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Biomedical subjects

R D Gordon

Publications and source records attributed to R D Gordon.

At least 91 records · Page 5Linked to original sources
PubMed1993

Renin-aldosterone response to dexamethasone in glucocorticoid-suppressible hyperaldosteronism is altered by coexistent renal artery stenosis.

The responses of renin, aldosterone, and blood pressure to ACTH suppression with dexamethasone in a 61-yr-old man with glucocorticoid-suppressible hyperaldosteronism were modified by coexistent atheromatous renal artery stenosis (RAS). The apparent responsiveness of aldosterone to angiotensin-II resulting from RAS has implications for the regulation of steroidogenesis in this condition. After successful surgical correction of the RAS, the response changed and resembled that seen in two younger males (one his son) with uncomplicated glucocorticoid-suppressible hyperaldosteronism.

Adolescent↗
PubMed1993

Molecular basis of congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency.

Congenital adrenal hyperplasia is the most frequent cause of adrenal insufficiency and ambiguous genitalia in newborn children. In contrast to congenital adrenal hyperplasia due to 21-hydroxylase and 11 beta-hydroxylase deficiencies, which impair steroid formation in the adrenal cortex, exclusively, classical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency affects steroid biosynthesis in the gonads as well as in the adrenals. The structures of the highly homologous type I and II 3 beta-HSD genes have been analyzed in three male pseudohermaphrodite 3 beta-HSD deficient patients from unrelated families in order to elucidate the molecular basis of classical 3 beta-HSD deficiency from patients exhibiting various degrees of severity of salt losing. The nucleotide sequence of DNA fragments generated by selective polymerase chain reaction amplification that span the four exons, the exon-intron boundaries, as well as the 5'-flanking region of each of the two 3 beta-HSD genes have been determined in the three male patients. The five point mutations characterized were all detected in the type II 3 beta-HSD gene, which is the gene predominantly expressed in the adrenals and gonads, while no mutation was detected in the type I 3 beta-HSD gene, predominantly expressed in the placenta and peripheral tissues. The two male patients suffering from severe salt-losing 3 beta-HSD deficiency are compound heterozygotes, one bearing the frame-shift mutation 186/insC/187 and the missense mutation Y253N, while the other bears the nonsense mutation W171X and the missense mutation E142K. The influence of the detected missense mutations on enzymatic activity was assessed by in vitro expression analysis of mutant recombinant enzymes generated by site-directed mutagenesis in heterologous mammalian cells. Recombinant mutant type II 3 beta-HSD enzymes carrying Y253N or E142K substitutions exhibit no detectable activity. On the other hand, the nonsalt-losing patient is homozygous for the missense mutation A245P. This mutation decreases 3 beta-HSD activity by approximately 90%. The present findings, describing the first missense mutations in the human type II 3 beta-HSD gene, provide unique information on the structure-activity relationships of the 3 beta-HSD superfamily. Moreover, the present findings provide a molecular explanation for the enzymatic heterogeneity responsible for the severe salt-losing form to the clinically inapparent salt-wasting form of classical 3 beta-HSD deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Hydroxysteroid Dehydrogenases↗
PubMed1993

Hormonal responses of elite swimmers to overtraining.

Fourteen elite swimmers had measurements of stress hormones taken at five points during a 6-month season: early-, mid- and late-season, during tapering for National Trials, and 1-3 d after the Trials. Training details and subjective ratings of fatigue were recorded daily in log books. Plasma norepinephrine and epinephrine concentrations were significantly correlated with swim training volume (r = 0.37 and 0.33, respectively, P < 0.05 for each). No significant differences were seen in norepinephrine or cortisol concentrations at the five sampling times. Epinephrine levels were significantly lower (P < 0.05) after competition compared with values early in the season and shortly before competition. Symptoms of the overtraining syndrome were identified in three of the swimmers, based on performance decrements and high, prolonged levels of fatigue. In these three swimmers, norepinephrine levels tended to be higher than those of the other swimmers from mid-season onward and were significantly higher (P < 0.01) during tapering. If these findings can be confirmed in larger numbers and different types of athletes, norepinephrine level may provide a useful marker of the overtraining syndrome.

Adolescent↗
PubMed1993

Pharmacological characterization of cloned human NK-2 (neurokinin A) receptor expressed in a baculovirus/Sf-21 insect cell system.

