Enhanced hypotensive, bradycardic, and hypnotic responses to alpha2-adrenergic agonists in spinophilin-null mice are accompanied by increased G protein coupling to the alpha2A-adrenergic receptor.

We previously identified spinophilin as a regulator of alpha(2) adrenergic receptor (alpha(2)AR) trafficking and signaling in vitro and in vivo (Science 304:1940-1944, 2004). To assess the generalized role of spinophilin in regulating alpha(2)AR functions in vivo, the present study examined the impact of eliminating spinophilin on alpha(2)AR-evoked cardiovascular and hypnotic responses, previously demonstrated to be mediated by the alpha(2A)AR subtype, after systemic administration of the alpha(2)-agonists 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK14,304) and clonidine in spinophilin-null mice. Mice lacking spinophilin expression display dramatically enhanced and prolonged hypotensive, bradycardic, and sedative-hypnotic responses to alpha(2)AR stimulation. Whereas these changes in sensitivity to alpha(2)AR agonists occur independent of any changes in alpha(2A)AR density or intrinsic affinity for agonist in the brains of spinophilin-null mice compared with wild-type control mice, the coupling of the alpha(2A)AR to cognate G proteins is enhanced in spinophilin-null mice. Thus, brain preparations from spinophilin-null mice demonstrate enhanced guanine nucleotide regulation of UK14,304 binding and evidence of a larger fraction of alpha(2A)AR in the guanine-nucleotide-sensitive higher affinity state compared with those from wild-type mice. These findings suggest that eliminating spinophilin expression in native tissues leads to an enhanced receptor/G protein coupling efficiency that contributes to sensitization of receptor mediated responses in vivo.

Flavonoids and age-related disease: risk, benefits and critical windows.

Plant derived products are consumed by a large percentage of the population to prevent, delay and ameliorate disease burden; however, relatively little is known about the efficacy, safety and underlying mechanisms of these traditional health products, especially when taken in concert with pharmaceutical agents. The flavonoids are a group of plant metabolites that are common in the diet and appear to provide some health benefits. While flavonoids are primarily derived from soy, many are found in fruits, nuts and more exotic sources, e.g., kudzu. Perhaps the strongest evidence for the benefits of flavonoids in diseases of aging relates to their effect on components of the metabolic syndrome. Flavonoids from soy, grape seed, kudzu and other sources all lower arterial pressure in hypertensive animal models and in a limited number of tests in humans. They also decrease the plasma concentration of lipids and buffer plasma glucose. The underlying mechanisms appear to include antioxidant actions, central nervous system effects, gut transport alterations, fatty acid sequestration and processing, PPAR activation and increases in insulin sensitivity. In animal models of disease, dietary flavonoids also demonstrate a protective effect against cognitive decline, cancer and metabolic disease. However, research also indicates that the flavonoids can be detrimental in some settings and, therefore, are not universally safe. Thus, as the population ages, it is important to determine the impact of these agents on prevention/attenuation of disease, including optimal exposure (intake, timing/duration) and potential contraindications.

The neointimal response to endovascular injury is increased in obese Zucker rats.

BACKGROUND: Restenosis after revascularization procedures is accelerated in persons with type 2 diabetes. AIM: The current study tested the hypothesis that the neointimal response to endovascular injury is enhanced in female obese Zucker (OZ) rats, a model of type 2 diabetes. METHODS: Animals were randomized to receive either a standard diet (SD) or a diabetogenic diet (DD) for 6 weeks. Four weeks later, balloon injury of the right common carotid artery was induced. All rats were euthanized 2 weeks after injury. Lean Zucker (LZ) rats served as controls. RESULTS: At the time of death, plasma glucose was elevated in OZ rats fed a SD (208 +/- 13 mg/dl) and a DD (288 +/- 21 mg/dl) compared to corresponding LZ rats (SD: 153 +/- 8; DD: 132 +/- 7 mg/dl). The ratio of high-density lipoprotein cholesterol (HDLc) to total cholesterol (Totc), an index of atherogenicity, was reduced in OZ rats on both diets (SD: 0.77 +/- 0.06; DD: 0.80 +/- 0.09) compared to LZ controls (SD: 1.11 +/- 0.02; DD: 1.20 +/- 0.05). Histomorphometric analysis of injured arteries showed that the intima to media (I : M) ratio was significantly increased in OZ (1.37 +/- 0.07) compared to LZ (0.79 +/- 0.08) rats. Elevations in plasma glucose and triglycerides (Tg) correlated positively and decreases in HDLc negatively with an increased I : M ratio. Administration of the DD did not further enhance the I : M ratio in LZ (0.87 +/- 0.06) or OZ (1.29 +/- 0.09) rats. CONCLUSIONS: These results suggest that neointima formation following endoluminal injury of the carotid artery is enhanced at an early stage in the development of diabetes mellitus.

