Increased erythropoietin production after myocardial infarction in mice.
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Biomedical subjects
A L Siren
Publications and source records attributed to A L Siren.
Impaired sodium excretion, decreased glomerular filtration rate and elevated blood pressure in endothelin receptor type B deficient rats.
The renal endothelin (ET) system, particularly the ET type B receptor, has been implicated in the regulation of sodium excretion and glomerular filtration rate (GFR). We analyzed kidney morphology and function in a rat strain characterized by complete absence of a functional ETB receptor. Due to Hirschsprung's disease limiting lifetime in these rats, studies were performed in 23-day-old rats. Kidney size and morphology (glomerular and interstitial matrix content, glomerular size and cell density and intrarenal vascular morphology) were normal in ETB-deficient rats. There were also no evidence of altered kidney cell cycle regulation in these rats. GFR was significantly lower, by 72% (P<0.001), in homozygous ETB-deficient rats than in wild-type rats. Fractional sodium excretion was likewise markedly reduced by 84% in homozygous ETB-deficient rats (P<0.001 versus wild-type rats). Treatment with the specific epithelial sodium channel blocker amiloride led to a much higher increase in fractional sodium excretion in ETB-deficient rats (934.2+/-73% in ETB-deficient rats versus 297+/-20% in wild-type rats, expressed as percentage of corresponding placebo treated control; P<0.001). Mean arterial blood pressure was elevated by 7.9 mmHg in homozygous ETB-deficient rats (P<0.05 versus wild-type rats). Our study demonstrates that ETB-deficiency causes early onset kidney dysfunction characterized by a markedly reduced sodium excretion, decreased GFR, and slightly elevated blood pressure. The complete absence of the ETB receptor causes in the kidney--in contrast to the colon--a functional rather than a developmental, neural crest cell dependent disease, since kidney morphology was normal in ETB-deficient rats. The much higher increase in the fractional sodium excretion in ETB-deficient rats after pharmacological blockade of the epithelial sodium channel indicates that the decreased fractional sodium excretion in ETB-deficient rats is most probably due to a lack of the inhibitory property of the ETB receptor on the epithelial sodium channel activity.
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Prolonged expression of interferon-inducible protein-10 in ischemic cortex after permanent occlusion of the middle cerebral artery in rat.
Focal cerebral ischemia elicits local inflammatory reaction as demonstrated by the accumulation of inflammatory cells and mediators in the ischemic brain. Interferon-inducible protein-10 (IP-10) is a member of the C-X-C chemokine family that possesses potent chemoattractant actions for monocytes, T cells, and smooth muscle cells. To investigate a potential role of IP-10 in focal stroke, we studied the temporal expression of IP-10 mRNA after occlusion of the middle cerebral artery in rat by means of northern analysis. IP-10 mRNA expression after focal stroke demonstrated a unique biphasic profile, with a marked increase early at 3 h (4.9-fold over control; p < 0.01), a peak level at 6 h (14.5-fold; p < 0.001) after occlusion of the middle cerebral artery, and a second wave induction 10-15 days after ischemic injury (7.2- and 9.3-fold increase for 10 and 15 days, respectively; p < 0.001). In situ hybridization confirmed the induced expression of IP-10 mRNA and revealed its spatial distribution after focal stroke. Immunohistochemical studies demonstrated the expression of IP-10 peptide in neurons (3-12 h) and astroglial cells (6 h to 15 days) of the ischemic zone. To explore further the potential role of IP-10 in focal stroke, we demonstrated a dose-dependent chemotactic action of IP-10 on C6 glial cells and enhanced attachment of rat cerebellar granule neurons. Taken together, the data suggest that ischemia induces IP-10, which may play a pleiotropic role in prolonged leukocyte recruitment, astrocyte migration/activation, and neuron attachment/sprouting after focal stroke.
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Upregulation of intercellular adhesion molecule 1 (ICAM-1) on brain microvascular endothelial cells in rat ischemic cortex.
The expression of intercellular adhesion molecule 1 (ICAM-1) was studied in rat focal ischemic cortex. A significant increase in ICAM-1 mRNA expression in the ischemic cortex over levels in contralateral (nonischemic) site was observed by means of Northern blot analysis following either permanent or temporary occlusion with reperfusion of the middle cerebral artery (PMCAO or MCAO with reperfusion) in spontaneously hypertensive rats. In the ischemic cortex, levels of ICAM-1 mRNA increased significantly at 3 h (2.6-fold, n = 3, P < 0.05), peaked at 6 to 12 h (6.0-fold, P < 0.01) and remained elevated up to 5 days (2.5-fold, P < 0.05) after PMCAO. The profile of ICAM-1 mRNA expression in the ischemic cortex following MCAO with reperfusion was similar to that following PMCAO, except that ICAM-1 mRNA was significantly increased as early as 1 h (6.3-fold, n = 3, P < 0.05) and then gradually reached a peak at 12 h (12-fold, P < 0.01) after reperfusion. ICAM-1 mRNA expression in ischemic cortex following PMCAO was significantly greater in hypertensive rats than in two normotensive rat strains. Immunostaining using anti-ICAM-1 antibodies indicated that upregulated ICAM-1 expression was localized to endothelial cells of intraparenchymal blood vessels in the ischemic but not contralateral cortex. The data suggest that an upregulation of ICAM-1 mRNA and protein on brain capillary endothelium may play an important role in leukocyte migration into ischemic brain tissue.
