Development Of Experimental Hypertension Research Articles

Deactivation of 12(S)-HETE through (ω-1)-hydroxylation and β-oxidation in alternatively activated macrophages

Polarization of macrophages to proinflammatory M1 and to antiinflammatory alternatively activated M2 states has physiological implications in the development of experimental hypertension and other pathological conditions. 12/15-Lipoxygenase (12/15-LO) and its enzymatic products 12(S)- and 15(S)-hydroxyeicosatetraenoic acid (HETE) are essential in the process since disruption of the gene encoding 12/15-LO renders the mice unsusceptible to hypertension. The objective was to test the hypothesis that M2 macrophages catabolize 12(S)-HETE into products that are incapable of promoting vasoconstriction. Cultured M2 macrophages metabolized externally added [14C]12(S)-HETE into more polar metabolites, while M1 macrophages had little effect on the catabolism. The major metabolites were identified by mass spectrometry as (ω-1)-hydroxylation and β-oxidation products. The conversion was inhibited by both peroxisomal β-oxidation inhibitor, thioridazine, and cytochrome P450 inhibitors. Quantitative PCR analysis confirmed that several cytochrome P450 enzymes (CYP2E1 and CYP1B1) and peroxisomal β-oxidation markers were upregulated upon M2 polarization. The identified 12,19-dihydroxy-5,8,10,14-eicosatetraenoic acid and 8-hydroxy-6,10-hexadecadienoic acid metabolites were tested on abdominal aortic rings for biological activity. While 12(S)-HETE enhanced vasoconstrictions to angiotensin II from 15% to 25%, the metabolites did not. These results indicate that M2, but not M1, macrophages degrade 12(S)-HETE into products that no longer enhance the angiotensin II-induced vascular constriction, supporting a possible antihypertensive role of M2 macrophages.

Dynamics of Distribution of Capillaries with Matrix Metalloproteinase-2 and Its Tissue Inhibitor in Rat Brain during Development of Experimental Hypertension.

The capillaries containing MMP-2 and its tissue inhibitor TIMP-2 were examined in cerebral cortex and white matter obtained from intact Wistar rats (n=5) and the rats with progressing experimental renovascular hypertension (n=35). In hypertensive rats, the changes in intensity of the immunohistochemical reaction and in the density of capillaries expressing TIMP-2 significantly differed from the corresponding values in MMP-2-positive capillaries, which resulted in pronounced deviation of MMP-2/TIMP-2 index from the control level (especially in cerebral cortex) probably attesting to enhanced risk of complications in cases with arterial hypertension.

Deactivation of 12‐HETE by Peroxisomal β‐Oxidation by Alternatively Activated Macrophages

Polarization of macrophages to pro‐inflammatory M1 and to anti‐inflammatory or alternatively activated M2 state has important physiological implications in development of experimental hypertension and inflammation. 12‐ and 15‐hydroxyeicosatetraenoic acids (12‐ and 15‐HETE), the two major arachidonic acid metabolites of 12/15‐lipoxygenase, are essential in the process since the disruption of the encoding gene, Alox15, renders the mice unsusceptible to variety of types of experimental hypertension. The objective of this study was to test the hypothesis that alternatively activated M2 macrophages catabolize 12‐HETE into products that do not enhance angiotensin II‐mediated arterial constriction.We used cultures of M1‐ or M2‐polarized macrophages to study the metabolism of externally added [14C]‐12‐HETE. The 12‐HETE metabolites were separated by a reverse phase HPLC and identified by mass spectrometry.M2 polarized peritoneal macrophages converted most of the 12‐HETE into more polar metabolites within 2 hours of incubation. M1 macrophages, however, had little effect on the 12‐HETE catabolism. The same effect was observed in cultures of M1 or M2 polarized bone marrow‐derived macrophages. The major metabolite peaks were identified by mass‐spectrometry as β‐oxidation products. The conversion of 12‐HETE was inhibited by 50 μM thioridazine, a peroxisomal β‐oxidation inhibitor. Mitochondrial β‐oxidation inhibitors, 4‐pentenoic acid and etomoxir, had no effect on conversion. qPCR analysis of peroxisomal and mitochondrial β‐oxidation markers confirmed that only peroxisomal markers were upregulated upon M2 polarization. The major 12‐HETE metabolite peaks were collected and their activities were tested on abdominal aortic rings. While 12‐HETE (100 nM) pre‐incubation enhanced constrictions to angiotensin II (1–100 nM) from 15 % to 25 %, the metabolites lacked such an activity.Our results indicate that alternatively activated M2 macrophages are capable of degrading 12‐HETE and eliminating 12‐HETE's enhancement of angiotensin II‐induced vascular constriction, while M1 macrophages are not. These data support an antihypertensive role of M2 macrophages.Support or Funding InformationThis research was supported by the grant: NIH HL103673

