Cancer of endometrium and prolonged estrogen therapy.
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Amenorrhea↗
Biomedical subjects
R M Graham
Publications and source records attributed to R M Graham.
Specificity of serine proteases for cleavage sites on proatrial natriuretic factor.
An immunological approach was used to investigate the specificity of protease cleavage sites on proANF. Cleavage of 35S-cysteine biosynthetically-labeled proANF by whole serum, thrombin and kallikrein was examined. Reaction products were immunoprecipitated with two antibodies directed to different epitopes: a previously characterized antibody directed toward the carboxy-terminus of ANF103-126, which cross reacts with proANF, ANF99-126 and ANF103-126, and a newly prepared antisera to synthetic ANF99-105, which uniquely recognizes ANF99-126, but not proANF or ANF103-126. With increasing time of incubation with rat serum, proANF is sequentially cleaved at the C-terminus of a monobasic Pro-Arg dipeptide sequence to form ANF99-126, and then at the C-terminus of a dibasic Arg-Arg dipeptide sequence to yield ANF103-126. This cleavage activity of serum is blocked by leupeptin (40 micrograms/ml), but not by hirudin (100 nM), a specific inhibitor of thrombin, or by aprotinin (200 KIU/ml), a kallikrein inhibitor. When 100-fold purified serum cleavage enzyme was used in place of crude serum, similar results were obtained. Thrombin cleaves proANF only at the monobasic site to produce ANF99-126 while kallikrein cleaves only at the dibasic site to produce ANF103-126. As expected, the generation of these cleavage products can be inhibited by hirudin or aprotinin respectively. These data indicate that the substrate specificity of the serum cleavage activity is broader than that of thrombin or kallikrein, and that cleavage of proANF by serum proteases may be influenced by conformational restraints. The methods developed here should help in the future characterization of the physiological proANF cleaving enzyme.
Amino Acid Sequence↗
Anti-platelet activity of beta-adrenergic antagonists: inhibition of thromboxane synthesis and platelet aggregation in patients receiving long-term propranolol treatment.
Treatment of hypertensive patients with dl-propranolol (640 mg/day) significantly inhibited thromboxane synthesis by their platelets and platelet aggregation induced by thrombin or arachidonic acid. The effects were dose-related and were also caused by the stereoisomer, d-propranolol (640 mg/day), which has very little beta-blocking activity. These findings suggest that the cardioprotective effects of propranolol may be due partly to this anti-platelet activity, to a reduction in thromboxane-induced coronary-artery vasoconstriction, or to both. d-Propranolol treatment may be particularly useful, since this isomer provides similar benefits without causing pronounced beta-adrenergic blockade.
Adrenergic beta-Antagonists↗
Effects of prazosin and phentolamine on arterial pressure, heart rate, and renin activity: evidence in the conscious rat for the functional significance of the presynaptic alpha-receptor.
We examined the functional significance of the presynaptic alpha-adrenergic receptor, to stimulus-induced norepinephrine release. The effects of prazosin and phentolamine, alpha-adrenergic receptor antagonists with different in vitro selectivities for the presynaptic alpha-receptor, on mean arterial pressure and serum renin activity were determined in the conscious rat. Both drugs resulted in dose-related reductions in mean arterial pressure and dose-related increase in heart rate and serum renin activity. However, consistent with the greater selectivity of prazosin for the postsynaptic alpha-receptor, a given reduction in arterial pressure was associated with a lesser increment in heart rate and serum renin activity after prazosin than after the nonselective agent phentolamine. The differential effects of these agents on heart rate and serum renin activity are consistent with different degrees of blockade of a functionally significant presynaptic alpha-receptor.
Animals↗
Differing effects of the vasodilator drugs, prazosin and diazoxide on plasma renin activity in the dog.
