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Chapter 21 The central vasopressinergic system in experimental left ventricular hypertrophy and dysfunction
D. Poulain, S. Oliet and D. Theodosis (Eds.) Progress in Brain Research, Vol. 139 O 2002 Elsevier Science B.V. All rights reserved
CHAPTER 21
The central vasopressinergic system in experimental left ventricular hypertrophy and dysfunction Frank Muders 1,,, Gtinter A.J. Riegger
1, Udo
Bahner 2 and Miklos Palkovits 3
I Klinik und Poliklinikfiir lnnere Medizin 11, University ofRegensburg, Regensburg, Germany 2 Medizinische Universitiitklinik, Wiirzburg, German), 3 Laboratory ofNeuromorphology, Semmelweis University, Budapest, Hungary
Introduction While the pathophysiological role of compensatory neurohumoral mechanisms in heart failure has been widely investigated, the significance of the centrally acting cardiovascular neuropeptide systems remains largely unclear. Measurements of metabolic markers such as hexokinase, cFos and NADPH-diaphorase suggest increased neuron activity in hypothalamic areas of the brain, the locus coeruleus and in other nuclei of the brain involved in central circulatory regulation in rats 6 weeks after myocardial infarction (Patel et al., 1993, 2000; Zhang et al., 1998). There have been only isolated investigations of the functional state of central neuropeptide systems involved in cardiocirculatory regulation in heart failure. With regard to the central renin-angiotensin system, there have been two experimental studies suggesting stimulation. Intracerebroventricular administration of the AT1 receptor antagonist, losartan, in sheep with heart failure due to rapid ventricular pacing led to hemodynamic changes, including a fall in blood pressure, which did not occur in healthy animals (Rademaker
*Correspondence to: E Muders, Klinik und Poliklinik ftir Innere Medizin II, Universit~itsklinikum, FranzJosef-Strauss-Allee 11, 93053 Regensburg, Germany. Tel.: +49-941-9447211; Fax: +49-941-9447213; E-mail: [email protected]
et al., 1995). In rats with an aortocaval fistula, there was increased AT1 receptor expression in the nucleus paraventricularis, nucleus tractus solitarius and subfornical organ (Yoshimura et al., 2000). Investigations of the central vasopressinergic system in heart failure have not been conducted to date. Our aim, therefore, was to investigate the central vasopressinergic system in a model of myocardial hypertrophy and left ventricular dysfunction (supravalvular aortic stenosis model). Banding of the ascending aorta in 8-weeks-old Wistar rats produces severe ventricular hypertrophy after 12 weeks of pressure overload. At this stage, this model is characterized by a transition of LV hypertrophy into cardiac failure, as suggested by functional and molecular studies, as well as by an increased mortality (Weinberg et al., 1994; Bruckschlegel et al., 1995). Neurohumoral vasoconstrictor systems were stimulated in this model in order to maintain blood pressure in the chronic aortic stenosis with a reduced cardiac index. In comparison to healthy control animals, vasopressin plasma levels and plasma renin activities were significantly increased, while levels of plasma norepinephrine and 24-h urinary excretion were unchanged (Muders et al., 1995), parameters both indicating the activity of the sympathetic nervous system (Goldstein et al., 1983). Increased levels of plasma vasopressin can be attributed to non-osmotic stimuli in this model since plasma osmolality was unchanged in comparison to
276 control animals. In an earlier investigation of the same animal model, at a later time (after 15 weeks), enhanced vasopressin plasma levels, not related to plasma osmolality, were found in animals which had developed a marked left ventricular dysfunction (Riegger et al., 1988). Our studies support the hypothesis that non-osmotic stimuli play an important role in the regulation of vasopressin in cardiovascular disorders. In the model of supravalvular aortic stenosis, baroreceptor stimulation and/or angiotensin IImediated stimulation of vasopressin release is possible: the supravalvular position of the silver clip leads to a weakened signal to baroreceptors in the aorta and carotid artery and, consequently, to stimulation of vasopressin secretion. In contrast, cardiac baroreceptors are exposed to increased left ventricular filling pressure and, consequently, counteract increased vasopressin release. However, cardiopulmonary receptors play a subordinate role in the regulation of vasopressin release under physiological conditions in the presence of intact arterial baroreceptors (Chen et al., 1991). In order to test the hypothesis that levels of vasopressin change centrally as well as peripherally, levels of vasopressin were measured in 20 different areas of the brain involved in central cardiocirculatory regulation. The brain areas were obtained by the micropunch technique of Palkovits (Palkovits, 1973). In the hypothalamus, different changes were found in the areas producing vasopressin. While vasopressin content in the paraventricular and suprachiasmatic nuclei was significantly raised in rats with aortic stenosis, no changes were found in the supraoptic nucleus, compared to healthy control animals. This aspect is of particular interest, since the paraventricular and suprachiasmatic nuclei are involved in central cardiocirculatory regulation through their vasopressinergic connections to the brainstem while the supraoptic nucleus does not have these connections. These different changes in vasopressin content in these hypothalamic brain areas indicate an alteration in the central vasopressinergic cardiocirculatory control in animals with supravalvular aortic stenosis. In addition, there was a significantly increased content of vasopressin in the median eminence, an area which is part of the hypothalamo-hypophysial axis. This implies that stimulation of the axis in animals with aortic stenosis consequently raises plasma levels of vasopressin.
