Effects of anti-androgen treatment on the catecholamine synthetic pathway in the adrenal medulla of spontaneously hypertensive rats

We investigated the effects of the antiandrogen flutamide on the activity of tyrosine hydroxylase, the levels of its encoding mRNA, and catecholamine levels in the adrenal medulla of male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Flutamide (30 mg/kg) was administered subcutaneously daily (between 9 and 15 weeks of age). The systolic blood pressure of flutamide-treated SHR rats was lower than that of control SHR. Epinephrine and norepinephrine levels, tyrosine hydroxylase activity, and the levels of encoding mRNA in the adrenal medulla were significantly lower in flutamide-treated SHR rats than in paired controls. Systolic blood pressure, epinephrine and norepinephrine levels, tyrosine hydroxylase activity, and encoding mRNA in the adrenal medulla of WKY rats showed no significant differences between flutamide-treated and control groups. These findings suggested that flutamide may have cardiovascular effects through alteration of the catecholamine synthetic pathway caused by removal of androgen receptor stimulation on the expression of tyrosine hydroxylase in the adrenal medulla of male SHR rats. Received: 12 January 1998 / Accepted: 2 April 1998     

Adrenomedullary and beta-adrenergic participation in enhanced sympathetic pressor responses of spontaneously hypertensive rats

The beta-adrenergic and adrenomedullary components of pressor responses to sympathetic nerve stimulation were studied in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). The effects of electrical stimulation of the entire spinal cord of pithed rats pretreated with tubocurarine and atropine were studied on systolic blood pressure, heart rate and plasma cyclic AMP levels. The heart rate increase upon low frequency stimulation (1 Hz) and the blood pressure elevation upon stimulation at higher frequencies (3 and 5 Hz) were higher in SHR than in WKY whereas the increase in circulating cyclic AMP level was not different in the two strains. Pretreatment with propranolol (2.5 mg X kg-1) further enhanced the pressor responses in SHR but not in WKY, although it inhibited the heart rate acceleration and decreased the circulating level of cyclic AMP similarly in the two strains. After acute adrenalectomy, the elevations of blood pressure and circulating cyclic AMP levels were reduced to an identical level in SHR and WKY. These results show that the marked enhancement of the pressor response observed in SHR upon stimulation of the entire sympathetic outflow is mostly of adrenomedullary origin and includes a hypotensive component due to beta-adrenoceptor stimulation which is not present in WKY.     

Mechanism of chlorpromazine action on plasma glucose and cyclic AMP levels

The s.c. administration of chlorpromazine (CPZ) caused an elevation of plasma glucose and cyclic AMP levels in fed intact mice, but not in fed adrenalectomized mice. The pretreatment with reserpine partially blocked the elevation of plasma glucose and cyclic AMP. The pretreatment with 6-hydroxydopamine or alpha-methyl-p-tyrosine failed to inhibit the increase of plasma glucose and cyclic AMP induced by CPZ. These findings suggest that CPZ acts on the central nervous system and increases plasma glucose and cyclic AMP through epinephrine release from the adrenal medulla. The elevations of plasma glucose and cyclic AMP induced by epinephrine were enhanced by CPZ. CPZ increased plasma glucose and cyclic AMP significantly at high room temperatures (28 and 33 degrees C) at which CPZ did not decrease body temperature. The mechanism of CPZ action is discussed in relation to the increase in the plasma glucose and cyclic AMP levels.     

Effect of narcotic analgesics on plasma cyclic AMP levels in male mice.

Systemic administration of morphine, as well as pethidine and pentazocine, increased plasma cyclic AMP levels in male mice. Intracerebroventricular administration of morphine and β-endorphin also increased plasma cyclic AMP levels. The effect of morphine and β-endorphin was antagonized by naloxone indicating the involvement of opiate receptors in the central nervous system for the effect of morphine on cyclic AMP levels. Tolerance was shown to develop to the action of morphine in increasing the plasma cyclic AMP. The morphine-induced increase in plasma cyclic AMP was abolished by treatment with propranolol or pentolinium or by adrenalectomy but not by treatment with atropine, phentolamine, 6-hydroxydopamine or α-methyltyrosine. These findings suggest that morphine increases plasma cyclic AMP levels mainly by releasing catecholamines, from the adrenal medulla, and these activate adenylate cyclase via the stimulation of β-adrenoceptors.     