1. The effects of intravenous (i.v.) administration of the vasodilator drugs prazosin or diazoxide on blood pressure and plasma renin activity were evaluated in the anaesthetized dog. 2. Prazosin and diazoxide both induced a rapid reduction in the mean arterial pressure to 73% and 75% of control values respectively. 3. Prazosin lowered plasma renin activity to 62% (P less than 0-025) of the control value whereas diazoxide raised plasma renin activity to 178% (P less than 0.05) of the control value. 4. The combination of vasodilatation and low renin activity observed following the administration of prazosin is unique, and may have clinical significance if these factors reduce the vascular complications of hypertension.
Animals↗
Saralasin-induced renin release: its blockade by prostaglandin synthesis inhibitors in the conscious rat.
The angiotensin antagonist, saralasin, (10 and 30 mg/kg), increased serum renin activity (SRA) in normal, conscious rats from 2.7 +/- 0.4 to 16.2 +/- 3.7 and 22.5 +/- 2.4 ng/ml/hr (p less than 0.001), respectively, without markedly altering blood pressure or heart rate. Indomethacin, in a dose which inhibited the urinary excretion of prostaglandin E2 (PGE2) by 75%, and arachidonate-induced hypotension by 83%, failed to alter basal SRA but inhibited saralasin-induced renin release by 99% and 87% at the 10 and 30 mg/kg doses, respectively. Indomethacin failed to alter basal hemodynamics or the hemodynamic response to saralasin. Propranolol (1.5 mg/kg) inhibited saralasin-induced renin release by 93% and enhanced the suppressant effect of indomethacin from 79% to 100%. Meclofenamate, another prostaglandin synthesis inhibitor, also blocked saralasin-induced renin release by 99% and 72% at the 10 and 30 mg/kg doses, respectively (p less than 0.001). In sodium-depleted rats, saralasin (0.3 mg/kg) increased SRA from 12 +/- 2 to 119 +/- 6 ng/ml/hr (p less than 0.001) and decreased blood pressure by 6% (p less than 0.01). In these animals, indomethacin failed to alter basal SRA, but inhibited saralasin-induced renin release by 82%, urinary excretion of PGE2 by 79%, and arachidonate-induced hypotension by 81%. These findings suggest 1) that saralasin-induced renin release is mediated by renal prostaglandins, and 2) an interrelationship exists between the receptor controlling AII-mediated inhibition of renin release, which is blocked by saralasin, and the juxtaglomerular beta-adrenergic receptor.
Animals↗
Effects of clonidine on 24-hour hormonal secretory patterns, cardiovascular hemodynamics, and central nervous function in hypertensive adolescents.
To assess the potential of antihypertensive drugs for interference with somatic growth and sexual development in hypertensive children, the effect of clonidine therapy on various endocrine, cardiovascular, and neuromuscular functions has been examined in five male adolescents with idiopathic hypertension. In studies done before and at the end of 4 weeks of twice-daily clonidine therapy, in an average daily dose of 0.31 mg, no significant effects were noted in the secretory patterns of growth hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, cortisol, aldosterone, or testosterone, measured in blood obtained every 20 minutes for 24 hours. In blood obtained while the patients were supine and then erect, plasma renin activity and norepinephrine levels were significantly lowered after clonidine therapy. Cardiovascular responses to dynamic exercise were little altered beyond a 17% decrease in maximal oxygen consumption. The performance of fine motor skills was minimally altered. These data provide preliminary evidence that clonidine, an antihypertensive drug that affects the adrenergic nervous system, may not interfere with normal growth and maturation in adolescent males.
Adolescent↗
Renal alpha-adrenergic receptor abnormality in the spontaneously hypertensive rat.
