Pharmacist-involved care for patients with heart failure and acute coronary syndrome: a systematic review with qualitative and quantitative meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Many trials have indicated that interventions by pharmacists resulted in beneficial outcomes with positive effects on cardiovascular diseases. The interventions through pharmacist-involved pharmaceutical care in patients with heart failure (HF) and acute coronary syndrome (ACS) were reviewed systemically and examined. METHODS: A systematic literature search was conducted to identify relevant articles describing pharmacist interventions in HF and ACS. Most studies were evaluated qualitatively, and the strength of evidence was graded according to the Agency for Healthcare Research and Quality (AHRQ) guidelines. Some of the studies were also assessed by a meta-analysis. RESULTS: A total of 26 studies containing data on 9415 patients were identified. For all studies, the strength of the body of evidence was reviewed and graded, and 14 studies among them were meta-analysed. The evidence was not strong enough to determine the effects of pharmaceutical care on major and patient-centred outcomes, except the prescription rates of angiotensin-converting-enzyme inhibitors (ACEI) with a high strength of evidence. In the meta-analysis, all-cause hospitalization [odds ratio (OR), 0·74; 95% confidence interval (CI), 0·58-0·94] was reduced and the prescription rates of angiotensin-converting-enzyme inhibitors (ACEI; OR 1·43; 95% CI, 1·07-1·91) and beta-blockers (OR 1·92; 95% CI, 1·24-2·96) were significantly higher in the pharmaceutical care group compared with the usual care group. WHAT IS NEW AND CONCLUSIONS: All-cause hospitalization showed improvement in the pharmaceutical care group. However, the strength of evidence for the majority of outcomes with pharmaceutical care, except direct performance measures such as prescription rates, was either insufficient or low. This could be explained by the presence of imprecision and inconsistency derived from the diversity of pharmaceutical care, the heterogeneity of patient populations or clinical settings. Moreover, it may indicate the necessity for homogeneous applicable criteria for assessment. A standardized consensus of the guidelines for pharmaceutical care service should be considered to improve homogeneity.

Sequence-based typing of HLA-A gene in 930 patients with nasopharyngeal carcinoma in Hunan province, southern China.

In this study, we typed 930 cases of nasopharyngeal carcinoma (NPC) and 1134 normal controls recruited from Hunan province, southern China for human leukocyte antigen-A (HLA-A) locus by sequencing exons 2-4. Very significant associations between HLA-A*02:07, HLA-A*11:01 and NPC were established [25.7% vs 16.18%; odds ratio, OR (95% confidence interval, CI) = 1.79 (1.54-2.09), P < 0.0001 and 21.1% vs 30.42%, OR (95% CI) = 0.61 (0.53-0.70), P<0.0001, respectively]. Further analysis of the molecular basis underlying these associations suggests that cysteine (C) at codon 99 of α2-helix of HLA-A protein is probably deleterious and confers risk to NPC. Convincing evidence was uncovered for negative association of a rare allele in southern Chinese populations, HLA-A*31:01, with NPC [0.22% vs 2.12%, OR (95% CI) = 0.1 (0.04-0.28), P < 0.0001]. rs1059449-A, which encodes arginine (R) at codon 56 of α1-helix of HLA-A protein, was postulated to be crucial for such a pattern of negative association with NPC. A subset of NPC cases (N = 632) and normal controls (N=712) were tested for anti-virus capsid antigen (anti-VCA) immunoglobulin A (IgA), very significant difference in seropositivity for anti-VCA IgA was observed between the two groups [67.56% vs 6.46%, OR (95% CI) = 30.16 (21.42-42.46), P < 0.0001]. However, seropositivity for anti-VCA IgA did not correlate with HLA-A allelic typing in both groups.

Blockade of endogenous anterior hypothalamic atrial natriuretic peptide with monoclonal antibody lowers blood pressure in spontaneously hypertensive rats.

