Dependence of changes in the luliberin level in the synaptosomal fraction of the olfactory bulbs and various areas of the hypothalamus on the level of sexual activity in male rats

The paper is devoted to a study of the level of LH-RH in the synaptosomal fraction of the olfactory bulbs, preoptic area and mediobasal hypothalamus, and the blood level of HL in adult male rats with sexual activity after noradrenergic denervation of the preoptic area using 6-hydroxydopamine. A neurotoxic effect of 0.1% solution of ascorbic acid, preventing 6-hydroxydopamine disintegration, was noted. Both sexual activity and the level of LH-RH in synaptosomes of the preoptic area were lowered in male rats with noradrenergic denervation of the preoptic area. The maximum blood level of LH was observed during exposure to a recipient female rat. LH-RH concentration in the synaptosomal fraction of the olfactory bulbs being raised, that in the mediobasal hypothalamus lowered. The results were indicative of the involvement of HL-RH-synthesizing cerebral neurons with terminals in the olfactory bulbs, preoptic area and mediobasal hypothalamus in the regulation of sexual behavior, and the interaction of LH-RH-containing terminals with noradrenergic nerve endings at the level of the preoptic area.     

Hypertrophy in the denervated heart: a comparison of central sympatholytic treatment with 6-hydroxydopamine and peripheral sympathectomy with nerve growth factor antiserum.

The effects of widespread destruction of central catecholaminergic structures on systemic hemodynamics, ventricular performance, myocardial hypertrophy and the renin-angiotensin system in developing male spontaneously hypertensive rats of the Okamoto strain (SHR) and control normotensive Kyoto Wistar (WKY) rats were examined and contrasted with the effects of peripheral sympathectomy. Both centrally administered 6-hydroxydopamine (6-OHDA) and nerve growth factor antiserum (NGFAS) prevented the development of hypertension in the spontaneously hypertensive rats but did not affect blood pressure in the control rats. Peripheral vascular resistance remained elevated and cardiac and stroke indexes depressed in both 6-OHDA- and NGFAS-treated spontaneously hypertensive rats despite preservation of normal blood pressure. Ventricular performance was depressed in the sham-treated spontaneously hypertensive rats and was not improved by either treatment. Neither 6-OHDA nor NGFAS treatment prevented the development of left ventricular hypertrophy in the spontaneously hypertensive rats despite the decrease in blood pressure. Plasma renin activity was elevated in the 6-OHDA-treated spontaneously hypertensive rats compared with the sham-treated spontaneously hypertensive control rats but was unaffected by treatment with NGFAS.The data indicate that destruction of central and peripheral noradrenergic structures in the immature spontaneously hypertensive rats prevents the development of hypertension by different physiologic mechanisms but does not alter the suppressed ventricular function, the increased peripheral resistance or the development of myocardial hypertrophy. These results support the concept that increased sympathetic activity is necessary for the development of hypertension in spontaneously hypertensive rats but not for the development of myocardial dysfunction or hypertrophy.     

Neurotransmitter Release,Vascular Responsiveness and Their Suppression by Ca-Antagonist in Perfused Mesenteric Vasculature of Doca-Salt Hypertensive Rats

To investigate the role of norepinephrine release from the sympathetic nerve endings and vascular responsiveness in the pathogenesis of hypertension, the perfused mesenteric preparations were used in DOCA-salt hypertensive rats (acute phase: 10 days after operation, chronic phase: 7–8 weeks).

In addition, the effects of a Ca-antagonist (verapamil) on the norepinephrine release and vascular responsiveness were also examined.

Vasoconstrictor responses to the electrical nerve stimulation were significantly greater in DOCA-salt hypertension in the chronic phase than the age-matched normotensive controls. The pressor responses to exogenous norepinephrine were significantly enhanced in DOCA-salt hypertension both in acute and chronic phases.

Endogenous norepinephrine overflow from the sympathetic nerve endings during the electrical nerve stimulation was enhanced in the chronic phase of DOCA-salt hypertension, but not in the acute phase, compared with the age-matched normotensive controls.