The vasopressin content was also significantly increased in four other 'extrahypothalamic' brain areas involved in central cardiocirculatory control. Interestingly, vasopressin content in the locus coeruleus was markedly diminished compared to control animals. In association with the unchanged norepinephrine plasma levels and urinary excretion in rats with aortic stenosis, the results suggest an important central circulatory regulating mechanism, in which a reduced vasopressin concentration in the locus coeruleus may counteract activation of the sympathetic nervous system. In summary, our studies of the central vasopressinergic system in experimental left ventricular hypertrophy and dysfunction show that, in addition to stimulation of peripheral neurohumoral factors, a central neuropeptide system is altered which, in rats, is involved with supravalvular aortic stenosis through its cardiovascular regulatory effects (Muders et al., 1995).
Modulation of the central vasopressinergic system by blockade of the renin-angiotensin system In the 1980s, an association was found between the renin-angiotensin system and vasopressin in patients with heart failure. In these patients, who had plasma levels that were increased inappropriately relative to the plasma osmolality, chronic treatment with the ACE inhibitor, Captopril, led to a significant reduction in the vasopressin plasma levels and to a restoration of the relationship between plasma osmolality and vasopressin (Lee and Packer, 1986; Riegger and Kochsiek, 1986). Nowadays, blockade of the reninangiotensin system by ACE inhibitors and AT~ receptor antagonists is established in the treatment of heart failure, left ventricular hypertrophy and hypertension. The therapeutic efficacy of these medications, including a reduction in the mortality of these cardiovascular disorders, has been confirmed in animal models as well as in patients (The SOLVD Investigators, 1992; The Acute Infarction Ramipril Efficacy Study Investigators, 1993; Remme, 1995). This also includes investigations that were performed using the model of supravalvular aortic stenosis in the rat. Despite persisting strain on the left ventricle, treatment with an ACE inhibitor and ATj receptor antagonist, carried out from the 6th postoperative week, led to a signif-
277 icant regression of left ventricular hypertrophy and to a reduction in mortality, in both treatment groups (Bruckschlegel et al., 1995). It is not known whether chronic treatment with an ACE inhibitor and ATI receptor antagonist, respectively, also produces modulation of central neuropeptide systems involved in cardiocirculatory regulation, like the vasopressinergic system. In order to pursue this question, we measured vasopressin in plasma and in individual brain areas in rats with supravalvular aortic stenosis, which were treated chronically either with an ACE inhibitor or with an ATI receptor antagonist. Twelve weeks after placement of the aortic clip, plasma vasopressin levels were reduced in both treatment groups compared to untreated aortic stenosis animals and showed no significant differences with healthy animals. Treatment with the ACE inhibitor and ATI receptor antagonist also led to a reduction in vasopressin concentrations in specific areas of the hypothalamus and brainstem. These effects were different in some brain areas, which can be attributed to a different distribution of ACE and angiotensin II receptors in these areas (Muders et al., 1999). The fact that treatment of rats with supravalvular aortic stenosis with an ACE inhibitor and AT1 receptor antagonist, respectively, led not to activation but to suppression of the vasopressinergic system, despite a further fall in blood pressure, is of particular interest pathophysiologically and can be explained by (1) modulation of the baroreceptor reflex, and (2) direct peripheral or central inhibition of vasopressin synthesis and release. As explained above, the dysregulation of baroreceptors with consequent restriction of sympathoadrenal and humoral inhibition is a pathophysiological characteristic of chronic heart failure, which includes increased vasopressin synthesis and release (Zucker and Gilmore, 1985; Hirsch et al., 1987). The ability of the baroreceptors to shift their baseline in the direction of the surrounding pressure (reflex resetting) is absent and the sensitivity of the baroreceptors is reduced, as we also found in the model of supravalvular aortic stenosis (unpublished data). As has already been shown in rabbits with experimental heart failure and in patients, treatment with an ACE inhibitor or AT1 receptor antagonist leads to an improvement in the sensitivity of the arterial baroreceptors and restores the ability of the pressure
discharge curve to be readjusted (Murakami et al., 1996; Grassi et al., 1997). Whether chronic blockade of the renin-angiotensin system in the model of supravalvular aortic stenosis leads to an improvement in the baroreceptor reflex is unknown and should be investigated further. In addition to these effects mediated by the baroreceptor reflex, a 'direct' effect of the ACE inhibitor and AT~ receptor antagonist, respectively, on the vasopressinergic system is possible, in which vasopressin synthesis and release are suppressed either through angiotensin II receptors of the circumventricular organs or through direct inhibition of central ACE or angiotensin II receptors in specific areas of the brain.