We have previously shown that the atrial natriuretic peptide (ANP) content of the anterior hypothalamic region of NaCl-sensitive spontaneously hypertensive rats (SHR-S) is higher than that of Wistar-Kyoto (WKY) rats. ANP has been shown to inhibit neuronal norepinephrine release and to reduce the excitability of hypothalamic neurons. This study tested the hypothesis that blockade of endogenous ANP in the anterior hypothalamus by local microinjection of a monoclonal antibody to ANP (MAb KY-ANP-II) lowers blood pressure in SHR-S. Purified MAb KY-ANP-II (0.055 and 0.55 micrograms) or control mouse IgG in 200 nl saline was microinjected into the anterior hypothalamic area (AHA) of conscious SHR-S and control WKY rats. As a further control, Mab KY-ANP-II (0.55 microgram) was microinjected into the posterior hypothalamic area (PHA) of SHR-S. Anterior hypothalamic microinjection of MAb KY-ANP-II caused significant dose-related decreases in mean arterial pressure (MAP) and heart rate (HR) in SHR-S but not in WKY rats. Control injections of equal volumes of IgG had no effect on MAP or HR. Microinjection of Mab KY-ANP-II into PHA produced no significant alteration in MAP or HR in SHR-S. These data provide the first demonstration that endogenous ANP in a region of brain known to influence cardiovascular function mediates BP and HR control in the rat. These findings suggest that the increased endogenous ANP in the anterior hypothalamus of SHR-S may be involved in the central regulation of BP in the model.

Interleukin-2 does not attenuate hypertension in spontaneously hypertensive rats.

It was recently reported that interleukin-2, when administered as a single bolus injection (5,000 units/kg), could prevent the development of hypertension in young spontaneously hypertensive rats and lower blood pressure to normotensive levels in spontaneously hypertensive rats with established hypertension. Consequently, efforts were made to duplicate this finding. Male spontaneously hypertensive rats (35 days old) were injected subcutaneously with 50,000 units/kg (3,500 units/rat) of recombinant interleukin-2 (Amgen) and had systolic blood pressure measured twice weekly by the tail-cuff technique. Systolic blood pressure in the interleukin-2-treated group was not significantly different from the vehicle-treated control group at any time point over 32 days of follow-up. A second injection of recombinant interleukin-2 (5,000 units/kg) was administered 32 days after the first injection. Again, no reduction in blood pressure was observed in the interleukin-2-treated group over an additional 38 days. Mean arterial pressure (+/- SEM) measured via intra-arterial cannula in conscious rats at age 105 days (38 days after the second treatment) was 168.5 +/- 3.5 mm Hg in interleukin-2-treated spontaneously hypertensive rats and 170.3 +/- 3.6 mm Hg in vehicle-treated controls. Both recombinant interleukin-2 preparations conformed to their respective manufacturer's indicated specific activity as determined by the ability of the interleukin-2 to induce proliferation of the interleukin-2-dependent cell line HT-2. Thus, this study demonstrated that interleukin-2 was ineffective in preventing or attenuating hypertension in spontaneously hypertensive rats.

Atrial natriuretic factor prevents NaCl-sensitive hypertension in spontaneously hypertensive rats.

Our previous studies demonstrated that acute infusion of atrial natriuretic factor (ANF) produces an enhanced depressor response in NaCl-sensitive spontaneously hypertensive rats (SHR-S) fed a high (8%) NaCl diet compared with control SHR-S fed a normal (1%) NaCl diet and that dietary NaCl loading increases circulating ANF levels in Wistar-Kyoto (WKY) rats but not in SHR-S. The current study tested the hypotheses that 1) long-term infusion of ANF at a dose that elevates plasma ANF to levels comparable with those seen in high NaCl-fed WKY rats prevents the NaCl-induced exacerbation of hypertension in SHR-S and 2) ANF lowers blood pressure in this model by a sympatholytic effect. Male SHR-S received infusions of ANF (0.1 microgram/hr) or vehicle intravenously via osmotic minipump for 3 weeks beginning immediately before initiation of 1% or 8% NaCl diets at age 7 weeks. Chronic ANF infusion prevented the increase in arterial pressure in response to a high NaCl diet in SHR-S but had no effect in 1% NaCl-fed SHR-S. Thus, the NaCl-sensitive component of hypertension in SHR-S was more sensitive to ANF than the non-NaCl-sensitive component. Plasma norepinephrine was significantly increased in ANF-treated, 8% NaCl-fed SHR-S compared with vehicle controls, suggesting that ANF did not prevent NaCl-sensitive hypertension by a sympatholytic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrahypothalamic clonidine infusion prevents NaCl-sensitive hypertension.