Excessive Respiratory Modulation of Blood Pressure Triggers Hypertension

The etiology of hypertension, the world's biggest killer, remains poorly understood, with treatments targeting the established symptom, not the cause. The development of hypertension involves increased sympathetic nerve activity that, in experimental hypertension, may be driven by excessive respiratory modulation. Using selective viral and cell lesion techniques, we identify adrenergic C1 neurons in the medulla oblongata as critical for respiratory-sympathetic entrainment and the development of experimental hypertension. We also show that a cohort of young, normotensive humans, selected for an exaggerated blood pressure response to exercise and thus increased hypertension risk, has enhanced respiratory-related blood pressure fluctuations. These studies pinpoint a specific neuronal target for ameliorating excessive sympathetic activity during the developmental phase of hypertension and identify a group of pre-hypertensive subjects that would benefit from targeting these cells.

High Salt Activates Dendritic Cells to Promote Hypertension

Both inflammation and dietary salt intake have been implicated in the pathogenesis of hypertension. We have previously shown that the formation of immunogenic isoketal‐protein adducts in dendritic cells (DCs) plays an important role in the development of experimental hypertension. Recently, it has been shown that salt can accumulate in the interstitial space and promote inflammation. In the current study, we tested the hypothesis that exposure to high salt drives DCs toward an activated state, leading to the production of immunogenic isoketals and the promotion of hypertension. To test this hypothesis, mouse splenic DCs were cultured in media with either normal salt (NS, 150 mM NaCl) or high salt (HS, 190 mM NaCl) for 24 hours. Exposure to HS caused a 2‐fold increase in superoxide production in DCs compared to NS. This was NADPH oxidase‐dependent since incubation with the gp91ds‐tat peptide prevented the increase. HS exposure also led to an increase in the activation markers CD80 and CD86, and doubled the number of DCs containing isoketal‐protein adducts. Moreover, DCs exposed to HS but not NS drove proliferation of both CD4+ (5198.2±2398.6 vs. 15.3±7.1 proliferated cells, p<0.01) and CD8+ (25381.6±9495.6 vs. 9.8±4.1 proliferated cells, p<0.01) T cells. None of these effects were mediated by increased osmolality as addition of mannitol (80 mM) to the media had no effect. Western blots of protein extracts from DCs indicated that all NADPH subunits (p47phox, p22phox, gp91phox and p67phox) were increased by exposure of cells to HS, and that these effects were prevented by inhibition of the serum‐and‐glucocorticoid‐inducible kinase‐1 (SGK1). In additional experiments, mice received adoptive transfer of splenic DCs that were cultured for 24 hours in either NS (n = 5); HS (n = 5); HS plus the SGK1 inhibitor, GSK 650394 (HS+GSK, n = 5) or HS plus the isoketal scavenger, 2‐hydroxybenzylamine (HS+2‐HOBA, n=5). Mice were then implanted with radiotelemeters to measure arterial pressure. Following recovery and two days of baseline, subcutaneous osmotic minipumps were implanted for administration of a generally sub‐pressor dose of angiotensin II (140 ng/kg/min). This caused no increase in blood pressure in mice that received NS DCs, whereas mean arterial pressure increased significantly (14 ± 4 mmHg, p<0.05) by one week of angiotensinogen II infusion in mice that received salt‐activated DCs. The pro‐hypertensive effect of salt on DCs was completely blocked by inhibition of SGK1 and scavenging of isoketals during their salt exposure. Taken together, our data indicate that DCs can be activated by exposure to a high salt environment which can exist in pro‐hypertensive states, and that this likely involves increased NADPH oxidase mediated superoxide production and formation of isoketal‐protein adducts. Moreover, high salt exposure can cause DCs to become pro‐hypertensive. These studies define a new pathway linking salt to immune activation and identify a previously undefined role of SGK1 in this process.Support or Funding InformationThis work is supported by National Institutes of Health grants R01HL039006, P01HL058000, P01HL095070, P01GM015431, R01HL108701, R01HL105294, VITA award HHSN268201400010C and the Strategically Focused Research Network Award from the American Heart Association.

