The effect of daidzein on renal injury in ovariectomized rats: interaction of angiotensin receptors and long non-coding RNAs H19, GAS5, MIAT, and Rian.

Background: Renin-angiotensin system (RAS) is prominently associated with renal pathophysiology in postmenopausal women. Long non-coding RNAs (lncRNAs) H19, GAS5, MIAT, and Rian have been linked to the pathogenesis of renal injury. Aims: This study aimed to evaluate the beneficial effects of daidzein on unilateral ureteral obstruction (UUO) induced-renal injury in ovariectomized (OVX) rats through interaction with angiotensin AT1, Mas receptors, and lncRNAs. Methods: 84 female rats were ovariectomized (OVX) two weeks before performing obstruction of the left kidney ureter (UUO). The animals were then randomly divided into four main groups (n=21): Sham+DMSO, UUO+DMSO, UUO+17ß-Estradiol (E2) (positive control), and UUO+daidzein. Each main group comprised three subgroups (n=7) and were treated with saline, A779 (MasR antagonist), or losartan (AT1R antagonist) for 15 days. On day 16, the animals were euthanized, and the left kidneys were harvested for histopathology and lncRNAs expression assays. Results: UUO significantly increased kidney tissue damage score (KTDS) in the UUO rats, increased the expression of H19 and MIAT, and decreased the expression of GAS5 and Rian. Daidzein alone and in co-treatment with losartan or A779 reversed these effects. Daidzein with 1 mg/kg dose was more effective than E2. Conclusion: Daidzein alone and in co-treatment with A779 and losartan improved renal injury in UUO rats and recovered dysregulated expression of UUO-related lncRNAs through modulating MasR and AT1R receptors, associating with modulation of the expression of lncRNAs. Daidzein could be considered a renoprotective phytoestrogen substitute for E2 therapy in postmenopausal women suffering from renal diseases.

Anti-inflammatory and anti-remodeling effects of myrtenol in the lungs of asthmatic rats: Histopathological and biochemical findings

Introduction: Asthma is a chronic inflammatory disease of the airways. In this study, we evaluated the anti-inflammatory effects of myrtenol on the inflammatory indices in the pulmonary parenchyma and airways and on the inflammatory and oxidative indices of the bronchoalveolar lavage fluid (BALF) of asthmatic rats. Methods: The allergic asthma was induced by sensitization (two weeks) followed by the inhalation of ovalbumin (four weeks). Animals were divided into two main groups: (1) Histopathology, and (2) measurement of inflammatory and oxidative biomarkers in the BALF. Each main group was subdivided into four subgroups: Control, Asthma, Asthma+Dexamethasone and Asthma + Myrtenol. (-)-Myrtenol (50 mg/kg) or Dexamethasone (2.5 mg/kg) was administered intraperitoneally once a day for one week, at the end of the inhalation period. On day 50, lung histopathologic parameters and inflammatory indices in BALF including INF-gamma, IL-10, IL-1Beta, and TNF-alfa and oxidative stress biomarkers (MDA, SOD, and GPX) were measured. Result: In the Asthma group, leukocyte infiltration, the thickness of smooth muscle and epithelium of airways wall and the number of goblet cells increased. Myrtenol reduced all of the above-mentioned indices except the epithelium thickness. It also inhibited the increase in BALF IL-1Beta, TNF-alfa and MDA and increased the levels of INF-gamma, IL-10 and SOD. Conclusion: Our results suggest that myrtenol reduced damage caused by experimental asthma by reducing the inflammatory indices, normalizing the level of interleukins and balancing oxidative stress in the lungs. It also prevented airway remodeling. Myrtenol may be suggested as a potent herbal medicine for the treatment of allergic asthma

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Anti-inflammatory and anti-remodeling effects of myrtenol in the lungs of asthmatic rats: Histopathological and biochemical findings.

