Angiotensin facilitation of 3H-norepinephrine release in central tissue of spontaneously hypertensive rats but not in Wistar-Kyoto rats: effects of sodium depletion

The purpose of the present study was to determine the ability of angiotensin II to facilitate the field stimulation-induced release of 3H-norepinephrine from brain areas of three ages of normal or salt-restricted spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Angiotensin II facilitated the stimulation-induced release of 3H-norepinephrine from the anterior hypothalamus of 5-6, 10-11, and 28-30 week-old SHR but not age-matched WKY. Angiotensin II failed to alter 3H-norepinephrine release in the A2 region of the nucleus tractus solitarius of either SHR or WKY, at all ages tested. Placement of rats on a sodium-restricted diet for 7 days abolished the facilitation of induced 3H-norepinephrine release by angiotensin, seen in the SHR at 5-6 and 10-11 weeks, but not that at 28-30 weeks. These results suggest that angiotensin II can facilitate noradrenergic release in the anterior hypothalamus of SHR but not WKY. This facilitation by angiotensin II in SHR can be altered by placement of the rats (5-6, 10-11 week-old) on a sodium-restricted diet.     

Effects of calcitonin gene-related peptide on [3H]norepinephrine release in medulla oblongata of spontaneously hypertensive rats

We now describe the effects of calcitonin gene-related peptide (CGRP) on [3H]norepinephrine (NE) release in medulla oblongata of spontaneously hypertensive rats (SHR). CGRP inhibited stimulation-evoked [3H]NE release in a dose-dependent manner in Sprague-Dawley rats, although the basal release of [3H]NE was not affected by the peptide. In SHR, the inhibitory effect of CGRP on stimulation-evoked [3H]NE release was significantly attenuated compared with Wistar Kyoto rats. These results suggest that CGRP might be involved in the regulation of central sympathetic nervous activity in hypertension.     

Effect of tissue norepinephrine depletion by 6-hydroxydopamine on blood pressure in spontaneously hypertensive rats

Blood pressure was studied in normotensive and spontaneously hypertensive rats (SHR) in which catecholamine depletion had been produced by 6-hydroxydopamine. After i.v. administration of 80–200 mg/kg 6-hydroxydopamine, norepinephrine (NE) levels in heart, spleen, and kidney were markedly reduced (14–66% of control value) while brain NE remained unchanged. These doses did not affect development of hypertension in SHR or the blood pressure in normotensive control rats during a 20 day period of study. A transient decrease of blood pressure was observed acutely (1–3 days) after an 80 mg/kg dose in normotensive and hypertensive animals. Depletion of NE in the brainstem (to 33–42% of control value) after intraventricular injection of 6-hydroxydopamine, 50–300 μg, had no effect on blood pressure of SHR and normotensive rats. It is concluded that only a small portion of tissue NE content is sufficient for development and maintenance of hypertension in the SHR.     

Effects of adenosine on [3H]norepinephrine release from perfused mesenteric arteries of SHR and renal hypertensive rats

Adenosine (10-30 microM) inhibited the 3H-efflux evoked by sympathetic nerve stimulation in the perfused rat mesenteric arteries preincubated with [3H]norepinephrine. The inhibition was smaller in the prehypertensive (5 weeks old) as well as hypertensive (15-18 weeks) SHR (spontaneously hypertensive rats), compared with age-matched normotensive Wistar Kyoto rats. However, it was not diminished in Wistar rats rendered hypertensive by left renal artery occlusion. Thus, a diminished adenosine-mediated presynaptic inhibition of adrenergic transmission appears to be genetically inherent in SHR.     

Effects of verapamil on [3H]acetylcholine release in the striatum of spontaneously hypertensive rats.

In the present study, we describe the effects of Ca2+ channel antagonist (verapamil) on [3H]acetylcholine (ACh) release in the central nervous system of spontaneously hypertensive rats (SHR). The electrically stimulated release of [3H]ACh from striatal slices was not different between SHR and normotensive Wistar Kyoto (WKY) rats. Verapamil inhibited electrically stimulated [3H]ACh release in a dose-related fashion. The inhibitory effect of verapamil was significantly greater in SHR than in WKY rats. These results suggest that the Ca2+ sensitivity of central cholinergic neurons might be enhanced in SHR, which could attribute, at least partially, to the pathogenesis of hypertension.     

Age-related changes of norepinephrine content in kidneys of spontaneously hypertensive and Wistar-Kyoto rats

Renal norepinephrine (NE) content was determined during the development of spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) rats in an attempt to correlate biochemical changes with the reported functional changes occurring in hypertension development in the SHR. In contrast to WKY rats, in which the levels of NE remained relatively constant with age, renal NE content in the SHR was highest at the 4th week of age, decreasing transiently during the 5th, 6th, and 7th weeks, and then again reaching a plateau during the 8th week. The fall in NE content in the kidney is associated with a rise in blood pressure with age in SHR and suggests a relationship between NE levels and hypertension.     

