Biomedical subjects
Publications and source records attributed to D Ganten.
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The use of affinity purified ANG II antiserum as opposed to crude antiserum greatly enhanced the staining resolution in rat brain. This improved resolution was due to a complete loss of background staining and an apparent increase in specific staining that was totally blockable by preabsorption. With the purified antibody it was easily possible to visualise the finest fibres in rats not treated with colchicine. Furthermore, the improved technique permitted a clearer visualisation of an ANG II-like immunoreactive product in cell bodies. This use of affinity purified antibody should greatly facilitate the mapping of central angiotensinergic pathways.
Local renin-angiotensin systems have been described in organ controlling cardiovascular function. Following oral administration of converting enzyme (CE) inhibitors the enzyme was inhibited not only in lung vascular endothelium and blood, but also in the heart, kidney, vascular wall, brain and other organs. Evidence for a contribution of tissue CE inhibition to the cardiovascular actions of CE inhibitors is provided by the antihypertensive effect of brain CE inhibition in spontaneously hypertensive rats, by the concomitant persistence of blood pressure decrease and CE inhibition in vascular wall and kidney after chronic oral CE inhibitor treatment, and by the marked effects of oral CE inhibitor pretreatment on cardiac function in isolated rat hearts. Local inhibition of tissue renin-angiotensin systems may therefore be an important factor involved in the beneficial effects of CE inhibitors in cardiovascular diseases such as arterial hypertension, congestive heart failure, and cardiac arrhythmias.
Central catecholamine (CA)-neuropeptide Y (NPY) interactions and their regulation by glucocorticoids have been analyzed in vivo and in vitro, especially in the dorsal cardiovascular center of the medulla oblongata, including the nucleus tractus solitarius (nTS), using immunocytochemical, receptor autoradiographical, biochemical, and physiological techniques. Intraventricular (i.v.t.) injections of NPY in a low (7.5 pmol) or a high (1.25 nmol) dose increased adrenaline levels 4 h later in the caudal part of the dorsomedial medulla. Furthermore, NPY immunoreactivity (IR) tended to decrease in the rostral part of the dorsomedial medulla 5 min after injection of clonidine (1 microgram) in the alpha-chloralose anaesthetized rat. Thus, presynaptic interaction between NPY and adrenaline (A) mechanisms may exist in the dorsal cardiovascular center taking place at the network local circuit level or the membrane level of the NPY/A costoring synapses of the dorsomedial medulla. In vitro NPY (10 nM) reduced the affinity of the alpha 2-adrenergic agonist binding sites in the nTS, and clonidine (10 nM) reduced the 125I-NPY binding in the dorsomedial medulla. These results indicate the existence of postsynaptic receptor-receptor interactions between alpha 2-adrenergic and NPY receptors in the dorsal cardiovascular center. This interaction may in part take place at the level of the Ni protein, since NPY (300 nM) inhibited cyclic AMP (cAMP) accumulation in slices of the dorsomedial medulla. However, the interactions also probably take place at the proteins carrying the recognition sites, since NPY and adrenaline together given i.v.t. significantly antagonized the hypotensive effects of one another. Thus, the reduced affinity of the alpha 2-adrenergic receptor induced by NPY may reflect a reduced efficiency of this receptor and not an increased coupling of Ni protein to the adenylate cyclase. Thus, the postsynaptic interaction between the two receptors represents inter alia a sensitivity regulation of the two receptors. Evidence is also presented for the existence of a glucocorticoid regulation of NPY IR neurons, especially of those innervating the locus coeruleus, since after 2 weeks adrenalectomy reduced NPY IR in this area. Furthermore, glucocorticoid receptor IR was demonstrated in the nuclei of NPY nerve cell bodies of the nTS. Thus, glucocorticoids exert direct actions on cardiovascular NPY/CA costoring neurons, actions that may contribute to their hypertensive effects in humans.(ABSTRACT TRUNCATED AT 400 WORDS)
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To test the effect of exogenous atrial natriuretic factor (ANF) on the kidney function of rats with chronic renal insufficiency, we examined the responses to bolus infusions of atriopeptin III in two models of renal insufficiency, namely, nephrosclerosis and glomerulonephritis. Hypertensive Dahl S rats receiving a high (8%) NaCl diet for 12 weeks, and rats with anti-glomerular basement membrane nephritis, both of which had glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) less than half those of respective control rats, exhibited similar relative increases In GFR and ERPF in response to atriopeptin III as did controls. Natriuresis, diuresis, and decreased blood pressure were as prominent in rats with either form of renal disease as in control rats. Rats receiving high NaCl intake, irrespective of renal function, had relatively exaggerated responses compared with rats receiving a normal NaCl diet. We conclude that rats with chronic renal insufficiency of diverse causes respond briskly to ANF despite presumed hyperperfused and hyperfiltering nephrons. Thus, diseased kidneys exhibit substantial renal functional "reserve." The renal response to ANF appears to be influenced by NaCl intake in both normal animals and those with renal insufficiency.