INTRODUCTION: Asthma is a chronic inflammatory disease of the airways. In this study, we evaluated the anti-inflammatory effects of myrtenol on the inflammatory indices in the pulmonary parenchyma and airways and on the inflammatory and oxidative indices of the bronchoalveolar lavage fluid (BALF) of asthmatic rats. METHODS: The allergic asthma was induced by sensitization (two weeks) followed by the inhalation of ovalbumin (four weeks). Animals were divided into two main groups: (1) Histopathology, and (2) measurement of inflammatory and oxidative biomarkers in the BALF. Each main group was subdivided into four subgroups: Control, Asthma, Asthma+Dexamethasone and Asthma+Myrtenol. (-)-Myrtenol (50mg/kg) or Dexamethasone (2.5mg/kg) was administered intraperitoneally once a day for one week, at the end of the inhalation period. On day 50, lung histopathologic parameters and inflammatory indices in BALF including INF-γ, IL-10, IL-1ß, and TNF-α and oxidative stress biomarkers (MDA, SOD, and GPX) were measured. RESULT: In the Asthma group, leukocyte infiltration, the thickness of smooth muscle and epithelium of airways wall and the number of goblet cells increased. Myrtenol reduced all of the above-mentioned indices except the epithelium thickness. It also inhibited the increase in BALF IL-1ß, TNF-α and MDA and increased the levels of INF-γ, IL-10 and SOD. CONCLUSION: Our results suggest that myrtenol reduced damage caused by experimental asthma by reducing the inflammatory indices, normalizing the level of interleukins and balancing oxidative stress in the lungs. It also prevented airway remodeling. Myrtenol may be suggested as a potent herbal medicine for the treatment of allergic asthma.

Low-intensity endurance exercise plus nandrolone decanoate modulates cardiac adiponectin and its receptors.

Vast adverse effects of anabolic-androgenic steroids (AASs) on athletes' cardiovascular systems have been reported. However, there is still a lack of adequate information regarding the pathways and mechanisms involved. We tested the hypothesis that adiponectin and its receptors in the heart may be affected by long-term use of AASs alongside exercising. Male Wistar rats were randomized into the control (CTL), exercise (EX), nandrolone (Nan), arachis (Arach) group which treated with arachis as vehicle, trained vehicle (EX+Arach) and trained nandrolone (EX+Nan) groups that were treated for 8 weeks. One day after the end of the protocol, animals were sacrificed and their hearts were frozen. TNF-α and adiponectin proteins of hearts were evaluated quantitatively by ELISA kits, and Western blot analysis was used for measuring adiponectin receptor protein expression. TNF-α protein increased significantly in the EX+Nan group (P<.05 vs CTL group). The AdipoR1 protein was significantly higher in the presence of nandrolone alongside exercise (P<.05 vs Nan and EX+Arach groups, P<.01 vs CTL and Arach groups). In addition, AdipoR2 protein enhanced in the EX+Nan group when compared with the other groups (P<.05 vs EX and EX+Arach groups, P<.01 vs CTL, Arach and Nan groups). Chronic nandrolone plus mild endurance exercise may be associated with imbalance in pro-/anti-inflammatory cytokines and may induce a positive modulatory effect on cardiac adiporeceptors in rat. Further studies are required before these findings can be generalized to humans.

Circulating levels of interleukin-35 in patients with multiple sclerosis: evaluation of the influences of FOXP3 gene polymorphism and treatment program.

The regulatory T (Treg) cells play a major role in the control of the autoimmunity and inflammation, and IL-35 has been described as an immunosuppressive cytokine that is mainly produced by CD4(+)FOXP3(+) Treg cells. The aim of this study was to evaluate the serum levels of IL-35 and a single nucleotide polymorphism (SNP), rs3761548, in FOXP3 gene in patients with multiple sclerosis. The blood samples were collected from 140 multiple sclerosis (MS) patients (including 51 untreated and 89 treated patients) and 140 healthy subjects as a control group. The serum levels of IL-35 were measured by ELISA. The DNA was analyzed for SNP rs3761548 in FOXP3 gene using SSP-PCR. There was no significant difference between untreated MS patients and control group regarding the mean serum levels of IL-35, although this parameter was higher in untreated patients. However, the mean serum level of IL-35 in treated MS patients was significantly higher than that in the control group (P < 0.008). The mean serum levels of IL-35 in patients who were treated with interferon-ß, methylprednisolone, or with the both interferon-ß and methylprednisolone were significantly higher than that in the healthy group (P < 0.01, P < 0.01, and P < 0.2, respectively). The frequencies of AA and AC genotypes at rs3761548 in the FOXP3 gene were significantly higher in MS group as compared with healthy subjects (P < 0.05). The frequency of CC genotype at rs3761548 was significantly lower in the MS group in comparison with healthy control subjects (P < 0.001). Moreover, the frequency of A allele was significantly higher whereas the frequency of C allele was significantly lower in MS patients in comparison to healthy subjects (P < 0.001). The mean serum level of IL-35 was significantly lower in MS patients or healthy subjects with AA genotype as compared with those with CC genotype at rs3761548 in FOXP3 gene (P < 0.01 and P < 0.001, respectively). These results showed higher serum levels of IL-35 in treated MS patients representing that the benefit effects of treatment may in part performed through the upregulation of the IL-35 production. The SNP rs3761548 may influence the susceptibility to MS disease and the serum levels of IL-35.

