Established Hypertension Research Articles

Histone Deacetylation Inhibition in Pulmonary Hypertension

Background— Epigenetic programming, dynamically regulated by histone acetylation, is a key mechanism regulating cell proliferation and survival. Little is known about the contribution of histone deacetylase (HDAC) activity to the development of pulmonary arterial hypertension, a condition characterized by profound structural remodeling of pulmonary arteries and arterioles. Methods and Results— HDAC1 and HDAC5 protein levels were elevated in lungs from human idiopathic pulmonary arterial hypertension and in lungs and right ventricles from rats exposed to hypoxia. Immunohistochemistry localized increased expression to remodeled vessels in the lung. Both valproic acid, a class I HDAC inhibitor, and suberoylanilide hydroxamic acid (vorinostat), an inhibitor of class I, II, and IV HDACs, mitigated the development of and reduced established hypoxia-induced pulmonary hypertension in the rat. Both valproic acid and suberoylanilide hydroxamic acid inhibited the imprinted highly proliferative phenotype of fibroblasts and R-cells from pulmonary hypertensive bovine vessels and platelet-derived growth factor–stimulated growth of human vascular smooth muscle cells in culture. Exposure to valproic acid and suberoylanilide hydroxamic acid was associated with increased levels of p21 and FOXO3 and reduced expression of survivin. The significantly higher levels of expression of cKIT, monocyte chemoattractant protein-1, interleukin-6, stromal-derived factor-1, platelet-derived growth factor-b, and S100A4 in R-cells were downregulated by valproic acid and suberoylanilide hydroxamic acid treatment. Conclusions— Increased HDAC activity contributes to the vascular pathology of pulmonary hypertension. The effectiveness of HDAC inhibitors, valproic acid, and suberoylanilide hydroxamic acid, in models of pulmonary arterial hypertension supports a therapeutic strategy based on HDAC inhibition in pulmonary arterial hypertension.

Old dog, new tricks: Therapeutic potential of the NO pathway in pulmonary hypertension

The NO signaling pathway is of major importance for regulation of pulmonary vascular tone. Inhalation of exogenous NO in patients with pulmonary arterial hypertension (PAH) results in selective pulmonary vasodilation, while limitations of chronic NO therapy in pulmonary hypertension include the need of continuous administration, methaemoglobinemia formation and the fact that NO does not induce pulmonary vasodilation in all PAH patients. A major breakthrough for treatment of PAH was the introduction of the phosphodiesterase (PDE) type 5 inhibitor sildenafil. PDE 5 inhibition stabilizes the second messenger cGMP that is produced by the soluble guanylate cyclase (sGC) upon binding of NO. However, the efficacy of PDE5 inhibitors is critically dependent on the synthesis of cGMP by an intact NO pathway. Reduced cGMP production might be explained by limited NO bioavailability either by reduced biosynthesis (down regulation or dysfunction of eNOS) or increased NO scavenging (e.g. oxidative stress). Therefore, stimulation of the NO/sGC/cGMP pathway downstream to NO seems an appealing therapeutical strategy. Recently, the pharmacological sGC stimulator Riociguat was shown to be a systemic and pulmonary vasodilator. Moreover, this compound has shown to produce beneficial effects in animal models of pulmonary hypertension. Chronic treatment of animals with established pulmonary hypertension with Riociguat could reverse right ventricular hypertrophy and structural remodeling of the lung vasculature. Riociguat has also been investigated clinically in terms of pharmacokinetics, pharmacodynamics, safety, tolerability and efficacy. Based on positive clinical findings, the efficacy of Riociguat is currently addressed in two placebo controlled multicenter phase 3 trials in pulmonary arterial hypertension (PATENT) and chronic thromboembolic pulmonary hypertension (CHEST).

Exercise-Induced Pulmonary Hypertension

Exercise stress tests of the pulmonary circulation show promise for the detection of early or latent pulmonary vascular disease and may help us understand the clinical evolution and effects of treatments in patients with established disease. Exercise stresses the pulmonary circulation through increases in cardiac output and left atrial pressure. Recent studies have shown that exercise-induced increase in pulmonary artery pressure is associated with dyspnea-fatigue symptomatology, validating the notion of exercise-induced pulmonary hypertension. Exercise in established pulmonary hypertension has no diagnostic relevance, but may help in the understanding of changes in functional state and the effects of therapies.