Effect of hypothalamic stimulation in spontaneously hypertensive and Wistar-Kyoto rats

This study was undertaken to determine if central nervous system differences in blood pressure regulation exist between spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls. Central control mechanisms were examined by observing the effects of posterior hypothalamic (PH) stimulation upon preganglionic sympathetic activity in 14–18 week old SHR and WKY rats. A bipolar, concentric electrode was stereotaxically placed in the PH. Stimulation was delivered at 20, 60 and 100 Hz (3-sec duration, 0.1 msec pulse width) at a voltage twice that producing an increase in blood pressure (? 5 mm Hg) at 60 Hz. Sympathetic activity was recorded from a portion of the splanchnic nerve just distal to the diaphragm. Blood pressure was measuredfrom a femoral artery catherer. SHR responded with greater increases in symphathetic activity than WKY; the differences were statistically significant at 60 and 100 Hz. SHR also responded with significantly greater increases in blood pressure at all frequencies of stimulation. To determine if the enhanced sympathetic response to PH stimulation seen in adult SHR is an intrinsic difference rather than secondary to sustained hypertension, we maintained SHR normotensive from four weeks of age with antihypertensive drug therapy (clonidine or hydralazine). Chronically treated animals were then tested at 14–18 weeks of age while on antihypertensives of four days after drug discontinuance. Sympathetic and blood pressure responses to PH stimulation were significantly greater in SHR maintained normotensive than untreated or chronically treated WKY. These data support the concept that a central factor is involved in the etiology of hypertension in the SHR.     

Effect of soman on N-methyl-d-aspartate-stimulated [3H]norepinephrine release from rat cortical slices

Effects of soman on N-methyl-d-aspartate (NMDA) evoked [³H]norepinephrine (NE) release were examined in rat brain cortical slices. NMDA increased [³H]NE release in a concentration-dependent manner. Soman could inhibit the increase evoked by NMDA, but carbachol, an agonist of cholinergic receptor, could potentiate the increase evoked by NMDA. Atropine (a selective muscarinic antagonist) attenuated the release of [³H]NE induced by NMDA in the presence of carbachol or acetylcholine (ACh), but had no effect on the release of [³H]NE induced by NMDA alone. Both d-tubocurarine (an antagonist of nicotinic receptor) and atropine had no effect on the release of [³H]NE induced by NMDA in the presence of soman. These results suggested that soman has a direct action at non-cholinergic sites, probably at NMDA receptors.     

Effects of verapamil on [3H]norepinephrine release

If calcium entry blocking drugs affect norepinephrine release, this may alter their cardiovascular action by modifying the activity of baroreceptor reflexes. We investigated the effect of verapamil on 3H-release in [3H]norepinephrine-incubated rat arteries and guinea pig vas deferens. Superfusion of tail artery with verapamil (10(-6) - 10(-4) M) increased the 3H-overflow induced by transmural stimulation (1 Hz, 2 ms, 10 V) both in Wistar Kyoto and in spontaneously hypertensive rats. The effect was present also in vessels pretreated with cocaine to inhibit neuronal uptake or with yohimbine to block alpha 2-adrenoceptors. The greatest increase in 3H-overflow--around 400% in the various groups--was observed after perfusion with 10(-4) M verapamil. In other experiments, we found that verapamil also enhanced 3H-overflow from vessels not stimulated transmurally; this effect again was dose-related (p less than 0.001). In the vas deferens of the guinea pig, 10(-5) M verapamil increased spontaneous and electrical stimulation-induced 3H-release (p less than 0.001), whereas superfusion of the tissue with 10(-9) and 10(-7) M verapamil was ineffective. The results indicate that verapamil can act on sympathetic nerves to release norepinephrine.     

Effects of Bay K 8644, a Ca2+ channel agonist, on [3H]norepinephrine release in hypothalamus of spontaneously hypertensive rats.

We describe the effects of Bay K 8644, a dihydropyridine-sensitive Ca2+ channel agonist, on [3H]norepinephrine (NE) release from the hypothalamus of spontaneously hypertensive rats (SHR). The electrical stimulation-evoked [3H]NE release was greater in hypothalamic slice of SHR than in those of Wistar Kyoto (WKY) rats. Bay K 8644 (10(-6) M) significantly increased the stimulation-evoked [3H]NE release in SHR. However, the agonist showed no significant effects in normotensive WKY rats. The results suggest that the dihydropyridine-sensitive Ca2+ channels might participate actively in the regulation of the central sympathetic tone of hypertension.     