Abstract 002: Dynamic T Cell-Antigen Presenting Cell Interactions and Direct T Cell Activation Within the Vascular Wall During Hypertension

T cells are now known to be vital to the development of experimental hypertension. Hypertension is associated with significant accumulation of T cells into the perivascular fat surrounding the aorta and renal vasculature. While a hypertension-specific neoantigen has been implicated in T cell activation, it is not known whether vascular-infiltrating T cells recognize and are locally activated by an antigen within the vessel wall. We developed live-cell imaging of explanted aortas to identify whether cognate antigens are presented to T cells within the vessel wall of hypertensive mice, evidenced by slower T cell velocities and a greater number of T cells interacting with antigen presenting cells (APCs). Splenic T cells were isolated from normotensive vehicle-treated (nT cells) and hypertensive angiotensin II (Ang II)-infused (0.7mg/kg/day; 14 days; hT cells) C57BL6/J mice. Following anti-CD3/CD28 stimulation (48 hours), cells were fluorescently labelled and co-incubated simultaneously (16 hours) with explanted aorta from normotensive or hypertensive CD11c-YFP mice, where APCs are fluorescently labelled. In CD11c-YFP mouse aorta alone, we detected a ~2-fold increase in CCR5 ligand (CCL3, CCL4 and CCL5) secretion from hypertensive mouse aorta compared to vehicle-treated mouse aorta (*P<0.05; n = 4). Using 2-photon microscopy, we observed a greater number (~2-fold) of hT cells compared to nT cells within Ang II-infused mouse aorta (390 ± 113 Vs 198 ± 49). Importantly, time-lapse recordings of hypertensive mouse aorta revealed hT cells exhibited significantly slower velocity (hT cells 2.0 μm/min Vs nT cells 4.8 μm/min; **P<0.01, n=8-12), and a greater proportion of interactions with APCs (hT cells 4.4 ± 1.1 Vs nT cells 0.8 ± 0.4%). Moreover, activation of local vascular T cells by incubating hypertensive aorta with anti-CD3/CD28 antibodies (16 hours) augmented Ang II-induced endothelial dysfunction (67.5 ± 2.0 Vs Ang II alone 54.5 ± 3.7% maximal relaxation). We have the first evidence that vascular-infiltrating T cells are presented with cognate antigens by APCs within the vessel wall during hypertension; direct activation of these T cell infiltrates further impairs endothelial function, which may promote the development of hypertension.

Abstract 078: Angiotensin Converting Enzyme type 2 shedding in the central nervous system of hypertensive patients