We have previously shown that dietary NaCl supplementation increases blood pressure and sympathetic nervous system activity in association with decreased norepinephrine release and increased alpha 2-adrenergic receptor number in the anterior hypothalamic area of salt-sensitive spontaneously hypertensive rats (SHR-S) but not in salt-resistant spontaneously hypertensive rats (SHR-R) or Wistar-Kyoto (WKY) rats. Further, acute microinjection of clonidine into the anterior hypothalamic area produced depressor responses that were augmented by high salt feeding in SHR-S but not in SHR-R or WKY rats. The current study tested the hypothesis that chronic infusion of clonidine into the anterior hypothalamic area prevents salt-sensitive hypertension in SHR-S. Beginning at age 7 weeks, immediately before initiation of 1% or 8% salt diets, clonidine (2 ng/min) or saline vehicle was infused into the anterior hypothalamic area or femoral vein of male SHR-S via osmotic minipump for 20 days. In SHR-S fed an 8% salt diet, chronic microinfusion of clonidine into the anterior hypothalamic area offset the hypertensive effect of the dietary salt supplementation and reduced the enhancing effects of dietary salt on left ventricular weight and plasma norepinephrine levels. In contrast, chronic microinfusion of clonidine into the anterior hypothalamic area did not significantly affect any of these measures in 1% salt-fed SHR-S. Intravenous infusion of clonidine at the rate used for the anterior hypothalamic area infusion did not alter any of these measures in 8% salt-fed SHR-S.(ABSTRACT TRUNCATED AT 250 WORDS)

Pressor effect of blocking atrial natriuretic peptide in nucleus tractus solitarii.

Previous studies have shown that microinjection of atrial natriuretic peptide into the caudal nucleus tractus solitarii produces significant increases in local neuronal firing rate associated with reductions in arterial pressure in anesthetized Wistar rats. Single units excited by microinjection of atrial natriuretic peptide into the caudal nucleus tractus solitarii were also excited by activation of arterial baroreceptors and inhibited by baroreceptor unloading. To test the hypothesis that endogenous atrial natriuretic peptide in caudal nucleus tractus solitarii is involved in the tonic control of blood pressure in the rat, we administered a blocking monoclonal antibody to atrial natriuretic peptide in a volume of 50 nl artificial cerebrospinal fluid via microinjection into the caudal nucleus tractus solitarii of spontaneously hypertensive and Wistar-Kyoto rats and observed the effects on mean arterial pressure and heart rate. Control injections of monoclonal antibody were administered into the rostral nucleus tractus solitarii, hypoglossal nucleus, spinal trigeminal nucleus, and cuneate nucleus of spontaneously hypertensive rats. Microinjection of monoclonal antibody into the caudal nucleus tractus solitarii caused significant increases in mean arterial pressure in spontaneously hypertensive rats but not in Wistar-Kyoto rats. There was no concomitant change in heart rate. Control injections of purified mouse immunoglobulin into the caudal nucleus tractus solitarii and of monoclonal antibody into the control neuronal groups listed above had no effect on mean arterial pressure. These results suggest that endogenous atrial natriuretic peptide in the caudal nucleus tractus solitarii mediates tonic control of blood pressure in spontaneously hypertensive rats but not in normotensive Wistar-Kyoto rats.

Impaired release of atrial natriuretic factor in NaCl-loaded spontaneously hypertensive rats.