After infusion of verapamil, the pressor responses and norepinephrine overflow by the electrical nerve stimulation were significantly inhibited, and the suppression was greater in chronic DOCA-salt hypertension than in the normotensive controls.

These results demonstrate that the vascular responsiveness was increased in both acute and chronic phases of DOCA-salt hypertensive rats, while the norepinephrine overflow from the adrenergic nerve terminals was enhanced only in the chronic phase. More marked inhibition of the vasoconstrictor responses and norepinephrine overflow in the presence of a Ca-antagonist in chronic DOCA-salt hypertension might represent the higher Ca-dependency in the neurotransmission of the peripheral resistance vessels, especially in the mechanism of presynaptic norepinephrine release, than their normotensive controls, and it could partly contribute to the development and maintenance of DOCA-salt hypertension.     

Blockade of steroid-induced leuteinizing hormone release by selective depletion of anterior hypothalamic norepinephrine activity.

Female Sprague-Dawley rats, weighing 200--225 g, were ovariectomized and, 10 days later, were given a single sc injection of 10 micrograms estradiol benzoate/100 g BW. Three days after estradiol benzoate treatment, animals received 50 micrograms progesterone (P)/100 g BW, resulting in a surge in LH release 7 and 9 h later. To determine the locus of the noradrenergic component of the P-induced LH surge, 6-hydroxydopamine (6-OH-DA), a neutrotoxin, was implanted into either the suprachiasmatic region or the median eminence (ME) 24 h before P administration. An implant of 6-OH-DA in the suprachiasmatic region decreased anterior hypothalamic norepinephrine concentration by 83%, anterior hypothalamic dopamine concentration by 24%, and eliminated the P-induced LH surge. ME implant of 6-OH-DA decreased norepinephrine concentration by 57% without affecting dopamine concentration, but was unable to alter the P. induced LH surge. These results indicate that the anterior hypothalamic noradrenergic system is necessary for the P-induced LH surge in ovariectomized rats and that noradrenergic nerve terminals in the ME are not involved in this process.     

Plasma catecholamines determination using high pressure liquid chromatography and their roles in blood pressure regulation and experimental hypertension in rats.

Plasma catecholamine levels have been used experiemtally and clinically as the indices of the sympathetic nerve activity. We measured plasma catecholamines using high pressure liquid chromatography in rats to assess the significance of plasma catecholamines as an index of the sympathetic nerve activity and its role in hypertension. Pentobarbital anesthesia depressed plasma catecholamine levels, especially plasma adrenaline. Sodium loading for 5 weeks suppressed plasma noradrenaline, while administration of furosemide (1 mg/kg) produced the elevation of plasma noradrenaline. Experimental hypertension, one-kidney and two-kidney types of Goldblatt hypertension and DOCA-salt hypertension, raised plasma noradrenalines both in acute and chronic phases. The infusion of pressor doses of angiotensin II suppressed plasma noradrenaline by the reflex mechanism. Sar1, Ile8-angiotensin II and SQ 14,225 did not suppress plasma cathecholamine elevation due to hemorrhage. L-Hydroxyldopamine produced elevation of plasma catecholamines in experimental nypertension and controls in rats. After adrenal demedullation, plasma noradrenaline was decreased by the administration of 6-hydroxy-dopamine. Acute reduction of circulating blood volume and blood pressure fall produced the elevation of plasma catecholamine, especially plasma adrenaline. In rats, the adrenal medulla plays an important role in the regulation of blood pressure.     

Stress-induced renin and corticosterone secretion is mediated by catecholaminergic nerve terminals in the hypothalamic paraventricular nucleus