Central action of ACE inhibitors and AT~ receptor antagonists: in vitro autoradiography of the brain The existence of a central renin-angiotensin system and the significance of central angiotensin II in cardiocirculatory regulation are recognized today. In addition to synaptic inhibition of the baroreceptor reflex, central angiotensin II causes stimulation of sympathetic nervous activity and vasopressin synthesis and release, which can be suppressed by prior administration of an ATI receptor antagonist (Unger et al., 1988; Wright and Harding, 1995). On the other hand, the central efficacy of systemically administered ACE inhibitors and ATI receptor antagonists is controversial. Since chronic oral treatment with an ACE inhibitor and AT~ receptor antagonist in rats with supravalvular aortic stenosis produces suppression of central vasopressin and may be attributed to a central effect of these drugs, we studied the central efficacy of an ACE inhibitor and ATI receptor antagonist, using in vitro autoradiography after systemic administration for 2 and 4 weeks, respectively (Muders et al., 1997, 2001). We were able to show that both medications caused significant ACE inhibition and angiotensin lI receptor blockade in specific brain areas. Moreover, we recorded diminished ACE activities and angiotensin II receptor densities in brain areas that have no blood-brain barrier (and were thus accessible to the drug circulating in the blood) as well as in areas situated inside the brain.
278 A precondition for the central efficacy of an orally administered medication in specific brain areas is penetration of the blood-brain barrier. Studies of the distribution of orally administered radioactively marked drugs often show an absence of accumulation of the ACE inhibitor and AT1 receptor antagonists after a single dose. However, autoradiographic investigations that employed chronic administration as in this investigation, revealed a central blockade of the renin-angiotensin system. Chronic therapy with an ACE inhibitor or AT1 receptor antagonist (as is usual in the treatment of cardiovascular diseases) therefore includes central effects (Gohlke et al., 1989; Song et al., 1991; Polidori et al., 1996). There has been evidence of a central action, even for treatment with Captopril, the most hydrophitic drug of all the ACE inhibitors. Neurophysiological investigations showed for Captopril a marked improvement in cognitive abilities in comparison with placebo-treated patients (Zubenko and Nixon, 1984). In summary, mechanisms of the blood-brain barrier are complex and the penetration of a drug is dependent on many factors, including the duration of use, lipophilia of individual drugs and dosage. The central efficacy of ACE inhibitors and ATl receptor antagonists is of interest insofar as the modulation of central cardiocirculatory mechanisms contributes to the therapeutic effects of these medications in the treatment of cardiovascular diseases.
centrations in the locus coeruleus, an important regulatory area of sympathetic nervous activity, suggest a central regulatory mechanism through which stimulation of the sympathetic nervous activity can be prevented. Our investigations showed that non-osmotic factors like the baroreceptor reflex and angiotensin II, are important stimuli of the vasopressinergic system. We were also able to show that the central vasopressinergic system in rats with experimental heart failure and myocardial hypertrophy is inhibited by treatment with an ACE inhibitor and AT~ receptor antagonist. As seen with autoradiography, this effect is mediated by a central effect of the drugs. Research into central regulatory mechanisms in cardiovascular diseases is, on the one hand, of crucial importance to our understanding of complex pathophysiological processes, and on the other hand, it serves the development of new therapeutic approaches with the goal of influencing these mechanisms directly pharmacologically and for the elucidation of central, currently unknown effects of cardiovascular drugs.