Our previous studies demonstrated that NaCl-sensitive spontaneously hypertensive rats (SHR) of the Okamoto strain exhibit increased blood pressure and reduced noradrenergic input to the anterior hypothalamus area when fed high NaCl diets. The current study tested the hypotheses that 1) release of atrial natriuretic factor (ANF) into the plasma is impaired in NaCl-loaded SHR, a defect that would tend to elevate blood pressure, and 2) ANF levels in regions of brain involved in blood pressure regulation, such as the anterior hypothalamic area, are altered in SHR. SHR and control Wistar-Kyoto rats (WKY) were placed on 1% or 8% NaCl diets at age 7 weeks; 2 weeks later, ANF levels were measured in plasma, left and right atria, anterior hypothalamic area, ventral hypothalamic area, posterior hypothalamic area, pons, and medulla by radioimmunoassay. Blood for ANF assay was obtained from intra-arterial cannulas in conscious, unrestrained rats studied in the resting state. The 8% NaCl diet produced an increase in blood pressure in the SHR, but not in the WKY. Plasma ANF levels were significantly greater in WKY fed 8% NaCl than in WKY fed 1% NaCl, but dietary NaCl loading did not produce similar increases in plasma ANF in the SHR. Plasma ANF levels were not significantly different between SHR and WKY fed the 1% NaCl diet. The observation that dietary NaCl loading stimulated ANF release into the plasma in WKY but not in SHR suggests that the exacerbation in hypertension seen in NaCl-loaded SHR may be related to an impairment in ANF release.(ABSTRACT TRUNCATED AT 250 WORDS)

NaCl does not affect hypothalamic noradrenergic input in deoxycorticosterone acetate/NaCl and Dahl salt-sensitive rats.

Previous studies from our laboratories demonstrated that dietary NaCl supplementation in NaCl-sensitive spontaneously hypertensive rats elevates blood pressure, increases peripheral sympathetic nervous system activity, and depresses endogenous norepinephrine stores and turnover in the anterior hypothalamus. These findings suggest that reduced noradrenergic input to sympathoinhibitory neurons in anterior hypothalamus contributes to NaCl-sensitive hypertension in spontaneously hypertensive rats. The current study tested the hypothesis that dietary NaCl supplementation depresses endogenous norepinephrine stores and turnover in anterior hypothalamus of two other NaCl-sensitive models of hypertension, the Dahl salt-sensitive rat and the deoxycorticosterone acetate/NaCl hypertensive rat, thus increasing blood pressure by reducing noradrenergic input to the anterior hypothalamus. Dahl salt-sensitive rats were fed a high (8%) NaCl diet, and deoxycorticosterone acetate/NaCl rats rats drank 1% NaCl solution ad libitum for 2 or 4 weeks. Age-matched Dahl salt-sensitive rats fed a basal 1% NaCl diet and uninephrectomized Sprague-Dawley rats drinking tap water were controls. Regional brain catecholamines were determined by high-performance liquid chromatography with electrochemical detection. Norepinephrine turnover in hypothalamus (anterior, posterior, and ventral regions) and brain stem (pons and medulla) was assessed using the dopamine beta-hydroxylase inhibitor 1-cyclohexyl-2-mercapto-imidazole. High NaCl treatment caused significant elevations in blood pressure in Dahl salt-sensitive and deoxycorticosterone acetate/NaCl rats, but endogenous norepinephrine levels and turnover rates were not significantly different in anterior hypothalamus or any other brain region studied between the NaCl-supplemented and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary Ca2+ prevents NaCl-sensitive hypertension in spontaneously hypertensive rats via sympatholytic and renal effects.

NaCl-sensitive spontaneously hypertensive rats (SHR-S) were used to test the hypotheses that dietary Ca2+ supplementation 1) prevents NaCl-sensitive hypertension via a sympatholytic mechanism, and 2) increases diuretic and natriuretic responses to acute volume loading. SHR-S and control WKY rats were begun on one of four diets at age 8 wk: control, high NaCl, high Ca2+, or high NaCl and high Ca2+. In SHR-S, dietary Ca2+ supplementation prevented the NaCl-induced increases in blood pressure and plasma norepinephrine concentrations, the reductions in anterior hypothalamic norepinephrine stores and turnover, and the secondary increases in alpha 2 adrenoceptor number. Thus, Ca2+ prevented NaCl-sensitive hypertension in SHR-S by increasing noradrenergic input to the anterior hypothalamus. High-NaCl-fed SHR-S had impaired diuretic and natriuretic responses to an isotonic volume load; Ca2+ enhanced the ability of these animals to adjust fluid volume rapidly via diuresis and natriuresis. This alteration in renal function may contribute to the hypotensive effect of a high Ca2+ diet in NaCl-sensitive hypertension.

The roles of Nramp1 and Tnfa genes in nitric oxide production and their effect on the growth of Salmonella typhimurium in macrophages from Nramp1 congenic and tumor necrosis factor-alpha-/- mice.