Glucose perturbations and cardiovascular risk: Challenges and opportunities

People with disturbed glucose metabolism are at an increased risk for cardiovascular disease. This risk starts before diabetes, according to present definitions, is established. Early detection of impaired glucose tolerance and target-driven multifactorial management incorporating all risk factors in a broad sense may effectively improve the prognosis for these persons. Management includes early detection of glucose perturbations and preventing or delaying future diabetes among people with impaired glucose tolerance. In people with established diabetes, hypertension, hyperlipidaemia and hyperglycaemia are all important factors to monitor and, if these are above the recommended levels, to treat, first hand with lifestyle-oriented recommendations, although usually supported by pharmacological interventions. Since impaired glucose tolerance and type 2 diabetes mellitus are rapidly increasing in the population, glucose perturbations as the cause of cardiovascular disease manifestations will become more common. Development of macrovascular complications substantially impacts care costs, and proper management of these individuals will therefore not only decrease personal suffering but also clearly impact health care expenditures.

Cardiac sympathetic hyperinnervation in deoxycorticosterone acetate-salt hypertensive rats

Sympathetic activities are elevated in the central SNSs (sympathetic nervous systems) of hypertensive animals, but it is not known whether sympathetic innervation is also elevated in the heart. Sympathetic hyper-responsiveness in hypertension may result from oxidative stress. The aim of the present study was to investigate sympathetic hyperinnervation in DOCA (deoxycorticosterone acetate)-salt hypertensive rats with established hypertension. At 4 weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 8 weeks: vehicle, NAC (N-acetylcysteine) and triple therapy (hydralazine, hydrochlorothiazide and reserpine). DOCA-salt was associated with increased oxidant release. DOCA-salt produced concentric left ventricular hypertrophy and cardiomyocyte hypertrophy. Sympathetic hyperinnervation was observed in DOCA-salt rats, as assessed by myocardial noradrenaline levels, immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and Western blotting and real-time quantitative RT-PCR (reverse transcription-PCR) of NGF (nerve growth factor). Arrhythmic scores during programmed stimulation in DOCA-salt rats were significantly higher than those in the control rats. Triple therapy, despite being effective on BP (blood pressure), offered neither attenuated cardiomyocyte hypertrophy nor anti-arrhythmia. The effects of DOCA-salt treatment on NGF expression, sympathetic hyperinnervation and arrhythmias were attenuated by NAC. Furthermore, the effects of NAC on NGF were abolished by administering BSO (L-buthionine sulfoximine), an inhibitor of glutamate-cysteine ligase. In conclusion, DOCA-salt treatment contributes to up-regulation of NGF proteins probably through a free radical-dependent pathway in a BP-independent manner. DOCA-salt rats treated with NAC attenuate sympathetic hyperinnervation and thus show a beneficial effect on arrhythmogenic response to programmed electrical stimulation.

Abstract 118: Home Blood Pressure Monitoring Program improves Management of Hypertension

Objectives: Regular self-monitoring of blood pressure is an important aspect of the management of hypertension; it enables the hypertensive patient makes better lifestyle choices informed by the measurements obtained from their blood pressure devices. The BP monitoring program by the Center for Connected Health is aimed at empowering patients to better self-manage their health and facilitating improved communication between patients and providers. This study aimed to evaluate the effectiveness of the blood pressure connect program on lowering blood pressures of participants in the program. Methods: The Blood Pressure Connect is a home monitoring program enabling patients to easily collect their blood pressure readings, monitor trends and also share their readings with their providers. Patients measure their blood pressures and upload to a secure web-based platform via modem connection with a home telephone line. Of the 277 hypertensive patients from several Partners affiliated centers enrolled in the program between 7/10/2009 and 11/18/2011, 219 patients aged 22-90 years (59±13 years) were included in the analysis; and 58 (21%) patients were excluded from analysis because they either have only one blood pressure reading or did not upload their blood measurements at all. Paired t-test was used to assess mean change in systolic blood pressure (SBP). Results: Average interval between baseline and final blood pressure measurements was 154 days. According to the JNC-7 classification of blood pressures, 11% had normal SBP, 48% were pre-hypertensive, 30% had stage 1 hypertension and 11% had stage 2 hypertension. Overall, SBP decreased by 6mmHg (95% CI= 4 -8mmHg, p-value <0.0001). SBP decreased by 1mmHg (95% CI=-2 -3mmHg p-value = 0.51), 12mmHg (95% CI= 8 -15mmHg, p-value < 0.0001) and 25mmHg (95% CI=18 - 32mmHg p-value <0.0001) in pre-hypertensive, stage 1 and stage 2 hypertension respectively but increased by -7mmHg (95% CI= -13 - 1mmHg) in those with normal blood pressure. Conclusion: The results show that the program is extremely successful in helping lower the blood pressures of patients with hypertension. These patients belong to a variety of practices, are on different medications and for disparate lengths of time. Despite these differences, all active patients had very similar changes in blood pressure, varying only by their starting blood pressure. Those with established hypertension (stage 1 or 2) saw the most significant change, indicating where the maximum rewards of this program lie. These results reflect the applicability of remote monitoring tools in managing chronic conditions effectively and efficaciously.