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The results of biochemical, immunohistochemical and autoradiographic studies have led to the description of the endogenous brain angiotensin II system as a highly localized network of angiotensin II-containing cell bodies and fibers as well as characteristic sites with high angiotensin II receptor density. The specific localization of this system predominantly within limbic, hypothalamic and brain stem structures that are known to be involved in central cardiovascular regulation and the control of volume homeostasis suggests a possible functional role of brain angiotensin II in the control of these homeostatic functions. In particular, brain angiotensin II may function to help maintaining adequate tissue perfusion to vital parts of the body at times, when body fluid and cardiovascular homeostasis are jeopardized. In addition, there is evidence that brain angiotensin II may participate in the control of hormone release from the anterior and posterior pituitary gland, regulation of body temperature and the processing of learning contents. Future research may profitably be directed towards an exact functional characterization of central angiotensinergic pathways as well as an detailed analysis of the mechanisms that underly central angiotensin II-induced responses.
In male rats, two-week orchidectomy induced a significant increase in the pituitary content of oxytocin-immunoreactivity and a significant fall in its hypothalamic concentration, without detectable changes in plasma. Testosterone replacement therapy in castrated animals abolished the stimulant effect of orchidectomy on pituitary accumulation of oxytocin. The present study demonstrates an inhibitory effect of testicular androgens on oxytocin release. These results and previous observations suggest that the neurohypophysial hormone oxytocin may play a role in male reproductive system.
The influence of GABA-ergic stimulation on the centrally evoked pressor and tachycardic responses to substance P (SP) was investigated in conscious rats. Intracerebroventricular (i.c.v.) pretreatment with the potent GABA agonist muscimol attenuated the pressor responses to i.c.v. administered SP in a dose-dependent and reversible fashion. Inhibition was maximal 5-60 min after muscimol injection and lasted up to 3 h. In contrast, the increases in heart rate in response to i.c.v. administered SP were not consistently inhibited by muscimol. Central pretreatment with muscimol prevented the increase of plasma adrenaline but not of plasma noradrenaline in response to i.c.v. administered SP. Our results demonstrate that the GABA-ergic system can exert an inhibitory control on pathways mediating the central pressor actions of SP. The selective inhibition of adrenaline secretion by muscimol implies that suppression of sympathetic outflow to the adrenal gland may be involved as an important mechanism. In addition, our findings point to a dissociation between pathways mediating the pressor and tachycardic effects of SP.
The role of intracellular signals in the regulation of atrial natriuretic peptide (ANP) release was studied using the isolated perfused rat heart. The phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), known to activate the protein kinase C pathway, produced a dose-dependent increase in perfusate ANP immunoreactivity. Bay k8644, a putative calcium channel activator, and forskolin, which stimulates adenylate cyclase, induced a sustained increase in ANP secretory rate. TPA in combination with either Bay k8644 or forskolin induced higher ANP secretion than the calculated additive value for each agent. 8-bromo-cyclic GMP and sodium nitroprusside, when given alone, had no effect on ANP secretion, but delayed the TPA-stimulated increase in perfusate ANP. ANP secretion appears therefore to be mediated both by the phosphoinositide and the cAMP system, whereas the cGMP pathway may be inhibitory.
