Influence of combined hypertension and renal failure on functional alpha(1)-adrenoceptor subtypes in the rat kidney.
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ABSTRACT:
SUBMITTER: Hye Khan MA
PROVIDER: S-EPMC2275443 | biostudies-other | 2008 Mar
REPOSITORIES: biostudies-other
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Project description:alpha(1)-adrenoceptor subtypes in human skeletal muscle resistance arteries were characterized using agonists noradrenaline (non-selective) and A61603 (alpha(1A)-selective), the antagonists prazosin (non-selective), 5-methyl-urapidil (alpha(1A)-selective) and BMY7378 (alpha(1D)-selective) and the alkylating agent chloroethylclonidine (preferential for alpha(1B)). Small arteries were obtained from the non-ischaemic skeletal muscle of limbs amputated for critical limb ischaemia and isometric tension recorded using wire myography. Prazosin antagonized responses to noradrenaline with a pA(2) value of 9.18, consistent with the presence of alpha(1)-adrenoceptors, although the Schild slope (1.32) was significantly different from unity. 5-Methyl-urapidil competitively antagonized responses to noradrenaline with a pK(B) value of 8.48 and a Schild slope of 0.99, consistent with the presence of alpha(1A)-adrenoceptors. In the presence of 300 nM 5-methyl-urapidil, noradrenaline exhibited biphasic concentration response curves, indicating the presence of a minor population of a 5-methyl-urapidil-resistant subtype. Contractile responses to noradrenaline were not affected by 1 microM chloroethylclonidine suggesting the absence of alpha(1B)-adrenoceptors. Maximum responses to noradrenaline and A61603 were reduced to a similar extent by 10 microM chloroethylclonidine, suggesting an effect of chloroethylclonidine at alpha(1A)-adrenoceptors at the higher concentration. BMY7378 (10 and 100 nM) had no effect on responses to noradrenaline. BMY7378 (1 microM) poorly shifted the potency of noradrenaline giving a pA(2) of 6.52. These results rule out the presence of the alpha(1D)-subtype. These results show that contractile responses to noradrenaline in human skeletal muscle resistance arteries are predominantly mediated by the alpha(1A)-adrenoceptor subtype with a minor population of an unknown alpha(1)-adrenoceptor subtype.
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Project description:Background and purposeMesenteric and carotid arteries from the alpha(1B/D)-adrenoceptor knockout (alpha(1B/D)-KO) were employed to isolate alpha(1A)-adrenoceptor pharmacology and location and to reveal these features in the wild-type (WT) mouse.Experimental approachFunctional pharmacology by wire myography and receptor localization by confocal microscopy, using the fluorescent alpha(1)-adrenoceptor ligand BODIPY FL-Prazosin (QAPB), on mesenteric (an 'alpha(1A)-adrenoceptor' tissue) and carotid (an 'alpha(1D)-adrenoceptor' tissue) arteries.Key resultsAlpha(1B/D)-KO mesenteric arteries showed straightforward alpha(1A)-adrenoceptor agonist/antagonist pharmacology. WT had complex pharmacology with alpha(1A)- and alpha(1D)-adrenoceptor components. alpha(1B/D)-KO had a larger alpha(1A)-adrenoceptor response suggesting compensatory up-regulation: no increase in fluorescent ligand binding suggests up-regulation of signalling. alpha(1B/D)-KO carotid arteries had low efficacy alpha(1A)-adrenoceptor responses. WT had complex pharmacology consistent with co-activation of all three subtypes. Fluorescent binding had straightforward alpha(1A)-adrenoceptor characteristics in both arteries of alpha(1B/D)-KO. Fluorescent binding varied between cells in relative intracellular and surface distribution. Total fluorescence was reduced in the alpha(1B/D)-KO due to fewer smooth muscle cells showing fluorescent binding. WT binding was greater and sensitive to alpha(1A)- and alpha(1D)-adrenoceptor antagonists.Conclusions and implicationsThe straightforward pharmacology and fluorescent binding in the alpha(1B/D)-KO was used to interpret the properties of the alpha(1A)-adrenoceptor in the WT. Reduced total fluorescence in alpha(1B/D)-KO arteries, despite a clear difference in the functionally dominant subtype, indicates that measurement of receptor protein is unlikely to correlate with function. Fewer cells bound QAPB in the alpha(1B/D)-KO suggesting different cellular phenotypes of alpha(1A)-adrenoceptor exist. The alpha(1B/D)-KO provides robust assays for the alpha(1A)-adrenoceptor and takes us closer to understanding multi-receptor subtype interactions.