Cell bodies in the hypothalamic paraventricular nucleus (PVN) mediate stress-induced increases in renin and corticosterone secretion. Since the PVN has an extensive catecholaminergic innervation, we wanted to determine the role of catecholamines in the neuroendocrine response to stress. The stressor was a conditioned emotional (fear) response paradigm (CER). The catecholamine neurotoxin, 6-hydroxydopamine (6-OHDA), was injected into the PVN 14 days before the rats were subjected to the CER procedure. Damage to noradrenergic nerve terminals was verified immunocytochemically, using an antibody against dopamine beta-hydroxylase. Injection of 6-OHDa into the PVN prevented the stress-induced increase in plasma renin activity (PRA), plasma renin concentration (PRC) and plasma corticosterone concentration, suggesting that intact catecholaminergic innervation of neurons in the PVN is necessary for the stress-induced increase in renin and corticosterone secretion. To determine if beta-adrenoceptors in the PVN mediate the effect of stress on renin and corticosterone secretion, the beta-adrenoceptor antagonist sotalol was injected into the PVN through chronically implanted bilateral cannulae. The injection was performed on the 4th day of the CER paradigm, just before the rats were placed into the CER chamber. Sotalol prevented the stress-induced increase in corticosterone concentration, but did not diminish the stress-induced increase in PRA and PRC. These results suggest that the stress-induced increase in corticosterone concentration is influenced by beta-adrenoceptors in the PVN. The stress-induced increase in PRA and PRC is mediated by different receptors whose ligands might be catecholamines acting at non-beta-receptors or other neuroactive substances colocalized in catecholaminergic nerve terminals.     

Axonal transport of noradrenaline and noradrenergic transmission in rats with streptozotocin-induced diabetes

Summary The accumulation of noradrenaline in constricted sciatic nerves was measured in 6 month diabetic rats (streptozotocin 35 mg/kg) and 4 day diabetic rats (streptozotocin 70 mg/kg) together with two groups of age-matched control animals. There was no alteration in the amount of noradrenaline accumulated in the nerves of the diabetic animals when compared with the controls. The vasa deferentia of the long-term diabetic animals showed an impaired response to stimulation of their noradrenergic nerves and a hypersensitivity to exogenous noradrenaline. These vasa were not wasted and showed a normal contractility in response to potassium chloride. Vasa deferentia from the short-term diabetic rats showed no abnormalities of function. Vasa deferentia from all groups of rats were also examined at the ultrastructural level. Specimens from all the chronically diabetic animals contained many abnormal nerve terminals. These lesions were not seen in vasa from the shortterm diabetic rats. Taken together these findings indicate that rats with chronic streptozotocin-induced diabetes exhibit pathological changes in the noradrenergic nerves supplying the vas deferens. These animals do not, however, show an impairment of the axonal transport of noradrenaline.     

Re-expression of alpha skeletal actin and regulation of alpha 1 adrenoceptor signalling in DOCA-salt hypertension in rats.

OBJECTIVE: To determine the effects of increased sympathetic nervous system activity in humoral hypertension on the regulation of surface alpha 1 adrenoceptors and signal transduction, deoxycorticosterone acetate (DOCA) salt hypertension was induced in rats and the animals killed three weeks following the initiation of hypertension. METHODS: Experiments were performed on male Sprague-Dawley rats, weighing 250-300 g, divided into two groups: DOCA-salt (n = 75), and control (n = 60). Radioligand binding studies of the alpha 1 adrenoceptors, noradrenaline stimulated phosphoinositol turnover, ADP ribosylation of 41 kD substrate by pertussis toxin, and myocardial noradrenaline content were measured in the ventricular myocardium. The expression of sarcomeric actin isoforms was examined by northern blot and hybridisation with specific oligonucleotide probes. RESULTS: The density of alpha 1 adrenoceptors was decreased by 51% in DOCA-salt treated rats. However, noradrenaline stimulated phosphoinositol turnover in myocytes from DOCA-salt hearts was not diminished. The relative quantities of pertussis toxin labelled substrates did not differ in experimental and control hearts. Myocardial noradrenaline content was reduced by 60% in DOCA-salt hearts. Northern blots on RNA extracted from hypertrophic hearts of DOCA-salt treated rats showed an upregulation of alpha skeletal actin. CONCLUSIONS: The adrenergic state present in short term DOCA-salt hypertensive hypertrophy is characterised by enhanced signal transduction via the alpha 1 adrenoceptors and the re-expression of alpha skeletal actin in enlarging myocytes.     