Coronary Artery Disease Risk Factors in an Urban and Peri-urban Setting, Kerman, Southeastern Iran (KERCADR Study): Methodology and Preliminary Report.

BACKGROUND: This article was to present the sampling and measurements methods and the main preliminary findings of the KERCADR cohort study (first round) in an urban and peri-urban setting, Kerman, southeastern Iran 2009-11. METHOD: 5900 (3238 female) people aged between 15 to 75 years were recruited in the household survey by non-proportional to size one-stage cluster sampling. Trained internal specialists, general practitioners, clinical psychologists and dentists have assessed the study subjects by person-assisted questionnaires regarding different NCD risk factors including cigarette and opium smoking, physical activity, nutrition habits, anxiety, depression, obesity, hypertension and oral health. Blood samples were also collected for determining FBS, HbA1c, cholesterol and triglyceride. Weighted standardized prevalence estimates were calculated by STATA 10 survey analysis package. RESULTS: The participation rate was more than 95% in all subgroups. Cigarette smoking (18.4% vs. 1.2%), opium use (17.8% vs. 3.0%) and triglyceridemia (16.1% vs. 12.0%) were significantly higher among men than women. In contrast, women were presented with higher level of sever anxiety (29.1% vs. 16.7%), obesity (16.8% vs. 9.2%), low-physical activity (45.1% vs. 39.2%) and uncontrolled diabetes (60.2% vs. 31.0%). More than 68% of all subjects have presented with moderate to severe gingival index scores. CONCLUSION: The first round of the KERCADR cohort with sufficient sample size and response rate provided precise estimates for the main clinical and para-clinical NCD risk factors. These evidences need to be translated into public health interventions and monitored in the next rounds of the cohort.

The receptors and role of angiotensin II in knee joint blood flow regulation and role of nitric oxide in modulation of their function.

OBJECTIVES: Angiotensin-converting enzyme (ACE) upregulation in the stroma cells of arthritis rheumatoid joints may produce a higher tissue concentration of angiotensin II (angII), which is a vasoconstrictor and mitogen factor that causes local hypoxia and synovial proliferation. No study in the literature has examined the role of angII in joint blood flow (JBF) regulation and the potential effect of ACE inhibitors on JBF. METHODS: The study was performed on 20 Dutch white rabbits to examine the JBF response to angII, angII receptor subtypes, and the role of nitric oxide (NO) in angII effects in knee joint blood vessels. Drugs were administered locally through retrograde saphenous artery cannulation. Joint vascular resistance (JVR) was calculated by dividing the arterial blood pressure by the JBF. RESULTS: AngII increased JVR dose dependently. The angII type 1 (AT(1)) receptor antagonist losartan did not change the basal JVR but completely blocked the effect of angII on JVR. N(omega)-nitro-L-arginin methyl ester (L-NAME) increased JVR by a mean (+/-SEM) of 25.8 +/- 8.7% (p < 0.05) but did not affect the joint vessel response to angII and losartan. CONCLUSIONS: AngII receptors are from the AT(1) subtype in normal joint blood vessels, but angII plays no significant role in JBF regulation. The basal release of NO plays a role in resting JBF regulation, but NO does not affect the AT(1) receptor-mediated vasoconstriction of joint blood vessels.

Synthesis and calcium channel antagonist activity of nifedipine analogues with methylthioimidazole substituent.

Various diester analogues of nifedipine, in which the orthonitrophenyl group at position 4 is replaced by 1-methyl-2-methylthio-5-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists on guinea-pig ileal smooth muscle. Nifedipine was used as standard. Comparison of the activities of symmetrical esters (3a-e) indicate that increasing the length of alkyl chain in C3 and C5 ester substituents increases the antagonist activity and the n-propyl ester being preferred (IC50= 2.66 x 10(-9) M). In asymmetrical series (6a-g), compound 6g having ethyl and n-butyl ester at C3 and C5 positions of basic dihydropyridine structure was found to be the most active (IC50= 1.32 x 10(-9) M).