Possible muscarinic regulation of catecholamine secretion mediated by cyclic GMP in isolated bovine adrenal chromaffin cells

Catecholamine secretion and cyclic GMP levels were measured in chromaffin cells isolated from bovine adrenal medulla. Acetylcholine (ACh) and nicotine, but not muscarine, induced 8- to 10-fold increases in catecholamine secretion, with respective ED₅₀ values of 10 and 2 M. Cyclic GMP levels were also increased from 3- to 5-fold in the presence of ACh, and this stimulation was mimicked by muscarine but not by nicotine. Half-maximum stimulations of cyclic GMP levels with ACh and muscarine were observed at 0.1 and 0.3 M respectively. The order of potency of various cholinergic drugs for cyclic GMP stimulation was as follows: ACh > oxotremorine > methacholine > muscarine > carbamylcholine > furthretonium > arecholine > bethanechol. Pilocarpine, McN-A-343, and AHR-602 were inactive at concentrations between 10^?8 and 10^?3 M. Isobutylmethylxanthine (1 mM), a specific phosphodiesterase inhibitor, caused a 7-fold increase in cyclic GMP and potentiated 3-fold the stimulation of cyclic GMP by ACh. The nicotine-induced catecholamine secretion was inhibited 19 and 33 per cent by the co-stimulation of the muscarinic receptor with 0.2 and 0.5 M ACh, respectively. Isobutylmethylxanthine (1 mM) also caused a 44 per cent inhibition of nicotine-induced catecholamine secretion, and its effect was additive to that of ACh. Atropine (0.1 M) selectively abolished the inhibition caused by ACh. Similar inhibitions were also obtained in the presence of exogenous dibutyryl cyclic GMP or 8-bromo cyclic GMP. These data indicate that the nicotinic stimulation of catecholamine secretion from bovine adrenal chromaffin cells may be regulated by cyclic GMP via the stimulation of a muscarinic receptor.     

Age-related changes of in vivo beta-adrenergic responsiveness in normotensive and spontaneously hypertensive rats

The variations of plasma cyclic AMP concentration caused by propranolol and isoproterenol were studied in order to investigate endogenous stimulation and responsiveness of the beta-adrenoceptor-cyclic AMP system in vivo, in 7 and 18 week old unanaesthetized male SHR and WKY. In both age groups, the basal cyclic AMP level was higher in SHR than in controls but was significantly reduced to a comparable value in the two strains after intraperitoneal injection of 2.5 mg X kg-1 propranolol, a dose which markedly depressed or even abolished the effect of isoproterenol. Cumulative dose-response curves of plasma cyclic AMP concentration obtained in another group of rats after successive subcutaneous injections of isoproterenol showed that the ED50 value of this drug was higher in SHR than in WKY and increased in a parallel manner in the two strains between 7 and 18 weeks of age (respectively from 0.21 +/- 0.01 to 0.34 +/- 0.02 mumol X kg-1 in WKY and from 0.32 +/- 0.02 to 0.52 +/- 0.03 mumol X kg-1 in SHR). At the same time blood pressure increased much less markedly in WKY (from 115 +/- 4 to 119 +/- 2 mm Hg) than in SHR (from 134 +/- 3 to 179 +/- 3 mm Hg). Altogether these results show that endogenous beta-adrenergic stimulation of the cyclic AMP system was higher in SHR of both ages in spite of a diminished responsiveness of this system to exogenous isoproterenol.     

Effect of chlorpromazine on plasma adenosine 3′,5′-cyclic phosphate level

A subcutaneous injection of chlorpromazine hydrochloride (CPZ) at a dose of 10 mg/kg caused an increase in the plasma cyclic AMP level in male mice. Propranolol (2 mg/kg) and hexamethonium (50 mg/kg) abolished the elevation of plasma cyclic AMP induced by CPZ. Phentolamine (5 mg/kg) could not inhibit the effect of CPZ. Adrenalectomy completely inhibited the elevation of plasma cyclic AMP produced by CPZ. Pretreatment with 6-hydroxydopamine (100 mg/kg, i.v., 24 hr before) failed to reduce the elevation of the plasma cyclic AMP level produced by CPZ. Intracere-broventricular administration of CPZ (5–25 μg/mouse) also increased plasma cyclic AMP levels. These findings indicate that CPZ activated the sympathetic nervous system by acting on the CNS, thereby increasing plasma cyclic AMP levels through the stimulation of β-adrenoceptors mainly by catecholamines released from the adrenal medulla.     