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Adhesion molecules on normotensive and hypertensive rat brain endothelial cells.
The intercellular adhesion of circulating leukocytes to vascular endothelium is a prerequisite for leukocyte emigration from the blood to extravascular tissues. This process is facilitated by adhesion molecules on the surfaces of both the vascular endothelial cells and the leukocytes. The experiments presented here demonstrate for the first time that the leukocyte adhesion receptor, intercellular adhesion molecule-1, is constitutively expressed on cultured cerebromicrovascular endothelial cell lines derived from both spontaneously hypertensive (SHR) rats and normotensive Wistar-Kyoto (WKY) rats. Both cultures contained similar numbers of cells constitutively expressing this adhesion molecule (31.4% and 29.6%, respectively). Adhesion molecule expression was up-regulated by interleukin-1 beta, tumor necrosis factor-alpha, interferon-gamma and lipopolysaccharide in a dose- and time-dependent manner. Both cultures exhibited similar maximum levels of adhesion molecule up-regulation to optimal concentrations of all three cytokines. However, SHR endothelial cells were more sensitive to all three cytokines; significantly higher levels of intercellular adhesion molecule-1 expression were seen on SHR as opposed to WKY endothelial cells cultured with sub-optimal cytokine concentrations. It was also observed that lipopolysaccharide up-regulated intercellular adhesion molecule-1 expression on SHR endothelial cells to a greater extent than on WKY endothelial cells. The findings that intercellular adhesion molecule-1 can be up-regulated to a greater degree on SHR endothelial cells may have important implications for in vivo perivascular leukocyte accumulation under hypertensive conditions. These observations indicate a possible mechanism by which hypertension may predispose to the development of disorders such as atherosclerosis and stroke.
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Interleukin-1 beta mRNA expression in ischemic rat cortex.
BACKGROUND AND PURPOSE: Interleukin-1 beta is a proinflammatory cytokine produced by blood-borne and resident brain inflammatory cells. The present study was conducted to determine if interleukin-1 beta mRNA was produced in the brain of rats subjected to permanent focal ischemia. METHODS: Rat interleukin-1 beta cDNA, synthesized from stimulated rat peritoneal macrophage RNA by reverse transcription and polymerase chain reaction and cloned in plasmid Bluescript KS+, was used to evaluate the expression of interleukin-1 beta mRNA in cerebral cortex from spontaneously hypertensive rats and normotensive rats subjected to permanent middle cerebral artery occlusion. Interleukin-1 beta mRNA was quantified by Northern blot analysis and compared with rat macrophage RNA standard. To correct for gel loading, blots were also analyzed with cyclophilin cDNA, which encodes an abundant, conserved protein that was unchanged by the experimental conditions. RESULTS: Interleukin-1 beta mRNA produced in the ischemic zone was significantly increased from 6 hours to 120 hours, with a maximum of 211 +/- 24% of interleukin-1 beta reference standard, ie, 0.2 ng stimulated rat macrophage RNA, mRNA compared with the level in nonischemic cortices (4 +/- 2%) at 12 hours after ischemia (P < .01; n = 6). Interleukin-1 beta mRNA at 12 hours after ischemia was markedly elevated in hypertensive rats over levels found in two normotensive rat strains. Neurological deficits were also apparent only in the hypertensive rats. CONCLUSIONS: Brain interleukin-1 beta mRNA is elevated acutely after permanent focal ischemia and especially in hypertensive rats. These data suggest that this potent proinflammatory and procoagulant cytokine might have a role in brain damage following ischemia.
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The supraoptic nuclei in vasopressin and hemodynamic responses to hemorrhage in rats.
Cardiovascular and vasopressin (AVP) responses to hemorrhage were studied in rats with lesions of the hypothalamic supraoptic nuclei (SONL). Bleeding caused hypotension and increase in heart rate (HR) and AVP. SONL rats failed to fully recover from bleeding as compared to normal rats. Plasma AVP in SONL rats was in the normal in basal conditions, but failed to increase to levels attained in normal rats throughout the post-hemorrhage period. These data suggest that the supraoptic nuclei are the primary regulatory sites for AVP release in response to hemorrhage and that lack of adequate AVP release significantly retards blood pressure recovery after bleeding.