Attenuated cardiovascular and sympathetic nerve responses to aortic nerve stimulation in DOCA-salt hypertensive rats

In order to verify, whether baroreflex sensitivity is changed centrally in DOCA-salt hypertension, the left aortic depressor nerve (ADN) was electrically stimulated in DOCA-salt hypertensive rats. After 3 weeks, tail-cuff systolic pressure was significantly higher in DOCA-salt treated rats than in untreated rats (169 +/- 4 versus 130 +/- 4 mmHg, respectively; P less than 0.001). After cutting both ADN and the carotid sinus nerves, the central cut end of the left ADN was electrically stimulated and frequency dependent depressor, bradycardic and sympatho-inhibitory responses were elicited in both control and DOCA-salt hypertensive rats. However, these responses were significantly smaller in DOCA-salt hypertensive rats than in normotensive controls. Bradycardic and sympatho-inhibitory responses to i.v. injection of norepinephrine were also blunted in DOCA-salt hypertensive rats. These findings suggest that baroreflexes were centrally attenuated in DOCA-salt hypertensive rats and possibly contribute to overall baroreflex attenuation.     

Blockade of angiotensin receptors in the anterior hypothalamic preoptic area lowers blood pressure in DOCA-salt hypertensive rats.

It has been established that deoxycorticosterone acetate (DOCA)-salt hypertensive rats have an overactive brain angiotensin-system. The purpose of the present study was to identify the brain sites showing enhanced angiotensin-system activity responsible for the pathogenesis of hypertension in DOCA-salt hypertensive rats. The angiotensin receptor antagonist, losartan, was injected into brain ventricles or into tissues around the rostral parts of the third ventricle in conscious DOCA-salt hypertensive rats. Losartan (1 microg) injection into the lateral ventricle or into the rostral parts of the third ventricle produced a depressor response, whereas the agent did not affect blood pressure when injected into the caudal parts of the third ventricle or into the fourth ventricle. Losartan (0.1 microg) injection into the anterior hypothalamic preoptic area, anterior (AHA) produced a depressor response. Angiotensin II (0.1-1 ng) injection into the AHA produced a pressor response in sham-operated and DOCA-salt hypertensive rats, and the pressor response to angiotensin II (1 ng) was greater in DOCA-salt hypertensive rats than that in sham-operated rats. Release of angiotensin peptides in the AHA was greater in DOCA-salt hypertensive rats than that in sham-operated rats. These findings suggest that the angiotensin-system in the AHA is enhanced, and that this enhancement is involved in the maintenance of hypertension in DOCA-salt hypertensive rats. Both increased pressor reactivity to angiotensin II and increased release of angiotensin peptides in the AHA appear to be related to this enhancement of the angiotensin-system in DOCA-salt hypertensive rats.     

Selected Abstracts

The bilateral destruction of the ventral noradrenergic pathway induced by 6-hydroxydopamine (6-OHDA) administration into the ventral pons led to an increase in arterial blood pressure (ABP) and norepinephrine depletion in the amygdaloid complex, nucleus accumbens, septal area and olfactory bulb. Specific angiotensin converting enzyme (ACE) activity was significantly increased only in the amygdaloid complex (Control: 4.56 ± 0.95; Vehicle: 4.08 ± 1.07; 6-OHDA: 11.76 ± 1.84). A significant correlation between arterial blood pressure and specific ACE activity levels in the amygdaloid complex was observed (r: 0.775; p < 0.002). These results suggest that an increase in specific ACE activity of the amygdaloid complex after norepinephrine depletion could play a role in the development of hypertension in this model.     

Inhibition of norepinephrine release by presynaptic alpha 2-adrenoceptors in mesenteric vasculature preparations from chronic DOCA-salt hypertensive rats

This study investigated norepinephrine release during electrical nerve stimulation and inhibitory characteristics of presynaptic alpha 2-adrenoceptors in perfused mesenteric vasculature from deoxycorticosterone acetate (DOCA)-salt hypertensive rats (7-8 weeks after surgery). Electrical stimulation of sympathetic innervation caused a significantly greater release of endogenous norepinephrine into the mesenteric vasculature of DOCA-salt hypertensive rats than in age-matched normotensive controls. Pressor responses to electrical nerve stimulation were also enhanced in DOCA-salt hypertension. Yohimbine, a potent alpha 2-adrenoceptor blocking agent, potentiated the stimulation-evoked release of norepinephrine into the vasculature in normotensive rats. This effect was blunted in DOCA-salt hypertension. These results suggest that increased norepinephrine release from the sympathetic nerve endings in DOCA-salt hypertension might partly reflect an impaired presynaptic alpha 2-adrenoceptor-mediated inhibition, which could enhance vascular sympathetic tone in this model of hypertension.     