Impaired cardiac norepinephrine transport in the hypertensive rat

Hypertension is associated with upregulation of sympathetic cardiac responsiveness both pre and post‐synaptically. Enhanced cardiac norepinephrine (NE) release has been reported in prehypertensive and hypertensive spontaneously hypertensive rats (SHR) compared to normotensive controls (WKY). This phenotype might result from defective NET‐1 transport (uptake‐1). A novel fluorescent substrate of the NE reuptake transporter (NET) was used to investigate NE reuptake kinetics in isolated sympathetic stellate and superior cervical ganglia (SCG) neural cells from SHRs and age‐matched WKY rats. Pre‐hypertensive SHR, and those with established hypertension were studied. Decreased rate of NET (~24%) in stellate ganglion neurons from the SHR at both developmental ages (4 week SHR, n=24, WKY, n=21, P<0.05, unpaired t test, 16 week SHR, n=20, WKY, n=19, P<0.05, unpaired t test) was observed when compared to the WKY response. No difference in re‐uptake rate was seen in cells from the SCG, a major sympathetic ganglia whose innervations predominantly supplies the face. Electrical stimulation of stellate neurons exacerbated the re‐uptake difference of NE between SHR and WKY cells. These results suggest that cardiac sympathetic hyper‐responsiveness is in part due to slowed NE reuptake in the SHR, and this defect occurs before the actual onset of hypertension. Furthermore the NET impairment was not observed in another (non‐cardiac) sympathetic ganglia.

Does hypertension affect morphometric parameters of phrenic nerves?

We previously reported [1] important differences in phrenic nerve morphology between normotensive Wistar‐Kyoto and spontaneoulsy hypertensive rats (SHR) but the question whether the differences are due to hypertension or intrinsic to the rat strains still remains. We aimed to investigate the phrenic nerve morphology in young normotensive SHR and adult SHR with well established hypertension. Female SHR aged 5 (N=6) or 20 (N=6) weeks were anesthetized for arterial pressure (AP) recording. Proximal and distal segments of the right and left phrenic nerves were removed and prepared for epoxy resin embedding and light microscopy morphometry. Adult rats showed significantly higher body weight and AP, compared to young animals. Phrenic nerves showed morphologic and morphometric lateral and longitudinal symmetry for both groups but were significantly larger on older animals. Myelinated fiber area and diameter were also larger on older animals but their number was not different between groups. Myelinated axons were larger on older animals but the G ratio was not different between groups. As expected, aging affected phrenic nerve fascicle and myelinated fibers size with no alteration in fiber number. Also, hypertension development did not affect morphological parameters considered important for myelinated fiber function.Grant Funding Source : FAPESP, CNPq, CAPES and FAEPA

Angiotensin-(1–7) upregulates central nitric oxide synthase in spontaneously hypertensive rats