Role of stimulatory GTP-binding protein (Gs) in reduced beta-adrenoceptor coupling in the femoral artery of spontaneously hypertensive rats.

1. Arterial relaxant responses to beta-adrenoceptor agonists are decreased in spontaneously hypertensive rats (SHR) when compared with normotensive Wistar-Kyoto rats (WKY). To establish which component of the beta-adrenoceptor.adenylate cyclase (AC) system is impaired in the SHR arteries, effects of two activators of AC--cholera toxin (CTX) and forskolin--and of dibutyryl cyclic AMP (db cyclic AMP) were compared between strips of femoral arteries isolated from 13 week-old SHR and age-matched WKY. 2. In the absence of timolol, a beta-adrenoceptor antagonist, contractile responses of the strips to noradrenaline (NA) were significantly greater in the SHR than in the WKY. Timolol augmented the contractile responses to NA to a smaller extent in the SHR than in the WKY. 3. After blockade by timolol of beta-adrenoceptors, contractile responses of the strips to NA through the activation of alpha-adrenoceptors were not significantly different between the two strains. 4. Pre-treatment of the strips with CTX, an activator of the stimulatory GTP-binding protein (Gs), produced a slow-onset and long-lived antagonism of the alpha-adrenoceptor-mediated contractions. The antagonism was much smaller in the SHR than in the WKY. 5. The dose-response curves of the strips from both strains for alpha-adrenoceptor stimulation with NA determined after pretreatment with CTX were comparable to those determined in the absence of timolol. 6. Forskolin, an activator of the catalytic subunit of AC, and DB cyclic AMP also antagonized the alpha-adrenoceptor-mediated contractions. However, these antagonisms were not significantly different between the two strains. 7. Isobutyl methylxanthine (IBMX), an inhibitor of cyclic AMP phosphodiesterase, produced a similar antagonism of the alpha-adrenoceptor-mediated contractions between the two strains. 8. These results suggest that a reduced function of Gs is the main factor responsible for the decreased responsiveness to beta-adrenoceptor stimulation in the SHR femoral artery.     

Increases in plasma cyclic AMP dependent on endogenous catecholamines.

Administration of tyramine (with or without phentolamine) as well as induction of ether anesthesia or insulin hypoglycemia caused a sharp increase in plasma cyclic AMP in rats. Based on the findings that the treatment of rats with reserpine, 6-hydroxydopamine, cocaine or propranolol totally abolished tyramine-induced increases in plasma cyclic AMP, it was concluded that catecholamines released from sympathetic neuronal terminals by tyramine could activate adenylate cyclase via the stimulation of postsynaptic beta-adrenoceptors. In contrast, catecholamines secreted from adrenal medulla were largely responsible for the increase in plasma cyclic AMP induced by ether anesthesia; whereas glucagon, in addition to adrenal catecholamines, played a significant role in hypoglycemia-induced increases in plasma cyclic AMP. Assay of plasma cyclic AMP following these stimuli is very promising as a test for adrenergic activities in experimental and clinical studies.     

Endothelin regulation of adrenal function

1. The goal of the present review is to recount the evidence that endothelin (ET) has a significant influence on the peripheral sympathetic nervous system by regulating the function of the adrenal medulla. 2. The presence of an active ET system in the adrenal medulla has been clearly demonstrated. Endothelin protein, mRNA, binding sites and ET-converting enzyme have been identified in adrenal tissue and medullary chromaffin cells, suggesting that this peptide may contribute to the regulation of adrenal medullary function. 3. Studies investigating the function of ET in the adrenal gland have demonstrated that ET has a stimulatory effect on the adrenal medulla. Endothelin elicits an increase in catecholamine release from perfused intact adrenal glands as well as from cultured chromaffin cells. This effect has been shown to be mediated by ETA and ETB receptors. 4. The mechanism by which ET causes an increase in catecholamine release from the adrenal medulla appears to be independent of cholinergic activation of chromaffin cells. Endothelin has been shown to act directly at chromaffin cells to increase intracellular calcium, which results in catecholamine release. 5. Endothelin can indirectly affect catecholamine release by its effect on adrenal blood flow. Studies indicate that ET has both vasoconstrictor and vasodilator effects in the adrenal gland, which suggests a role for ET in the regulation of adrenal blood flow. Endothelin has also been proposed to participate in the selective contraction of the adrenomedullary veins, which enhances the discharge of catecholamines from the adrenal gland during activation.     