Abbreviations ACE AT LV NADPH
angiotensin converting enzyme angiotensin left ventricular nicotinamide adenine dinucleotide phosphate
Summary References In the course of cardiac diseases, various neurohormonal systems in the plasma are activated. So far there have been only isolated results of investigations about the functional state of central neuropeptide systems in cardiac diseases and, in particular, in heart failure. We investigated, therefore, the central vasopressinergic system, an important neuropeptide system in cardiocirculatory regulation in a model of myocardial hypertrophy and left ventricular dysfunction, a model of supravalvular aortic stenosis. In addition to increased vasopressin concentrations in plasma, central vasopressin is also altered in this model. A differential stimulation of vasopressin in the hypothalamic areas and in the areas of the brain stem that are involved in central cardiocirculatory regulation was detected. Reduced vasopressin con-
Bruckschlegel, G., Holmer, S.R., Jandeleit, K., Grimm, D., Muders, E, Kromer, E.E, Riegger, G.A. and Schunkert, H. (1995) Blockade of the renin-angiotensin system in cardiac pressureoverload hypertrophyin rats. Hypertension, 25: 250-259. Chen, J.S., Wang, W., Bartholet, T. and Zucker, I.H. (1991) Analysis of baroreflex control of heart rate in conscious dogs with pacing-induced heart failure. Circulation, 83: 260-267. Gohlke, P., Scholkens, B., Henning, R., Urbach, H. and Unger, T. (1989) Inhibition of converting enzyme in brain tissue and cerebrospinal fluid of rats following chronic oral treatment with the converting enzyme inhibitors ramipril and Hoe 288. J. Cardiovasc. Pharmacol., 14(Suppl. 4): $32-36. Goldstein, D.S., Mc Carty, R., Polinsky, R.J. and Kopin,I. (1983) Relationship between plasma norepinephrine and sympathetic neuronal activity.Hypertension, 5: 552-559. Grassi, G., Cattaneo, B.M., Seravalle, G., Lanfranchi, A., Pozzi, M., Morganti, A., Carugo, S. and Mancia, G. (1997) Effects of chronic ACE inhibition on sympathetic nerve traffic and
279
baroreflex control of circulation in heart failure. Circulation, 96: 1173-1179. Hirsch, A.T., Dzau, V.J. and Creager, M.A. (1987) Baroreceptor function in congestive heart failure: effect on neurohumoral activation and regional vascular resistance. Circulation, 75: 1136-1148.
Lee, W.H. and Packer, M. (1986) Prognostic importance of serum sodium concentration and its modification by convertingenzyme inhibition in patients with severe chronic heart failure. Circulation, 73: 257-267. Muders, F., Kromer, E.P., Bahner, U., Elsner, D., Ackermann, B., Schunkert, H., Palkovits, M. and Riegger, G.A. (1995) Central vasopressin in experimental aortic stenosis in the rat. Cardiovasc. Res., 29: 416-421. Muders, E, Elsner, D., Jandeleit, K., Bahner, U., Kromer, E.E, Kirst, I., Riegger, G.A. and Palkovits, M. (1997) Chronic ACE inhibition by quinapril modulates central vasopressinergic system. Cardiovasc. Res., 34: 575-581. Muders, F., Eisner, D., Schunkert, H., Riegger, G.A. and Palkovits, M. (1999) Central vasopressin is modulated by chronic blockade of the renin-angiotensin system in experimental left ventricular hypertrophy. Am. J. Hypertens., 12: 311-314. Muders, E, Palkovits, M., Bahner, U., Kirst, I., Elsner, D. and Jandeleit-Dahm, K. (2001) Central inhibition of AT1 receptors by eprosartan - - in vitro autoradiography in the brain. Pharmacol. Res., 43: 251-255. Murakami, H., Liu, J.L. and Zucker, I.H. (1996) Blockade of ATI receptors enhances baroreflex control of heart rate in conscious rabbits with heart failure. Am. J. Physiol., 271: R303-R309. Palkovits, M. (1973) Isolated removal of hypothalamic or other brain nuclei of the rat. Brain Res., 59: 449-450. Patel, K.P., Zhang, EL. and Krukoff, T.L. (1993) Alterations in brain hexokinase activity associated with heart failure in rats. Am. J. Physiol., 265: R923-R928. Patel, K.P., Zhang, K., Kenney, M.J., Weiss, M. and Mayhan, W.G. (2000) Neuronal expression of Fos protein in the hypothalamus of rats with heart failure. Brain Res., 865: 2734. Polidori, C., Ciccocioppo, R., Pompei, E, Cirillo, R. and Massi, M. (1996) Functional evidence for the ability of angiotensin AT1 receptor antagonists to cross the blood-brain barrier in rats. Eur. J. Pharrnacol., 307: 259-267. Rademaker, M.T., Fitzpatrick, M.A., Charles, C.J., Frampton, C.M., Richards, A.M., Nicholls, M.G. and Espiner, E.A. (1995) Central angiotensin II ATl-receptor antagonism in normal and heart-failed sheep. Am. J. Physiol., 269: H425-H432.