Effect of mono- and diaminopyridines on release of [3H]norepinephrine from isolated guinea-pig atrium

Neurochemical evidence has been obtained that 4-aminopyridine, 3,4-diaminopyridine and 3,3-dimethyl-1-(4-amino-3-pyridyl)urea HBr (LF-14), concentration-dependently enhanced the stimulation-evoked release of [3H]norepinephrine ([3H]NE) from isolated guinea-pig atrium. The effects of aminopyridines, compounds known to inhibit potassium channels, were Ca0-dependent. High pressure liquid chromatography, combined with radiochemical detection, indicated that the increased stimulated release of radioactivity was due to [3H]NE. Since the aminopyridines studied also enhanced the release of [3H]NE from atrium treated with cocaine, a blocker of uptake1, it seems likely that the increased release of NE caused by the aminopyridines is due to the enhanced release of NE from sympathetic axon terminals and not to the inhibition of reuptake. It is probable that the sympathomimetic cardiac effects (positive inotropic and chronotropic effect) of aminopyridines observed in animal experiments is due to the increased release of NE, caused by these compounds.     

Capsaicin treatment in adult Wistar-Kyoto and spontaneously hypertensive rats: effects on substance P contents of peripheral and central nervous system tissues

The effects of s.c. capsaicin treatment on the contents of immunoreactive substance P (ISP) in several peripheral and central nervous system tissues were examined in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Significant differences between vehicle-treated subjects of the WKY and SHR strains were observed in the ISP contents of both superior cervical and celiac sympathetic ganglia. Capsaicin pretreatment significantly reduced the ISP contents of both sympathetic ganglia in both strains. Capsaicin pretreatment significantly elevated the ISP contents of adrenal medullae only in rats of the SHR strain. The effects of s.c. capsaicin administration on the ISP contents of several selected isolated brain nuclei were also examined. No statistically significant strain or treatment differences in the SIP contents of the nucleus tractus solitarii nucleus locus ceruleus and periaqueductal central gray were observed. The ISP contents of the nucleus raphe magnus, periventricular preoptic area, and nucleus amygdaloideus medialis were significantly greater in vehicle-treated SHR rats than in vehicle-treated WKY animals. Capsaicin pretreatment significantly increased the ISP contents of both the periventricular preoptic area and nucleus amygdaloideus medialis in SHR rats. These results indicate that the effects of capsaicin treatment of the ISP contents of nervous systems tissues vary with both the tissues examined and the strain of rat. In addition, the previously reported long-lasting hypotensive effect produced by capsaicin in both the WKY and SHR strains may be related to the significant depletion of the ISP contents in peripheral sympathetic ganglia in both strains.     

3H-norepinephrine release in caudal artery of spontaneously hypertensive and Wistar-Kyoto rats: effects of altered salt diets.

The potassium-induced release of 3H-norepinephrine (3H-NE) was examined in the rat caudal artery. A simple and reliable method was developed to examine stimulated neurotransmitter release from this highly innervated resistance vessel. The potassium-induced release of 3H-NE was dose- and calcium-dependent. Stimulated 3H-NE release was elevated in the spontaneously hypertensive (SHR) compared to age-matched Wistar-Kyoto (WKY) animals (p less than 0.05). However, in animals at 5-6 weeks of age, where the blood pressure was not different between the SHR and WKY, the stimulation-induced release of 3H-NE was also not significantly different. Low salt diets for 7 days significantly decreased the potassium-induced release of 3H-NE from both 10- to 11-week-old SHR and WKY animals. High salt diets did not significantly effect 3H-NE release, even though the high salt diets for 7 days significantly increased the blood pressure in the SHR. The results suggest that the caudal artery is a good model to study stimulation-induced transmitter release and that elevated 3H-NE release plays a role in the development of hypertension in the SHR. Low salt diets, which did not lower blood pressure, were shown to decrease 3H-NE release. High salt diets elevated the blood pressure in the SHR but had no significant effect on stimulated 3H-NE release.     

Effects of neuropeptide Y on norepinephrine release in hypothalamic slices of spontaneously hypertensive rats

We describe the effects of neuropeptide Y (NPY) on [3H]norepinephrine (NE) release from hypothalamic slices of spontaneously hypertensive rats (SHR). The electrical stimulation (1 Hz)-evoked [3H]NE release was significantly greater in hypothalamic slices of SHR than in those of Wistar Kyoto rats (WKY). NPY inhibited the stimulation-evoked [3H]NE release in a dose-dependent manner. The inhibitory effect of NPY was significantly attenuated in SHR compared with WKY. The results may indicate that the less inhibitory effect of NPY on NE release induces increased sympathetic nerve activity in the hypothalamus of SHR.     