Increased blood pressure in hypertension is hypothesized to be caused by high sympathetic nervous system (SNS) activity. Since Ang (1–7) exerts an inhibitory neuromodulatory effect on the SNS through a NO-mediated mechanism, we tested the hypothesis that Ang (1–7) alters centrally nitric oxide synthase (NOS) activity and expression in spontaneously hypertensive rats (SHR). Since NOS activity is altered in relation to the development of hypertension in rats, we evaluated the effect of Ang-(1–7) on hypothalamic NOS activity in two different ages in SHR, corresponding to a prehypertensive phase (3–4weeks) and a established hypertension (13–14weeks) and compared with age-matched Wistar-Kyoto (WKY) rats. NOS activity was measured by the conversion of [3H]l-arginine to citrulline . Ang-(1–7) caused an impairment in NOS activity in prehypertensive SHR (26±4% reduction), while it induced an increase in NOS activity at established hypertension (48±9% increase). In contrast, Ang-(1–7) did not modify NOS activity in age-matched WKY rats. In another set of experiments, Ang-(1–7) was injected into the anterior hypothalamic area, mean arterial blood pressure (MAP) was registered and after 30, 60 and 180min nNOS expression was evaluated by Western-blot. Ang-(1–7) decreased MAP after 10min of injection and this effect was blocked by a NOS inhibitor. nNOS expression increased after 180min of Ang-(1–7) intrahypothalamic injection in both WKY and SHR (WKY: 3.6-fold increase above basal; SHR: 1.85-fold increase above basal). Our results suggest that Ang-(1–7) upregulates hypothalamic NOS in a hypertensive state as a compensatory and protective mechanism to combat hypertension.

The effects of repeated delivery of angiotensin II AT1 receptor antisense on distinct vasoactive systems in Ren-2 transgenic rats: young vs. adult animals

Although Ren-2 transgenic rat (TGR) is defined as a model of angiotensin II-dependent hypertension, we studied whether the renin-angiotensin system (RAS) is really the main contributor to blood pressure (BP) elevation in hetero- and homozygous TGRs. Moreover, we examined whether repeated antisense (AS) therapy against AT(1) receptors would have a similar effect on the BP and the contribution of the principle vasoconstrictor/vasodilator systems to BP regulation in young and adult TGRs. From the age of 30 (young) and 100 (adult) days, rats were injected with AS for 40 days in 10-day intervals. After 10 and 40 days of AS therapy, the basal BP and acute BP responses to the sequential blockade of the RAS, sympathetic nervous (SNS) and nitric oxide systems were determined in conscious rats. The RAS system was the major system maintaining elevated BP in young homozygous animals, whereas there was an increasing contribution of the SNS in heterozygous TGR with age. The AS therapy in the young TGR had a transient BP-lowering effect that was associated with reduced cardiac hypertrophy; the AS therapy was most effective in young homozygous TGR, causing a substantial reduction of angiotensin-dependent vasoconstriction. In heterozygous rats, AS therapy at earlier stages was related to an inhibition of sympathetic vasoconstriction, whereas to RAS inhibition in established hypertension. In conclusion, repeated AS therapy had transient antihypertensive effects exclusively in young TGR. The contribution of the RAS to BP maintenance is highly important only in homozygous TGRs, whereas it is surpassed by SNS in heterozygous TGR.

Hypertension in women

Hypertension is an important modifiable risk factor for cardiovascular (CV) morbidity and mortality, and a highly prevalent condition in both men and women. However, the prevalence of hypertension is predicted to increase more among women than men. Combined oral contraceptives (COCs) can induce hypertension in a small group of women and, increase CV risk especially among those with hypertension. Both COC-related increased CV risk and blood pressure (BP) returns to pretreatment levels by 3 months of its discontinuation. The effects of menopause and hormone replacement therapy (HRT) on BP are controversial, and COCs and HRT containing the new generation progestin drospirenone are preferred in women with established hypertension. Despite the high incidence of cancer in women, CV disease remains the major cause of death in women and comparable benefit of antihypertensive treatment have been demonstrated in both women and men.

Therapeutic efficacy of TBC3711 in monocrotaline-induced pulmonary hypertension.

BackgroundEndothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats.MethodsMonocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed.ResultsThe novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling.ConclusionThe results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension.

Heme oxygenase, a novel target for the treatment of hypertension and obesity?

