Zusammenfassung
Die Frage nach einer möglichen Beteiligung cAMP-abhängiger Vorgänge bei der zentralen Blutdruck-Regulation wurde am Modell der spontan-hypertensiven Ratte (SHR) untersucht. Hierzu wurden in 36, durch Mikrodissektion gewonnenen, spezifischen Hirnarealen — eingeschlossen insbesondere die primären und die sog. modulatorisch wirkenden höheren cardiovasculären Zentren — die Konzentrationen von cAMP bei erwachsenen SHR mit bereits stabilisierten Bluthochdruck und normotensiven Kontroll-Ratten des gleichen Stammes bestimmt.
Bei den SHR fanden sich in verschiedenen Hirnarealen, die in enger Beziehung zur zentralen Blutdruck-Regulation stehen, veränderte cAMP-Konzentrationen. Erhöht war cAMP im Nucleus tractus solitarii, in den katecholaminergen A1- und A2-Zellgruppen der Medulla oblongata, im Locus coeruleus, im Zentralen Höhlengrau (Subnucleus medialis) und in verschiedenen corticalen Arealen (Cortex cinguli, Cortex parietalis, Cortex frontalis, Hippocampus). Erniedrigungen der cAMP-Konzentration fanden sich vor allem in hypothalamischen Strukturen (Nucleus paraventricularis, anterior, ventromedialis, dorsomedialis und posterior hypothalami). Die Daten von weiteren 19 Hirnarealen der spontan-hypertensiven Ratten unterschieden sich nicht von den entsprechenden Kontroll-Werten.
Die Ergebnisse zeigen, daß cAMP-abhängige Vorgänge in biochemische Mechanismen der zentralen Blutdruck-Regulation beim genetischen Hochdruck einbezogen sind. Die Areale, die cAMP-Konzentrationsänderungen aufzeigen, stehen — wie neuroanatomische Untersuchungen zeigen — in enger neuronaler Beziehung zum primären Barorezeptoren-Reflexbogen. Vermutlich handelt es sich bei diesen Arealen um auf den Barorezeptoren-Reflexbogen modulierend wirkende Zentren.
Summary
The possible participation of cAMP in central regulation of arterial blood pressure was investigated in spontaneously hypertensive rats (SHR).
Cyclic AMP concentrations of 36 microdissected individual brain areas — including primary and higher cardiovascular centers — were measured in adult SHR and compared with those of normotensive control rats of the same strain and age.
In the adult SHR, elevated cAMP concentrations were found in brain areas which are in close connection with the central regulation of blood pressure: nucleus tractus solitarii, A1- and A2- catecholaminergic cell groups in the medulla oblongata, locus coeruleus, central grey matter (subnucleus medialis), and certain cortical areas (especially cingulate cortex and hippocampus).
On the other hand, hypothalamic cell groups which have been also suggested to control blood pressure, such as paraventricular, anterior, ventromedial, dorsomedial and posterior hypothalamic nuclei, show lower concentrations of cAMP in the SHR than in normotensive controls.
Cyclic AMP levels in 19 other brain areas of SHR which seem to be not involved in mechanisms of central blood pressure regulation practically do not differ from the values of normotensive rats.
The results suggest that cAMP-dependent processe are involved in the regulatory mechanisms of central blood pressure control. The brain areas which show alterations of cAMP-levels are also distinguished by close neuronal connections to the baroreceptor reflex arc. It is supposed that these areas represent modulatory higher centers capable to affect baroreceptor reflex function.
References
Appleman MM, Thompson WJ, Russell TR (1973) Cyclic nucleotide phosphodiesterase. Adv. Cyclic Nucleotide Res 3:65–98
Brodal A, Szabo T, Torvik A (1956) Corticofugal fibres to sensory trigeminal nuclei and nucleus of solitary tract. J Comp Neurol 106:527–556
Carlsson A, Magnusson T, Rosengreen E (1963) 5-hydroxy-tryptamine of the spinal cord normally and after transection. Experientia 19:359–363
Cramer H, Paul MI, Silbergeld S, Forn J (1971) Determination of regional distribution of adenosine 3′5′-monophosphate in rat brain. J Neurochem 18:1605–1608
Delbarre B, Senon D, Schmitt H (1975) Study on the cardiovascular action of dibutyryl-3,5-cyclic AMP (DB·AMP) following the intraventricular administration to cats. 6th International Congress of Pharmacology, Helsinki, 1975 (Abstract No 516)
Delbarre B, Senon D, Schmitt H (1977) Cyclic 3′5′-adenosine monophosphate and central circulatory control in cats and dogs. Clin Exp Pharmacol Physiol 4:341–348
Hilton SM, Zbrozyna AW (1963) Amygdaloid region for defence reactions and its efferent pathway to the brain stem. J Physiol (Lond) 165:160–173
Kebabian JW (1977) Biochemical regulation and physiological significance of cyclic nucleotides in the nervous system. Adv Cyclic Nucleotide Res 8:421–508
Korner PJ (1971) Integrative neural cardiovascular control. Physiol Rev 51:312–367
Langan T (1973) Protein kinases and protein kinase substrates. Adv Cyclic Nucleotide Res 3:99–154
Lindgren P, Rosen A, Strandberg P, Uvnäs B (1956) The sympathetic vasodilator outflow: a corticospinal autonomic pathway. J Comp Neurol 105:95–110
Löfving B (1961) Cardiovascular adjustments induced from the rostral cingulate gyrus. With special reference to sympathoinhibitory mechanisms. Acta Physiol Scand 53 [Suppl 184]:1–82
