Robert J. Workman
Vanderbilt University
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Featured researches published by Robert J. Workman.
The New England Journal of Medicine | 1986
John J. Murray; Andre Bernard Tonnel; Alan R. Brash; L. Jackson Roberts; Phillippe Gosset; Robert J. Workman; André Capron; John A. Oates
Among the many possible mediators of the early asthmatic response, prostaglandin D2, a bronchoconstrictor, is the principal cyclooxygenase metabolite of arachidonic acid that is released upon the activation of mast cells and is also synthesized by human alveolar macrophages. We performed bronchoalveolar lavage in five patients with chronic stable asthma, before and up to nine minutes after local provocative challenge with Dermatophagoides pteronyssinus. The lavage fluid was analyzed for products of arachidonic acid metabolism. Prostaglandin D2 levels in all five patients rose an average of 150-fold, from less than 8 to 332 +/- 114 pg per milliliter (mean +/- SEM; P less than 0.050), after local instillation of the antigen. Levels of 15-hydroxyeicosatetraenoic acid, which may also have a role in the pulmonary allergic response, were detectable in lavage fluid before challenge and increased after provocation with the antigen in four of the five patients. The activity of beta-glucuronidase, an enzyme released by macrophages and mast cells upon stimulation, tended to increase in the lavage fluid after provocation in all patients. These studies provide evidence that the release of prostaglandin D2 into the airways is an early event after the instillation of D. pteronyssinus in patients who are sensitive to this antigen.
The American Journal of Medicine | 1984
David Robertson; Alan S. Hollister; Dawn Kincaid; Robert J. Workman; Michael R. Goldberg; Che-Se Tung; Bolton Smith
The effect of prolonged caffeine administration on blood pressure in hypertensive subjects was assessed in a double-blind placebo-controlled study. Eighteen hypertensive subjects participated, nine of whom received placebo throughout the study and nine of whom received placebo during the first three days, caffeine during the subsequent seven days, and placebo during the final four days of the two-week study. Those who received caffeine were given 250 mg with meals three times daily. There were no untoward reactions in the course of the study, but one subject with unacceptably high blood pressures while receiving placebo had to be discharged from the study to resume antihypertensive therapy. Systolic blood pressure was immediately increased (9.2 +/- 3.4 mm Hg) within 15 minutes after the first dose of 250 mg of caffeine. On the first day of caffeine, systolic pressure was increased a mean of 7.3 +/- 4.0 mm Hg, but this was no longer significant after the initial day of caffeine administration. Diastolic pressure showed a trend toward increasing, but this never reached significance. The minor increases in plasma catecholamine levels and plasma renin activity were not significant on either a short- or long-term basis. After discontinuation of caffeine, no overshoot phenomena were observed. It is concluded that prolonged administration of caffeine is not associated with significant elevation in blood pressure, plasma catecholamine levels, or plasma renin activity in patients with borderline hypertension.
Brain Research | 1980
Shigehisa Hirose; Hideyoshi Yokosawa; Tadashi Inagami; Robert J. Workman
With the objective of clarifying the nature of renin-like activity in the brain, we have devised methods to distinguish true renin from acid protease. These methods were used to determine the regional distribution of true renin in hog brain. The pineal was found to be the richest source of renin followed by the adenohypophysis and choroid plexus. The hypothalamus, cerebellum and amygdala contained moderately high concentrations of renin. Renin concentration in the neurohypophysis was negligible. Many regions contained activatable prorenin. The molecular weight and the pH-dependence of the brain renin were identical to these same properties of renal and plasma renins. Based upon its specific affinity to concanavalin A, brain renin was judged to be a glycoprotein. The electrofocusing pattern of renin from different regions of the brain differed from that of plasma and kidney renins, a discrepancy which could be interpreted as evidence for the endogenous synthesis of renin in the brain.