ACE2 (Angiotensin Converting Enzyme type 2) is involved in the conversion of the vasoconstrictor peptide Angiotensin (Ang)-II into its vasodilatory metabolite Ang-(1-7), thereby offering a new perspective for the treatment of cardiovascular diseases associated with over-activity of the renin-angiotensin system. Our group recently reported that ACE2 shedding, a process by which ACE2 is cleaved from the plasma membrane and secreted into the surrounding milieu, contributes to the loss of the enzyme’s compensatory activity in the central nervous system (CNS) during the development of experimental hypertension. The objective of this study was to determine whether ACE2 shedding is taking place in the CNS of patients during hypertension. Unused cerebrospinal fluid, collected from patients (17 males and 27 females, aged 22-66) for diagnostic purposes, was divided in 3 groups: normotensive (n=23), hypertensive (n=9), and hypertensive controlled with medication (n=12). In addition, blood pressure values and current medications were recorded. While ELISA lacked sensitivity, soluble levels of hACE2 (sACE2) could be detected by Mass spectrometry-based RAS-Fingerprint™ in all patients. Validation experiments (n=16) indicated that pre-treatment with MLN4760 (ACE2 inhibitor) abolished the conversion of Ang-II to Ang-(1-7) by 76 ±3 %, suggesting that ACE2 is the main enzyme converting Ang-II to Ang-(1-7) in human CSF. In hypertensive patients not taking blood pressure medications, (Systolic: 157 ±10, Diastolic: 95 ±7 mmHg; n=6) CSF sACE2 activity was significantly higher (21.7 ±8.3 AU; P<0.05) than in normotensive (Systolic: 114 ±4, Diastolic: 75 ±4 mmHg; n=15) patients (6.6 ±0.9 AU). However, in patients with controlled hypertension (Systolic: 129 ±6, Diastolic: 86 ±5 mmHg; n=5), CSF sACE2 levels were normalized (6.9 ±1.9 AU). Comparison of systolic or diastolic blood pressure vs. sACE2 activity levels showed no significant correlation. These data suggest that ACE2 shedding is taking place in the CNS of hypertensive patients. Soluble ACE2 activity in the CSF is correlated with high blood pressure and could be used as a biomarker of neurogenic hypertension. AU: arbitrary unit.

Autoimmunity in the pathogenesis of hypertension

Hypertension affects more than one-third of the adult population of the world. However, the cause of high blood pressure is unknown in the vast majority of patients, classified as patients with essential hypertension. Evidence accumulated over the past decade supports the participation of inflammation in the development of experimental hypertension. Investigations have also demonstrated that immune reactivity to overexpressed heat shock protein 70 (HSP70) is involved in the pathogenesis of salt-induced hypertension. This article reviews, first, the role of T cell-induced inflammation in the arteries, kidney and central nervous system in hypertension and the amelioration of hypertension induced by regulatory T cells. Second, experiments showing that autoimmunity directed to HSP70 in the kidney impairs the pressure natriuresis relationship and has a pivotal role in the pathogenesis of salt sensitive hypertension. Finally, we highlight the clinical evidence that supports the participation of autoimmunity in essential hypertension.

Abstract 461: Macrophage 12/15-lipoxygenase Controls the Development of Experimental Hypertension through PPAR?

Targeted disruption of the 12/15-lipoxygenase (Alox15) gene in mice prevents the development of angiotensin II-, DOCA-salt-, and L-NAME-induced experimental hypertension. Macrophages are the primary source of Alox15. Using Alox15-/- and wild type (WT) mice, we previously demonstrated that macrophage Alox15 is essential for experimental hypertension; however, the underlying mechanism is not known. Since Alox15-derived metabolites of arachidonic and linoleic acids are potent PPARγ agonists, we hypothesized that activation of macrophage PPARγ is the key step in Alox15 mediation of L-NAME-induced hypertension. Thioglycollate (TG) injection, used to elicit peritoneal macrophages, upregulated PPARγ protein expression and expression of its target gene CD36 in peritoneal macrophages, but not in aorta or kidney, of both WT (6.8±0.3 and 9.3±0.5 fold increase for PPARγ and CD36, respectively) and Alox15-/- mice (4.7±0.4 and 11.1±0.6 fold increase for PPARγ and CD36, respectively). Thus, TG bypassed Alox15 to activate PPARγ selectively in macrophages. Upregulation of PPARγ by TG restored the sensitivity to L-NAME hypertension (100 mg/kg/day L-NAME for 7 days) in Alox15-/- mice (129.4±7.3 mmHg for TG vs. 94.8±5.6 mmHg for non-injected controls, p<0.005). A similar hypertensive effect to L-NAME was observed with the adoptive transfer of TG-elicited Alox15-/- macrophages into Alox15-/- recipient mice (122.4±5.5 mmHg for macrophage vs. 96.2±6.2 mmHg for vehicle, p<0.05). The role of PPARγ was further specified by using the selective PPARγ antagonist, GW9662. When WT mice were treated with GW9662, 50 μg/kg/day for 12 days, L-NAME-induced hypertension did not develop (97.6±4.8 mmHg for GW9662 vs. 131.7±6.5 mmHg for vehicle, p<0.01). The PPARγ antagonist also prevented L-NAME-induced hypertension in TG-injected Alox15-/- mice, indicating a PPARγ-mediated effect in macrophages that results in hypertension. These results demonstrate that TG selectively upregulates macrophage PPARγ, bypassing the missing component in Alox15-/- macrophages, and permitting L-NAME-induced hypertension in Alox15-/- mice. Thus, the macrophage Alox15/PPARγ pathway is an important checkpoint in the development of L-NAME-induced hypertension.

