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Biomedical subjects

S M Richards

Publications and source records attributed to S M Richards.

At least 19 recordsLinked to original sources
PubMed1995

Improved preservation of saphenous vein grafts by the use of glyceryl trinitrate-verapamil solution during harvesting.

BACKGROUND: High-pressure distension during harvesting damages the saphenous vein (SV) and may contribute to subsequent coronary artery bypass graft (CABG) occlusion. Application of vasodilator agents to the SV during harvesting may reduce the need for high-pressure distension and improve graft quality. We tested the effects of a vasodilator solution containing glyceryl trinitrate and verapamil (GV) or the conventional agent papaverine (Pap) on the pressure necessary to overcome SV spasm and on the structure and biochemistry of the SV graft. METHODS AND RESULTS: Thirty-six patients undergoing CABG were randomly allocated to receive an application of either topical and intraluminal GV solution, topical Pap, or topical and intraluminal Ringer's solution (untreated) to the SV during harvesting. The peak and mean pressures required to distend the vein were recorded. Samples of SV were taken for microscopy and biochemical analysis just before we performed the anastomosis. The percentage of endothelial coverage was calculated by area measurements of stained en face preparations of the vein intima. The results for peak pressures (mmHg) were: untreated, 479.2 +/- 27.5; Pap, 384.8 +/- 29.0; and GV, 309.5 +/- 28.3 (P < .001, GV plus Pap versus untreated); and the results for mean pressures (mm Hg) were untreated, 136.2 +/- 9.6; Pap, 102.2 +/- 10.8; and GV, 98.0 +/- 8.3 (P < .01, GV plus Pap versus untreated). The results for endothelial cover (%) were: untreated, 43.7 +/- 7.0; Pap, 44.1 +/- 9.2; and GV, 68.7 +/- 7.0 (P < .05, GV versus Pap); and the results for ATP (nmol/g wet wt) were: untreated, 67.3 +/- 12.7; Pap, 112.0 +/- 19.4; and GV, 132.5 +/- 22.7 (P < .05, GV plus Pap versus untreated). CONCLUSIONS: First, pharmacological treatment of SV during harvesting, especially with GV solution, allows the use of a lower distension pressure and reduces the breakdown of high-energy phosphates in the vein wall. Second, topical and intraluminal use of GV solution during vein harvesting improves endothelial coverage compared with the topical use of Pap or no pharmacological treatment.

Aged↗
PubMed1995

Multiple types of ryanodine receptor/Ca2+ release channels are expressed in vascular smooth muscle.

Functional studies on vascular smooth muscle suggest the presence of ryanodine receptors (RyRs) with differing properties. In an attempt to understand such differences we investigated, using reverse transcription-polymerase chain reaction (RT-PCR), the possibility that smooth muscle cells express multiple types of RyRs. RNA was extracted from rat aorta, superior and small mesenteric arterial vessels, purified aortic smooth muscle media, or cultured aortic smooth muscle cells for cDNA synthesis. The cDNAs encoding RyR1, RyR2, and RyR3 were amplified using PCR primers based on sequences close to the 3' coding region of the RyR genes and PCR products verified by restriction endonuclease analysis. All three members of the RyR gene family were found to be present in vascular smooth muscle. This finding of multiple types of RyRs expressed in the same cell type indicates a complex mechanism of RyR Ca2+ channel regulation involving the formation of homo- and/or heterotetrameric complexes.

Animals↗
PubMed1995

UK Medical Research Council randomised, multicentre trial of interferon-alpha n1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response. The UK Medical Research Council's Working Parties for Therapeutic Trials in Adult Leukaemia.