Activation of renal alpha-adrenergic receptors induces vasoconstriction, proximal tubular reabsorption of sodium, and inhibition of renal release. Excesses of these effects are present in varying degrees in animal models of, and in patients with, "essential" hypertension. Since essential hypertension is genetically determined, we sought abnormalities of renal alpha-adrenergic receptors in the Okamoto-Aoki strain of spontaneously hypertensive rats (sr-SHR) and their stroke-prone variant (sp-SHR). Total alpha-adrenergic receptor concentrations were determined by Scatchard analysis of [3H]dihydroergocryptine binding to a renal membrane fraction and were found to be increased (p less than 0.02) in male sr-SHR at 4, 16, and 32 weeks of age and in female sr-SHR at 16 weeks of age as compared to age- and sex-matched Wistar-Kyoto controls. They were also increased in 9-week-old sp-SHR renal membranes (p less than 0.005). Further studies revealed that this increase in renal alpha-adrenergic receptors was due entirely to an increase in alpha 2-receptors as measured by [3H]yohimbine binding rather than to an increase in alpha 1-receptors as quantitated by [3H]prazosin binding. No difference in binding affinities of the various radioligands could be demonstrated between any of the hypertensive and normotensive groups of rats. Plasma norepinephrine levels were elevated (p less than 0.01) in the 4-, 9- and 16-week-old SHR, but not in the 32-week-old hypertensive rats. Thus, high renal alpha 2-adrenergic receptor number is coupled with a significant increase in plasma norepinephrine concentrations during the development of hypertension in SHR. By mediating an enhanced receptor-coupled response, such as increased proximal tubular sodium reabsorption, this abnormality of renal alpha-adrenergic receptors may contribute to some or all of the pathophysiologic derangements leading to hypertension in SHR.
Age Factors↗
Synthesis and characterization of a radioiodinated photoaffinity probe for the alpha 1-adrenergic receptor.
A radioiodinated aryl azide analog, 2-[4-(4-azido-3- iodobenzoyl ) piperazin -1-yl]-4-amino-6, 7- dimethoxyquinazoline [(125I] CP65 ,526), of the highly selective alpha 1-adrenergic antagonist prazosin was synthesized and characterized using rat hepatic plasma membranes. Prior to photolysis, this ligand bound with high affinity (Kd 0.3 nM), stereoselectively and in a saturable manner to sites with an alpha 1-adrenergic specificity. When membranes pretreated with [125I] CP65 ,526 were irradiated with ultraviolet light, the ligand incorporated irreversibly into the receptor-binding sites, also with typical alpha 1-adrenergic specificity. Sodium dodecyl sulphate polyacrylamide gel electrophoresis of such labeled membranes followed by radioautography revealed major bands at Mr = 77,000, 68,000, and 59,000 daltons. Labeling of each of these bands was inhibitable by a variety of adrenergic ligands, stereoselectively and with a specificity typical of the alpha 1-adrenergic receptor. Smaller peptides with molecular weights of 42,000 and 31,000 daltons also displayed prazosin-inhibitable [125] CP65 ,526-binding. However, as the labeling of these protein species was not inhibitable by other adrenergic agonists or antagonists, they are unlikely to represent subunits of the receptor. Further evidence that [125I] CP65 ,526 incorporates covalently upon photolysis was the ability to specifically label immunoglobulin heavy and light chains of an antiserum that recognized both this ligand and the parent compound, prazosin. This new, radioiodinated, high-affinity probe should thus be uniquely valuable for the molecular characterization of the alpha 1-adrenergic receptor.
Affinity Labels↗
Molecular studies of the atrial natriuretic factor gene.
The molecular biology of human atrial natriuretic factor was studied. A cloned rat cDNA probe was used to analyze tissue for the synthesis of atrial natriuretic factor, and the human gene was identified and sequenced. Nucleotide sequence comparison of human and rodent atrial natriuretic factor genes suggests regions that are critical for regulated expression of this cardiac hormone.
Amino Acid Sequence↗
Adrenergic receptors: structure and function.
Adrenergic receptors are cell surface glycoproteins that recognize and selectively bind the catecholamines, norepinephrine and epinephrine, which are released from sympathetic nerve endings and the adrenal medulla. By transducing the external catecholamine stimulus into an intracellular signal, these receptors mediate the actions of the sympathetic nervous system, including a variety of responses such as arteriolar smooth muscle contraction and cardiac contraction, while are critically involved in cardiac function and blood pressure homeostasis. Activation or blockade of these receptors is, thus, a major therapeutic approach for the management of a number of cardiovascular disorders, including hypertension, angina pectoris, and cardiac arrhythmias. Additionally, alterations in these receptors or in their coupled intracellular effectors may contribute to or underlie the pathogenesis of cardiovascular diseases such as cardiac hypertrophy, congestive heart failure, and hypertension. Over the past few years, major insights have been gained into the physiology and pharmacology of these receptors, particularly in relationship to the molecular mechanisms involved in their ability to mediate "transmembrane signalling." These insights, which will be reviewed here, have resulted from the isolation and characterization of adrenergic receptors, from the determination of their deduced primary and secondary structures, and from structure-function studies using classical biochemistry and pharmacology as well as recombinant DNA techniques.