To examine the physiological role of atrial natriuretic factor (ANF) in the maintenance of sodium homeostasis under various conditions, we performed experiments in rats across a wide range of sodium intake, in rats with chronic renal insufficiency at extremes of sodium intake, and in rats given desoxycorticosterone acetate. After three weeks of a very low sodium diet, regular diet, or regular diet plus 1% saline as drinking water, no difference in plasma values of immunoreactive atrial natriuretic factor (IR-ANF) were identified, while rats at the lowest level of sodium intake had elevated atrial values. Normal rats, and rats with 5/6 nephrectomy has plasma values of IR-ANF which were no different irrespective of their sodium intake, nor were atrial values in these rats different. Although mineralocorticoid "escape" could be documented by changes in urine sodium excretion, neither plasma nor atrial IR-ANF values showed differences either at 24 or 72 hr after "escape". The data are consistent with previous observations that ANF serves the purpose of affecting rapid adjustments to large alterations in circulating fluid volume. Chronic high sodium intake, adaptation to renal insufficiency, and adjustment to the effect of mineralocorticoid do not appear to be associated with increased circulating plasma concentrations of IR-ANF.
The central cardiovascular actions of arginine vasopressin (AVP) and the role of this peptide in the modulation of baroreceptor reflex (BRR) sensitivity were investigated in conscious, chronically instrumented rats. Intracerebroventricular (i.c.v.) injections of AVP (1-100 ng) produced dose-dependent pressor effects together with increases in heart rate, splanchnic, and renal sympathetic nerve activity and a reduction of mesenteric blood flow. These responses were prevented by i.c.v. pretreatment with a V1-AVP receptor antagonist. Furthermore, the central pressor effects of AVP were abolished by peripheral alpha-adrenoceptor blockade with phentolamine. In contrast to the i.c.v. injections, intravenous (i.v.) or intracarotid injections of AVP produced pressor responses accompanied by bradycardia and a decrease in sympathetic nerve activity. Intracerebroventricular pretreatment with a V1-AVP receptor antagonist shifted the slope of the BRR curve (increases in pulse interval plotted against increases in systolic blood pressure in response to i.v. methoxamine) toward higher sensitivity, whereas i.v. pretreatment with a V2-AVP receptor antagonist shifted the slope of the BRR curve toward lower sensitivity of the reflex. These findings suggest that central (neuronal) AVP, by acting on V1-AVP receptors in the brain, participates in central pressor mechanisms, activates the sympathetic nervous system, and desensitizes the BRR. Conversely, circulating (hormonal) AVP can sensitize the BRR by acting on V2-AVP receptors accessible from the blood. Our data provide evidence pointing to a direct interaction between the neuronal and the hormonal axis of the AVP system within cardiovascular control.
The discovery of tissue renin-angiotensin systems (RAS) in organs controlling the cardiovascular system has opened new perspectives for our understanding of the cardiovascular actions of converting enzyme (CE) inhibitors. Direct application of CE inhibitors to the brain and heart entails distinct cardiovascular effects. Systemic treatment with CE inhibitors leads not only to an inhibition of the plasma RAS, but it also inhibits tissue CE in various organs and reduces local angiotensin II concentrations. Evidence is presented that oral CE inhibitor treatment markedly influences organ function of the heart, brain, and vascular wall independently of the plasma RAS. These findings are compatible with the concept that tissue CE inhibition contributes to the beneficial actions of CE inhibitors in cardiovascular disease.