Interferon-alpha may be better than cytotoxic drugs in the long-term management of patients with chronic myeloid leukaemia (CML) in chronic phase. To test this possibility 587 patients with CML in chronic phase were randomly allocated to receive lymphoblastoid cell-line interferon-alpha n1 (IFN-alpha, n = 293) or chemotherapy with busulphan or hydroxyurea (no IFN-alpha, n = 294) as maintenance after initial induction treatment with cytotoxic drugs. There was a significant survival benefit for patients in the IFN-alpha arm when analysed on the basis of intention to treat (2p = 0.0009). The median survival for those allocated IFN-alpha was 61 months and no IFN-alpha was 41 months. Out of 269 patients with Philadelphia-positive CML in the IFN-alpha arm with at least 6 months follow-up, 211 were evaluable for haematological response: 145 (68%) achieved good responses (A+ or A type), 37 (18%) had partial responses (B type) and 29 (14%) had poor responses (C type). Patients with types A and B responses had a better survival than those in the no IFN-alpha arm; patients with type C responses had survival equivalent to the no IFN-alpha arm. Of these 269 patients, 26 of whom had not started IFN-alpha, 59 (22%) achieved a significant degree of cytogenetic response but 210 (78%) did not have a response. Cytogenetic responders survived significantly longer than non-responders and even non-responders survived longer than patients in the no IFN-alpha arm. Since cytogenetic non-responders had worse than average prognostic features, they may also benefit from IFN-alpha therapy. We conclude that treatment with IFN-alpha prolongs the survival of patients with CML; benefits of IFN-alpha are not confined to cytogenetic responders but may extend to most, if not all patients receiving IFN-alpha treatment; and cytogenetic response to IFN-alpha treatment identifies patients with a relatively good prognosis.

Adult↗
PubMed1995

Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Medical Research Council Working Party on Childhood Leukaemia.

The UK Medical Research Council trial MRC UKALL X was designed to investigate the benefit of one or two courses of additional intensification therapy in children with acute lymphoblastic leukaemia receiving standard treatment. From 1985 to 1990 1612 children, comprising more than 90% of eligible cases in the UK, were treated with intensive induction therapy, central nervous system directed therapy with cranial irradiation and intrathecal methotrexate, and continuing treatment for 2 years. 1171 children were randomised to receive additional intensification therapy at 5 weeks, 20 weeks, both, or neither. At follow-up of at least 3 years disease-free survival for all children at 5 years was 62% (95% confidence interval [Cl] 60.0-64.4), a significant improvement over the 56% (53.0-59.6) found in the preceding MRC UKALL trial. The 5-year disease-free survival was 71% (65.5-76.1) for children randomised to two blocks of intensification therapy, this being significantly better than the 62% (56.6-68.0), 61% (55.7-67.1), and 57% (50.9-62.7) rates for the groups randomised to one intensification block at 5 weeks, one at 20 weeks, and no intensification, respectively. The benefits of intensification therapy were seen irrespective of clinical factors known to influence outcome such as age, sex, and initial leucocyte count. We conclude that the addition of two courses of intensification therapy has produced a 14% improvement in disease-free survival and an 11% improvement in overall survival for the randomised patients. This additional treatment is of benefit to all children with acute lymphoblastic leukaemia, even those traditionally deemed at lower risk of relapse.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Differing protection with aspartate and glutamate cardioplegia in the isolated rat heart.

Aspartate and glutamate each have been shown to improve cardiac recovery after hypoxia or ischemia under normothermic conditions, but whether their effects are additive and to what extent they are modified by hypothermia has not been studied systematically. We set out to compare the individual and combined protective effects of aspartate and glutamate during cardioplegic arrest under normothermic and hypothermic conditions in the rat. Using isolated working rat hearts, functional and metabolic recovery was assessed after 0.5 hours of potassium arrest at 37 degrees C or 5 hours at 2 degrees C in control hearts (C) and in hearts in which 20 mmol/L glutamate (G), 20 mmol/L aspartate (A), or both (A + G) was added to the cardioplegic solution. Under normothermic conditions, percentage recovery of prearrest work (mean +/- standard error of the mean) was as follows: C = 31.7 +/- 2.8, G = 34.8 +/- 0.2, A = 49.6 +/- 2.8*, A + G = 53.7 +/- 2.3*. Under hypothermic conditions, the values were as follows: C = 40.4 +/- 4.0, G = 45.2 +/- 2.3, A = 59.4 +/- 1.8*, A + G = 54.1 +/- 1.2* (*p < 0.01 versus C and G). Recovery of postischemic high-energy phosphate content followed the same pattern: A = A + G > G or C. Measurement of postischemic myocardial content of amino acids showed that recovery of function and energy status correlated with maintenance of myocardial levels of aspartate (r = 0.9; p < 0.01) but not glutamate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗
PubMed1995

Meta-analyses and overviews of randomised trials.