Neuregulin-1beta modulates in vivo entorhinal-hippocampal synaptic transmission in adult rats.

Neuregulin-1 (NRG-1) proteins and their erbB receptors are essential for neuronal development during embryogenesis and may contribute importantly to neuronal function in the adult brain. This study tests the hypothesis that NRG-1beta acts as a modulator of synaptic activity in the adult brain, specifically at hippocampal formation synapses. Adult, male Sprague-Dawley rats were anesthetized and a recording electrode with an attached stainless steel microinjector was stereotaxically positioned to record field potentials (fEPSP) in either the dentate gyrus or the cornu ammonis (CA) 1 field of the hippocampus. The entorhinal cortex was continuously stimulated via a paired stainless steel electrode. Microinjection of NRG-1beta significantly increased the slope of the fEPSP in the dentate gyrus in a dose-dependent manner. Compared with a low dose (20 nM), a high dose (100 nM) of NRG-1beta induced a shorter latency response that was of greater magnitude. Responses to NRG-1beta were abolished by pretreatment with a selective, reversible erbB tyrosine kinase inhibitor, PD158780 (100 microM). Further, PD158780 (100 microM) itself significantly decreased the entorhinal-dentate fESPS slope by about 15%. Neither equimolar (100 nM) nor hypermolar (100 microM) sucrose or heat-inactivated NRG-1beta (100 nM) significantly altered the entorhinal-dentate fEPSP slope. In contrast to its effect at the entorhinal-dentate synapse, NRG-1beta (100 nM) depressed, and PD158780 potentiated entorhinal-CA1 synaptic transmission. Thus, in adult rats NRG-1beta potentiates transmission at the entorhinal-dentate synapse but suppresses transmission at the entorhinal-CA1 synapse. These observations indicate that NRG-1 is not only a developmental growth factor, but also modifies synaptic transmission in adult rat brain.

Estrogen depletion induces NaCl-sensitive hypertension in female spontaneously hypertensive rats.

In women, arterial pressure generally increases after menopause, but several studies suggest that women who eat large amounts of plant estrogens (phytoestrogens) experience a slower rise in the incidence of postmenopausal hypertension. This suggests that both ovarian hormones (principally estrogen) and phytoestrogens may protect at least some women from hypertension. The present study tests the hypothesis that phytoestrogens blunt hypertension in estrogen-depleted female spontaneously hypertensive rats (SHR). Three-week-old ovariectomized SHR were fed one of four diets that contained basal (0.6%) or high (8%) NaCl with or without dietary phytoestrogens for 9 wk. In SHR on the basal NaCl diet, arterial pressure was unaffected by the removal of dietary phytoestrogens. In contrast, in SHR on the high-NaCl diet, arterial pressure was significantly higher in rats on the phytoestrogen-free (204 +/- 4 mmHg) compared with the phytoestrogen-replete (153 +/- 4 mmHg) diet. Ganglionic blockade resulted in reductions in arterial pressure that were directly related to the dietary NaCl-induced increases in arterial pressure. Together, these data indicate that dietary phytoestrogens protect ovariectomized female SHR from dietary NaCl-sensitive hypertension and that the sympathetic nervous system plays an important role in this effect. Furthermore, these results demonstrate that dietary phytoestrogens can have a major impact on the interpretation of studies into the physiological role of estrogen in females.

The role of the central nervous system in NaCl-sensitive hypertension in spontaneously hypertensive rats.