Alteration in alpha- and beta-adrenoceptor profile of rabbit knee joint blood vessels due to acute inflammation.

Experiments were performed to investigate the nature of - and -adrenoceptors in blood vessels supplying the posterior capsule of the acutely inflamed rabbit knee joint, and results were compared to findings from previous experiments on the normal joint, to assess any alteration which may occur in the adrenoceptor profile due to the inflammation process. Electrical stimulation of the posterior articular nerve resulted in vasoconstriction which was reversed to vasodilatation by phentolamine and yohimbine. The dose-response curves to close intra-arterial injection of -adrenoceptor agonists showed a rank-order potency of: adrenaline = phenylephrine = clonidine. The adrenaline dose-response curve was shifted to the right by administration of antagonists with a rank-order potency of: phentolamine = yohimbine = prazosin. At this stage of the experiments there was an equal response of 1- and 2-adrenoceptors in blood vessels of the acutely inflamed rabbit knee joint. In another group of animals the neurally mediated vasodilatation, which appeared after administration of phentolamine, was completely blocked by propranolol, and was reduced by about 50 % by atenolol. The dose-response curves to close intra-arterial injection of -adrenoceptor agonists showed a rank-order potency of: isoprenaline > salbutamol = dobutamine. The isoprenaline dose-response curve was shifted to the right by administration of antagonists with a rank-order potency of: propranolol > atenolol. These experiments also showed an almost equal response of 1- and 2-adrenoceptors in blood vessels of the acutely inflamed rabbit knee joint. Overall, compared to previous experiments on the normal joint in which 2- and 1-adrenoceptor responses predominated, acute inflammation resulted in a shift from 2- towards 1- and from 1- towards 2-adrenoceptor responses.

Comparison of synovial PO2 and sympathetic vasoconstrictor responses in normal and acutely inflamed rabbit knee joints.

Experiments were performed to assess the effect of acute inflammation of the rabbit knee joint on the partial pressure of oxygen in synovial fluid (Ps,O2) and nerve-mediated vasoconstrictor responses of articular blood vessels. With the hypodermic needle oxygen electrode sited within the synovial cavity in the posterior region of the knee joint, mean (+/- S.E.M.). Ps,O2 was 37.4 +/- 3.6 mmHg (n = 10) in the inflamed group, which differed significantly (P < 0.05) from that occurring in the normal group from a different series (48.2 +/- 3.1 mmHg; n = 18). Ps,O2 was found to decrease with increasing depth of penetration of the oxygen electrode into the joint cavity of the inflamed knee, as in the normal knee. The lowest values were observed close to articular cartilage. Absolute blood flow was measured using radiolabelled microspheres whilst relative changes in blood flow were assessed using laser Doppler flowmetry. The former technique showed that the inflamed joints had a significantly higher blood flow. Electrical stimulation of the posterior articular nerve (PAN) of the knee resulted in vasoconstriction of knee joint blood vessels, which was accompanied by a reduction in Ps,O2. The frequency-response and voltage-response profiles to electrical stimulation of the PAN, although differing in magnitude, showed a high degree of correlation between blood flow and Ps,O2. The frequency-response profile to electrical stimulation of the PAN shifted to the right in inflamed joints compared with normal joints, suggesting a reduction in the efficacy of the sympathetic nervous system in regulating blood flow to the inflamed joints. Although the inflamed joint had a higher blood flow, Ps,O2 was lower compared with the normal joint. The results of this study show significantly altered blood flow, Ps,O2 and nerve-mediated constrictor responses in the acutely inflamed joint. These are related to the inflammatory response and may contribute to the pathogenesis of arthritis.

Role of prostaglandins in regulation of blood flow and modulation of sympathetic vasoconstriction in normal and acutely inflamed rabbit knee joints.