Enhanced nicotinic acetylcholine receptor-mediated [3H]norepinephrine release from neonatal rat hypothalamus

Nicotinic acetylcholine receptor (nAChR)-evoked release of norepinephrine (NE) has been demonstrated in a number of brain regions that receive sole noradrenergic innervation from the locus coeruleus (LC). Many of these structures display enhanced nicotine-stimulated NE release in the neonate. We have examined the hypothalamus in order to determine if this region, which receives NE projections from both the LC and medullary catecholaminergic nuclei, also demonstrates maturational changes in nAChR-mediated NE release. Quantification of radiolabeled-NE release from rat hypothalamus slices by a maximally effective dose of nicotine revealed a peak response during the first postnatal week. This was followed by a decrease at postnatal day (P) 14, and a second peak at P21. Thereafter, release was equivalent to that observed at P14. Comparison of the pharmacological properties of nAChRs mediating NE release in neonatal (P7) and mature hypothalamus suggested involvement of different nAChR subtypes at the two ages. Using the selective toxin, DSP-4, nAChR-mediated NE release in the neonatal hypothalamus was shown to be from LC terminals. Our findings demonstrate an early sensitivity of hypothalamic LC terminals to nAChR regulation that may be associated with development of systems controlling critical homeostatic functions such as stress, feeding and cardiovascular regulation.     

Effect of cyclo(leucyl-glycine) on [3H]spiroperidol binding in the corpus striatum and hypothalamus of spontaneously hypertensive rats

These experiments were performed to detect changes in renal function produced by acute infusions of small amounts of ethanol into the isolated kidney of the rat. Ethanol was infused for 10 min beginning at 40 min to reach a final concentration of approximately 80 mg/100 ml in the recirculating perfusate. Control kidneys were perfused for 90 min without the addition of ethanol. Control and ethanol infused kidneys were compared with respect to the following measurements: glomerular filtration rate, urine volume, urine protein concentration, pressure and fractional excretion of sodium, chloride, potassium, calcium and magnesium. Ethanol concentration in the perfusate was measured by gas chromatography. The only parameter affected by these concentrations of ethanol was pressure. During the ten min ethanol infusion, the pressure in the system rose significantly (P less than 0.01) from 110 +/- 0.3 to 120 +/- 2.8 mmHg. After the ethanol infusion, the pressure decreased towards pre-ethanol levels at a faster rate than the decrease in ethanol concentration in the perfusate.     

阿片受体在自发性高血压大鼠和正常大鼠中的不同分布(英文)

目的:比较16周自发性高血压大鼠(SHR)和对照组Wistar-Kyoto(WKY)大鼠中枢神经系统中与血压调节有关的核团内阿片受体密度的变化.方法:用放射自显影方法,运用氚标依托啡作配基检测阿片受体的分布. 结果:在海马(P<0.01)、中央灰质、孤束核、胸髓(P<0.05)几处,SHR阿片受体密度较WKY大鼠低;而在杏仁核(P<0.01)、僵核(P<0.05)和下丘脑核群包括弓状核(P<0.01),SHR却有较高的阿片受体密度. 结论:不同分布的阿片受体与自发性高血压大鼠的血压有关.     

Stimulation of [3H]norepinephrine release from hippocampal slices by excitatory amino acids

[3H]norepinephrine efflux from preloaded rat hippocampal slices was increased in a dose-dependent manner by excitatory amino acids (EAA) in the following potency order: N-methyl-D-aspartic acid (NMDA) greater than kainic acid greater than L-glutamic acid greater than or equal to D,L-homocysteic acid greater than L-aspartic acid greater than quinolinic acid greater than quisqualic acid. The effect of EAA was blocked by physiological concentration of Mg2+, with the exception of kainic acid. D,L-2-amino-7-phosphonoheptanoic acid (APH) dose-dependently inhibited NMDA effect (IC50 = 69 mumol/L), whereas at 1 mmol/L it was ineffective versus kainic acid. The release of [3H]norepinephrine induced by quinolinic acid was blocked by APH 0.1 mmol/L. gamma-D-glutamylglycine dose-dependently inhibited kainic acid effect with an IC50 = 1.15 mmol/L. Tetrodotoxin 2 mumol/L reduced NMDA and kainic acid effects by 40 and 20%, respectively. The data indicate a possible involvement of central noradrenergic system in the modulation of excitotoxic action of EAA and offer a reliable system for testing new compounds acting at EAA-receptors by measuring norepinephrine release in vitro.