The central and peripheral nervous system is typically considered to be a short-term modifier of sympathetic nervous system activity, but several lines of evidence suggest that they contribute to chronic elevation of arterial pressure in at least some forms of hypertension. Our studies focus on the mechanisms underlying NaCl-sensitive hypertension in the spontaneously hypertensive rat (SHR). When these rats are fed a high NaCl diet, their arterial pressure rapidly increases and is maintained about 30 mm Hg higher than those of pair fed controls. The increase in arterial pressure is associated with a decrease in norepinephrine release, specifically in the anterior hypothalamic nucleus (AHN), resulting in increased sympathetic nervous system activity, peripheral vasoconstriction, and arterial pressure. Furthermore, administration of an alpha2-adrenergic receptor agonist in this area blocks the NaCl-sensitive increase in arterial pressure in the SHR but has no significant effect on arterial pressure in normotensive controls. We have identified three intermediary steps by which dietary NaCl reduces AHN norepinephrine release. First, dietary NaCl causes an increase in plasma NaCl and a blunting of the plasma NaCl circadian rhythm. Second, alterations in plasma NaCl activate osmosensitive neurons in the organum vasculosum of the lamina terminalis (OVLT). Third, OVLT input to the AHN appears to increase the release of atrial natriuretic peptide with a resultant decrease in the local release of norepinephrine. Finally, our evidence demonstrates that these factors lead to an increased rise in sympathetic nervous system activity during the early wake phase in SHR on a high NaCl diet, contributing to NaCl-sensitive hypertension in SHR.

The role of the nervous system in hypertension.

The central nervous system plays an important role in the minute-to-minute regulation of arterial pressure, but its contribution to chronic regulation of arterial pressure is less clear. A nervous system role in essential hypertension in humans has been postulated for decades, but conclusive data on the relationship has been lacking. However, several lines of evidence in animal models and in humans suggest that the sympathetic nervous system is a primary contributor to the development and maintenance of some forms of essential hypertension. The primary final common pathway for the nervous system's contribution to hypertension is the sympathetic nervous system. Sympathetic nervous system overactivity may result from either inappropriately elevated sympathetic drive from brain centers, an increase in synaptically released neurotransmitters in the periphery, or amplification of the neurotransmitter signal at the target tissue. This review examines recent evidence for the central and peripheral nervous systems' roles in hypertension, and considers recent findings in this area that suggest that sex steroids and circadian rhythms are important considerations in the nervous system's regulation of arterial pressure.

ErbB transmembrane tyrosine kinase receptors are differentially expressed throughout the adult rat central nervous system.

The neuregulin (NRG) family of growth and differentiation factors and their erbB receptors contribute importantly to the development of the nervous system, but their distribution and function in the adult brain are poorly understood. The present study showed that erbB2, erbB3, and erbB4 transcripts and protein are distributed throughout all areas of adult rat brain. These three receptors were differentially expressed in neurons and glia. Some neurons expressed only a subset of erbB kinases, whereas other neurons expressed all three erbB receptors but sequestered each of these polypeptides into distinct cellular compartments. In synapse-rich regions, erbB immunoreactivity appeared as punctate-, axon-, and/or dendrite-associated staining, suggesting that NRGs are involved in the formation and maintenance of synapses in adult brain. ErbB labeling also was present in neuronal soma, indicating that NRGs act at sites in addition to the synapse. Glia in adult brain also differentially expressed erbB3 and erbB4. Approximately half of the erbB3 labeling in white matter was associated with S100beta+/glial fibrillary acidic protein negative macroglia (i.e., oligodendrocytes or glial fibrillary acidic protein negative astrocytes). In contrast, macroglia in gray matter did not express erbB3. The remaining erbB3 immunoreactivity in white matter and erbB4 glial staining seemed to be associated with microglia. These results showed that erbB receptors are expressed widely in adult rat brain and that each erbB receptor subtype has a distinct distribution. The differential distributions of erbB receptors in neurons and glia and the known functional differences between these kinases suggest that NRGs have distinct effects on these cells. The continued expression of NRGs and their erbB receptors in mature brain also implies that these molecules perform important functions in the brain throughout life.