Experiments were performed to investigate, in the normal and acutely inflamed rabbit knee joint, the role of prostaglandins in the regulation of joint blood flow, measured by laser Doppler flowmetry, as well as their modulation of sympathetic vasoconstriction. Close intra-arterial injection of prostaglandin E2 (PGE2) produced a dose-dependent vasodilatation in control joints, but the responses in inflamed joints were much smaller. Close intra-arterial infusion of indomethacin significantly increased the responses of the control joints to PGE2, but had no effect on the responsiveness of the inflamed joints. Nerve-mediated vasoconstrictor responses did not change significantly with close intra-arterial infusion of indomethacin, either in control or in inflamed joints. Indomethacin infusions decreased basal joint blood flow in the control joint significantly more than in the inflamed joint. The systemic blood pressure was elevated slightly only in the control group. The results of this study show that although prostaglandins have a role to play in regulation of basal blood flow in both normal and acutely inflamed rabbit knee joints, they do not appear to play a significant role in modulation of sympathetic vasoconstrictor responses. Prostaglandin E2 receptors are functional in normal knee joint blood vessels, but they may be disabled by the process of inflammation.

Nitric oxide modulates sympathetic vasoconstriction and basal blood flow in normal and acutely inflamed rabbit knee joints.

Experiments were performed to investigate the role of nitric oxide (NO) in the regulation of joint blood flow and in modulating sympathetic vasoconstrictor influences in normal and acutely inflamed rabbit knees. Close intra-arterial infusion of N omega-nitro_L-arginine methyl ester (L-NAME), a NO production inhibitor, reduced basal joint blood flow, measured by laser Doppler flowmetry, by 36.4 +/- 5.1% (mean +/- S.E.M.) in normal (control) and 21.4 +/- 7.8% in carrageenan-inflamed knee joints. Mean systemic arterial blood pressure was increased by 20 +/- 3.1 and 17.9 +/- 2% in control and test animal groups respectively. Joint vascular resistance was increased by 101 +/- 19% in normal and 68.9 +/- 13.7% in carrageenan-treated animals. Vasoconstrictor responses to electrical stimulation of the posterior articular nerve (PAN) were significantly smaller in the inflamed joint compared to normal. Infusion of L-NAME for 45 min resulted in an increased vasoconstrictor response by 78% in normal and 79% in inflamed joints. Subsequent close intra-arterial infusion of L-arginine failed to return the enhanced vasoconstrictor responses induced by L-NAME to their control levels in both normal and test animal groups, but partially restored blood flow changes. In both normal and inflamed joints, vasoconstriction produced by separate intra-arterial injection of the alpha 1-agonist phenylephrine (2.5 nmol) or either of the alpha 2-agonists clonidine (250 pmol) and UK-14304 (250 pmol) was increased significantly by L-NAME infusion but not completely restored to basal values by L-arginine infusion. The control responses to all three agents did not differ significantly between normal and inflamed knees.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic innervation and beta-adrenoceptor profile of blood vessels in the posterior region of the rabbit knee joint.

Experiments were performed to investigate the presence and nature of beta-adrenoceptors in blood vessels supplying the posterior capsule of the rabbit knee joint. Electrical stimulation of the posterior articular nerve (PAN) and close intra-arterial injection of adrenaline produced vasoconstriction which reversed to vasodilatation with administration of the alpha-adrenoceptor antagonist phenoxybenzamine. In almost all animals close intra-arterial injection of the beta-adrenoceptor agonist isoprenaline resulted in vasodilatation. Injection of the more selective beta-agonists dobutamine, salbutamol and terbutaline also produced vasodilatation with a rank potency order of isoprenaline > dobutamine > salbutamol > or = terbutaline. The beta-adrenoceptor antagonist propranolol abolished the dilator responses to adrenaline and isoprenaline, and significantly reduced the dilator responses to PAN stimulation in phenoxybenzamine-treated animals. Nerve-mediated vasodilatation was also reduced by the substance P antagonist D-Pro4 D-Trp7,9,10 SP4-11, suggesting that substance P contributes to this dilatation. Dobutamine, a selective beta 1-agonist, produced vasodilatation which was abolished by administration of the selective beta 1-antagonist atenolol. Isoprenaline-induced vasodilatation was substantially reduced by atenolol. The dilator response to isoprenaline appeared to be unaffected by the selective beta 2-antagonist ICI118551, but the weak dilator responses to the selective beta 2-agonists salbutamol and terbutaline were significantly reduced by this antagonist. The results of this study suggest that beta-adrenoceptors appear to be involved in the sympathetic regulation of rabbit knee joint blood flow, and that this is predominantly mediated via beta 1-adrenoceptors.

Localized neural control of blood flow in the posterior region of the knee joint in anaesthetized rabbits.