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Project description:?(2)-Adrenoceptors belong to the family of adrenergic receptors, which regulate the neuronal release of norepinephrine as part of a negative feedback loop. Among the ?(2)-adrenoceptors, the ?(2B)-subtype may also influence developmental signaling pathways involved in angiogenesis of the placenta. Thus, the aim of the present study was to determine whether ?(2B)-adrenoceptors are also involved in other developmental processes beyond placental angiogenesis. Ablation of ?(2B)-adrenoceptors led to lethality of mutant mice during the first hours after birth. Despite normal breathing and drinking behavior, mutant mice developed cyanosis, which could be traced back to a defect in lung morphology with significantly reduced alveolar volume and thickened interalveolar septi. In ?(2B)-deficient lungs and in isolated alveolar type II cells, expression of sonic hedgehog (SHH) was significantly increased, resulting in mesenchymal proliferation. In vitro ?(2B)-adrenoreceptor stimulation suppressed expression of sonic hedgehog and the cell cycle genes cyclin D1 and Ki67. In vivo inhibition of enhanced SHH signaling by the smoothened antagonist cyclopamine partially rescued perinatal lethality, lung morphology, and altered gene expression in mutant mice. Thus, ?(2B)-adrenoceptors in lung epithelia play an important role in suppressing sonic hedgehog-mediated proliferation of mesenchymal cells and thus prevent respiratory failure.
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Project description:We investigated subtypes of alpha-1 adrenoceptor (AR) in rabbit ocular tissues using reverse transcription-polymerase chain reaction (RT - PCR), in situ hybridization (ISH) and binding studies. Competitive RT - PCR assays specific for the subtypes of alpha-1 AR revealed that the mRNA expression of alpha-1a AR was dominant, and that of each alpha-1b and alpha-1d was less than 10% and 0.5% of total alpha-1 ARs mRNA, respectively, in the iris, ciliary body, choroid and retina. In alpha-1a AR splice isoform-specific RT - PCR assays, we found a distinct proportion of each isoform mRNA in the iris, ciliary body and choroid. The results of the ISH assays for alpha-1a AR subtype showed that hybridization signals were clearly observed in the iris dilator muscle and in the epithelium of the ciliary processes. In binding studies, alpha-1A AR was a dominant subtype in the iris, choroid and retina in contrast to the ciliary body that had more alpha-1B than alpha-1A AR subtype at protein level.
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Project description:Hyperglycemia is associated with adverse outcomes in hospitalized patients. We aimed to assess the impact of glucose levels upon admission on the subsequent deterioration or improvement of kidney function in inpatients with a focus on diabetes or reduced baseline kidney function as possible modifiers of this effect. Running a retrospective cohort analysis, we compared patients with normal vs. high glucose levels upon admission. We applied multivariable logistic regression models to study the association between baseline glucose levels with subsequent renal and clinical outcomes. Interaction terms were used to study a possible modifier effect of diabetes. Among 95,556 inpatients (52% males, mean age 61 years), 15,675 (16.5%) had plasma glucose higher than 180 mg/dL, and 72% of them were diabetics. Patients with higher glucose at presentation were older, with a higher proportion of co-morbid conditions. Rates of acute kidney injury (AKI), acute kidney functional recovery (AKR), and mortality were proportional to reduced renal function. AKI, AKR, and mortality were almost doubled in patients with high baseline glucose upon admission. Multivariable analysis with interaction terms demonstrated an increasing adjusted probability of all events as glucose increased, yet this association was observed principally in non-diabetic patients. Hyperglycemia is associated with AKI, AKR, and mortality in non-diabetic inpatients in proportion to the severity of their acute illness. This association diminishes in diabetic patients, suggesting a possible impact of treatable and easily reversible renal derangement in this population.