The macrophages from Nramp1 congenic mice and tumor necrosis factor (TNF)-alpha(-/-) mice were used to examine the functions of Nramp1 and Tnfa genes in nitric oxide (NO) production and Salmonella typhimurium infection. It was confirmed that the level of inducible NO synthase (iNOS)-mediated NO production in Nramp1(r) peritoneal macrophages was generally higher than that of Nramp1(s) macrophages after stimulation by interferon-gamma (IFN-gamma), lipopolysaccharide (LPS), and tumor necrosis factor-alpha (TNF-alpha) alone or in combination. Nramp1 mRNA expression in both Nramp1 congenic macrophages was constitutive notwithstanding cytokine stimulation. During infection with S. typhimurium strain 6203, Nramp1(r) macrophages produced a lower amount of NO because of an initial strong reaction and unsustained iNOS gene expression as compared with Nramp1(s) macrophages. An inhibitory effect of the Nramp1(r) gene on bacterial replication was also observed during the early stage of S. typhimurium infection, whereas the effect of TNF-alpha occurred later. NO production and iNOS expression in TNF-alpha(-/-) macrophages were not detected from the start of the bacterial infection or at 24 h after infection. We also observed that S. typhimurium strain 6203 grew more profoundly without TNF-alpha, especially in Nramp1(s) macrophages. These data, therefore, demonstrate that there is cooperation of the Nramp1 and Tnfa genes in NO production and a growth inhibitory effect in response to S. typhimurium infection.

Hypothalamic microinjection of alpha 2-adrenoceptor agonists causes greater sympathoinhibition in spontaneously hypertensive rats on high NaCl diets.

We tested the hypothesis that in NaCl-sensitive spontaneously hypertensive rats (SHR-S) maintained on high NaCl diets, sympathoinhibitory neurons in the anterior hypothalamic area display increased responsiveness to alpha 2-adrenergic receptor stimulation, giving rise to exaggerated depressor responses. Clonidine (0.6-2.5 micrograms) was microinjected directly into the anterior hypothalamic area of SHR-S maintained for 2 weeks on high (8%) and normal (1%) NaCl diets, and blood pressure and heart rate responses were monitored. Controls were NaCl-resistant SHR (SHR-R) and normotensive Wistar-Kyoto (WKY) rats. Clonidine microinjection into the anterior hypothalamic area resulted in dose-dependent rapid-onset depressor and bradycardic responses that were significantly greater in SHR-S fed on a high NaCl diet. In SHR-R and WKY rats, the high NaCl diet had no significant effect on blood pressure or heart rate responses to clonidine. Further studies demonstrated that the response to microinjection of clonidine into the rat anterior hypothalamic area was location-specific, since injections into surrounding hypothalamic nuclei gave a longer latency in the onset of either depressor and bradycardic responses or pressor and tachycardic responses. The response of clonidine was blocked by concurrent microinjection of the selective alpha 2-adrenergic antagonist rauwolscine but not by the alpha 1-adrenergic antagonist prazosin, confirming that the response was alpha 2-adrenoceptor-specific. Microinjection of the selective alpha 2-agonist guanabenz into the anterior hypothalamic area produced depressor and bradycardic responses in SHR-S and Sprague-Dawley rats, while microinjection of the selective alpha 1-agonist phenylephrine into the anterior hypothalamic area had no effect on either blood pressure or heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary Ca2+ prevents NaCl-induced exacerbation of hypertension and increases hypothalamic norepinephrine turnover in spontaneously hypertensive rats.