Remme, W.J. (1995) Neurohormonal modulation in heart failure: ACE inhibition and beyond. Eur. Heart J., 16(Suppl. N): 7378. Riegger, G.A. and Kochsiek, K. (1986) Vasopressin, renin and norepinephrine levels before and after captopril administration in patients with congestive heart failure due to idiopathic dilated cardiomyopathy. Am. J. Cardiol., 58: 300-303. Riegger, G.A:, Wolf, E and Kochsiek, K. (1988) Vasoconstrictor role of vasopressin and angiotensin in experimental aortic stenosis in the rat. J. Cardiovasc. Pharmacol., 11 : 538-542. Song, K.E, Zhuo, J.L. and Mendelsohn, EA. (1991) Access of peripherally administered DuP 753 to rat brain angiotensin II receptors. Br. J. Pharmacol., 104: 771-772. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators (1993) Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet, 342:821-828. The SOLVD Investigators (1992) Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. N. Engl. J. Med., 327: 685-691. Unger, T., Badoer, E., Ganten, D., Lang, R.E. and Rettig, R. (1988) Brain angiotensin: pathways and pharmacology. Circulation, 77: 140-154. Weinberg, E.O., Schoen, EJ., George, D., Kagaya, Y., Douglas, ES., Litwin, S.E., Schunkert, H., Benedict, C.R. and Lorell, B.H. (1994) Angiotensin-converting enzyme inhibition prolongs survival and modifies the transition to heart failure in rats with pressure overload hypertrophy due to ascending aortic stenosis. Circulation, 90: 1410-1422. Wright, J.W. and Harding, J.W. (1995) Brain angiotensin receptor subtypes AT1, AT2, and AT4 and their functions. Regul. Pept., 59" 269-295. Yoshimura, R., Sato, T., Kawada, T., Shishido, T., Inagaki, M., Miyano, H., Nakahara, T., Miyashita, H., Takaki, H., Tatewaki, T., Yanagiya, Y., Sugimachi, M. and Sunagawa, K. (2000) Increased brain angiotensin receptor in rats with chronic highoutput heart failure. J. Card. Fail,, 6: 66-72. Zhang, K., Zucker, I.H. and Patel, K.E (1998) Altered number of diaphorase (NOS) positive neurons in the hypothalamus of rats with heart failure. Brain Res., 786: 219-225. Zubenko, G.S. and Nixon, R.A. (1984) Mood-elevating effect of captopril in depressed patients. Am. J. Psychiatry, 141: 110111. Zucker, I.H. and Gilmore, J.P. (1985) Aspects of cardiovascular reflexes in pathologic states. Fed. Proc., 44: 2400-2407.