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Project description:BACKGROUND AND PURPOSE: This study investigates the role of alpha(2)-adrenoceptor subtypes, alpha(2A), alpha(2B) and alpha(2C), on catecholamine synthesis and catabolism in the central nervous system of mice. EXPERIMENTAL APPROACH: Activities of the main catecholamine synthetic and catabolic enzymes were determined in whole brains obtained from alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptor knockout (KO) and C56Bl\7 wild-type (WT) mice. KEY RESULTS: Although no significant differences were found in tyrosine hydroxylase activity and expression, brain tissue levels of 3,4-dihydroxyphenylalanine were threefold higher in alpha(2A)- and alpha(2C)-adrenoceptor KO mice. Brain tissue levels of dopamine and noradrenaline were significantly higher in alpha(2A) and alpha(2C)KOs compared with WT [WT: 2.8 +/- 0.5, 1.1 +/- 0.1; alpha(2A)KO: 6.9 +/- 0.7, 1.9 +/- 0.1; alpha(2B)KO: 2.3 +/- 0.2, 1.0 +/- 0.1; alpha(2C)KO: 4.6 +/- 0.8, 1.5 +/- 0.2 nmol.(g tissue)(-1), for dopamine and noradrenaline respectively]. Aromatic L-amino acid decarboxylase activity was significantly higher in alpha(2A) and alpha(2C)KO [WT: 40 +/- 1; alpha(2A): 77 +/- 2; alpha(2B): 40 +/- 1; alpha(2C): 50 +/- 1, maximum velocity (V(max)) in nmol.(mg protein)(-1).h(-1)], but no significant differences were found in dopamine beta-hydroxylase. Of the catabolic enzymes, catechol-O-methyltransferase enzyme activity was significantly higher in all three alpha(2)KO mice [WT: 2.0 +/- 0.0; alpha(2A): 2.4 +/- 0.1; alpha(2B): 2.2 +/- 0.0; alpha(2C): 2.2 +/- 0.0 nmol.(mg protein)(-1).h(-1)], but no significant differences were found in monoamine oxidase activity between all alpha(2)KOs and WT mice. CONCLUSIONS AND IMPLICATIONS: In mouse brain, deletion of alpha(2A)- or alpha(2C)-adrenoceptors increased cerebral aromatic L-amino acid decarboxylase activity and catecholamine tissue levels. Deletion of any alpha(2)-adrenoceptor subtypes resulted in increased activity of catechol-O-methyltransferase. Higher 3,4-dihydroxyphenylalanine tissue levels in alpha(2A) and alpha(2C)KO mice could be explained by increased 3,4-dihydroxyphenylalanine transport.
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Project description:Background and purposeMyocardial automatism and arrhythmias may ensue during strong sympathetic stimulation. We sought to investigate the relevant types of adrenoceptor, as well as the role of phosphodiesterase (PDE) activity, in the production of catecholaminergic automatism in atrial and ventricular rat myocardium.Experimental approachThe effects of adrenoceptor agonists on the rate of spontaneous contractions (automatic response) and the amplitude of electrically evoked contractions (inotropic response) were determined in left atria and ventricular myocytes isolated from Wistar rats.Key resultsCatecholaminergic automatism was Ca(2+) -dependent, as it required a functional sarcoplasmic reticulum to be exhibited. Although both ?- and ?-adrenoceptor activation caused inotropic stimulation, only ?(1) -adrenoceptors seemed to mediate the induction of spontaneous activity. Catecholaminergic automatism was enhanced and suppressed by ?(2) -adrenoceptor blockade and stimulation respectively. Inhibition of either PDE3 or PDE4 (by milrinone and rolipram, respectively) potentiated the automatic response of myocytes to catecholamines. However, only rolipram abolished the attenuation of automatism produced by ?(2) -adrenoceptor stimulation.Conclusions and implications?- and ?(2) -adrenoceptors do not seem to be involved in the mediation of catecholaminergic stimulation of spontaneous activity in atrial and ventricular myocardium. However, a functional antagonism of ?(1) - and ?(2) -adrenoceptor activation was identified, the former mediating catecholaminergic myocardial automatism and the latter attenuating this effect. Results suggest that hydrolysis of cAMP by PDE4 is involved in the protective effect mediated by ?(2) -adrenoceptor stimulation.
