpressor doses induce a fall of both renal blood flow (and filtration fraction) and fractional sodium excretion. Prevention of AngIl formation by ACE-inhibition will lead to a rise in renal blood flow and natriuresis. Importantly. these ACEi effects on endogenous AngII are attenuated by exogenous AngII. Clinical data on alterations of cellular growth are hard to get. Interestingly. ACEi also has a marked and rather specific antiproteinuric effect. In contrast to the instantaneous hemodynamic and sodium effects, the proteinuria lowering has a slow onset, reaching a maximum after 4 weeks of trealment. Moreover, the antiproteinuric effect appears not to be attenuated by short-term exogenous AnglI infusion. These data may suggest that glomerular permeability is slowly altering through cellular (growth?) changes. Alternatively, the antiproteinuric effect may be the result of intervention in non-AngIl pathways. However. recent data on the effect of specific AngIl receptor blockade with losanan, show both the short-term hemodynamic effects as well as the more long-term antiproteinuric effects. Since both renal hemodynamic as well as proteinuria are implicated in causing progressive renal function loss Inhibition of AngII formation and/or blockade of the Angii receptor are successful approaches for long term renal protection.
Key Words:
angiotensin II, kidney. proteinuria
Wednesday, May 15, West Ballroom, 8:30 am A II: A New Target for Intervention in Hypertension
Wednesday, May 15, West Ballroom, 8:30 am A II: A New Target for Intervention in Hypertension
ANGIOTENSIN II - A TARGET FOR TREATMENT. John L. Reid. Department of Medicine & Therapeutics. University of Glasgow. Glasgow Gil 6NT. Scotland.
Angiotensin II Receptors: Signalling Pathways, Cell Growth and Differentiation Th. Unger. Department of Pharmacology. University of Klel end German Institute of High Blood Pressure Research. Heidelberg, Germany
Angiotensin II (All) is an octapeptide hormone which not only plays a role as a circulating hormone. but also has local paracrine and autocrine functions. In addition to short-term effects on blood pressure and on renal salt and water handling. All has long-lasting effects on blood pressure and vascular resistance resulting. in part. from structural changes. What are the clinical consequences of these short-term functional and longer-term structural effects of All? The level of neurohumoral activation as assessed by plasma renin activity. or plasma All concentrations. has been shown in heart failure patients to directly correlate with morbidity and outcome. More controversially it has been claimed that All levels (or plasma renin activity) is an independent risk factor for cardiovascular disease. While the association of poor outcome with high renin states is acknowledged. causality is disputed. Thus. excess All has influences on functional and structural changes and may accelerate atherosclerosis and its complications. Therapeutic strategies. such as converting enzyme inhibition or angiotensin receptor antagonism. may prevent the "adverse" effect of Allan vaacular structure and function.
Key Words:
Angiotensin II, receptor antagonists, hypertension, morbidity.
The octapeptide angiotensin II (ANG II), the potent effector molecule of the renin-angiotensin system (RAS), plays an important part in the pathology of hypertension, in cardiovascular diseases like cardiac left ventricular hypertrophy (LVH) and in structural alterations of the heart such as postinfarct remodeling. The development of highly selective ANG II receptor ligands. such as losartan, PO 123177 and others, allowed the identification of ANG II receptor subtypes, designated AT" AT,. AT, and AT,. Most ofthe known effects of this peptide can be attributed to the AT. receptor, e.g. vasoconstriction,
aldosterone and vasopressin release and proliferative effects on vascular smooth muscle and other cells. The AT, receptor, which can be subdivided into AT'A and AT,•• is coupled to G-proteins and stimulates classical second messenger systems, for example activation of phopholipase C or inhibition of adenylate cyclase. In contrast, the function and the signal transduction pathway of the AT, receptor, which exhibits only a 32 to 34% homology to the AT, receptor. are so far not fully understood. The coupling of the AT, receptor to a phosphotyrosine phosphatase (PTPase) and inh'bitory actions on AT, receptor- and growth factor mediated proliferation in endothelial cells have been demonstrated. Due to its wide distribution in foetal tissues including the central nervous system the AT, receptor has been associated with differentiation and development. However, because of its expression in the adult brain the question to the function of the AT, receptor in these brain nuclei .ises. The application of losarlan. the first orslly active AT, receptor antagonist, as an antihypertensive drug has, compared to angiotensin converting enzyme (ACE) inhibitors, the potential advantage of not interfering with the bradykinin system. On the other hand, losartan may fail to exert some of the organ-protective properties of ACE inhibitors mediated by the kininpotentiating actions, although in hypertensive animal studies positive effects of AT, receptor antagonists on cardiac and vascular structure have also been demonstrated. The mechanisms of these organ-protective actions of AT, receptor antagonists are not yet understood. It is conceivable that the AT. receptor, which is left unopposed by the AT, receptor antagonist, is involved. Key Words: Angiotensin II, AT,-receptor, ATI-receptor,losartan, PO \23177, crowth, dilTerentiation, signalling pathwl)'S.