CHAPTER 21
The central vasopressinergic system in experimental left ventricular hypertrophy and dysfunction Frank Muders 1,,, Gtinter A.J. Riegger
1, Udo
Bahner 2 and Miklos Palkovits 3
I Klinik und Poliklinikfiir lnnere Medizin 11, University ofRegensburg, Regensburg, Germany 2 Medizinische Universitiitklinik, Wiirzburg, German), 3 Laboratory ofNeuromorphology, Semmelweis University, Budapest, Hungary
Introduction While the pathophysiological role of compensatory neurohumoral mechanisms in heart failure has been widely investigated, the significance of the centrally acting cardiovascular neuropeptide systems remains largely unclear. Measurements of metabolic markers such as hexokinase, cFos and NADPH-diaphorase suggest increased neuron activity in hypothalamic areas of the brain, the locus coeruleus and in other nuclei of the brain involved in central circulatory regulation in rats 6 weeks after myocardial infarction (Patel et al., 1993, 2000; Zhang et al., 1998). There have been only isolated investigations of the functional state of central neuropeptide systems involved in cardiocirculatory regulation in heart failure. With regard to the central renin-angiotensin system, there have been two experimental studies suggesting stimulation. Intracerebroventricular administration of the AT1 receptor antagonist, losartan, in sheep with heart failure due to rapid ventricular pacing led to hemodynamic changes, including a fall in blood pressure, which did not occur in healthy animals (Rademaker
*Correspondence to: E Muders, Klinik und Poliklinik ftir Innere Medizin II, Universit~itsklinikum, FranzJosef-Strauss-Allee 11, 93053 Regensburg, Germany. Tel.: +49-941-9447211; Fax: +49-941-9447213; E-mail: [email protected]
et al., 1995). In rats with an aortocaval fistula, there was increased AT1 receptor expression in the nucleus paraventricularis, nucleus tractus solitarius and subfornical organ (Yoshimura et al., 2000). Investigations of the central vasopressinergic system in heart failure have not been conducted to date. Our aim, therefore, was to investigate the central vasopressinergic system in a model of myocardial hypertrophy and left ventricular dysfunction (supravalvular aortic stenosis model). Banding of the ascending aorta in 8-weeks-old Wistar rats produces severe ventricular hypertrophy after 12 weeks of pressure overload. At this stage, this model is characterized by a transition of LV hypertrophy into cardiac failure, as suggested by functional and molecular studies, as well as by an increased mortality (Weinberg et al., 1994; Bruckschlegel et al., 1995). Neurohumoral vasoconstrictor systems were stimulated in this model in order to maintain blood pressure in the chronic aortic stenosis with a reduced cardiac index. In comparison to healthy control animals, vasopressin plasma levels and plasma renin activities were significantly increased, while levels of plasma norepinephrine and 24-h urinary excretion were unchanged (Muders et al., 1995), parameters both indicating the activity of the sympathetic nervous system (Goldstein et al., 1983). Increased levels of plasma vasopressin can be attributed to non-osmotic stimuli in this model since plasma osmolality was unchanged in comparison to
276 control animals. In an earlier investigation of the same animal model, at a later time (after 15 weeks), enhanced vasopressin plasma levels, not related to plasma osmolality, were found in animals which had developed a marked left ventricular dysfunction (Riegger et al., 1988). Our studies support the hypothesis that non-osmotic stimuli play an important role in the regulation of vasopressin in cardiovascular disorders. In the model of supravalvular aortic stenosis, baroreceptor stimulation and/or angiotensin IImediated stimulation of vasopressin release is possible: the supravalvular position of the silver clip leads to a weakened signal to baroreceptors in the aorta and carotid artery and, consequently, to stimulation of vasopressin secretion. In contrast, cardiac baroreceptors are exposed to increased left ventricular filling pressure and, consequently, counteract increased vasopressin release. However, cardiopulmonary receptors play a subordinate role in the regulation of vasopressin release under physiological conditions in the presence of intact arterial baroreceptors (Chen et al., 1991). In order to test the hypothesis that levels of vasopressin change centrally as well as peripherally, levels of vasopressin were measured in 20 different areas of the brain involved in central cardiocirculatory regulation. The brain areas were obtained by the micropunch technique of Palkovits (Palkovits, 1973). In the hypothalamus, different changes were found in the areas producing vasopressin. While vasopressin content in the paraventricular and suprachiasmatic nuclei was significantly raised in rats with aortic stenosis, no changes were found in the supraoptic nucleus, compared to healthy control animals. This aspect is of particular interest, since the paraventricular and suprachiasmatic nuclei are involved in central cardiocirculatory regulation through their vasopressinergic connections to the brainstem while the supraoptic nucleus does not have these connections. These different changes in vasopressin content in these hypothalamic brain areas indicate an alteration in the central vasopressinergic cardiocirculatory control in animals with supravalvular aortic stenosis. In addition, there was a significantly increased content of vasopressin in the median eminence, an area which is part of the hypothalamo-hypophysial axis. This implies that stimulation of the axis in animals with aortic stenosis consequently raises plasma levels of vasopressin.