Animals↗
Cyclosporine: mechanisms of action and toxicity.
BACKGROUND: Newer immunosuppressive agents are permitting transplantation to be performed more frequently. OBJECTIVES: To review the mechanisms of action and toxicity of cyclosporine. DISCUSSION: Graft rejection is mainly cell-mediated, although a humoral (antibody) response may also be involved. Cyclosporine and related agents such as FK-506 and rapamycin selectively inhibit adaptive immune responses by blocking T cell-dependent biosynthesis of lymphokines, particularly interleukin 2 at the level of messenger ribonucleic acid (mRNA) transcription. Because cyclosporine is metabolized in the liver by P-450 enzymes, drugs that affect the P-450 system also affect the metabolism of cyclosporine. Hypertension is the most common side effect of cyclosporine. Cyclosporine-induced "nephrotoxicity" may be functional rather than anatomic, caused primarily by preferential constriction of the afferent renal arteriole. Bacterial and fungal infections are less common with regimens of cyclosporine plus prednisone than with azathioprine plus prednisone. Nevertheless, cyclosporine-treated patients are vulnerable to viral infections. CONCLUSIONS: Although cyclosporine and related compounds represent an improvement over earlier immunosuppressive agents, they produce serious side effects with which the practitioner should be familiar.
Cyclosporine↗
A shopper's guide to appraisal instruments.
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Actuarial Analysis↗
Antibodies to the alpha 1- and alpha 2-selective antagonists prazosin and yohimbine as probes of the alpha-adrenergic binding sites.
Antibodies were raised against a newly synthesized analog (CP57,609) of the alpha 1-selective antagonist prazosin, and against the alpha 2-selective antagonist, yohimbine, by immunization of rabbits with antigens prepared by covalent linkage of these ligands to albumin. Competitive inhibition of [3H]prazosin binding to anti-CP57,609 antiserum by a variety of unlabeled ligands revealed a spectrum of antibody specificity, with alpha 1-selective agents competing more potently than alpha 2-selective ligands. In contrast, alpha 2-selective ligands competed more potently with the binding of [3H]yohimbine to the anti-yohimbine antiserum than alpha 1-selective agents. These respective antisera were subjected to affinity fractionation of a CP57,609- or yohimbine-Sepharose 4B resin. Fractions from the CP57,609 resin were eluted successively with phentolamine (10(-3)M), prazosin (10(-4)M), and guanidine (5M), and from the yohimbine resin with prazosin (10(-4)M), yohimbine (10(-4)M), and guanidine (5M). The binding profiles of these fractions differed, and in certain fractions the relative order of potency of adrenergic agents was almost identical to that observed with membrane alpha-adrenergic receptors. Moreover, using these eluted fractions as immunogens, antisera have been obtained which, in the initial bleeds, already possess antiidiotypic activity. These findings therefore suggest that affinity fractionation of antibodies raised against alpha 1- and alpha 2-selective antagonists may provide useful analogs for the further study of the ligand recognition properties of alpha-adrenergic receptors. Additionally, it is probable that antiidiotypic antisera will be developed which will recognize the alpha-adrenergic binding sites.
Animals↗
F. Merlin Bumpus, PhD.
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History, 20th Century↗
Pyogenic granuloma: an unusual presentation.
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Granuloma, Pyogenic↗
Comparative effects of prazosin and phenoxybenzamine on arterial blood pressure, heart rate, and plasma catecholamines in essential hypertension.
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Adult↗