The number of meta-analyses or overviews appearing in the literature is rapidly increasing. Because of the problems inherent in non-randomised studies, which are not diminished by using meta-analysis techniques, this paper only refers to meta-analyses of randomised trials. Examples are given of the value of meta-analyses of randomised trials in many different circumstances and the different methods that have been used are discussed. The most reliable type of meta-analysis uses individual patient data and includes all trials fitting the pre-defined criteria, published and unpublished. As with a single randomised trial, large numbers of randomised patients are needed to give reliable results. Well-conducted meta-analyses or overviews are the best method of summarising all available unbiased evidence on the relative effects of treatments.

Humans↗
PubMed1995

Gender and treatment outcome in childhood lymphoblastic leukaemia: report from the MRC UKALL trials.

We have examined the factors influencing prognosis in over 4000 children with acute lymphoblastic leukaemia (ALL) aged 1-14 who have been treated on consecutive MRC UKALL trials from 1972 to 1990. During this time the results of treatment have improved steadily but are consistently superior in girls when compared with boys; the 5-year event-free survival in girls improving from 51% to 71% and in boys from 31% to 57%. These results were independent of age and presenting leucocyte count. Boys not only had a testicular relapse rate of 10% but an excess of bone marrow relapse, particularly evident after 2 years from diagnosis. Other prognostic factors included organomegaly and the morphology of leukaemic blast cells; immunophenotype of the leukaemia, however, had no independent significance after allowance for age, sex and leucocyte count. The influence of sex on prognosis was reaffirmed when we examined various methods of identifying children at highest risk of treatment failure for whom alternative therapy such as bone marrow transplantation might be justified. In MRC UKALL X children had been deemed 'high risk' on the basis of leucocyte count alone, but with further follow-up it has become apparent that girls with an initial leucocyte count of > 100 x 10(9)/l have a similar prognosis to boys with a lower count. We therefore derived a risk score based on sex, age and count which has given better discrimination between standard risk (66% 5-year survival) and poor risk (39%) survival than other methods. This group of worse-risk children includes 16% of boys but only 3% of all girls. Gender remains an important prognostic factor in UKALL trials and there are very few girls who are at highest risk of treatment failure. The reasons for this remain unclear, but the pattern of relapses suggests that boys more often get inadequate systemic therapy. We postulate that the reasons for treatment failure may relate to sensitivity to continuing (maintenance) chemotherapy.

Adolescent↗
PubMed1995

Infection of a human respiratory epithelial cell line with rhinovirus. Induction of cytokine release and modulation of susceptibility to infection by cytokine exposure.

Rhinovirus infections cause over one third of all colds and are a contributing factor to exacerbations of asthma. To gain insights into the early biochemical events that occur in infected epithelial cells, we develop, for the first time, a model in which a pure respiratory epithelial cell population can be routinely infected by rhinovirus. Viral infection was confirmed by demonstrating that viral titers of supernatants and lysates from infected cell increased with time and by PCR. Infection by rhinovirus 14 was inhibited by homotypic antiserum and by antibodies to intercellular adhesion molecule-1 (ICAM-1), the receptor for this virus. Susceptibility of epithelial cells to infection by rhinovirus 14 (but not rhinovirus 2, an ICAM-1 independent strain) can be increased by preexposure of cells to TNF alpha, whereas IFN gamma reduces susceptibility to infection by both rhinovirus strains. Rhinovirus infection per se does not markedly alter ICAM-1 expression on epithelial cells. Finally, we demonstrate that rhinovirus infection induced increased production of IL-8, IL-6, and GM-CSF from epithelial cells. Production of IL-8 correlated with viral replication during the first 24 h after infection. This model should provide useful insights into the pathogenesis of rhinovirus infections.

Base Sequence↗
PubMed1995

Studies on the microheterogeneity and in vitro activity of glycosylated and nonglycosylated recombinant human prolactin separated using a novel purification process.