Mice lacking macrophage 12/15-lipoxygenase are resistant to experimental hypertension

In mouse arteries, Alox15 [leukocyte-type 12/15-lipoxygenase (LO)] is assumed to regulate vascular function by metabolizing arachidonic acid (AA) to dilator eicosanoids that mediate the endothelium-dependent relaxations to AA and acetylcholine (ACh). We used Alox15(-/-) mice, made by targeted disruption of the Alox15 gene, to characterize its role in the regulation of blood pressure and vascular tone. Systolic blood pressures did not differ between wild-type (WT) and Alox15(-/-) mice between 8-12 wk of age, but Alox15(-/-) mice exhibited resistance toward both N(G)-nitro-L-arginine-methyl ester (L-NAME)- and deoxycorticosterone acetate (DOCA)/high-salt-induced hypertension. ACh relaxed mesenteric arteries and abdominal aortas of WT and Alox15(-/-) mice to an identical extent. The LO inhibitor nordihydroguaiaretic acid attenuated the ACh relaxations by 35% in arteries from both WT and Alox15(-/-) mice. Reverse-phase HPLC analysis of [(14)C]AA metabolites in aorta and peritoneal macrophages (PM) revealed differences. Unlike PM, aorta tissue did not produce detectable amounts of 15-hydroxyeicosatetraenoic acid. Although Alox15 mRNA was detected in aorta, high-resolution gel electrophoresis with immunodetection revealed no Alox15 protein expression. Unlike aorta, Alox15 protein was detected in PM, intestine, fat, lung, spleen, and skin from WT, but not Alox15(-/-), mice. Injection of WT PM, a primary source of Alox15 protein, into Alox15(-/-) mice abolished their resistance toward L-NAME-induced hypertension. On the other hand, WT mice acquired resistance to L-NAME-induced hypertension after depletion of macrophages by clodronate injection. These studies indicate that Alox15 is involved in development of experimental hypertension by altering macrophage functions but not via synthesis of the vasoactive LO metabolites in mouse arteries.

Effect of Castration on Renin-Angiotensin System of Hypertensive Rats Submitted to Chronic Hypobaric Hypoxia (Simulated Altitude: 4400 m)

The aim of the present study was to provide an overview of the role of circulating gonadal steroids on the adaptive changes of the renin-angiotensin system to chronic hypobaric hypoxia (CHH: 4400 m simulated altitude in an hypobaric chamber) and the development of experimental hypertension by bilateral renal ischemia. In order to fulfill this goal, blood pressure (BP), plasma renin activity (PRA) and plasma angiotensinogen concentration (PAoC) as well as haematocrit (Htc) and body weight (BW) of intact and post-puberal castrated normotensive (Nt) and hypertensive (Ht) rats of both sexes were studied following an experimental design similar to that of previous works. Post-puberal castration decreased BP of Nt and Ht rats subjected to CHH. Sexual dimorphism in BP, PRA and PAoC was maintained while that in haematocrit disappeared after castration. Results suggest that circulating sexual steroid hormones are involved in the response of the renin-angiotensin system to the experimental conditions of environmental reduced O 2 partial pressure.