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Mesenteric vascular responses to i.v. administration of lipoxin A4 and lipoxin B4 in the conscious rat.
Lipoxin A4 and lipoxin B4 are newly discovered lipoxygenase-interacting products of leukocytes which might have a role in cardiovascular events associated with anaphylaxis. We have tested this possibility by systemic administration of both LXA4 and LXB4 to the conscious rat while monitoring systemic and regional hemodynamic changes. LXA4 and LXB4 (1-100 micrograms/kg) produced dose-dependent constriction of the mesenteric vessels, up to +123 +/- 23% and +50 +/- 9% for LXA4/B4, respectively. Dose-related changes were not observed in arterial blood pressure, heart rate, renal (LXB4) and hindquarter blood flow. We suggest that LXA4 and LXB4 might affect selective vascular beds, such as the mesenteric vessels, and contribute to variations in blood flow in specific pathophysiological states.
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N-acetyl-leukotriene E4 is a potent constrictor of rat mesenteric vessels.
N-Acetyl-leukotriene E4 administered to conscious freely moving rats produced a dose-dependent vasoconstriction in the mesenteric vessels which led to profound reduction of blood flow to the gut. Renal and hindquarter blood flow and vascular resistance were not affected even by high doses of N-Acetyl-leukotriene E4. N-Acetyl-leukotriene E4 was 10-fold more potent than the thromboxane analog U-46619 and 1000-fold more potent than prostaglandin F2 alpha but 2-5-fold less potent than leukotriene D4/E4 to induce mesenteric vasoconstriction. These data indicate that N-acetyl-leukotriene E4 is a biologically active metabolite of peptide leukotrienes, and might play a role in cardiovascular derangements mediated by leukotrienes.
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Platelet-activating factor and shock.
The aim of this chapter was to highlight the major components of PAF actions which lead to a state of shock, i.e. inadequate perfusion of essential organs which if sustained over a critical period of time, leads to irreversible damage in essential organs and eventually death. The heart, the pulmonary vessels and the microcirculation seem to be the primary target organs to PAF-induced hypotension. The effects of PAF on the pulmonary airways in some species (bronchoconstriction) might lead to hypoxemia and further exacerbate organ function. Thrombocytopenia, leukopenia and activation of the complement system are also important in PAF-induced shock by promoting thrombi formation and generation of multiple secondary mediators (e.g. histamine kinins, TXA2, leukotrienes, oxygen radicals). Identification of PAF production during specific or generalized pathophysiological processes is a critical step to implicate this vasoactive lipid in disease processes. So far, only limited information has been derived from studies involving immune responses (anaphylaxis) or bacterial endotoxins. Yet, the growing number of selective and potent PAF antagonists provide important information on the potential role of PAF in shock states. Such evidence, summarized in table I, is of great importance in designing new therapeutic strategies to a highly complex and lethal disease such as septicemia. However, the data summarized in table I clearly show that little is known on the mechanism of action of the various PAF antagonists. It is also important to note that PAF-induced shock and death can be prevented by drugs which are not necessarily PAF antagonists. For example, dexamethasone is extremely efficient in preventing PAF-induced shock and death in the mouse [24, 39] and thyrotropin releasing hormone in the guinea pig [15]. Therefore, it is conceivable that pathological conditions in which PAF might play a fundamental role might be reversed by pharmacological interventions which activate physiological mechanisms which can overcome and reverse the pathological processes activated by PAF. In conclusion, PAF is a powerful vasoactive lipid which can produce severe derangements in essential biological functions which can lead to death. The role of PAF in pathological processes in vivo is well supported in conditions such as anaphylaxis and endotoxemia. Yet, direct proof for PAF production in other shock states, such as multiple trauma, ischemia, inflammation and hemorrhage, is still missing. Furthermore, it is important to keep in mind that in shock, trauma or inflammation, multiple mediators in addition to PAF are formed.(ABSTRACT TRUNCATED AT 400 WORDS)
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Dissociation of the cardiovascular and prolactin-releasing activities of norvaline2-TRH.
The effects of thyrotropin-releasing hormone (TRH) and norvaline2-TRH (Nva2-TRH) on blood pressure, heart rate and plasma prolactin levels in conscious rats have been compared. Systemic injection of TRH or Nva2-TRH (1 mg/kg or 5 mg/kg) produced equipotent increases in plasma prolactin. On the other hand, while TRH significantly increases blood pressure and heart rate, Nva2-TRH was essentially inactive. Thus, two contrasting analogues are now available: 4-NO2-Im-TRH (Neuropeptides, 8, 63, 1986) has full cardiovascular activity and no PRL-releasing activity, while Nva2-TRH has no cardiovascular activity and full PRL-releasing activity of TRH.