Adrenergic regulation of clock gene expression in mouse liver

A main oscillator in the suprachiasmatic nucleus (SCN) conveys circadian information to the peripheral clock systems for the regulation of fundamental physiological functions. Although polysynaptic autonomic neural pathways between the SCN and the liver were observed in rats, whether activation of the sympathetic nervous system entrains clock gene expression in the liver has yet to be understood. To assess sympathetic innervation from the SCN to liver tissue, we investigated whether injection of adrenaline/noradrenaline (epinephrine/norepinephrine) or sympathetic nerve stimulation could induce mPer gene expression in mouse liver. Acute administration of adrenaline or noradrenaline increased mPer1 but not mPer2 expression in the liver of mice in vivo and in hepatic slices in vitro. Electrical stimulation of the sympathetic nerves or adrenaline injection caused an elevation of bioluminescence in the liver area of transgenic mice carrying mPer1 promoter-luciferase. Under a light-dark cycle, destruction of the SCN flattened the daily rhythms of not only mPer1, mPer2, and mBmal1 genes but also noradrenaline content in the liver. Daily injection of adrenaline, administered at a fixed time for 6 days, recovered oscillations of mPer2 and mBmal1 gene expression in the liver of mice with SCN lesion on day 7. Sympathetic nerve denervation by 6-hydroxydopamine flattened the daily rhythm of mPer1 and mPer2 gene expression. Thus, on the basis of the present results, activation of the sympathetic nerves through noradrenaline and/or adrenaline release was a factor controlling the peripheral clock.     

Naloxone Attenuates Development of Hypertension in DOCA-Salt Hypertensive Rats

The effects of naloxone on the development of hypertension were studied in unilaterally nephrectomized rats implanted with deoxycorticosterone acetate (DOCA; 200 mg/kg) and given saline to drink. Intraperitoneal (i.p.) infusion of naloxone at 150 μg/hr significantly lowered systolic blood pressure (SBP) compared to rats not receiving naloxone, (135 ± 4.4 vs 158 ± 5.9 mmHg on day 16). IP infusion of naloxone at 300 μg/hr produced the same reductions of SBP as that at 150 μg/hr in DOCA-salt treated rats. In other experiments intracerebroventricular (i.c.v.) infusion of naloxone at 7 μg/hr also significantly attenuated the DOCA-salt hypertension. The same dose given i.p. had no effect on the development of hypertension. Naloxone had no effect on plasma renin activity (PRA), plasma atrial natriuretic peptide (ANP), or concentrations of Na⁺ and K⁺ in plasma. The present data demonstrate that naloxone significantly attenuates the development of hypertension in rats given DOCA and fed a high salt diet. The attenuation of blood pressure could not be associated with the changes in PRA or plasma ANP. These results imply that the central opiate receptors play an important role in the pathogenesis of this model of hypertension.     

Central and peripheral adrenergic mechanisms in the development of deoxycorticosterone-saline hypertension in rats.