Chronic, severe hypertension does not impair spatial learning and memory in Sprague-Dawley rats.

This study tested the hypothesis that long-term hypertension impairs spatial learning and memory in rats. In 6-wk-old Sprague-Dawley rats, chronic hypertension was induced by placing one of three sizes of stainless steel clips around the descending aorta (above the renal artery), resulting in a 20-80-mm Hg increase of arterial pressure in all arteries above the clip, that is, the upper trunk and head. Ten months later, the rats were tested for 5 d in a repeated-acquisition water maze task, and on the fifth day, they were tested in a probe trial; that is, there was no escape platform present. At the end of the testing period, the nonsurgical and sham control groups had similar final escape latencies (16 +/- 4 sec and 23 +/- 9 sec, respectively) that were not significantly different from those of the three hypertensive groups. Rats with mild hypertension (140-160 mm Hg) had a final escape latency of 25 +/- 6 sec, whereas severely hypertensive rats (170-199 mm Hg) had a final escape latency of 21 +/- 7 sec and extremely hypertensive rats (>200 Hg) had a final escape latency of 19 +/- 5 sec. All five groups also displayed a similar preference for the correct quadrant in the probe trial. Together, these data suggest that sustained, severe hypertension for over 10 mo is not sufficient to impair spatial learning and memory deficits in otherwise normal rats.

Age-related decline in water maze learning and memory in rats: strain differences.

Rats display an age-related impairment in learning and memory; however, few studies have systematically examined this relationship in multiple strains. The present study used a repeated acquisition water maze task to test the hypothesis that age-related decreases in learning and memory occur at different rates in three strains of rats, i.e. Sprague-Dawley (SD), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats. All three strains of rats displayed age-related decreases in spatial learning and memory; however, the rate of decline differed between the strains. Compared to young rats of the same strain, only SHR were significantly impaired at 12 months of age. All three strains displayed moderate impairment in learning the task at 18 months of age, and at 24 months of age all three strains of rats were severely impaired in the task, but SD performed best at 18 and 24 months of age. Further, SD and SHR displayed a probe trial bias at 3 months of age, but only SD had a bias at 12 months of age and none of the rats showed the bias at later ages. Thus, in these three strains, age-related impairment of spatial memory proceeds at different rates.

The organum vasculosum of the lamina terminalis regulates noradrenaline release in the anterior hypothalamic nucleus.

Changes in either plasma sodium concentration or arterial pressure can differentially affect hypothalamic neurons. For instance, increases in plasma NaCl concentration decrease noradrenaline release from nerve terminals in the anterior hypothalamic nucleus, while increases in arterial pressure unrelated to an elevation in plasma NaCl enhance noradrenaline release in anterior hypothalamic nucleus. The present study tests the hypothesis that in the rat the organum vasculosum of the lamina terminalis (an osmosensitive area of the brain) detects rises in plasma NaCl concentration and conveys this information to anterior hypothalamic nucleus. The axons projecting from the organum vasculosum of the lamina terminalis to the hypothalamus were unilaterally cut immediately caudal to organum vasculosum of the lamina terminalis, and five days later, 3-methoxy-4-hydroxy phenylglycol (the major metabolite of noradrenaline in brain) was continuously monitored in the ipsilateral or contralateral anterior hypothalamic nucleus in response to an intravenous infusion of hypertonic saline. In spontaneously hypertensive rats, the infusion decreased the 3-methoxy-4-hydroxy phenylglycol concentration by 24+/-2% in the anterior hypothalamic nucleus contralateral to the lesion, and in control spontaneously hypertensive rats. In contrast, in the anterior hypothalamic nucleus ipsilateral to the lesion, hypertonic saline infusion caused a 58+/-3% increase in 3-methoxy-4-hydroxy phenylglycol. These data support the hypothesis that the organum vasculosum of the lamina terminalis is part of the circuit that transmits information concerning plasma NaCl concentration to anterior hypothalamic nucleus.

Circadian rhythm of plasma sodium is disrupted in spontaneously hypertensive rats fed a high-NaCl diet.