Radiolabelled microspheres were used to measure blood flow of structures in and around the rabbit knee joint and to determine the effect of electrical stimulation of the posterior articular nerve (PAN) supplying the knee. Surgical exposure of the posterior aspect of the knee joint 'capsule' and section of PAN resulted in an increase in flow restricted to this region. Electrical stimulation produced frequency-dependent reductions of blood flow in the posterior region, but no alterations occurred in the anterior region or in any other surrounding structures, suggesting that the neural supply is specific to the posterior joint capsule.

Sympathetic innervation and alpha-adrenoceptor profile of blood vessels in the posterior region of the rabbit knee joint.

1. Experiments were performed to determine the nature of adrenoceptors mediating neurally-induced vasoconstriction of blood vessels in the posterior region of the rabbit knee joint capsule. 2. Electrical stimulation of the posterior articular nerve resulted in frequency-dependent vasoconstriction which was maximal at 10 Hz. This response was mediated predominantly by alpha 2-adrenoceptors as it was only slightly reduced by prazosin administration and was not only abolished but converted into a dilator response by the alpha 2-adrenoceptor antagonist rauwolscine. Further experiments with another specific alpha 1-adrenoceptor antagonist YM-12617 showed that the frequency-response curve in the presence of this antagonist did not differ significantly from control. 3. Neurally-induced vasoconstriction did not appear to have a purinergic component as it was unaffected by the P2x-purinoceptor desensitiser alpha, beta methylene ATP. 4. The rank-order of potency of alpha-adrenoceptor agonists given as a bolus by close intra-arterial injection was: adrenaline = UK-14304 > clonidine > phenylephrine, suggesting that the vasoconstrictor effects were mediated predominantly by postjunctional alpha 2-adrenoceptors. 5. The alpha 2-adrenoceptor antagonist rauwolscine converted the constrictor response to close intra-arterial injection of adrenaline into a dilator response. The vasoconstrictor responses to UK-14304, clonidine and phenylephrine were substantially inhibited by rauwolscine. The alpha 1-adrenoceptor antagonist prazosin failed to inhibit the vasoconstrictor responses to adrenaline, clonidine and UK-14304 and resulted in enhancement of their constrictor effects. 6. The enhancement of the responses to the a, and a2 agonists by prazosin appeared to be specifically related to this agent as administration of YM-12617 did not show such enhancement. The dose-response curves to both clonidine and UK-14304 in the presence of YM-12617 did not differ significantly from control responses. Responses to phenylephrine were significantly reduced by YM-12617, indicating the presence of post-junctional a,-adrenoceptors.7. These results show almost complete reversal of the adrenoceptor profile compared to results obtained in an earlier in vitro study, where responses were mediated predominantly by ax,-adrenoceptors with a small population of postjunctional a2-adrenoceptors (Ferrell & Khoshbaten, 1989). This suggests that the differing environment in vitro may not completely reflect the conditions prevailing in vivo.

Changes in synovial PO2 and blood flow in the rabbit knee joint due to stimulation of the posterior articular nerve.

1. Experiments were performed to measure the partial pressure of oxygen in the synovial fluid (Ps,O2) of the normal rabbit knee joint and assess the extent to which this varied with changes in knee joint blood flow. 2. With the hypodermic needle oxygen electrode sited just within the synovial cavity, Ps,O2 values ranged from 25 to 72 mmHg with a mean of 48.2 +/- 3.1 (S.E.M.; n = 18). 3. Ps,O2 was found to decrease with increasing depth of penetration of the oxygen electrode. Lowest values were observed close to the articular cartilage. 4. Electrical stimulation of the posterior articular nerve (PAN) of the knee resulted in vasoconstriction of knee joint blood vessels which was accompanied by a decrease in Ps,O2. The frequency-response and voltage-response profiles to electrical stimulation of PAN, although differing in magnitude, showed a high degree of correlation between blood flow and Ps,O2. 5. As judged by the conduction velocity, the vasoconstrictor response to nerve stimulation was mediated by unmyelinated nerve fibres, presumed to be sympathetic postganglionic fibres. 6. In view of the low Ps,O2 values occurring deep within the joint, avascular structures such as cartilage could be subject to injury if sustained reduction in synovial blood flow occurred. This could be a contributory factor in the pathogenesis of degenerative and inflammatory joint diseases.