Arterial compliance and its control by the baroreflex in hypertensive dogs

The effect of the carotid baroreflex on systemic arterial compliance was tested in normotensive and Goldblatt hypertensive dogs. After the development of experimental hypertension, dogs were acutely anesthetized with pentobarbital sodium and vagotomized. The carotid sinuses were then isolated and held at controlled carotid sinus pressures (CSP) of 50, 125, and 200 mmHg. The dogs were placed on constant flow, constant venous pressure, cardiopulmonary bypass. Arterial compliance was determined from the time constant of the exponential fall in arterial pressure, which occurred when the flow was stopped at three different levels of CSP. The reflex characteristic curve (mean arterial pressure vs. CSP) was shifted upward and to the right in the hypertensive group. Arterial compliance significantly decreased with decreasing CSP, but at any given level of CSP, arterial compliance was not different in the normotensive and hypertensive groups. A nonlinear analysis revealed that the arterial compliance-arterial pressure relationship was not altered by Goldblatt experimental hypertension. The results of this study indicate that the arterial compliance is primarily a function of the absolute level of arterial pressure. Baroreflex control of arterial compliance is important at lower levels of arterial pressure.

Hemodynamic and respiratory responses to carotid sinus pressure alteration in experimental hypertension.

The purpose of this study was to determine whether baroreflex control of respiratory responses is diminished in hypertension. Ten dogs were made chronically hypertensive with use of a bilateral renal wrap technique. Eight sham-operated dogs served as normotensive controls. After the development of experimental hypertension, carotid baroreflex control of arterial pressure, heart rate, respiratory frequency, tidal volume, and ventilation was acutely assessed. Under pentobarbital anesthesia and with bilateral vagotomy, the carotid sinuses were isolated and perfused at controlled pressures. Before the carotid sinus region was manipulated, the mean arterial pressure was significantly higher (P < 0.005) in the hypertensive group (146.4 +/- 2.3 mmHg) than in the normotensive group (124.7 +/- 2.6 mmHg). The mean arterial pressures and heart rates measured at every level of carotid sinus pressure were significantly higher in the hypertensive group. Reflex gain of heart rate, but not mean arterial pressure, was significantly reduced in the hypertensive group. Respiratory frequency, tidal volume, and ventilatory responses to changes in carotid sinus pressure were significant and resulted in an approximately 40% reflex change in ventilation. These responses were not diminished in the hypertensive group. We conclude that respiratory baroreflex responses are preserved in experimental hypertension.

Rapid resetting of baroreflexes in hypertensive dogs.

The hypothesis tested was that the rapid resetting of the arterial baroreflex control of arterial pressure in normotension could be demonstrated in experimental hypertension. After the development of experimental hypertension (using a bilateral renal wrap technique), rapid resetting of arterial pressure and heart rate (HR) was acutely assessed under pentobarbital sodium anesthesia in hypertensive and normotensive vagotomized dogs. The carotid sinus area was isolated and perfused at controlled carotid sinus pressures (CSPs). Baroreflex response [mean arterial pressure (MAP) and HR] curves were measured after three carotid sinus conditioning pressures (50, 125, and 200 mmHg) were applied. For the MAP response, the CSPo (CSP at point of maximum reflex gain) increased significantly to the same extent in both groups with increasing conditioning pressures (with 22.2 and 16.7% resetting in the normotensive group, and 20.3 and 14.2% resetting in the hypertensive group). We conclude that short-term adjustments to changes in prevailing pressure (rapid resetting) occur in the arterial pressure response in experimental hypertension to the same extent seen in normotension.

Intracellular pH in rat resistance arteries during the development of experimental hypertension.