High-NaCl diets elevate arterial pressure in NaCl-sensitive individuals, and increases in plasma sodium may trigger this effect. The present study tests the hypotheses that 1) plasma sodium displays a circadian rhythm in rats, 2) the plasma sodium rhythm is disturbed in spontaneously hypertensive rats (SHR), and 3) excess dietary NaCl elevates plasma sodium concentration in SHR. The results demonstrate that plasma sodium has a circadian rhythm that is inversely related to the circadian rhythm of arterial pressure. Although the plasma sodium rhythms of SHR and control rats are nearly identical, the plasma sodium concentrations are significantly higher in SHR throughout the 24-h cycle. Maintenance on a high-NaCl diet increases plasma sodium concentration similarly in both SHR and control rats, but it blunts the plasma sodium rhythm only in SHR. These results demonstrate that in rats, plasma sodium has a circadian rhythm and that high-NaCl diets increase plasma sodium concentration.

Descending projections of infralimbic cortex that mediate stimulation-evoked changes in arterial pressure.

The infralimbic cortex (IL) of the rat can modify autonomic nervous system activity, but the critical pathway(s) that mediate this influence are unclear. To define the potential pathways, the first series of experiments characterizes the descending projections of IL and the neighboring cortical areas using Phaseolus vulgaris leucoagglutinin (PHA-L). IL has prominent projections to the central nucleus of the amygdala (Ce), the mediodorsal nucleus of the thalamus (MD), the lateral hypothalamic area (LHA), the periaqueductal gray (PAG), the parabrachial nucleus (Pb), and the nucleus of the solitary tract (NTS). The density and selectivity of these projections suggest that the LHA and the PAG mediate the ability of the IL to regulate cardiovascular function. The second series of experiments demonstrates that locally anesthetizing neurons in either the LHA or PAG with lidocaine attenuates the hypotensive effects produced by electrical stimulation of the IL. Similarly, microinjections of cobalt chloride (a neurotransmission blocker) into the anterior portion of the LHA also decrease the arterial pressure responses to IL stimulation, suggesting that the ability of lidocaine to reversibly block the evoked response is due to inactivation of neurons in the LHA. These data indicate that hypotension evoked by stimulation of IL is mediated, at least in part, by direct or indirect projections to the LHA and through the PAG.

Long-term telemetric recording of arterial pressure and heart rate in mice fed basal and high NaCl diets.

Research examining the control of arterial pressure in mice has primarily relied on tail-cuff plethysmography and, more recently, on tethered arterial catheters. In contrast, the radiotelemetry method has largely become the "gold standard" for long-term monitoring of arterial pressure and heart rate in rats. Whereas smaller telemetry probes have recently been developed, no published studies have used radiotelemetric monitoring of arterial pressure in mice, largely because of a relatively low success rate in small mice (ie, <30 g body weight). We report on the development of a protocol for the use of these probes to continuously monitor arterial pressure and heart rate in mice as small as 19 g body weight. To test the accuracy and reliability of this method, adult C57/BL6 mice were monitored for 3 weeks during exposure to a basal followed by a high NaCl diet. The results demonstrate that carotid and aortic placements of the telemetry probe provide equally accurate monitoring of arterial pressure and heart rate, but the carotid placement has a much greater rate of success. Exposure to a high NaCl diet increases both the amplitude of the arterial pressure rhythm (+ 6.0+/-0.6 mm Hg, approximately 32%) and the average mean arterial pressure (+ 8.6+/-1.1 mm Hg, approximately 8%), as would be predicted from previous studies in NaCl-resistant rats. Thus, the data demonstrate that telemetric recording of long-term arterial pressure and heart rate provides a powerful tool with which to define the mechanisms of cardiovascular control in mice.

Elevated sympathetic activity contributes to hypertension and salt sensitivity in diabetic obese Zucker rats.