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Project description:Background The prevalence of hypertension subtypes changes with age. However, little is known regarding the age-dependent association of hypertension subtypes with incident heart failure (HF). Methods and Results We conducted an observational cohort study including 2 612 570 people (mean age, 44.0 years; 55.0% men). No participants were taking blood pressure-lowering medications or had a known history of cardiovascular disease. Participants were categorized as aged 20 to 49 years (n=1 825 756), 50 to 59 years (n=571 574), or 60 to 75 years (n=215 240). We defined stage 1 hypertension as systolic blood pressure (SBP) 130 to 139 mm Hg or diastolic blood pressure (DBP) 80 to 89 mm Hg and stage 2 hypertension as SBP ≥140 mm Hg or DBP ≥90 mm Hg. Among participants with stage 2 hypertension, isolated diastolic hypertension was defined as SBP <140 mm Hg and DBP ≥90 mm Hg, isolated systolic hypertension as SBP ≥140 mm Hg and DBP <90 mm Hg, and systolic diastolic hypertension as SBP ≥140 mm Hg and DBP ≥90 mm Hg. During a mean follow-up of 1205±934 days, 43 415 HF, 4807 myocardial infarction, 45 365 angina pectoris, 22 179 stroke, and 10 420 atrial fibrillation events occurred. Although the incidence of HF and other cardiovascular disease events increased with age, hazard ratios and relative risk reductions of each hypertension subtype for HF decreased with age. An age-dependent relationship between hypertension subtypes and incident HF was similarly observed in both men and women. Conclusions The contribution of isolated diastolic hypertension, isolated systolic hypertension, and systolic diastolic hypertension to the development of HF and other cardiovascular disease events was attenuated with age, suggesting that preventive efforts for blood pressure control could provide a greater benefit in younger individuals.
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Project description:Rhabdomyolysis can be life threatening if complicated by AKI. Macrophage infiltration has been observed in rat kidneys after glycerol-induced rhabdomyolysis, but the role of macrophages in rhabdomyolysis-induced AKI remains unknown. Here, in a patient diagnosed with rhabdomyolysis, we detected substantial macrophage infiltration in the kidney. In a mouse model of rhabdomyolysis-induced AKI, diverse renal macrophage phenotypes were observed depending on the stage of the disease. Two days after rhabdomyolysis, F4/80(low)CD11b(high)Ly6b(high)CD206(low) kidney macrophages were dominant, whereas by day 8, F4/80(high)CD11b(+)Ly6b(low)CD206(high) cells became the most abundant. Single-cell gene expression analyses of FACS-sorted macrophages revealed that these subpopulations were heterogeneous and that individual cells simultaneously expressed both M1 and M2 markers. Liposomal clodronate-mediated macrophage depletion significantly reduced the early infiltration of F4/80(low)CD11b(high)Ly6b(high)CD206(low) macrophages. Furthermore, transcriptionally regulated targets potentially involved in disease progression, including fibronectin, collagen III, and chemoattractants that were identified via single-cell analysis, were verified as macrophage-dependent in situ. In vitro, myoglobin treatment induced proximal tubular cells to secrete chemoattractants and macrophages to express proinflammatory markers. At day 30, liposomal clodronate-mediated macrophage depletion reduced fibrosis and improved both kidney repair and mouse survival. Seven months after rhabdomyolysis, histologic lesions were still present but were substantially reduced with prior depletion of macrophages. These results suggest an important role for macrophages in rhabdomyolysis-induced AKI progression and advocate the utility of long-term follow-up for patients with this disease.
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Project description:Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure.Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations.Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death.Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.
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