To test the hypothesis that the hypotensive action of urapidil is in part related to a direct action on the brain, the central (intracerebroventricular) and peripheral (intravenous) effects of urapidil were studied and compared with those obtained with clonidine and prazosin. All studies were conducted in conscious, chronically instrumented stroke-prone spontaneously hypertensive rats (SHRSP). Efferent sympathetic nervous system activity was estimated by means of a bipolar electrode implanted on the splanchnic nerve. Only clonidine, administered intracerebroventricularly and intravenously, decreased sympathetic nerve activity. Urapidil and prazosin either did not affect sympathetic nerve activity after central administration or increased it after peripheral administration at low and high doses, respectively. Centrally administered urapidil and prazosin lowered blood pressure but also blocked the response to intravenously administered phenylephrine; this result suggests a peripheral effect. Centrally administered urapidil decreased heart rate. Urapidil given either intracerebroventricularly or into the cisterna magna had no influence on baroreceptor responses. Intravenous infusions of urapidil and prazosin in sufficient doses to lower blood pressure in spontaneously hypertensive rats by 50 mm Hg completely blocked the actions of phenylephrine. These data suggest that in conscious SHRSP urapidil lowers blood pressure through peripheral blockade of alpha 1-adrenergic receptors rather than by means of central sympathetic suppression. In this regard urapidil resembles prazosin rather than clonidine; however, the effect of urapidil on heart rate is consistent with a central mode of action.
Plasma vasopressin sensitizes the baroreceptor reflex, whereas vasopressin given into the cerebral ventricle overrides the baroreceptor reflex by means of sympathetic stimulation. To test the hypothesis that arginine vasopressin stimulates two different receptor subtypes (V1 and V2) in the central nervous system, we measured the baroreceptor reflex (change in pulse interval vs change in blood pressure) after administering methoxamine (10-300 micrograms/kg i.v.) in conscious rats. Animals were pretreated either with a V1 vasopressin receptor antagonist administered intravenously or intracerebroventricularly, or with a V2 receptor antagonist administered intravenously. The central V1 antagonist caused sensitization of the baroreceptor reflex, whereas the intravenous V2 antagonist attenuated it. The intravenous V1 vasopressin antagonist had no effect on baroreceptor reflex sensitivity. When the experiments were repeated in rats with hereditary diabetes insipidus, neither antagonist influenced the baroreceptor reflex. Volume expansion lowered circulating vasopressin levels and also attenuated the baroreceptor reflex--effects similar to those observed with the intravenous V2 antagonist. We conclude that vasopressin sensitizes the baroreceptor reflex through V2 receptors accessible from the blood and inhibits the reflex through V1 receptors in the brain that cannot be reached from the blood. These observations suggest a direct interaction between hormonal and neuronal vasopressin in cardiovascular control.
The effect of volume changes on the plasma concentration of atrial natriuretic peptide (ANP) was investigated. In children with chronic renal failure predialysis plasma ANP was higher as compared to normal children and decreased significantly during hemodialysis. The decrease in plasma ANP correlated with body weight reduction. On the other hand, increase in plasma volume by infusion of albumin in children with nephrotic syndrome caused significant rise in plasma ANP and an increased natriuresis. Our data demonstrate that an expanded extracellular fluid volume and/or plasma volume appears to be a major stimulus for the release in ANP in children.
To elucidate the disposition of atriopeptin III in plasma we performed experiments in normal and anephric rats. Bolus, i.v. atriopeptin III (250 ng) was given after which the rats were decapitated at 30-sec intervals. The half-life of atriopeptin III in normal rats was 26.5 sec, the volume of distribution was 352 ml and the plasma clearance was 500 ml/min. In anephric rats the half-life was 56.8 sec, the volume of distribution was 345 ml and the plasma clearance was 206 ml/min. In other rats atriopeptin III was given and urine was collected simultaneously. No atriopeptin III could be measured in the urine. We gave 0.0, 0.067, 0.125, 0.25, 0.5 and 1.0 ng/kg of bolus atriopeptin III to normal rats and measured effects on blood pressure, heart rate and plasma concentration at 30 sec, the time at which maximum effect on blood pressure occurred. Dose, change in blood pressure and plasma concentration were correlated. Heart rate increased, but not in a dose-dependent fashion. We conclude that atriopeptin III is cleared from rat plasma rapidly and that the kidneys account for 59% of its elimination by degradation rather than excretion. Because the effect of atriopeptin III on blood pressure is concentration-dependent, the transient changes exerted by atriopeptin III may be related to its rapid disappearance from plasma.