The vasopressin content was also significantly increased in four other 'extrahypothalamic' brain areas involved in central cardiocirculatory control. Interestingly, vasopressin content in the locus coeruleus was markedly diminished compared to control animals. In association with the unchanged norepinephrine plasma levels and urinary excretion in rats with aortic stenosis, the results suggest an important central circulatory regulating mechanism, in which a reduced vasopressin concentration in the locus coeruleus may counteract activation of the sympathetic nervous system. In summary, our studies of the central vasopressinergic system in experimental left ventricular hypertrophy and dysfunction show that, in addition to stimulation of peripheral neurohumoral factors, a central neuropeptide system is altered which, in rats, is involved with supravalvular aortic stenosis through its cardiovascular regulatory effects (Muders et al., 1995).
Modulation of the central vasopressinergic system by blockade of the renin-angiotensin system In the 1980s, an association was found between the renin-angiotensin system and vasopressin in patients with heart failure. In these patients, who had plasma levels that were increased inappropriately relative to the plasma osmolality, chronic treatment with the ACE inhibitor, Captopril, led to a significant reduction in the vasopressin plasma levels and to a restoration of the relationship between plasma osmolality and vasopressin (Lee and Packer, 1986; Riegger and Kochsiek, 1986). Nowadays, blockade of the reninangiotensin system by ACE inhibitors and AT~ receptor antagonists is established in the treatment of heart failure, left ventricular hypertrophy and hypertension. The therapeutic efficacy of these medications, including a reduction in the mortality of these cardiovascular disorders, has been confirmed in animal models as well as in patients (The SOLVD Investigators, 1992; The Acute Infarction Ramipril Efficacy Study Investigators, 1993; Remme, 1995). This also includes investigations that were performed using the model of supravalvular aortic stenosis in the rat. Despite persisting strain on the left ventricle, treatment with an ACE inhibitor and ATj receptor antagonist, carried out from the 6th postoperative week, led to a signif-
277 icant regression of left ventricular hypertrophy and to a reduction in mortality, in both treatment groups (Bruckschlegel et al., 1995). It is not known whether chronic treatment with an ACE inhibitor and ATI receptor antagonist, respectively, also produces modulation of central neuropeptide systems involved in cardiocirculatory regulation, like the vasopressinergic system. In order to pursue this question, we measured vasopressin in plasma and in individual brain areas in rats with supravalvular aortic stenosis, which were treated chronically either with an ACE inhibitor or with an ATI receptor antagonist. Twelve weeks after placement of the aortic clip, plasma vasopressin levels were reduced in both treatment groups compared to untreated aortic stenosis animals and showed no significant differences with healthy animals. Treatment with the ACE inhibitor and ATI receptor antagonist also led to a reduction in vasopressin concentrations in specific areas of the hypothalamus and brainstem. These effects were different in some brain areas, which can be attributed to a different distribution of ACE and angiotensin II receptors in these areas (Muders et al., 1999). The fact that treatment of rats with supravalvular aortic stenosis with an ACE inhibitor and AT1 receptor antagonist, respectively, led not to activation but to suppression of the vasopressinergic system, despite a further fall in blood pressure, is of particular interest pathophysiologically and can be explained by (1) modulation of the baroreceptor reflex, and (2) direct peripheral or central inhibition of vasopressin synthesis and release. As explained above, the dysregulation of baroreceptors with consequent restriction of sympathoadrenal and humoral inhibition is a pathophysiological characteristic of chronic heart failure, which includes increased vasopressin synthesis and release (Zucker and Gilmore, 1985; Hirsch et al., 1987). The ability of the baroreceptors to shift their baseline in the direction of the surrounding pressure (reflex resetting) is absent and the sensitivity of the baroreceptors is reduced, as we also found in the model of supravalvular aortic stenosis (unpublished data). As has already been shown in rabbits with experimental heart failure and in patients, treatment with an ACE inhibitor or AT1 receptor antagonist leads to an improvement in the sensitivity of the arterial baroreceptors and restores the ability of the pressure
discharge curve to be readjusted (Murakami et al., 1996; Grassi et al., 1997). Whether chronic blockade of the renin-angiotensin system in the model of supravalvular aortic stenosis leads to an improvement in the baroreceptor reflex is unknown and should be investigated further. In addition to these effects mediated by the baroreceptor reflex, a 'direct' effect of the ACE inhibitor and AT~ receptor antagonist, respectively, on the vasopressinergic system is possible, in which vasopressin synthesis and release are suppressed either through angiotensin II receptors of the circumventricular organs or through direct inhibition of central ACE or angiotensin II receptors in specific areas of the brain.