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Protective effect of a PAF-acether antagonist, BN 52021, in trichothecene toxicosis.
Trichothecenes are mycotoxins which produce lethal toxicosis in humans and animals, yet no adequate therapeutic regimen has been developed. This study provides evidence that the selective platelet activating factor (PAF) antagonist, BN 52021 (5-15 mg/kg i.v.) can prolong the survival of conscious rats exposed to a highly lethal T-2 toxicosis. These data also suggest that PAF is an important mediator of this unique toxicosis.
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Injection of thyrotropin releasing hormone into the locus coeruleus increases blood pressure.
Thyrotropin releasing hormone (TRH), 10 pmol kg-1 injected in the region of locus coeruleus, caused a rapid (within 1 min) rise of mean arterial pressure in the urethane-anaesthetized rat. No clear-cut effects in heart rate or ventilation were observed. When TRH was injected into the lateral ventricle, a dose more than 10-fold higher was required to achieve a comparable rise in arterial pressure. It is concluded that TRH may have a physiological role in central cardiovascular regulation.
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The opioid peptides. A role in hypertension?
This review is an attempt to highlight evidence that may implicate the endogenous opioid system in the pathogenesis of hypertension in humans. The evidence raised includes biochemical, physiological, pharmacological, and behavioral studies conducted in in vitro and in vivo systems, experimental models of hypertension, and humans with essential hypertension. While the compelling biochemical and pharmacological evidence in experimental animals clearly shows the presence of opioid peptides and their receptors in strategic sites of cardiovascular control and potent cardiovascular response to opioid peptides, opioid antagonists show no consistent blockade or reversal of hypertension in experimental animals or humans. One possible explanation for this phenomenon could be the vast redundancy in systems regulating blood pressure (i.e., the blockade of one system still leaves many other systems fully able to rapidly offset the eliminated system). Regarding the opioid system, the situation is much more complex, since some opioid receptors (mu-type) mediate pressor responses, while other receptors (kappa-type) mediate depressor responses. Therefore, nonselective opioid receptor antagonists (e.g., naloxone), which block both types of receptors, can be devoid of any cardiovascular activity, while a selective mu-receptor antagonist or a selective and potent kappa-receptor agonist may produce the desired antihypertensive effect. A combination of both actions (i.e., a drug that is both a mu-antagonist and a kappa-agonist) might be even more advantageous. Until such compounds are developed, this hypothesis will be hard to prove.
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Effect of thyrotropin releasing hormone and some of its histidine analogs on the cardiovascular system and prolactin release in the conscious rat.
The cardiovascular and endocrine activity of three analogs of thyrotropin releasing hormone (TRH), 4-nitro-imidazole TRH (4-nitro-TRH), 2-trifluoro-methyl-imidazole TRH (2-TFM-TRH) and 4-trifluoro-methyl-imidazole TRH (4-TFM-TRH), was compared to TRH in conscious rats. Injection of TRH or the three analogs (1 mg/kg or 5 mg/kg) into the arterial line induced increases in mean arterial pressure, pulse pressure and heart rate and raised plasma prolactin (PRL). None of the analogs were more potent than TRH in inducing cardiovascular changes. The 4-TFM-TRH was significantly less potent than the 2-TFM-TRH in increasing blood pressure, while the nitro-TRH was more potent than the 2-TFM-TRH in producing tachycardia. TRH induced a two-fold increase in PRL at the 5 mg/kg dose, while both the fluorinated analogs elicited a 4 to 5 fold increase in PRL at the higher dose. The present results suggest that the receptors for TRH-elicited PRL release differ from TRH-receptors involved in its cardiovascular actions.
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Effect of naloxone and morphine on survival of conscious rats after hemorrhage.
The endogenous opioid system has been reported to depress the cardiovascular system during shock states, since naloxone, a potent opiate antagonist, enhances recovery of hemodynamic variables in various shock states. However, the effect of naloxone on long-term survival of experimental animals exposed to hypovolemic hypotension is not clear. The present studies tested the capacity of various doses of naloxone to protect conscious rats from mortality following various bleeding paradigms. In addition, the effect of morphine on survival of rats exposed to hemorrhage was also examined. In the six different experimental protocols tested, naloxone treatments failed to improve short- or long-term survival; in fact, naloxone treatment reduced short-term survival in two of the experimental protocols. Morphine injection, however, enhanced the mortality of rats exposed to hemorrhage in a dose-dependent manner. It is concluded that while opiates administered exogenously decrease survival after acute bleeding, naloxone has no protective action in such states and, like morphine, it may decrease survival in some situations.
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