Zucker rats are a useful model in which to define the mechanisms that link obesity to diabetes and associated cardiovascular disease. The present study tests the hypothesis that diabetic obese (compared with nondiabetic lean) Zucker rats are hypertensive and display a further increase in arterial pressure when fed a high salt diet. Male, nondiabetic lean and diabetic obese Zucker rats were chronically instrumented with telemetry probes and fed a basal salt diet for 3 weeks followed by exposure to a high salt diet for 11 days. On the basal diet, obese (vs lean) rats had significantly higher arterial pressures ( approximately 13 mm Hg), and the high salt diet significantly elevated mean arterial pressure (MAP) in obese (but not lean) Zucker rats ( approximately 12 mm Hg). Blockade of the sympathetic nervous system with hexamethonium caused a significantly larger decrease in MAP in obese (vs lean) Zucker rats fed the basal diet (51 vs 33 mm Hg), but the high salt diet did not increase the hexamethonium-induced reduction in arterial pressure in obese rats. Acute blockade of angiotensin receptors with losartan resulted in similar decreases in MAP in both groups on either diet. Acetylcholine-induced vasodilatory capacity of the carotid artery was significantly less in the obese (vs lean) Zucker rats. Together these data indicate that increased sympathetic nervous system activity and decreased vascular reactivity may contribute to elevated arterial pressure in type 2 diabetic, obese Zucker rats, but the sympathetic nervous system does not appear to contribute to the dietary salt-sensitive hypertension in this model.

Lifetime treatment with captopril improves renal function in spontaneously hypertensive rats.

Lifetime treatment with captopril prevents the development of hypertension in spontaneously hypertensive rats (SHR). This study tests the hypothesis that compared to untreated hypertensive SHR, captopril-treated SHR display similar diuretic and natriuretic responses to an isotonic saline infusion despite significantly lower arterial pressure. Eight-week-old, male SHR were instrumented with femoral arterial, venous, and bladder catheters. Forty-eight hours later, each rat was infused intravenously with an isotonic saline load (5% of body weight; 0.5 ml/min). Lifetime captopril-treated SHR and untreated control SHR displayed nearly identical natriuretic and diuretic responses to the saline infusion. Thus, although lifetime captopril treatment significantly reduces mean arterial pressure in SHR, renal excretory responses appear to be unaltered. Moreover, histological examination of the kidneys of the lifetime captopril-treated SHR did not reveal significant structural damage in the kidneys at either 8 weeks of age or at 12 months of age. Together, the data suggest that lifetime captopril treatment does not adversely affect renal function and structure in SHR.

Distribution of neurons in the anterior hypothalamic nucleus activated by blood pressure changes in the rat.

Electrophysiological and Fos-like protein immunocytochemical methods were used to identify the number and distribution of anterior hypothalamic neurons that are activated by changes in arterial pressure. First, in anesthetized, male Sprague-Dawley rats, arterial pressure increases and decreases led to differential activation of neurons in the anterior hypothalamic nucleus. Most of the units that responded to a rise in arterial pressure with a decrease in activity (pressor units) were located in the central part of the anterior hypothalamic nucleus, whereas units that increased firing when arterial pressure rose (the depressor units) were found throughout the nucleus. Second, in awake, male Sprague-Dawley rats, Fos-like protein immunoreactivity was mapped following sustained arterial pressure changes. Within the anterior hypothalamus, reduction in arterial pressure increased the number of Fos-labeled neurons primarily in the paraventricular nucleus and to a lesser extent in the anterior half of the anterior hypothalamic nucleus. In contrast, elevation in arterial pressure increased Fos labeling throughout the anterior hypothalamic nucleus and to a lesser extent in the paraventricular nucleus.

Efferent connections of the anteromedial nucleus of the thalamus of the rat.

The projections from the anteromedial nucleus of the thalamus (AM) were investigated using anterograde and retrograde tracing techniques. AM projects to nearly the entire rostrocaudal extent of limbic cortex and to visual cortex. Anteriorly, AM projects to medial orbital, frontal polar, precentral agranular, and infraradiata cortices. Posteriorly, AM projects to retrosplenial granular, entorhinal, perirhinal and presubicular cortices, and to the subiculum. Further, AM projects to visual cortical area 18b, and to the lateral and basolateral nuclei of the amygdala. AM projections are topographically organized, i.e., projections to different cortical areas arise from distinct parts of AM. The neurons projecting to rostral infraradiata cortex (IRalpha) are more caudally located in AM than the neurons projecting to caudal infraradiata cortex (IRbeta). The neuronal cell bodies that project to the terminal field in area 18b are located primarily in ventral and lateral parts of AM, whereas neurons projecting to perirhinal cortex and amygdala are more medially located in AM. Injections into the most caudal, medial part of AM (i.e., the interanteromedial [IAM] nucleus) label terminals in the rostral precentral agranular, caudal IRbeta, and caudal perirhinal cortices. Whereas most AM axons terminate in layers I and V-VI, exceptions to this pattern include area 18b (axons and terminals in layers I and IV-V), the retrosplenial granular cortex (axons and terminals in layers I and V), and the presubicular, perirhinal, and entorhinal cortices (axons and terminals predominantly in layer V). Together, these findings suggest that AM influences a widespread area of limbic cortex.