Guanosine 3': 5'-cyclic monophosphate-dependent pathway alterations in ventricular cardiomyocytes of spontaneously hypertensive rats

1. We investigated the effect of the NO-donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) on cardiomyocytes isolated from control normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. 2. Ventricular cardiomyocytes were isolated from SHR and WKY hearts and imaging analysis of fura-2-loaded cells was performed in order to evaluate calcium transient in electrical field paced (0.5 Hz) cells. 3. In WKY cardiomyocytes, 1 - 200 microM SNAP dose-dependently increased cyclic GMP content. In basal conditions, cyclic GMP content of SHR cardiomyocytes was significantly higher than in WKY, but SNAP failed to further increase cyclic GMP over the basal level. 4. In control conditions, the Delta F/F and decay time of the calcium transient were similar in both strains. In WKY cardiomyocytes, SNAP (1 - 100 microM) reduced the decay time. In SHR cardiomyocytes, SNAP was ineffective. Dibutyryl cyclic GMP (10(-6) - 10(-8) M), a membrane permeable cyclic GMP analogue, behaved similarly to SNAP. 5. In WKY and SHR cardiomyocytes, 10(-8) M isoprenaline similarly increased Delta F/F and decreased the decay time. SNAP and dibutyryl cyclic GMP prevented the effect of isoprenaline in WKY, whereas both molecules were ineffective in SHR cardiomyocytes. In WKY, SNAP effects were blocked by pretreating cells with the cGK inhibitor KT-5823. 6. Western blotting analysis of cGK type I showed that the enzyme was expressed in WKY isolated cardiomyocytes, but absent in four out of five SHR preparations. 7. We concluded that the low expression of cGKI may determine the lack of NO/cyclic GMP-dependent regulation on calcium transient in SHR cardiomyocytes. This alteration may contribute to the development of heart hypertrophy in hypertensive status.     

α₂-Adrenoceptor-mediated inhibition of catecholamine release from the adrenal medulla of spontaneously hypertensive rats is preserved in the early stages of hypertension

In this study, we evaluated the effect of α(2) -adrenoceptor activation on catecholamine release from the adrenal medulla of pre-hypertensive (6-week-old) and hypertensive (16-week-old) spontaneously hypertensive rats (SHR) and of age-matched normotensive control Wistar Kyoto (WKY) rats. Catecholamine overflow from isolated adrenal medullae was evoked by the nicotinic receptor agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) in the absence and presence of the α(2) -adrenoceptor agonist medetomidine (MED). The spontaneous outflow of adrenaline was similar between age-matched SHR and WKY rats. However, the spontaneous outflow of noradrenaline was significantly lower in SHR compared with age-matched WKY rats. DMPP (0.1-3 mM) increased the outflow of noradrenaline and adrenaline in a concentration-dependent manner. The E(max) values for adrenaline overflow were similar between strains, but the E(max) values for noradrenaline overflow were significantly lower in SHR. The EC(50) values for noradrenaline and adrenaline overflow were significantly higher in SHR compared with age-matched WKY rats. MED (0.1-300 nM) reduced the DMPP-evoked overflow (DMPP 500 μM) of noradrenaline and adrenaline in a concentration-dependent manner and was capable of totally inhibiting this effect. The inhibitory action of MED was similar between age-matched SHR and WKY rats. In the adrenals, the α(2A)- and α(2B)-adrenoceptor subtypes had the highest mRNA expression levels; the α(2C)-adrenoceptor subtype had the lowest mRNA expression levels. The mRNA levels for the three subtypes were similar between strains. In conclusion, in SHR during the development of hypertension, adrenal α(2) -adrenoceptor inhibitory function is conserved, accompanied by reduced noradrenaline release and unchanged adrenaline release.     

Anaphylaxis-induced increase in plasma cyclic AMP dependent on endogenous catecholamines in rats

Plasma cyclic AMP levels during anaphylactic shock in rats was studied in 7 groups of animals: (1) control rats; (2) rats with adrenomedullectomy; (3) rats treated with propranolol; (4) rats with reserpinization; (5) rats with 6-hydroxydopamine-induced chemical sympathectomy; (6) rats treated with hexamethonium, and (7) rats treated with cocaine (catecholamine uptake inhibitor). All experiments were carried out in ovalbumin-sensitized rats. Plasma cyclic AMP showed a rapid increase during anaphylactic shock in control rats. Adrenomedullectomy abolished the anaphylaxis-induced increase in plasma cyclic AMP, while hexamethonium had no effect. Propranolol caused a dose-dependent abolition of the increase. The treatment of rats with reserpine, 6-hydroxydopamine or cocaine partially inhibited the increase in plasma cyclic AMP. The results show that the adrenal medulla is the major source of catecholamines during anaphylactic shock, and that catecholamines in the adrenergic neuronal terminals may be partly responsible for the anaphylaxis-induced increase in plasma cyclic AMP.     