Dietary calcium (Ca2+) supplementation lowers blood pressure in many forms of genetically mediated and experimentally induced hypertension. The present study tested the hypothesis that neuronal mechanisms underlie the blood pressure-lowering effect of dietary Ca2+ in NaCl-sensitive spontaneously hypertensive rats (SHR-S). SHR-S were fed one of the following diets: control (0.75% NaCl/0.68% Ca2+); high NaCl (8.00% NaCl/0.68% Ca2+); high Ca2+ (0.75% NaCl/2.00% Ca2+), and high NaCl/high Ca2+ (8.00% NaCl/2.00% Ca2+). SHR-S on the 8% NaCl diet for 2 weeks displayed significantly elevated blood pressure (161 +/- 4 mmHg) compared with those on the control diet (139 +/- 3 mmHg). Ca2+ supplementation prevented a rise in blood pressure in rats on the high-NaCl diet but did not alter blood pressure in rats consuming 0.75% NaCl. Plasma norepinephrine stores and turnover in the hypothalamus (anterior and posterior regions), brainstem (pons and medulla) and thoracic spinal cord were assessed using the dopamine-beta-hydroxylase inhibitor 1-cyclohexyl-2-mercapto-imidazole. The 8% NaCl diets reduced anterior hypothalamic region norepinephrine stores and turnover. Concomitant Ca2+ supplementation restored norepinephrine turnover to normal, but did not alter norepinephrine stores in the anterior hypothalamic region. In other regions, no significant differences in norepinephrine content or turnover were observed among groups. In SHR that are resistant to high-NaCl diets (SHR-R), the diets did not alter blood pressure, and neither dietary NaCl nor Ca2+ supplementation affected norepinephrine turnover in any brain region studied. These data indicate that in SHR-S on a diet high in NaCl, Ca2+ supplementation may prevent the NaCl-induced exacerbation of hypertension by increasing norepinephrine turnover in the hypothalamus.

Suppression by a sesquiterpene lactone from Carpesium divaricatum of inducible nitric oxide synthase by inhibiting nuclear factor-kappaB activation.

Excessive nitric oxide (NO) produced by inducible NO synthase (iNOS) acts as a causative regulator in various inflammatory disease states. Carpesium divaricatum has been used in Korean traditional herbal medicine for its antipyretic, analgesic, vermifugic, and anti-inflammatory properties. We investigated the molecular mechanism for the suppression of lipopolysaccharide/interferon-gamma (LPS/IFN-gamma)-induced NO production in RAW 264.7 macrophages by the sesquiterpene lactone 2beta,5-epoxy-5,10-dihydroxy-6alpha-angeloyloxy-9beta-isobutyloxy-germacran-8alpha,12-olide (C-1), which has been identified recently as a new compound from C. divaricatum. C-1 decreased NO production in LPS/IFN-gamma-stimulated RAW 264.7 cells in a concentration-dependent manner, with an IC50 of approximately 2.16 microM; however, it had no direct effect on the iNOS activity of fully LPS/IFN-gamma-stimulated RAW 264.7 cells. Furthermore, treatment with C-1 led to a decrease in iNOS protein and mRNA. These effects appear to be due to inhibition of nuclear factor-kappaB (NF-kappaB) activation through a mechanism involving stabilization of the NF-kappaB/inhibitor of the kappaB (I-kappaB) complex, since inhibition of NF-kappaB DNA binding activity by C-1 was accompanied by a parallel reduction of nuclear translocation of subunit p65 of NF-kappaB and I-kappaBalpha degradation. Taken together, the results suggest that the ability of C-1 to inhibit iNOS gene expression may be responsible, in part, for its anti-inflammatory effects.

Altered stores of atrial natriuretic peptide in specific brain nuclei of NaCl-sensitive spontaneously hypertensive rats.

Previous studies from our laboratories have demonstrated a selective increase in stores of atrial natriuretic peptide (ANP) in the anterior hypothalamus of NaCl-sensitive spontaneously hypertensive rats (SHR-S) compared to NaCl-resistant Wistar-Kyoto (WKY) controls and have suggested that anterior hypothalamic ANP contributes to the pathogenesis of NaCl-sensitive hypertension in SHR-S by local inhibition of norepinephrine release. We have also observed blunting of cardiopulmonary and arterial baroreflex function in SHR-S compared to WKY. In the current study, ANP stores in 12 brain nuclei thought to participate in the pathogenesis of hypertension, including locus coeruleus (LC), A1/C1 area (A1/C1), nucleus tractus solitarii (NTS), medial preoptic nucleus (MPON), suprachiasmatic nucleus (SCN), supraoptic nucleus (SON), anterior hypothalamic area (AHA), paraventricular hypothalamic nucleus (PVN), ventromedial hypothalamic nucleus (VMN), dorsomedial hypothalamic nucleus (DMN), lateral hypothalamic nucleus (LN), and posterior hypothalamic area (PHA), were compared in 10-week-old male SHR-S and WKY rats following 3 weeks of 1% v 8% NaCl feeding. Individual brain nuclei were obtained by the micropunch technique and ANP content of bilateral brain nuclei from individual rats was measured by radioimmunoassay. ANP content was significantly decreased in NTS and LC and elevated in AHA of SHR-S compared to WKY rats on either diet. Dietary NaCl supplementation was associated with increased ANP content in PVN of both strains. These alterations in ANP content in SHR-S may be related to the reduced release of norepinephrine from nerve terminals in AHA and to the presumed central defect in baroreceptor function.