Recombinant human PRL was produced in a murine C127 cell expression system and purified to greater than 97% homogeneity using anion and cation exchange chromatography. This material was biologically equivalent to pituitary-derived PRL in both an enzyme-linked immunosorbent assay and the Nb2 lymphoma cell proliferation assay. The predominant PRL forms were identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting as being 23 and 25 kilodaltons (kDa). These mass values were confirmed by electrospray mass spectroscopy. Glycosidase digestions indicated that the 25-kDa PRL is N-glycosylated and sialylated, whereas 23-kDa PRL is nonglycosylated. Glycosylated and nonglycosylated forms of the hormone were individually purified to greater than 95% homogeneity using novel cation exchange chromatography. Isoelectric focusing demonstrated that both forms consist of multiple charge isomers, with the charge heterogeneity of the glycosylated form primarily due to differences in sialylation. Monosaccharide analysis of the glycosylated form suggested a minimal complex oligosaccharide chain that may be fucosylated and partially sialylated. Oligosaccharide mol wt were determined by electrospray ionization mass spectroscopy. Analysis of the oligosaccharides by fluorophore-assisted carbohydrate electrophoresis indicated that bi- and triantennary oligosaccharide forms are predominant and have multiple combinations of terminal sialylation. Both forms of PRL were active in the Nb2 lymphoma cell proliferation assay; however, the 23-kDa nonglycosylated form was 3-4 times more active in this assay than the 25-kDa glycosylated form.

Amino Acid Sequence↗
PubMed1994

Vasoconstrictor-mediated release of purines and pyrimidines from perfused rat hindlimb, perfused mesenteric arcade and incubated de-endothelialized aorta.

1. Reperfusion of hindlimbs that had previously been exposed to either 10 or 60 min global ischaemia resulted in transient washouts of uracil and uric acid in approximate proportion to the interval of ischaemia. However, changing the interval of sequential angiotensin II infusions from 10 to 60 min did not affect the magnitude of sustained uracil and uric acid release. 2. Perfused rat mesenteric artery arcade released uracil and uric acid and each was further increased approximately 2-fold by exposure to the vasoconstrictor, serotonin (6.7 microM). 3. Incubated de-endothelialized rat aorta also released purines and pyrimidines and this was increased further when subjected to increased work loads. 4. The increased rates of release of purines and pyrimidines from hindlimb, and the simpler vascular preparations of mesenteric arcade and aorta, were in proportion to the relative rates of increase in oxygen consumption under maximum vascular load. 5. It is concluded that the release of purine and pyrimidine nucleosides and their catabolites from perfused rat hindlimb occurring as a consequence of vasoconstriction is not the result of release from previously ischaemic tissue. In addition, release of purines and pyrimidines appears to be a general feature of vascular smooth muscle subjected to high workloads.

Analysis of Variance↗
PubMed1992

Bone marrow transplantation for high-risk childhood lymphoblastic leukaemia in first remission: experience in MRC UKALL X.

Bone marrow transplantation (BMT) has been recommended for children with high-risk acute lymphoblastic leukaemia (ALL) in first remission. The recent MRC UKALL X trial was designed to facilitate a non-randomised comparison between BMT and chemotherapy in children deemed to be at high risk of treatment failure. 198 children aged 1-15 had a presenting leucocyte count of more than 100 x 10(9)/l. All received induction and early intensification therapy. Children with an HLA-compatible sibling donor were eligible for BMT in first remission. All other children received cranial irradiation at 24Gy, late intensification, and two years of continuous treatment. 183 children achieved a stable remission of whom 111 were HLA typed; these tended to be older and to have T-cell ALL. A donor was identified in 41 cases, of whom 34 proceeded to BMT at a median time of 17 weeks; there was no difference in distribution of age, sex, or leucocyte count between the groups receiving BMT and chemotherapy. Comparison of the 144 children who were in remission at 17 weeks and received chemotherapy with the 34 proceeding to BMT showed no significant difference in event-free survival at five years (69% for BMT and 52% for chemotherapy). There were significantly more treatment-related deaths in the marrow transplant group (6 vs 4) and more relapses in the chemotherapy group (59 vs 4). There was no significant difference in event-free survival between children who were HLA typed and had a donor and those without a donor, although there were fewer relapses among the former. BMT can be evaluated in the context of a multicentre trial for paediatric ALL but the number of children with donors is too small to make a significant impact on overall survival. However, marrow transplantation was associated with a much lower relapse rate than that with the UK ALL protocol, and with better definition of higher risk patients BMT may be of benefit in some children with high-risk ALL in first remission.

Adolescent↗
PubMed1992

A close association between vasoconstrictor-mediated uracil and lactate release by the perfused rat hindlimb.