SPECIAL SYMPOSIA Wednesday, May 15, West Ballroom, 8:30 am II: A New Target for Intervention in Hypertension RENAL EFFECTS OF ANGIOTENSIN II (ANGII): PHYSIOLOGY AND PATHOLOGY. Dick de Zeeuw, Div of Nephrology, Univ Hospital, Groningen, The Netherlands Experimental in-vitro and in-vivo data suggest several renal Angll actions: glomerular capillary constriction, proximal tubular sodium reabsorption, and cell proliferation. In addition Angll may induce proteinuria. Oinical data for such effects has been gathered through two different approaches: exogenous Angll infusion and inhibition of endogenous AngII formation. Indeed. AngIl subpressor doses induce a fall of both renal blood flow (and filtration fraction) and fractional sodium excretion. Prevention of AngIl formation by ACE-inhibition will lead to a rise in renal blood flow and natriuresis. Importantly. these ACEi effects on endogenous AngII are attenuated by exogenous AngII. Clinical data on alterations of cellular growth are hard to get. Interestingly. ACEi also has a marked and rather specific antiproteinuric effect. In contrast to the instantaneous hemodynamic and sodium effects, the proteinuria lowering has a slow onset, reaching a maximum after 4 weeks of trealment. Moreover, the antiproteinuric effect appears not to be attenuated by short-term exogenous AnglI infusion. These data may suggest that glomerular permeability is slowly altering through cellular (growth?) changes. Alternatively, the antiproteinuric effect may be the result of intervention in non-AngIl pathways. However. recent data on the effect of specific AngIl receptor blockade with losanan, show both the short-term hemodynamic effects as well as the more long-term antiproteinuric effects. Since both renal hemodynamic as well as proteinuria are implicated in causing progressive renal function loss Inhibition of AngII formation and/or blockade of the Angii receptor are successful approaches for long term renal protection.
Key Words:
angiotensin II, kidney. proteinuria
Wednesday, May 15, West Ballroom, 8:30 am A II: A New Target for Intervention in Hypertension
Wednesday, May 15, West Ballroom, 8:30 am A II: A New Target for Intervention in Hypertension
ANGIOTENSIN II - A TARGET FOR TREATMENT. John L. Reid. Department of Medicine & Therapeutics. University of Glasgow. Glasgow Gil 6NT. Scotland.
Angiotensin II Receptors: Signalling Pathways, Cell Growth and Differentiation Th. Unger. Department of Pharmacology. University of Klel end German Institute of High Blood Pressure Research. Heidelberg, Germany
Angiotensin II (All) is an octapeptide hormone which not only plays a role as a circulating hormone. but also has local paracrine and autocrine functions. In addition to short-term effects on blood pressure and on renal salt and water handling. All has long-lasting effects on blood pressure and vascular resistance resulting. in part. from structural changes. What are the clinical consequences of these short-term functional and longer-term structural effects of All? The level of neurohumoral activation as assessed by plasma renin activity. or plasma All concentrations. has been shown in heart failure patients to directly correlate with morbidity and outcome. More controversially it has been claimed that All levels (or plasma renin activity) is an independent risk factor for cardiovascular disease. While the association of poor outcome with high renin states is acknowledged. causality is disputed. Thus. excess All has influences on functional and structural changes and may accelerate atherosclerosis and its complications. Therapeutic strategies. such as converting enzyme inhibition or angiotensin receptor antagonism. may prevent the "adverse" effect of Allan vaacular structure and function.
Key Words:
Angiotensin II, receptor antagonists, hypertension, morbidity.
The octapeptide angiotensin II (ANG II), the potent effector molecule of the renin-angiotensin system (RAS), plays an important part in the pathology of hypertension, in cardiovascular diseases like cardiac left ventricular hypertrophy (LVH) and in structural alterations of the heart such as postinfarct remodeling. The development of highly selective ANG II receptor ligands. such as losartan, PO 123177 and others, allowed the identification of ANG II receptor subtypes, designated AT" AT,. AT, and AT,. Most ofthe known effects of this peptide can be attributed to the AT. receptor, e.g. vasoconstriction,
aldosterone and vasopressin release and proliferative effects on vascular smooth muscle and other cells. The AT, receptor, which can be subdivided into AT'A and AT,•• is coupled to G-proteins and stimulates classical second messenger systems, for example activation of phopholipase C or inhibition of adenylate cyclase. In contrast, the function and the signal transduction pathway of the AT, receptor, which exhibits only a 32 to 34% homology to the AT, receptor. are so far not fully understood. The coupling of the AT, receptor to a phosphotyrosine phosphatase (PTPase) and inh'bitory actions on AT, receptor- and growth factor mediated proliferation in endothelial cells have been demonstrated. Due to its wide distribution in foetal tissues including the central nervous system the AT, receptor has been associated with differentiation and development. However, because of its expression in the adult brain the question to the function of the AT, receptor in these brain nuclei .ises. The application of losarlan. the first orslly active AT, receptor antagonist, as an antihypertensive drug has, compared to angiotensin converting enzyme (ACE) inhibitors, the potential advantage of not interfering with the bradykinin system. On the other hand, losartan may fail to exert some of the organ-protective properties of ACE inhibitors mediated by the kininpotentiating actions, although in hypertensive animal studies positive effects of AT, receptor antagonists on cardiac and vascular structure have also been demonstrated. The mechanisms of these organ-protective actions of AT, receptor antagonists are not yet understood. It is conceivable that the AT. receptor, which is left unopposed by the AT, receptor antagonist, is involved. Key Words: Angiotensin II, AT,-receptor, ATI-receptor,losartan, PO \23177, crowth, dilTerentiation, signalling pathwl)'S.