Circulation Research | 1979
Shigehisa Hirose; Robert J. Workman; Tadashi Inagami
We produced anti-hog renin antibodies using as antigens pure hog renal renin that either had been insolubilized or conjugated to tetanus toxoid. High titer antibodies were obtained, which demonstrated different cross-reactivity with renins from other species. A direct radioimmunoassay for renin was developed using antibody, monoiodinatedluI-hog renin, and various methods for separating free and antibody-bound trace. This assay was capable of detecting 40 pg of hog renin and was applied to the determination of renin in hog blood and other organs. Based on the direct measurement of renin by this radioimmunoassay, the renin-like activity (i.e., the ability to generate angiotensin I from renin substrate preparations) of the pituitary gland was found to be due mostly to true renin, whereas the renin activity of other hog tissues, including the adrenal gland, liver, lung, spleen, and submaxillary gland, was not identified as renin and may have been due to cathepsins. Cire Ret 45: 275-281, 1979
The American Journal of the Medical Sciences | 1993
Stephen S. Feman; Robert A. Mericle; George W. Reed; James M. May; Robert J. Workman
Serum angiotensin converting enzyme (ACE) levels are higher in patients with diabetes mellitus than in many others. Techniques are available to grade different degrees of diabetic retinopathy, which can demonstrate a relationship between ACE and diabetic retinopathy. In this study, patients with diabetic retinopathy had higher serum ACE levels (6.3 +/- 0.2) than nondiabetic patients (4.3 +/- 0.5) (p < 0.001). In addition, the mean serum ACE level in diabetic patients with nonproliferative retinopathy (5.55 +/- 0.4) was less than that in diabetic patients with proliferative retinopathy (6.63 +/- 0.25) (p = 0.02). Due to the variability in individual serum ACE levels and the frequent use of ACE inhibitors by hypertensive diabetics, these techniques are not suitable for retinopathy screening programs. However, the graded relationship demonstrated by these data may have relevance for the pathophysiology of diabetic retinopathy.
Journal of Cardiovascular Pharmacology | 1984
Howard D. Uderman; Edwin K. Jackson; David Puett; Robert J. Workman
Treatment of young spontaneously hypertensive rats (SHR) with a thromboxane synthetase inhibitor (TSI) attenuates their subsequent development of hypertension. In this study, treatment of adult SHR during the established phase of hypertension with the TSI UK38,485 (100 mg/kg daily) lowered systolic blood pressure from baseline after 4 days of treatment to a maximum depression of 25 mm Hg on day 10 of the study. Additional confirmation of the fact that this TSI does not lower blood pressure acutely was made via continuous intraarterial recordings in SHR administered their first dose of UK38,485. Urinary dinor-6-keto-PGF1 alpha excretion was measured by a highly specific chemical-ionization, negative-ion GC/MS assay in the selective ion monitoring mode. This metabolite of PGI2 was not significantly affected by 6 days of daily administration of UK38,485 to adult SHR and implies that there was not sufficient endoperoxide shunting to affect total body PGI2 production. The finding that UK38,485 exhibited antihypertensive activity during established SHR hypertension was unexpected and has considerable practical and theoretical significance.
Advances in Experimental Medicine and Biology | 1977
Tadashi Inagami; Kazuo Murakami; Kunio S. Misono; Robert J. Workman; Stanley N. Cohen; Yasunobu Suketa
Renin is an enzyme elaborated in juxta glomerular cells of the kidney and released into the blood stream by various stimuli. Although it is an endopeptidase, its function is strictly limited to the formation of angiotensin I from angiotensinogen by the cleavage of a unique leucyl-leucine peptide bond in this substrate molecule (Fig.l). Angiotensin I is converted into the octapeptide angiotensin II by a carboxydipeptidase, known as converting enzyme, and thenceforth to the heptapeptide angiotensin III by an aminopeptidase. Not only is angiotensin II the most potent pressor substance known, but both angiotensin II and III also stimulate the adrenal cortex to release the mineral corticoid aldosterone. Thus, renin triggers a chain of events aimed at elevating the blood pressure. Because of its strategically important position in the renin-angiosin-aldosterone system, the activity of renin in the circulation is tightly regulated by intricate multiple feedback control mechanisms. Excellent reviews on the control of renin release have been published recently (1–4).