Using the novel ligand [4,5-3H-Leu9]neurokinin A ([4,5-3H-Leu9] NKA) in a receptor binding assay, we characterized the pharmacology of a cloned neurokinin NK-2 receptor from human lung (hNK-2R), expressed in baculovirus-infected Sf-21 insect cells. Functional hNK-2R cDNA clones were isolated from human lung using a polymerase chain reaction-based methodology. hNK-2R was cloned into pAcYM1, a vector designed to couple expression to the polyhedrin promoter, and the recombinant baculovirus was isolated and used to infect Sf-21 insect cells. hNK-2R expression levels were monitored by Northern blots and 125-I-NKA binding assays. Isolates demonstrating the highest specific binding of 125-I-NKA were grown and membrane preparations from high-speed centrifugations were prepared from both hNK-2R-expressing and wild-type virus-infected cells. [3H]NKA bound in a protein-dependent, saturable (Bmax = 820 +/- 167 fmol/mg of protein), and highly specific (88 +/- 5%) manner to hNK-2R, but not to membranes from cells infected with wild-type virus (14 +/- 8%, 7 +/- 10 fmol/mg of protein). [3H]NKA binding was rapid (k1 = 0.085 nM-1 x min-1) and reversible (t1/2 = 4-5 min). Equilibrium binding experiments demonstrated binding to a mixture of receptors in high and low affinity states (Kd1 = 2.28 +/- 0.26 nM and Kd2 = 266 +/- 91 nM). Binding to hNK-2R was greatly enhanced (400%-600%) by Ca2+ and Mg2+ (EC50 values of 30 microM and 140 microM, respectively), whereas guanosine-5'-O-(3'-thio)triphosphate and guanosine-5'-(beta, gamma-imido)diphosphate were inhibitory. Competition experiments with agonists also demonstrated binding to high and low affinity states, with the following order of potency: NKA > [Nle10]NKA(4-10) > [beta-Ala8]NKA(4-10) >> substance P; Senktide and the NK-1 antagonist CP96,345 (10 microM) did not inhibit binding. Inhibition of binding by selective NK-2 antagonists was consistent with a single affinity state and demonstrated the following order of affinity: SR48,968 >> MEN10,376 > L659,877 > R396. These data suggest that infection of Sf-21 cells with baculovirus expression vector harboring the cDNA of hNK-2R resulted in expression of high affinity, G protein-coupled hNK-2R, with pharmacological selectivity compatible with the NK-2A receptor subtype.

Animals↗
PubMed1992

The chimeric gene linked to glucocorticoid-suppressible hyperaldosteronism encodes a fused P-450 protein possessing aldosterone synthase activity.

Glucocorticoid-suppressible hyperaldosteronism (GSH) is one variety of primary aldosteronism with hypertension and is inherited in an autosomal dominant mode. A recent report has indicated that GSH is caused by a gene duplication arising from unequal crossing over between the two genes, CYP11B1 and CYP11B2, encoding P-450(11 beta) and P-450C18, respectively (Lifton et al. Nature (1992) 355, 262-265). The nucleotide sequence analysis in the present study has demonstrated that unequal crossing over in the chimeric gene formed by the gene duplication occurs within the region from the 3'-portion of exon 4 through the 5'-portion of intron 4 in Australian GSH patients. Namely, the chimeric gene encodes a fused P-450 protein consisting of the amino-terminal side of P-450(11 beta) (encoded by exons 1-4 of CYP11B1) and the carboxyl-terminal side of P-450C18 (encoded by exons 5-9 of CYP11B2). When a cDNA corresponding to the chimeric gene is transfected into COS-7 cells, the fused P-450 protein expressed in the mitochondria exhibits steroid 18-hydroxylase or aldosterone synthase activity. These results provide the molecular genetic basis for the characteristic biochemical phenotype of GSH patients.

Animals↗
PubMed1992

Action of derivatives of mu-conotoxin GIIIA on sodium channels. Single amino acid substitutions in the toxin separately affect association and dissociation rates.