Heme oxygenase (HO) is the rate-limiting enzyme in the metabolism of heme-releasing bioactive molecules carbon monoxide (CO), biliverdin, and iron, each with beneficial cardiovascular actions. Biliverdin is rapidly reduced to bilirubin, a potent antioxidant, by the enzyme biliverdin reductase, and iron is rapidly sequestered by ferritin in the cell. Several studies have demonstrated that HO-1 induction can attenuate the development of hypertension as well as lower blood pressure in established hypertension in both genetic and experimental models. HO-1 induction can also reduce target organ injury and can be beneficial in cardiovascular diseases, such as heart attack and stroke. Recent studies have also identified a beneficial role for HO-1 in the regulation of body weight and metabolism in diabetes and obesity. Chronic HO-1 induction lowers body weight and corrects hyperglycemia and hyperinsulinemia. Chronic HO-1 induction also modifies the phenotype of adipocytes in obesity from one of large, cytokine producing to smaller, adiponectin producing. Finally, chronic induction of HO-1 increases oxygen consumption, CO(2), and heat production and activity in obese mice. This review will discuss the current understanding of the actions of the HO system to lower blood pressure and body weight and how HO or its metabolites may be ideal candidates for the development of drugs that can both reduce blood pressure and lower body weight.

How NaCl raises blood pressure: a new paradigm for the pathogenesis of salt-dependent hypertension

Excess dietary salt is a major cause of hypertension. Nevertheless, the specific mechanisms by which salt increases arterial constriction and peripheral vascular resistance, and thereby raises blood pressure (BP), are poorly understood. Here we summarize recent evidence that defines specific molecular links between Na(+) and the elevated vascular resistance that directly produces high BP. In this new paradigm, high dietary salt raises cerebrospinal fluid [Na(+)]. This leads, via the Na(+)-sensing circumventricular organs of the brain, to increased sympathetic nerve activity (SNA), a major trigger of vasoconstriction. Plasma levels of endogenous ouabain (EO), the Na(+) pump ligand, also become elevated. Remarkably, high cerebrospinal fluid [Na(+)]-evoked, locally secreted (hypothalamic) EO participates in a pathway that mediates the sustained increase in SNA. This hypothalamic signaling chain includes aldosterone, epithelial Na(+) channels, EO, ouabain-sensitive α(2) Na(+) pumps, and angiotensin II (ANG II). The EO increases (e.g.) hypothalamic ANG-II type-1 receptor and NADPH oxidase and decreases neuronal nitric oxide synthase protein expression. The aldosterone-epithelial Na(+) channel-EO-α(2) Na(+) pump-ANG-II pathway modulates the activity of brain cardiovascular control centers that regulate the BP set point and induce sustained changes in SNA. In the periphery, the EO secreted by the adrenal cortex directly enhances vasoconstriction via an EO-α(2) Na(+) pump-Na(+)/Ca(2+) exchanger-Ca(2+) signaling pathway. Circulating EO also activates an EO-α(2) Na(+) pump-Src kinase signaling cascade. This increases the expression of the Na(+)/Ca(2+) exchanger-transient receptor potential cation channel Ca(2+) signaling pathway in arterial smooth muscle but decreases the expression of endothelial vasodilator mechanisms. Additionally, EO is a growth factor and may directly participate in the arterial structural remodeling and lumen narrowing that is frequently observed in established hypertension. These several central and peripheral mechanisms are coordinated, in part by EO, to effect and maintain the salt-induced elevation of BP.

Isomer-specific effects of conjugated linoleic acid on blood pressure, adipocyte size and function

Obesity-related hypertension may be caused by activation of the local adipose tissue renin-angiotensin system, resulting in exaggerated production of the vasoconstrictor angiotensin II. Additionally, secretion of adiponectin from adipose tissue, which prevents endothelial dysfunction, is altered in obesity. Consumption of conjugated linoleic acid (CLA) has been shown to modulate cytokine release from adipocytes and positively influence blood pressure in younger rats, but its physiological actions in older models with established hypertension and isomer-specific effects on adipocyte size remain to be determined. Therefore, we investigated the effects of CLA isomers on adipocyte size in relation to blood pressure and adipokine production by hypertrophic adipocytes in older fa/fa Zucker rats with established hypertension. fa/fa Zucker rats were fed with cis(c)9, trans(t)11-CLA or t10, c12-CLA isomers for 8 weeks and compared with lean and obese rats fed with the control diet. Blood pressure and adipocyte size were subsequently measured. Collagenase-isolated adipocytes were size-separated and angiotensinogen and adiponectin protein levels quantified by Western blotting. The t10, c12-CLA group had reduced blood pressure, fewer large adipocytes and increased serum adiponectin. Angiotensinogen was present at higher levels in the large adipocytes, whereas the converse was observed for adiponectin. The beneficial effects of the t10, c12-CLA isomer on blood pressure and adipocyte size in vivo may be due to its ability to reduce the number of large adipocytes, which alters the levels of vasoactive molecules secreted from adipose tissue.