1. Angiotensin II (5 nM) increased perfusion pressure, O2 uptake and the release of lactate, uracil and uric acid from the perfused rat hindlimb. The release of all three substances was greatest 5 min after commencement of angiotensin II infusion and then decreased over the next 20 min to reach a plateau value that was approx. 2.5-fold basal values. Following removal of angiotensin, pressure, O2 uptake as well as lactate, uracil and uric acid release each returned to pre-infusion (basal) values. 2. Cyanide (1 mM) when added during angiotensin II (5 nM) infusion blocked the pressor effect and completely inhibited all O2 uptake. Cyanide (1 mM) also inhibited the angiotensin-induced increase in uric acid, uracil and lactate release, but the effects differed. Whereas uric acid release remained inhibited throughout the cyanide infusion, uracil and lactate release were only temporarily interrupted and a secondary release of both ensued. 3. Nitroprusside (0.5 mM) when added during angiotensin II (5 nM) infusion blocked pressure and O2 uptake. Lactate and uracil release were partly blocked and returned to pre-infusion (basal) values. However uric acid release was totally blocked and no release occurred when nitroprusside was present with angiotensin II. 4. Combined data showed a significant correlation (r = 0.831; P less than 0.001) between effluent lactate and effluent uracil. 5. It is concluded that lactate and uracil release which increase markedly during vasoconstriction of the hindlimb reflect an association between glycolysis and uracil nucleotide turnover within the same tissue, possibly vascular smooth muscle.

Angiotensin II↗
PubMed1992

Cytomorphology of childhood lymphoblastic leukaemia: a prospective study of 2000 patients. United Kingdom Medical Research Council's Working Party on Childhood Leukaemia.

Blast cell morphology of children with lymphoblastic leukaemia (ALL) entering two national multicentre trials was prospectively reviewed by three haematologists to define the clinical importance of (a) French-American-British (FAB) classification, (b) the presence of cytoplasmic vacuoles, and (c) the presence of 'hand-mirror' cells. Of 2135 evaluable children, 1907 (89%) had FAB L1 morphology and 228 (11%) L2. (L3 patients were not eligible for the trials in question). L2 patients more frequently had residual disease 14 d after starting treatment and had a significantly inferior disease-free survival, but not if the analysis was stratified for age, sex and diagnostic white cell count (WBC). 627 (29%) had blast cells with cytoplasmic vacuoles, and showed a significant survival advantage over the remainder. Vacuoles were positively associated with a low WBC, age range 1-6 years and blast cell positivity for CD10, but their benign influence was apparent even when these variables were taken into account. 'Hand-mirror' (HM) cells were only studied in UKALL X, and were noted in 316/1402 (23%) children. There appeared to be an inverse correlation between HM cells and cytoplasmic vacuoles and a weak association with T-cell immunophenotype, but no prognostic significance was evident. FAB classification appears to be of less prognostic importance than has previously been supposed, though L2 disease is more resistant to current remission induction regimens. Hand-mirror cells may be more common in T-ALL, but are seen in all types and are not related to prognosis. Cytoplasmic vacuoles are predictive of a good response to current therapeutic schedules even allowing for other prognostic variables, and are the single most important morphological feature relating to prognosis in childhood ALL.

Adolescent↗
PubMed1992

Serotonin and norepinephrine vasoconstriction in rat hindlimb have different oxygen requirements.

Serotonin (5-HT) and norepinephrine (NE) are potent vasoconstrictors in the non-erythrocyte constant-flow perfused hindlimb at 25 degrees C. Because 5-HT inhibits and NE stimulates oxygen uptake, these agonists may exert control at different sites in the vasculature that have different metabolic requirements. In this study, it was found that hypoxia, cyanide, or azide had no significant effect on 5-HT-mediated vasoconstriction; however, in the presence of cyanide and absence of glucose, vasoconstriction was transient. NE-mediated vasoconstriction displayed two prazosin-sensitive components. At low concentrations (less than 50 nM), NE-mediated vasoconstriction was totally blocked by hypoxia, cyanide, or azide. At concentrations of NE significantly greater than 50 nM, oxygen-independent vasoconstriction was observed. In conclusion, NE and 5-HT sites are biochemically distinguishable, with 5-HT sites probably located on larger vessels and supportable by anaerobic metabolism and oxygen-dependent NE sites probably located on smaller arteries or arterioles. Supraphysiological concentrations of NE may interact with a subgroup of vascular alpha 1-adrenoceptors on larger vessels giving results similar to 5-HT, thus highlighting problems with high levels of NE in the perfused rat hindlimb.

Animals↗
PubMed1992

Vasoconstrictor-mediated release of lactate from the perfused rat hindlimb.