1. In order to examine the effects of experimental hypertension on intracellular pH in mesenteric resistance arteries, intracellular pH was measured in mesenteric resistance arteries from rats with coarctation 72 h, 9 days and 28 days after the aorta was partially constricted between the origins of the renal arteries. Carotid arterial pressure was significantly raised at all time points. 2. Second-order mesenteric resistance arteries were mounted in a myograph and were loaded with the acetoxymethyl ester of the pH-sensitive dye 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein. Morphological measurements demonstrated that arteries from rats with coarctation had an increased media volume at 9 days and at 28 days compared with vessels from sham-operated control animals, but this was only statistically significant at 28 days. 3. Resting intracellular pH was not significantly different at any time point in arteries from rats with coarctation compared with control animals, although there was a rise in intracellular pH in both groups of rats between 72 h and 9 days. The application of 4,4-di-isothiocyanatostilbene-2,2'-disulphonic acid produced a fall in intracellular pH which was significantly greater in the sham-operated rats at 9 days; this difference was not found at 28 days. Blockade of Na+/H+ exchange with 60 mumol/l ethylisopropylamiloride led to a similar fall in intracellular pH in both groups of rats at 9 days but a significantly greater fall in intracellular pH in arteries of rats with coarctation at 28 days. Activation with noradrenaline (10 mumol/l) induced acid changes in intracellular pH that were similar in both groups of rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The measurement of intracellular pH in resistance arteries during the development of experimental hypertension

The measurement of intracellular pH in resistance arteries during the development of experimental hypertension

Chemoreceptors in the Kidney

The response of the mammalian kidney to changes in the composition of the urine seems to be mediated by intrarenal chemoreceptors. Two distinct populations of chemoreceptors have been identified in the rat kidney. One type responds to ischemia but not to changes in perfusion pressure;the other type is spontaneously active and is sensitive to the composition and concentration of intrarenal fluid. The author suggests that renal chemoreceptors may play a role in the development of experimental hypertension.

Effects of baroreceptor activation on single unit activity of the anteroventral third ventricle region of the rat

The anteroventral third ventricular (AV3V) region, part of the preoptic area, is involved in neurohumoral regulation of the cardiovascular system and in the development of experimental hypertension. Single unit activity within the AV3V region of the rat was recorded in response to the activation of arterial baroreceptors produced by intravenous phenylephrine or by aortic occulsion. Both inhibition and excitation of units was observed in response to an increase in arterial pressure with the highest incidence of responses in the median and periventricular subnuclei of the preoptic area. These data provide functional evidence for the neural projections from medullary baroreceptor fiber terminations to the AV3V region and preoptic area.

Effect of Dietary Fats on Experimental Hypertension

In an experiment on 95 Wistar rats weighing 330 g the effect was studied of partially hydrogenated marine oil and cod-liver oil as well as sunflowerseed oil and animal fat on arterial hypertension induced with administration of 1.5% NaCl in drinking water. During 5 weeks the animals received diets containing 37.8 kcal% derived from the studied fats. After the first week of 1.5% NaCl solution administration a significant rise of the systolic blood pressure and heart rate was observed in all animals without regard to the fat received by them with the diet. The rise of the blood pressure was greatest in the group of rats kept on the diet with animal fat, while in the groups of rats receiving diets with sunflowerseed oil or marine oils this rise was significantly smaller, especially with cod-liver oil. The hypotensive effect of marine oils, particularly cod-liver oil, was more pronounced than that of sunflowerseed oil. The hypotensive effect of partially hydrogenated fish oil was less pronounced than that of cod-liver oil. Our experiments demonstrated a significant effect of the amount of dietary fat on the development of experimental hypertension. Greater intake of salt and animal fats in human diet may be one of the causes of essential hypertension.

Prostaglandin synthetase activity in kidney medulla during the development of experimental hypertension in the rat.

The activity of the Pg-E2-synthetase in the rat renal medulla was observed for a period of 27 days during the development of a hypertension by clamping of the renal artery; an increased activity of Pg-E2-synthetase with a peak on the 18th day was observed in the kidneys of the 2-kidney model (2-KM=stenosing of the left arteria renalis) and the 1-kidney model (1-KM=stenosing of the left arteria renalis and additional nephrectomy of the right kidney). The initial values of the enzyme activities were reached again on the 21st (1-KM) resp. 24th (2-KM) day post operationem.