Praziquantel reverses pulmonary hypertension and vascular remodeling in murine schistosomiasis.

Schistosomiasis is the most common worldwide cause of pulmonary arterial hypertension. The anti-schistosome drug praziquantel has been shown to reverse the liver fibrosis associated with Schistosoma mansoni in mice. We sought to determine whether praziquantel reverses established pulmonary vascular remodeling and pulmonary hypertension in a mouse model of S. mansoni. Mice were infected percutaneously with S. mansoni. At 17 weeks after infection mice were either killed or received two doses of praziquantel or vehicle by oral gavage. Treated mice were studied at 25 weeks after infection. Vehicle-treated mice demonstrated significant increases in right ventricular systolic pressures (RVSP) and right ventricular hypertrophy (RVH) at 25 weeks, accompanied by pulmonary vascular remodeling. The degree of vascular remodeling correlated with proximity to granulomas. The elevation of RVSP and RVH at 25 weeks was dependent on the presence of eggs in the lung. Praziquantel eliminated the production of eggs in feces and led to clearance of eggs from the lung and to a lesser extent from liver. Praziquantel prevented the rise in RVSP and RVH seen in vehicle-treated mice and reversed established pulmonary vascular remodeling. Praziquantel significantly reduced lung mRNA expression of IL-13, IL-8, and IL-4, but did not reduce serum cytokine levels. The development of pulmonary hypertension associated with S. mansoni infection can be prevented by praziquantel, and established vascular remodeling can be reversed. The mechanism involves clearance of lung eggs and reduced local expression of lung cytokines.

Altered Neural and Vascular Mechanisms in Hypertension

Essential hypertension is a multifactorial disorder which belongs to the main risk factors responsible for renal and cardiovascular complications. This review is focused on the experimental research of neural and vascular mechanisms involved in the high blood pressure control. The attention is paid to the abnormalities in the regulation of sympathetic nervous system activity and adrenoceptor alterations as well as the changes of membrane and intracellular processes in the vascular smooth muscle cells of spontaneously hypertensive rats. These abnormalities lead to increased vascular tone arising from altered regulation of calcium influx through L-VDCC channels, which has a crucial role for excitation-contraction coupling, as well as for so-called "calcium sensitization" mediated by the RhoA/Rho-kinase pathway. Regulation of both pathways is dependent on the complex interplay of various vasodilator and vasoconstrictor stimuli. Two major antagonistic players in the regulation of blood pressure, i.e. sympathetic nervous system (by stimulation of adrenoceptors coupled to stimulatory and inhibitory G proteins) and nitric oxide (by cGMP signaling pathway), elicit their actions via the control of calcium influx through L-VDCC. However, L-type calcium current can also be regulated by the changes in membrane potential elicited by the activation of potassium channels, the impaired function of which was detected in hypertensive animals. The dominant role of enhanced calcium influx in the pathogenesis of high blood pressure of genetically hypertensive animals is confirmed not only by therapeutic efficacy of calcium antagonists but especially by the absence of hypertension in animals in which L-type calcium current was diminished by pertussis toxin-induced inactivation of inhibitory G proteins. Although there is considerable information on the complex neural and vascular alterations in rats with established hypertension, the detailed description of their appearance during the induction of hypertension is still missing.

Global identification of the genes and pathways differentially expressed in hypothalamus in early and established neurogenic hypertension