Studies on cyclic nucleotides in the adrenal gland. V. Adenylate cyclase in the adrenal medulla.

Effects of various chemical agents eliciting the catecholamine-release on the adenylate cyclase-cyclic AMP generating system have been studied in the secretory process of the bovine adrenal medulla slices. Cyclic AMP levels were not affected at the interval of the maximal increase of the catecholamine-release by acetylcholine, but increased gradually some time after the end of the release/or at the beginning of the restoration of catecholamine in the medulla tissue. This delayed increase in the medullary cyclic AMP is not attributed to a direct involvement in 'stimulus-secretion coupling process' of the medullary secretion, but rather may be caused by release of intracellular catecholamine.     

Effects of anesthesia on the levels of cyclic nucleotides in rat brain regions (author's transl)

The following 4 Wistar rat groups were sacrificed by microwave irradiation: 1) hypothermia-rebreathing anesthesia (kept 3 hr at 4 degrees C in a 4 1 box), 2) pentobarbital anesthesia (50 mg/kg, s.c., 1 hr after), 3) reserpinized rats (5 mg/kg/day, s.c. for 3 days), and 4) nontreated control rats. Cyclic nucleotides and noradrenaline were analyzed in seven brain regions: cerebellum, pons and medulla oblongata, hypothalamus, mid brain, striatum, hippocampus, and cerebral cortex. In most part of the brain regions, the levels of cyclic AMP, cycli GMP and noradrenaline had a tendency to decrease after the treatment by hypothermia-rebreathing or pentobarbital as compared with control animals. The levels of cyclic AMP in the cerebellum and cyclic GMP in the hypothalamus were not affected by these anesthesia. After reserpinization, the level of cyclic GMP markedly elevated in all regions of the brain except in the cerebellum. In all brain regions of the control and the hypothermia-rebreathing groups, the coefficients of correlation between cyclic AMP and noradrenaline, cyclic GMP and nonadrenaline, cyclic AMP and cyclic GMP were positive, negative and negative, respectively. The cyclic AMP/cyclic GMP ratio in most of the brain regions decreased in the reserpinized group, and increased in the hypothermia-rebreathing group as compared to the control and the pentobarbital groups. From these results, it is postulated that some other neurons, not only monoaminergic neuron, regulate the level of cyclic nucleotides, and that the different sensitivity of these neurons to the anesthesia brings about various effects on the metabolism of cyclic nucleotides in each brain region.     

AGE-RELATED CHANGES IN NEUROPEPTIDE Y CONTENT IN BRAIN AND PERIPHERAL TISSUES OF SPONTANEOUSLY HYPERTENSIVE RATS

1. This study examined neuropeptide Y (NPY) concentrations in brain regions and peripheral tissues of young (3–4 months) and old (17–18 months) normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. Neuropeptide Y-like immunoreactivity (NPY-LI) was determined in kidney, adrenal, heart ventricles, atria and four brain regions, cerebral cortex, hypothalamus, ventrolateral medulla (VLM) and dorsomedial medulla containing the nucleus tractus solitarius (NTS), by radio-immunoassay following acid extraction. 3. Significant age-related increases in organ weights were observed in atria, ventricle and kidney of both WKY and SHR (P<0.01). In order to take into account tissue hypertrophy, NPY-LI data were analysed as pmol/g tissue as well as total pmol/tissue. 4. At each age, similar NPY-LI concentrations were observed in WKY and SHR in all brain regions. A significant age-induced decrease in NPY-LI concentration and total NPY content was found in the hypothalamus of both WKY and SHR (P<0.01). 5. In the cardiac ventricle, decreases were observed in NPY-LI concentration with ageing, and in SHR relative to WKY; however, no differences were observed in total NPY-LI content. A significant age-related increase in adrenal NPY-LI concentration was observed. No age- or strain-related alterations in atrial or renal NPY-LI were detected, with the exception of an increase in total kidney NPY-LI in WKY with ageing. 6. Thus in the periphery, few changes in NPY-LI were observed with genetic hypertension or with ageing. A significant reduction in hypothalamic NPY-LI concentration occurred with age in both normotensive and hypertensive rats. Thus the previously reported age-related reduction in NPY-LI in the hypothalamus, an area where the peptide influences neuro-endocrine responses and food and water ingestion, is not affected by hypertension.     