We have studied binding and block of sodium channels by 12 derivatives of the 22-residue peptide mu-conotoxin GIIIA (mu-CTX) in which single amino acids were substituted as follows: Arg or Lys by Gln, Gln-18 by Lys, Asp by Asn, and HO-Pro by Pro. Derivatives were synthesized as described by Becker et al. [(1989) Eur. J. Biochem. 185, 79]. Binding was measured by displacement of labeled saxitoxin from eel electroplax membranes (100 mM choline chloride, 10 mM HEPES-NaOH, pH 7.4). Blocking kinetics were evaluated from steady-state, single-channel recordings from rat skeletal muscle sodium channels incorporated into planar, neutral phospholipid/decane bilayers (200 mM NaCl, 10 mM HEPES-NaOH, pH 7.0). Blocking events generally appeared as periods of seconds to minutes in which current through the single channel was completely eliminated. A notable exception was seen for the substitution Arg-13-Gln for which the "blocked" events showed measurable conductances of about 20-40% of the open state. The substitution of Arg-13 reduced binding to electroplax membranes to undetectable levels and increased the apparent dissociation constant determined for skeletal muscle channels by greater than 80-fold compared with the native peptide. Other substitutions caused smaller decreases in affinity. The decreased potency of the toxin derivatives resulted both from increases in the rates of dissociation from the channel, and from decreases in association rates. Our data support the suggestion by Sato et al. [(1991) J. Biol. Chem. 265, 16989] that Arg-13 associates intimately with the binding site on the channel. In addition, our results suggest that certain residues affect almost exclusively the approach and docking of the toxin with its binding site, others appear to be important only to the strength of the association once binding has taken place, and yet others affect both.

Amino Acid Sequence↗
PubMed1992

Primary aldosteronism: hypertension with a genetic basis.

Exciting developments in knowledge of primary aldosteronism include description of new subtypes and elucidation of the genetic basis of one variety. Furthermore, relatively simple biochemical screening (aldosterone/renin ratio) has disclosed that primary aldosteronism is more common than previously thought, by diagnosing patients at an earlier, normokalaemic stage. The mutant gene discovered in the glucocorticoid-suppressible variety (FHI) codes for an aldosterone biosynythetic enzyme normally controlled by angiotensin II, and now controlled by corticotropin. The zona fasciculata is hyperplastic and makes aldosterone and "hybrid steroids" 18-oxocortisol and 18-hydroxycortisol in excess, in response to ACTH but not to angiotensin II. Adrenal tumours have not yet been described in this condition. Aldosterone-producing adenomas (Conn's syndrome) are also commonly composed of zona fasciculata-like cells, make "hybrid steroids" in excess and are very sensitive to ACTH but not to angiotensin II. We have described a new variety of aldosterone-producing adenoma which is responsive to angiotensin II (AII-responsive APA), consists of at least 20% zona glomerulosa-like cells, and does not make "hybrid steroids" in excess. We have also described a new familial variety of primary aldosteronism that includes tumours and is not glucocorticoid-suppressible (FHII). We propose that primary aldosteronism is a spectrum of genetic diseases expressed as either hyperplasia or neoplasia, and that morphological and genetic diversity explains biochemical and clinical behaviour.

Adrenocorticotropic Hormone↗
PubMed1992

Elevation of plasma atrial natriuretic peptide occurs during adrenaline infusion in hypertensive but not normotensive subjects.

The levels of plasma atrial natriuretic peptide in response to graded adrenaline infusion were determined in six patients with essential hypertension and six healthy normotensive subjects (controls). Basal plasma adrenaline concentration was similar in both groups and rose progressively and to a similar level during adrenaline infusion. Plasma noradrenaline rose in both groups and to the same extent during the 26 and 39 ng/kg/min adrenaline infusion rates. Basal plasma atrial natriuretic peptide levels were higher in the hypertensives than in the controls. Graded adrenaline infusion had no effect on atrial natriuretic peptide levels in the controls but significantly raised atrial natriuretic peptide levels in the hypertensives. Systolic blood pressure rose progressively during adrenaline infusion at a lower infusion rate in the hypertensives than in the controls. Similarly, while heart rate rose during adrenaline infusion in both groups, there was a greater rise in the hypertensives. The increased cardiovascular responsiveness to adrenaline infusion in patients with essential hypertension may explain why plasma atrial natriuretic peptide levels rose only in this group and not the normotensive subjects.

Adult↗
PubMed1992

Inappropriately elevated levels of atrial natriuretic peptide may contribute to the pathophysiology of orthostatic hypotension.