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Nathanson JA (1977) Cyclic nucleotides and nervous system function. Physiol Rev 57:157–256
Palkovits M (1973) Isolated removal of hypothalamic or other brain nuclei of the rat. Brain Res 59:449–450
Palkovits M, Zaborszky L (1977) Neuroanatomy of central cardiovascular control. Nucleus tractus solitarii: afferent and efferent neuronal connections in relation to the baroreceptor reflex arc. Progr Brain Res 47:9–34
Palkovits M, Mezey E, Zaborszky L (1979) Neuroanatomical evidences for direct neural connections between the brain stem baroreceator centers and the forebrain areas involved in the neural regulation of the blood pressure. In: Meyer P, Schmitt H (eds) Nervous System and Hypertension. Wiley-Flammarion, Paris New York, pp 18–30
Palkovits M, Schmid G, Bahner U, Pfeuffer Th, Heidland A (1980) Distribution of adenosine 3′5′-monophosphate (cAMP) and adenyl cyclase in the rat brain. J Neurochem (submitted)
Perkins JP (1973) Adenyl cyclase. Adv Cyclic Nucleotide Res 3:1–64
Ricardo JA, Koh ET (1977) Direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Anat Rec 187:693–702
Saavedra JM, Grobecker H, Axelrod J (1978) Changes in central catecholaminergic neurons in the spontaneously (genetic) hypertensive rat. Circ Res 42:529–534
Saavedra JM, Grobecker H (1979) In: Meyer P, Schmitt H (eds) Nervous System and Hypertension. Wiley-Flammarion, Paris New York
Saper CB, Loewy AD, Swanson AD, Cowan WM (1976) Direct hypothalamic-authonomic connections. Brain Res 117:305–312
Schmid G, Hempel K, Heidland A (1978) Decreased cAMP content of the hypothalamus of genetically hypertensive rats. Naunyn-Schmiedeberg's Arch Pharmacol 302:341–343
Schmid G, Palkovits M, Müller I, Heidland A (1980) Effects of centrally administered substance P on cyclic AMP levels in specific brain areas of conscious rats. Neuroscience (submitted)
Schmid G, Palkovits M, Bahner U, Heidland A (1980) Effects of vasopressin deficiency on cyclic AMP levels in discrete areas of rat brain. Neuroendocrinology (submitted)
Schmid G, Palkovits M, Müller I, Heidland A (1980) Acute changes in cyclic AMP levels of certain brain areas following intraventricular injection of renin in rats. Neuropharmacology (in press)
Schmid G, Palkovits M, Fricke L, Heidland A (1980) Cyclic AMP levels in various brain nuclei during development of spontaneous hypertension in rats. (In preparation)
Schmidt MJ, Schmidt DE, Robinson GA (1971) Cyclic adenosine monophosphate in brain areas: microwave irradiation as a means of tissue fixation. Science 173:1142–1143
Schmidt MJ, Thornberry JF (1978) Cyclic AMP and cyclic GMP accumulation in vitro in brain regions of young, old and aged rats. Brain Res 139:169–177
Silver MA, Jacobowitz DM, Crowley W, O'Donohoue T (1978) Retrograde transport of dopamine-β-hydroxylase antibody (ADβH) by CNS noradrenergic neurons: hypothalamic noradrenergic innervations. Anat Rec 190:541–554
Steiner AL, Ferrendelli JA, Kippnis DM (1972) Radioimmunoassay for cyclic nucleotides. III. Effect of ischaemia, during development area and regional distribution of adenosine 3′,5′-monophosphate and guanosine 3′,5′-monophosphate in mouse brain. J Biol Chem 247:1121–1124
Swanson IW (1977) Immunohistochemical evidence for a neurophysin-containing autonomic pathway arisin in the paraventricular nucleus of the hypothalamus. Brain Res 128:346–353
Torvik A (1956) Afferent connections to the sensory trigeminal nuclei, the nucleus of the solitary tract and adjacent structures. An experimental study in the rat. J Comp Neurol 106:51–141
Versteeg GHG, Palkovits M, van der Gugten J, Wijnen HJLM, Smeets GWM, de Jong W (1977) The spontaneously hypertensive rat: catecholamine levels in individual brain regions. Progr Brain Res 47:111–116
Walland A (1975) cAMP as a second messenger in central blood pressure control. Naunyn-Schmiedeberg's Arch Pharmacol 290:419–423
Walland A (1977) Further evidence for the involvement of cAMP in central blood pressure regulation. Naunyn-Schmiedeberg's Arch Pharmacol 296:177–181
White AA (1974) Separation and purification of cyclic nucleotides by alumina column chromatography. In: Hardman JG, O'Malley BW (eds) Methods in enzymology, Vol. XXXVIII: Hormon action, Part C: Cyclic nucleotides. Academic Press, London New York, 41–46
Wijnen HJLM, Spierenburg HA, de Kloet R, de Jong W, Versteeg DHG (1980) Decrease in noradrenergic activity in hypothalamic nuclei during the development of spontaneous hypertension. Brain Res 184 (in press)
Williams JR, Harrison TR, Grollmann A (1939) Simple method for determining the systolic blood pressure of the unesthetized rat. J Clin Invest 18:373–383
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Schmid, G., Palkovits, M., Bahner, U. et al. Altered cyclic AMP levels in specific cardiovascular brain centers of spontaneously hypertensive rats (SHR). Klin Wochenschr 58, 1091–1097 (1980). https://doi.org/10.1007/BF01476879
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DOI: https://doi.org/10.1007/BF01476879