Central action of ACE inhibitors and AT~ receptor antagonists: in vitro autoradiography of the brain The existence of a central renin-angiotensin system and the significance of central angiotensin II in cardiocirculatory regulation are recognized today. In addition to synaptic inhibition of the baroreceptor reflex, central angiotensin II causes stimulation of sympathetic nervous activity and vasopressin synthesis and release, which can be suppressed by prior administration of an ATI receptor antagonist (Unger et al., 1988; Wright and Harding, 1995). On the other hand, the central efficacy of systemically administered ACE inhibitors and ATI receptor antagonists is controversial. Since chronic oral treatment with an ACE inhibitor and AT~ receptor antagonist in rats with supravalvular aortic stenosis produces suppression of central vasopressin and may be attributed to a central effect of these drugs, we studied the central efficacy of an ACE inhibitor and ATI receptor antagonist, using in vitro autoradiography after systemic administration for 2 and 4 weeks, respectively (Muders et al., 1997, 2001). We were able to show that both medications caused significant ACE inhibition and angiotensin lI receptor blockade in specific brain areas. Moreover, we recorded diminished ACE activities and angiotensin II receptor densities in brain areas that have no blood-brain barrier (and were thus accessible to the drug circulating in the blood) as well as in areas situated inside the brain.
278 A precondition for the central efficacy of an orally administered medication in specific brain areas is penetration of the blood-brain barrier. Studies of the distribution of orally administered radioactively marked drugs often show an absence of accumulation of the ACE inhibitor and AT1 receptor antagonists after a single dose. However, autoradiographic investigations that employed chronic administration as in this investigation, revealed a central blockade of the renin-angiotensin system. Chronic therapy with an ACE inhibitor or AT1 receptor antagonist (as is usual in the treatment of cardiovascular diseases) therefore includes central effects (Gohlke et al., 1989; Song et al., 1991; Polidori et al., 1996). There has been evidence of a central action, even for treatment with Captopril, the most hydrophitic drug of all the ACE inhibitors. Neurophysiological investigations showed for Captopril a marked improvement in cognitive abilities in comparison with placebo-treated patients (Zubenko and Nixon, 1984). In summary, mechanisms of the blood-brain barrier are complex and the penetration of a drug is dependent on many factors, including the duration of use, lipophilia of individual drugs and dosage. The central efficacy of ACE inhibitors and ATl receptor antagonists is of interest insofar as the modulation of central cardiocirculatory mechanisms contributes to the therapeutic effects of these medications in the treatment of cardiovascular diseases.
centrations in the locus coeruleus, an important regulatory area of sympathetic nervous activity, suggest a central regulatory mechanism through which stimulation of the sympathetic nervous activity can be prevented. Our investigations showed that non-osmotic factors like the baroreceptor reflex and angiotensin II, are important stimuli of the vasopressinergic system. We were also able to show that the central vasopressinergic system in rats with experimental heart failure and myocardial hypertrophy is inhibited by treatment with an ACE inhibitor and AT~ receptor antagonist. As seen with autoradiography, this effect is mediated by a central effect of the drugs. Research into central regulatory mechanisms in cardiovascular diseases is, on the one hand, of crucial importance to our understanding of complex pathophysiological processes, and on the other hand, it serves the development of new therapeutic approaches with the goal of influencing these mechanisms directly pharmacologically and for the elucidation of central, currently unknown effects of cardiovascular drugs.
Abbreviations ACE AT LV NADPH
angiotensin converting enzyme angiotensin left ventricular nicotinamide adenine dinucleotide phosphate
Summary References In the course of cardiac diseases, various neurohormonal systems in the plasma are activated. So far there have been only isolated results of investigations about the functional state of central neuropeptide systems in cardiac diseases and, in particular, in heart failure. We investigated, therefore, the central vasopressinergic system, an important neuropeptide system in cardiocirculatory regulation in a model of myocardial hypertrophy and left ventricular dysfunction, a model of supravalvular aortic stenosis. In addition to increased vasopressin concentrations in plasma, central vasopressin is also altered in this model. A differential stimulation of vasopressin in the hypothalamic areas and in the areas of the brain stem that are involved in central cardiocirculatory regulation was detected. Reduced vasopressin con-
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