The hypothalamus has an important etiological role in the onset and maintenance of hypertension and stress responses in the Schlager high blood pressure (BP) (BPH/2J) mouse, a genetic model of neurogenic hypertension. Using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays we identified 1,019 hypothalamic genes whose expression differed between 6 wk old BPH/2J and normal BP (BPN/3J) strains, and 466 for 26 wk old mice. Of these, 459 were in 21 mouse BP quantitative trait loci. We validated 46 genes by qPCR. Gene changes that would increase sympathetic outflow at both ages were: Dynll1 encoding dynein light chain LC8-type 1, which physically destabilizes neuronal nitric oxide synthase, decreasing neuronal nitric oxide, and Hcrt encoding hypocretin and Npsr1 encoding neuropeptide S receptor 1, each involved in sympathetic response to stress. At both ages we identified genes for inflammation, such as CC-chemokine ligand 19 (Ccl19), and oxidative stress. Via reactive oxygen species generation, these could contribute to oxidative damage. Other genes identified could be responding to such perturbations. Atp2b1, the major gene from genome-wide association studies of BP variation, was underexpressed in the early phase. Comparison of profiles of young and adult BPH/2J mice, after adjusting for maturation genes, pointed to the proopiomelanocortin-α gene (Pomc) and neuropeptide Y gene (Npy), among others, as potentially causative. The present study has identified a diversity of genes and possible mechanisms involved in hypertension etiology and maintenance in the hypothalamus of BPH/2J mice, highlighting both common and divergent processes in each phase of the condition.

Affinity constants and beta-adrenoceptor reserves for isoprenaline on cardiac tissue from normotensive and hypertensive rats.

To determine whether there are differences in cardiac beta-adrenoceptor responsiveness, isoprenaline affinity constants and fractional beta-adrenoceptor occupancy-response relationships for isoprenaline in the early stages of established hypertension, we studied the effects of bromoacetylalprenololmenthane (BAAM) and ([3,5-diamino-6-chloro-N-(1[N-beta-(2-hydroxyl-3-alpha-naphthoxypropy lamino)ethylcarbamoyl]-1-methylethyl)-pyrazine-2-carboxamide (ICI 147 798), slowly reversible beta-adrenoceptor antagonists, on the isoprenaline responses of the left ventricular papillary muscle and the left and right atria of 6-month-old Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The papillary muscles, but not the right and left atria, of the SHR were less responsive to isoprenaline than those of the WKY. The isoprenaline pD2 values (the negative logarithms of the molar concentrations of agonist producing 50% of the maximum response) were 7.72 and 8.00 on the SHR and WKY papillary muscles, respectively. On the WKY papillary muscle the isoprenaline KA values were 2-3 x 10(-6) M, which is as expected for isoprenaline at beta1 or beta2-adrenoceptors. Isoprenaline had 100-fold greater affinity on the WKY and SHR left atria than on the papillary muscles; the isoprenaline KA values were 2-4 x 10(-8) M. On the WKY papillary muscle and left atrium, isoprenaline had to occupy 3-4% of the beta-adrenoceptors to produce a 50% maximum response; on the WKY papillary muscle and left atrium isoprenaline had to occupy 25-35% and 55%, respectively, of the beta-adrenoceptors to produce a 90% maximum response. The SHR papillary muscles and left atrium had smaller beta-adrenoceptor reserves for isoprenaline than did the WKY tissues. We were unable to obtain isoprenaline KA values on the WKY right atrium. The isoprenaline KA value on the SHR right atrium was 1-4 x 10(-8) M. Because the isoprenaline KA values for the left and right atria are markedly different from those previously reported for isoprenaline at beta1 or beta2-adrenoceptors, we suggest that atypical beta-adrenoceptors might be present on the atria of WKY and SHR. We have also demonstrated a lower beta-adrenoceptor reserve on SHR papillary muscle and atria in the early stages of established hypertension.

α-Blockade on Blood Pressure and on Cardiac Noradrenaline Content in SHR and DOCA-salt Rats

The current study was designed to explore the effects of peripherally administered alpha-adrenoceptor inhibiting drugs (either prazosin or yohimbine) in spontaneously hypertensive (SHR) and DOCA-salt hypertensive rats before the development of established hypertension, as well as to characterize changes induced by prazosin and/or yohimbine in the cardiac noradrenaline (NA) content that might be responsible for the development of hypertension in these strains. The alpha-adrenoceptor blockade can prevent hypertension in DOCA and salt-treated animals in such a way that their blood pressure stabilizes at levels significantly lower than those observed in similarly treated normotensive controls. Significantly lower cardiac NA content was observed in DOCA-salt rats under basal and experimental conditions. The blood pressure of the treated rats and the heart NA content of the SHR were unaltered by treatment. Thus, administration of the alpha-adrenoceptor blocking agents, prazosin and/or yohimbine, throughout the developmental stage of SHR hypertension failed to alter either the progressive rise in blood pressure or in NA content. There may be differences between the cardiac adrenergic mechanisms responsible for the development of hypertension in each of these two models of hypertension.