1. Overnight recumbent and upright plasma atrial natriuretic peptide (ANP) levels were markedly elevated (P less than 0.001) in patients with orthostatic hypotension (OH). 2. Overnight urinary clearance of ANP was significantly lower (P less than 0.01) in patients with OH, and was inversely correlated with plasma ANP levels (r = -0.94, P less than 0.01). The same negative correlation (r = -0.87, P less than 0.01) was seen in normal subjects. 3. Reduced urinary clearance of ANP may be associated with reduced filtered load and increased binding of ANP to the neutral endopeptidase 24.11 receptor binding sites in the proximal renal tubule. 4. ANP may be involved in the pathophysiology of orthostatic hypotension.

Adolescent↗
PubMed1992

Effects of repeated doses of pseudoephedrine on blood pressure and plasma catecholamines in normal subjects and in patients with phaeochromocytoma.

1. Increases in blood pressure (BP) and in plasma noradrenaline concentration (NA) were observed after two doses of a non-prescription decongestant containing pseudoephedrine (PE) in two of three patients with phaeochromocytoma, before but not after removal of the tumour. The pressor response was terminated by oral phenoxybenzamine, and modified by prior exposure to this drug. 2. In eight normal subjects administration of the same two doses prevented falls in BP and in NA usually seen with prolonged recumbency, but neither BP nor NA increased. However, a pressor response was observed in a normal subject with a strong family history of hypertension. 3. Exposure to PE in non-prescription decongestants is not without risk in hypertension.

Adrenal Gland Neoplasms↗
PubMed1992

Concurrence of primary aldosteronism and renal artery stenosis.

1. An unusual clinical case is described in which renal artery stenosis (RAS) was found to coexist with adrenocortical hyperplasia, resulting in hypertension. 2. Partial relief of the hypertension was achieved by correction of RAS, and then further relief by extirpation of one adrenal gland affected by unilateral hyperplasia, in interventions 8 months apart. 3. Biochemical features typical of primary hyperaldosteronism were observed both before and after RAS repair but were not present after unilateral adrenalectomy. 4. The association of these two lesions could have occurred by chance, through genetic linkage, or by progression from RAS to tertiary aldosteronism.

Adrenal Cortex↗
PubMed1992

Subpressor calcium infusion increases isovolumic left ventricular relaxation time and atrial natriuretic peptide in humans.

1. Subpressor calcium infusion for 1 h, which raised calcium levels to the upper limit of normal in normal subjects, increased plasma and urinary levels of atrial natriuretic peptide (ANP). 2. Heart rate fell, presumably due to carotid baroreflex stimulation (supported by the fall in noradrenaline) and the resultant fall in cardiac output prevented the expected rise in blood pressure due to the rise in total peripheral resistance (TPR). Thus the increase in ANP was not explained by an increase in blood pressure or noradrenaline. 3. There was no evidence for increased atrial stretch (no increase in atrial area or early velocity of left ventricular filling) as a mechanism for increased ANP. 4. Isovolumic left ventricular relaxation time increased, early velocity of ventricular filling decreased and TPR increased, consistent with increased tone in left ventricular and arteriolar muscle. 5. This suggests a direct effect of calcium on the atrial myocyte, stimulating ANP either through contractile or secretory mechanisms.

Adult↗
PubMed1992

Evidence for presynaptic beta-adrenoceptor stimulation 24 hours after a 6 hour adrenaline infusion.

1. The effects of 6 h infusions of adrenaline (INF-A) and dextrose (INF-D) were compared in nine normal subjects. 2. A significant increase in systolic blood pressure was observed during INF-A compared with INF-D and, 24 h after infusion, diastolic blood pressure was higher after INF-A than after INF-D. 3. Heart rate (HR) was significantly higher during INF-A than during INF-D. 4. As expected, plasma ADR increased significantly during INF-A but, unexpectedly, remained elevated 60 min post infusion compared with INF-D. Levels during activity the next morning were somewhat higher after INF-A, but not significantly different from INF-D. 5. Plasma NA increased transiently during INF-A and decreased during INF-D. Urinary NA was significantly higher during INF-A than during INF-D, and insignificantly higher during overnight recumbency, consistent with enhanced noradrenergic transmission.

Adult↗