The role of the sympathetic nervous system in the development of deoxycorticosterone-sodium chloride (DOCA-saline) hypertension was investigated by measuring plasma levels of norepinephrine, total catecholamines, and dopamine-beta-hydroxylase activity at intervals after the initiation of the DOCA-saline regimen. Plasma norepinephrine was significantly higher in DOCA-saline-treated rats at 4 and 7 weeks and in rats treated with saline alone at 4 weeks compared with that in untreated controls. Total plasma catecholamine levels (epinephrine and norepinephrine) and dopamine-beta-hydroxylase activity were similar in hypertensive rats, untreated controls, and rats that received either DOCA or saline alone. The increases in plasma norepinephrine levels may have resulted from centrally mediated increases in peripheral sympathetic neuronal activity, since the destruction of central catecholaminergic neurons with intracerebroventricularly administered 6-hydroxydopamine (6-OHDA) prevented both the DOCA-saline-induced rise in blood pressure and the increases in plasma norepinephrine. Rats treated with 6-OHDA consistently drank less water or saline than did vehicle-treated controls. The actions of centrally administered 6-OHDA on blood pressure and plasma norepinephrine levels were not secondary to a reduction in salt intake, however, since intact rats given a similar reduced saline intake became hypertensive and demonstrated elevated plasma norepinephrine concentrations. Chronic salt loading may cause a centrally mediated increase in peripheral sympathetic neuronal activity with raised plasma concentrations of norepinephrine. The increased adrenergic activity in the presence of mineralocorticoid-induced sodium retention leads to the development of hypertension.     

Changes in Aortic Water and Sodium Contents Associated with Potassium Supplement in Doca-Salt Rats

Since waterlogging, increased vascular water and sodium contents, could contribute to the development of deoxycorticosterone acetate (DOCA)-salt hypertension, we have examined the effect of dietary potassium supplementation on the water and sodium contents of abdominal aorta after short-term (one week) treatment with DOCA while receiving a 1% NaCl solution to drink. Supplementation with 1% KCl solution could counteract blood-pressure rising action of DOCA-salt, associated with the inhibition of sodium retention. In addition, treatment with DOCA-salt was associated with increases in water (83.1±3.0%) wet weight) and sodium (118.7±2.8 μEq/g dry weight) contents of the aorta compared with those of the control rats (69.7±0.3%) wet weight and 103.0±4.0 μEq/g dry weight, respectively). In contrast, 1% KCl supplementation could attenuate the increase in water (73.2±1.5% wet weight) and sodium (110.3±2.3 μEq/g dry weight) contents of the aorta in DOCA-salt rats. Taken together, these results suggest that potassium supplement not only attenuates the sodium retention but also moderates the “waterlogging” in the vascular wall in DOCA-salt rats, thus leading to the antihypertensive action of potassium supplement in the early stage of DOCA-salt hypertension     

Inhibition of rat liver fibrogenesis through noradrenergic antagonism

The effect of adrenergic innervation and/or circulating catecholamines on the function of liver fibrogenic cells is poorly understood. Our aim was to investigate the effects of noradrenergic antagonism on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Two weeks of CCl4 induced an approximately 5-fold increase in the area of fibrosis as compared with controls. The addition of 6-hydroxydopamine (OHDA), a toxin that destroys noradrenergic fibers, decreased fibrosis by 60%. After 6 weeks of CCl4, the area of fibrosis increased about 30-fold in CCl4-treated animals and was decreased by 36% with OHDA. At 2 weeks, OHDA abrogated the CCl4-induced increase in mRNA level of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), an inhibitor of extracellular matrix degradation, and it greatly reduced it at 6 weeks. Finally, when rats treated with CCl4 for 2 weeks also received prazosin, an antagonist of alpha1-adrenergic receptors, fibrosis was decreased by 83%. In conclusion, destruction of noradrenergic fibers or antagonism of noradrenergic signaling through alpha1 receptors inhibited the development of liver fibrosis. Because adrenoreceptor antagonists have a very sound safety profile, they appear as attractive drugs to reduce liver fibrogenesis.     

Estrogen Metabolite 2-methoxyestradiol Prevents Hypertension in Deoxycorticosterone Acetate-salt Rats

Purpose

Our early work showed that the estrogen metabolite 2-methoxyestradiol (2ME) inhibits proliferation of vascular smooth muscle cells (SMCs) and vascular contractility through an endothelium-dependent mechanism. The aim of this study was to examine whether 2ME prevents the development of hypertension in rats.

Methods

A hypertensive model was established in uninephrectomized rats using deoxycorticosterone acetate (DOCA)-salt. Blood pressure in response to 2ME (treatment up to 10 weeks or single bolus) was monitored.