The effects of different vasomodulators on lactate release by the constant-flow-perfused rat hindlimb were examined and compared with that by perfused mesenteric artery, incubated preparations of aortas, soleus and epitrochlearis muscles, and perifused soleus muscles. Infusion of vasopressin (0.5 nM), angiotensin II (5 nM), norepinephrine (50 nM), and methoxamine (10 microM) into the hindlimbs of 180- to 200-g rats increased the perfusion pressure by 112-167% from 30.4 +/- 0.8 mmHg, O2 consumption by 26-68% from 6.4 +/- 0.2 mumol.g-1 x h-1, and lactate efflux by 148-380% from 5.41 +/- 0.25 mumol.g-1 x h-1. Hindlimbs of 100- to 120-g rats responded similarly to angiotensin II. Isoproterenol (1 microM) had no effect on O2 uptake or perfusion pressure but increased lactate release by 118%. Nitroprusside (0.5 mM) markedly inhibited the vasoconstrictor-mediated increases in lactate release, perfusion pressure, and O2 consumption by the hindlimb but had no effect on isoproterenol-mediated lactate efflux. Serotonin (6.7 microM) increased lactate release from the perfused mesenteric artery by 120% from 5.48 mol.g-1 x h-1. Lactate release by incubated aorta was increased by angiotensin II (50 nM), isoproterenol (1 microM), and mechanical stretch. The increase mediated by angiotensin II was blocked by glycerol trinitrate (2.2 microM), which had no effect on lactate release by isoproterenol. Neither angiotensin II (5 nM) nor vasopressin (0.5 nM) increased lactate release from incubated soleus and epitrochlearis muscles; however, lactate release was increased by isoproterenol, and this increase was unaffected by glycerol trinitrate (2.2 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Gaucher's disease: lack of antibody response in 12 patients following repeated intravenous infusions of mannose terminal glucocerebrosidase.

An amplified ELISA has been employed for monitoring the safety of repeated intravenous infusions of modified human placental glucocerebrosidase. The enzyme infusions consisted of biweekly injections of macrophage targeted glucocerebrosidase over a 6 month duration. Serum samples collected throughout the study were assayed by use of an ELISA using alkaline phosphatase coupled to alcohol dehydrogenase for amplification. Using this protocol, 0.2-5 ng affinity purified immunoglobulin specific for glucocerebrosidase can be detected. Occasional false positives necessitate multiple repeat assays over time to accurately assess immunogenic response. Blinded ELISAs were performed on sera from both infused patients with Gaucher's disease and uninfused control patients and compared with apparent immunoglobulin concentration in 54 normal control sera. Although several samples showed apparently elevated immunoglobulin levels, repeat analyses failed to demonstrate high levels reproducibly. Furthermore, these sera were unable to neutralize enzyme or to precipitate radiolabelled enzyme, confirming the absence of antibody. Problems with high sensitivity ELISA formats are discussed.

Animals↗
PubMed1990

Release of purine and pyrimidine nucleosides and their catabolites from the perfused rat hindlimb in response to noradrenaline, vasopressin, angiotensin II and sciatic-nerve stimulation.

Uric acid and uracil were released at constant rates (0.95 and 0.4 nmol/min per g respectively) by the perfused rat hindlimb. Noradrenaline, vasopressin or angiotensin II further increased the release of these substances 2-5-fold, coinciding with increases in both perfusion pressure (vasoconstriction) and O2 uptake. The hindlimb also released, but in lesser amounts, uridine, hypoxanthine, xanthine, inosine and guanosine, and all but hypoxanthine and guanosine were increased during intense vasoconstriction. Uric acid and uracil releases were increased by noradrenaline in a dose-dependent manner. However, the release of these substances did not fully correspond with the dose-dependent increase in O2 uptake and perfusion pressure, where changes in the latter occurred at lower doses of noradrenaline. Sciatic-nerve stimulation (skeletal-muscle contraction) did not increase the release of uracil, uric acid or uridine, but instead increased the release of inosine (7-fold) and hypoxanthine (2-fold). Since the UTP content as well as the UTP/ATP ratio are higher in smooth muscle than in skeletal muscle, it is proposed that release of uric acid and uracil arises from increased metabolism of the respective adenosine and uridine nucleotides during intense constriction of smooth muscle.

Angiotensin II↗