Central mechanisms of hypertension.

Central monoaminergic neurons, particularly noradrenergic neurons, are involved in the pathogenesis of hypertension. Dietary NaCl supplementation in NaCl-sensitive spontaneously hypertensive rats (SHR-S) elevates blood pressure, increases peripheral sympathetic nervous system activity, and depresses endogenous noradrenaline stores and noradrenaline release in the anterior hypothalamus (AHA). NaCl-resistant spontaneously hypertensive rats (SHR-R) and normotensive Wistar-Kyoto (WKY) rats are resistant to the NaCl-induced alterations in blood pressure and central and peripheral noradrenergic activity, whereas uninephrectomized Sprague-Dawley rats treated with DOCA + NaCl and Dahl-S rats receiving dietary NaCl supplementation develop NaCl-induced increments in blood pressure, but not depressed AHA noradrenaline release. The AHA is a major cardiovascular regulatory region, and depressor responses elicited by pharmacological (alpha 2-adrenoceptor) stimulation of this area are exaggerated in SHR-S fed a high NaCl diet compared to SHR-S fed a basal diet and SHR-R and WKY fed a high or basal NaCl diet. alpha 2-Adrenoceptors in the AHA are increased in number in SHR-S fed a high NaCl diet, presumably reflecting upregulation in response to reduced local noradrenaline release. These findings are consistent with the hypothesis that decreased noradrenergic activity of sympathoinhibitory neurons in the AHA may mediate the exacerbation in hypertension that occurs in SHR-S during dietary NaCl supplementation.

Dietary Ca2+ prevents NaCl-sensitive hypertension in spontaneously hypertensive rats by a sympatholytic mechanism.

The current study tested the hypothesis that dietary Ca2+ supplementation reverses the NaCl-sensitive component of hypertension and the associated neurochemical abnormalities in the NaCl-sensitive spontaneously hypertensive rat (SHR-S). Male SHR-S were begun on one of four diets at 8 weeks of age: control (0.75% NaCl/0.68% Ca2+); high NaCl (8.00% NaCl/0.68% Ca2+); high Ca2+ (0.75% NaCl/2.00% Ca2+); and high NaCl/high Ca2+ (8.00% NaCl/2.00% Ca2+). High NaCl SHR-S (X2 weeks) had higher mean arterial pressure (MAP) (161 +/- 4 mm Hg) than controls (149 +/- 3 mm Hg; P less than .05). Supplementation with Ca2+ prevented the rise in MAP in high NaCl rats, but did not alter MAP in controls. The 8% NaCl diet elevated plasma norepinephrine and reduced anterior hypothalamic (AHA) norepinephrine stores and turnover; concomitant Ca2+ supplementation restored both plasma norepinephrine and AHA norepinephrine turnover to normal. Clonidine was microinjected into the AHA of rats maintained on the four diets for 2 weeks to test the hypothesis that dietary Ca2+ supplementation prevents the previously observed NaCl-induced upregulation of alpha 2-adrenoceptors in AHA. Clonidine caused dose-dependent decreases in MAP that were greater in high NaCl rats than in controls. The Ca2+ supplementation prevented the exaggerated depressor response to clonidine in the high NaCl group, but not in the controls. The Ca2+ supplementation had no effect on pretreatment MAP or on MAP responses to clonidine in control NaCl-resistant SHR (SHR-R) or Wistar-Kyoto (WKY) rats. Thus, dietary Ca2+ supplementation prevents the NaCl-induced exacerbation of hypertension and augmented depressor response to clonidine in SHR-S by increasing noradrenergic input to AHA, thereby preventing the upregulation of AHA alpha 2-adrenoceptors.