Interaction between lifetime captopril treatment and NaCI-sensitive hypertension in spontaneously hypertensive rats and Wistar-Kyoto rats.

DESIGN: Previous studies that were based on daytime arterial pressure recordings indicate that lifetime treatment with captopril exacerbates the hypertensive response to a high NaCl diet in spontaneously hypertensive rats (SHR) but has no such effect in normotensive Wistar-Kyoto (WKY) rats. The present study used 24-h recording methods to examine the hypothesis that during the normal waking hours of rats (night-time) the hypertensive response to a high NaCl diet is exacerbated in SHR and induced in WKY rats treated with lifetime captopril. METHODS: SHR and WKY rats were (1) untreated, (2), lifetime captopril treated or (3) lifetime captopril treated but removed from the treatment 2 weeks prior to exposure to a high (8%) NaCl diet RESULTS: Compared to untreated SHR, in SHR that were continuously treated with captopril, the high NaCl diet caused a more rapid and greater rise in arterial pressure. Discontinuation of the captopril treatment did not significantly diminish this NaCl-sensitivity. In untreated WKY rats, the high NaCl diet did not alter mean arterial pressure, but in the lifetime captopril-treated WKY rats the high NaCl diet induced a rapid rise in arterial pressure. In WKY rats, discontinuation of the lifetime captopril treatment did not diminish this NaCl-induced rise in arterial pressure, even though baseline mean arterial pressure in this group is similar to that in untreated WKY rats. CONCLUSIONS: Lifetime captopril treatment accelerates the hypertensive response to a high NaCl diet in SHR, and it induces a similar response in WKY rats. In both strains, the lifetime captopril treatment causes a change in the response that is not dependent on concurrent administration of the drug. This finding further suggests that lifetime captopril treatment causes a long-term resetting of cardiovascular response mechanisms.

Hepatic denervation does not affect plasma vasopressin response to intragastric hypertonic saline in conscious rats.

Peripheral osmoreceptors monitor dietary NaCl and modify central nervous system and renal sympathetic nervous system activity accordingly. Experimental evidence suggests that these responses are dependent on the hepatic nerves. Peripheral osmoreceptors also modify arginine vasopressin (AVP) secretion. However, although hepatic denervation reportedly blunts activation of both supraoptic and paraventricular hypothalamic neurons after intraportal NaCl infusion, the role of the hepatic nerves in the AVP release has not been directly examined. The present study tests the hypothesis that the hepatic nerves modify AVP release in response to intragastric NaCl infusion. Wistar-Kyoto rats (WKY) received either hepatic denervation or a sham operation. Intragastric NaCl infusion significantly elevated plasma AVP in both sham-operated WKY and hepatic-denervated WKY, and the responses were not different between these groups. Second, previous studies suggest that both AVP secretion and baroreflexes are blunted in spontaneously hypertensive rats (SHR), deficits that contribute to the observed hypertension in SHR. We hypothesized that SHR also have a blunted peripheral osmoreceptor reflex and that this contributes to NaCl-sensitive hypertension. In contrast to our prediction, in SHR intragastric NaCl infusion induced an increase in plasma AVP that was similar to that in the WKY groups. Thus, although hepatic osmoreceptors are important for chronic regulation of arterial pressure, renal sympathetic nervous system activity, and the activity of hypothalamic neurons, they do not appear to influence plasma AVP concentration in response to intragastric NaCl.