Naunyn-schmiedebergs Archives of Pharmacology | 1988
Edwin K. Jackson; Fumio Goto; Howard D. Uderman; Robert J. Workman; William A. Herzer; Garret A. FitzGerald; Robert A. Branch
SummaryIn general the effects of thromboxane A2(TXA2) on renal function are opposite those produced by other prostanoids. TXA2 synthase inhibitors decrease the biosynthesis of TXA2 and may increase the production of other prostanoids by causing endoperoxide shunting. Therefore, in situations of increased kidney arachidonate mobilization, inhibition of renal TXA2 synthase might alter renal function by reducing TXA2 production and/or increasing prostaglandin (PG) biosynthesis. This hypothesis was tested by comparing the changes in renal function induced by suprarenal aortic constriction in anesthetized dogs pretreated with either a TXA2 synthase inhibitor (UK 38,485; n = 7 or OKY1581; n = 7) or vehicle (0.1 M Na2CO3; n = 9). Several renal function parameters were compared in control versus treated animals by analysis of variance. Neither UK38,485 (1 mg/kg, i. v.) nor OKY 1581 (10 mg/kg, i. v.) significantly altered renal artery hypotension-induced changes in mean arterial blood pressure, heart rate, renal blood flow, renal vascular resistance, glomerular filtration, filtration fraction, urine flow rate, sodium excretion rate, fractional sodium excretion, potassium excretion, or fractional potassium excretion. However, both UK 38,485 and OKY 1581 seemed to attenuate the increase in renal renin secretion rate induced by suprarenal aortic constriction. We conclude that acute administration of TXA2 synthase inhibitors does not modify acute renal artery hypotension-induced changes in either electrolyte excretion or renal hemodynamics. However, acute administration of TXA2 inhibitors attenuates suprarenal aortic constriction-induced increases in renin release in anesthetized dogs by unknown mechanisms.
Prostaglandins | 1983
Robert L. Forti; William M. Mitchell; Robert J. Workman; James T. Forbes; Walter C. Hubbard
Aspirin, indomethacin, and phenbutazone at 50 microM concentration inhibit cyclooxygenase in cultured human foreskin fibroblasts as evidenced by the suppression of the major prostaglandin species which accumulate in the culture medium. In contrast to data reported for mouse interferon on target mouse cells, these agents have no effect on the induction of antiviral activity by human alpha or beta interferons. Similarly, these agents have no effect on interferon induced inhibition of cell growth in vitro or on interferon induced natural killer cell activity.
European Journal of Pharmacology | 1986
Michael L. Watson; Robert J. Workman; William A. Herzer; Robert A. Branch; John A. Oates; Alan R. Brash
Acute infusion of pharmacological doses of angiotensin II stimulates the release of prostaglandin I2 (PGI2), which may modulate the vasoconstrictor response. It is uncertain whether sustained small increases in the plasma concentration of angiotensin II has the same effect. To investigate this further, low doses of angiotensin II were infused into conscious sodium replete dogs for 3 h. PGI2 synthesis was assessed by measurement of a major metabolite of PGI2, 2,3-dinor-6-keto PGF1 alpha, in urine and plasma, using gas chromatography mass spectrometry. Angiotensin II infusion (15 ng/min per kg body weight) resulted in a 3-fold increase in plasma angiotensin II (50.8 +/- 5.4 to 149 +/- 11.2 pg/ml, P less than 0.01). Mean blood pressure increased (84.8 +/- 4.3 to 108 +/- 4.7 mm Hg, P less than 0.02) and renal blood flow decreased (201 +/- 46 to 127 +/- 13 ml/min, P less than 0.01) throughout the infusion. However there was no change in either the plasma concentration (11.3 +/- 2.5 to 9.1 +/- 1.0 pg/ml) or rate of urinary excretion of dinor-6-keto PGF1 alpha (1.75 +/- 0.28 to 1.85 +/- 0.41 ng/30 min) during the angiotensin II infusion. The results suggest that small sustained elevations of the plasma concentration of angiotensin II such as are likely to occur in conscious animals, do not persistently stimulate release of PGI2 in the systemic circulation.