The nature of adrenergic mechanisms involved in anaphylatoxin activity in the guinea-pig

1. Evidence is presented to elucidate the nature of the adrenergic mechanisms involved in responses of the guinea-pig to anaphylatoxin (AT).2. Investigation by means of adrenalectomy, adrenergic neurone blockade, alpha- and beta- adrenoceptor blockade and exclusion of autonomic reflexes, revealed that the adrenergic mechanisms provoked included catecholamine release from the adrenal medulla, sympathetic reflex activity, stimulation of adrenergic neurones and alpha- and beta-adrenoceptor activity.3. The cardiovascular effects of AT, mediated by histamine release, were largely attributable to adrenal medullary and adrenergic neuronal mechanisms. These mechanisms also exerted a restraint on the predominantly histamine mediated bronchoconstrictor effect of AT.4. The cardiovascular effects of AT activity, not attributable to histamine release, were also probably associated with catecholamine release. However, the bronchoconstrictor component of this AT activity was not significantly affected by guanethidine, and it would, therefore, appear that neuronal bronchodilator mechanisms did not exert a restraint upon this aspect of AT activity.5. These findings are generally compatible with previous work showing that adrenergic mechanisms operate during AT-induced responses. In contrast to previous reports, however, the adrenergic activity was predominantly associated with the effects of released histamine.     

Influence of intracerebroventricular injections of N6, O2'-dibutyryl adenosine 3':5'-cyclic monophosphate on sodium pentobarbital-induced narcosis in rats.

Premedication with dibutyryl cyclic AMP (225 μg, i.c.v.) decreased the responsiveness of the central nervous system and lethality to sodium pentobarbital in the rat. The LD₅₀ of sodium pentobarbital was increased (79.9–116 $\text{solmg}\text{kg}$ i.p.) and the sleep time was decreased from 120min to 76 min in dibutyryl cyclic AMP pretreated animals. The brain and plasma pentobarbital concentrations at the time of awakening were higher in the dibutyryl cyclic AMP group as compared to saline pretreated rats. The threshold dose level of sodium pentobarbital as determined from the dose—response curves and the dose of intravenous infused pentobarbital necessary to suppress EEG activity was increased after administration of the cyclic nucleotide. Pretreatment with gradient doses of dibutyryl cyclic AMP produced a biphasic dose-response of pentobarbital sleep time with the shortest duration observed at 225 μg of dibutyryl cyclic AMP and a progressive increase in duration of sleep time from 250 and 275 μg was produced. Doses of dibutyryl cyclic AMP greater than 275 μg produced death in all animals. The cardiovascular depressant action of pentobarbital was antagonized by dibutyryl cyclic AMP. However, the hypothermic action of pentobarbital was not reversed. The results suggest dibutyryl cyclic AMP produces a generalized stimulation of the CNS and does not specifically antagonize barbiturate-induced toxicity.     

Role of the parasympathetic nervous system and interaction with the sympathetic nervous system in the early phase of hypertension

The role of the peripheral parasympathetic nervous system in the development of hypertension was investigated in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Animals were 5-7 weeks old, anesthetized, and in the open-chest condition. The decrement in heart rate evoked by parasympathetic nerve stimulation (62 +/- 8 beats/min) in SHR was greater (p < 0.01) than that in WKY rats (23 +/- 4 beats/min). Furthermore, the decrease in heart rate (73 +/- 9 beats/min) in response to combined stimulation of sympathetic and parasympathetic nerves in SHR was greater (p < 0.05) than that in response to vagal stimulation alone. The extent of the interaction of sympathetic and parasympathetic nerves was calculated as the difference between the decrease in heart rate during combined stimulation and that during vagal nerve stimulation alone. The extent of the interaction in SHR (-11 +/- 5) was not significantly different from that in WKY rats (-8 +/- 3 beats/min). Therefore, the influence of the peripheral parasympathetic nervous system in the early phase of hypertension may be greater than that in the normotensive state. Interaction between the two branches of the autonomic nervous system may occur as accentuated antagonism originating in the early phase of hypertension. The interaction during the early phase of hypertension may not be different in extent from that of the normotensive state.