Results

Our results showed that systolic blood pressure, as measured by tail-cuff plethysmography, was significantly increased in conscious rats treated with DOCA-salt for 3–10 weeks. Co-treatment with 2ME (100–300 μg/kg), but not dimethyl sulfoxide (DMSO), completely prevented the increase in blood pressure of DOCA-salt rats. After 10-week treatment, the mean arterial blood pressure (MABP) of anesthetized rats measured using PowerLab Data Acquisition System was: 84?±?16 mmHg in normotensive control rats and 150?±?9 mmHg in DOCA-salt rats, which was similar to that of DMSO-treated rats. Treatment with 2ME at low or high doses reduced MABP of DOCA-salt rats close to that of control normotensive rats. In addition, MABP of hypertensive DOCA-salt rats was significantly reduced in response to a single injection of 2ME. Delayed administration of 2ME reduced the further increase of blood pressure in DOCA-salt rats. However, inhibition of 2ME production by entacapone did not significantly affect blood pressure in either control or DOCA-salt rats.

Conclusions

2ME treatment prevents the development of hypertension in DOCA-salt rats, implicating a therapeutic potential of 2ME in hypertension treatment.     

The effects of long term oral treatment with indapamide on the development of DOCA-salt hypertension in rats: vascular reactivity studies

The onset of DOCA-salt hypertension in male Sprague-Dawley rats was prevented during 11 weeks of oral treatment with indapamide (0.5, or 10.0 mg/kg) or propranolol (60 mg/kg) administered in the diet. The body weights of the indapamide treated groups were significantly (P < 0.01) greater, at weeks 4, 5, 6, 7 and 11, while the body weights and food intake of the propranolol treated group were significantly (P < 0.05) lower at week 11, than the control group. A significant reduction in heart wet weight (P < 0.001) was measured in the indapamide treated animals only. No significant diuresis nor natriuresis was measured in any group during week 11 of treatment. When all groups were subjected to an increased salt load, four weeks after cessation of drug treatment only the indapamide (10 mg/kg) treated animals failed to show an increased blood pressure. Vascular reactivity studies carried out six weeks after termination of drug treatment, indicated a significant (P < 0.01) reduction in pressor activity elicited by electrical stimulation of the entire sympathetic outflow in indapamide (10 mg/kg) treated pithed rats. No significant difference in the pressor activity elicited by noradrenaline (5 x 10(-8) - 5 x 10(-6) g/kg, i.v.) or tyramine (10(-5) - 5 x 10(-5) g/kg i.v.) was observed in any treatment group. In conclusion, chronic oral treatment with indapamide or propranolol, prevented the onset of DOCA-salt hypertension in rats. A long lasting antihypertensive action of indapamide involving the sympathetic nervous system is also indicated.     

Experimental central hypertension produced by chemical degeneration of the locus coeruleus in the rat.

The role of noradrenergic neurons originating from the locus coeruleus (LC) in blood pressure regulation was studied by stereotaxic administration of 6-hydroxydopamine (6-OHDA) into the LC in Wistar-Kyoto rats. The administration of 6-OHDA (12 micrograms/6 microliters) into the bilateral LC resulted in hypertension and tachycardia, which lasted for 12 days and gradually returned to the levels observed before administration. The systolic blood pressure and heart rate were 172 mmHg and 460 beats/min on the mean respectively, one day after administration. The induced hypertension and tachycardia were closely correlated with the depletion of norepinephrine (NE) content in the cortex and the medulla-pons in rats in a hypertensive state. The correlation between the NE content of the cortex and blood pressure was particularly marked (r = -0.793, p less than 0.02). Furthermore, destructive change of the LC was observed histologically in the hypertensive rats. They hypertension was completely prevented by pretreatment with desipramine before 6-OHDA administration. These findings suggest that 6-OHDA induced degeneration, probably mainly in the dorsal bundle originating from the LC and in the LC itself. It is suggested, therefore, that localized chemical degeneration of the bilateral LC causes hypertension and tachycardia as a consequence of denervation of the dorsal bundle of noradrenergic neurons originating from the LC.