Dietary NaCl loading enhances antihypertensive effect of guanabenz in spontaneously hypertensive rats.

Our previous studies demonstrated that high dietary NaCl intake causes increases in blood pressure and plasma norepinephrine (NE) levels and a decrease in NE release associated with local upregulation of alpha 2-adrenoceptor number in the anterior hypothalamic area (AHA) of NaCl-sensitive spontaneously hypertensive rats (SHR-S). Further, acute microinjection of clonidine into the AHA of SHR-S fed a high NaCl diet resulted in greater depressor and bradycardic responses than in SHR-S receiving a normal NaCl diet. The current study tested the hypothesis that the antihypertensive effect of chronic systemic administration of guanabenz (0.24 micrograms/kg/min, IV) is enhanced in SHR-S maintained on a high (8%) NaCl diet than in control rats on a normal (1% NaCl) diet. After two weeks on the diets, mean arterial pressure (MAP) and heart rate (HR) were measured and blood for NE and epinephrine (E) assay was collected from intra-arterial cannulas in conscious, unrestrained rats. The ratio of left ventricle and septum to body weight (LV + S/BW) was determined. Chronic infusion of guanabenz significantly decreased MAP (P less than .05), HR (P less than .01) and LV + S/BW (P less than .01) in 8% NaCl fed SHR-S, but not in 1% NaCl fed SHR-S (P greater than .1). Guanabenz tended to reduce plasma NE levels in 8% NaCl fed SHR-S (.1 greater than P greater than .05), but not in 1% NaCl fed rats (P greater than .1).(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic peptide lowers pulmonary arterial pressure in hypoxia-adapted rats.

To test the hypothesis that atrial natriuretic peptide (ANP) has a direct vasodilator effect on the pulmonary vasculature that is enhanced in hypoxia-induced pulmonary hypertension in the rat, we determined the effects of ANP on mean pulmonary (MPAP) and systemic arterial pressure (MSAP) in intact conscious Sprague-Dawley rats exposed to 10% O2 or room air for 4 wk. Catheters were placed in the pulmonary artery through the right jugular vein by means of a closed-chest technique. MPAP and MSAP were monitored before and after intravenous injections of graded doses of ANP. ANP produced dose-related decreases in MPAP that were greater in the hypoxic group than in air controls. There were no significant between-group differences in the systemic depressor responses to ANP or in the ANP-induced reduction in cardiac output. ANP lowered MPAP significantly in isolated perfused lungs from both hypoxia-adapted and air control rats, and this effect was significantly greater in the hypoxic than the air control lungs. These data indicate that ANP lowers pulmonary arterial pressure in rats with hypoxia-induced pulmonary hypertension, mainly by a direct vasodilator effect on the pulmonary vasculature.

Hemodynamic effects of arginine vasopressin in rats adapted to chronic hypoxia.

Acute and chronic pulmonary and systemic hemodynamic responses to arginine vasopressin (AVP) were examined in 4-wk hypoxia-adapted and air control rats. AVP, administered intravenously as bolus injections or sustained infusions, produced major dose-dependent V1-receptor-mediated reductions in mean pulmonary arterial pressure in hypoxia-adapted rats. These effects were comparable in pentobarbital-anesthetized, thoracotomized animals and in conscious, intact rats. Chronic infusions of AVP induced a sustained reduction in mean pulmonary arterial pressure and partially prevented the development of pulmonary hypertension without changing systemic arterial pressure. AVP induced significant decreases in cardiac output in both groups; the cardiac output response was not significantly different in hypoxia-adapted and air control animals. AVP induced almost no change in MPAP in air control rats. Furthermore the systemic pressor effects of AVP were significantly blunted in hypoxia-adapted rats compared with air controls. We conclude that the pulmonary depressor and blunted systemic pressor effects of AVP observed in hypoxia-adapted rats may be related to release of a vasodilator, such as endothelium-derived relaxing factor, vasodilator prostaglandins, or atrial natriuretic peptides. Further study is needed to elucidate these mechanisms and assess the usefulness of AVP and/or its analogues in the treatment and prevention of hypoxia-induced pulmonary hypertension.