Renal inner medullary prostaglandin synthesis. A calcium-calmodulin-dependent process suppressed by urea.

Craven, Patricia A.; Studer, Rebecca K.; DeRubertis, Frederick R.

doi:10.1172/jci110308

Cited by 43 publications

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References 34 publications

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“…iPGE content was assessed as previously reported (2,14,15 Extraction and assay of DNA. DNA content of the colonic mucosa was extracted as previously described (6).…”

Section: Methodsmentioning

confidence: 99%

Role of local prostaglandin synthesis in the modulation of proliferative activity of rat colonic epithelium.

Craven¹,

Saito²,

DeRubertis³

1983

J. Clin. Invest.

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A B S T R A C T The role of local prostaglandin (PG) synthesis in the modulation of the proliferative activity of colonic epithelium was examined in rat colon. Experimental rats were given either indomethacin (5 mg/kg s.c. every 8 h for three doses) or aspirin (0.5 g/100 g diet for 3 d). In rats treated with indomethacin or aspirin, the incorporation of [3H]thymidine (dThd) into DNA in vivo was increased approximately twofold over control in mucosal scrapings from distal colon, and approximately threefold over control in the proliferating pool of epithelial cells isolated from distal colon.[3H]dThd incorporation into DNA was also examined ex vivo immediately after distal colonic resection. It was approximately twofold higher in mucosa of colonic segments (1-h incubation) from rats treated with indomethacin or aspirin in vivo, compared with corresponding values of segments from control rats. Immunoreactive (i) prostaglandin E (PGE), the dominant PG product of colon segment incubates by high-performance liquid chromatography analysis of [14C]arachidonate metabolites, was markedly (95%) reduced in the media of 1-h colon incubates from indomethacin-or aspirin-treated rats, compared with control rats. Moreover, the cyclic (c)AMP content of mucosa of segments from indomethacin-or aspirintreated rats was significantly lower than that of control rats. Prolonged incubation (4-24 h) of colonic segments from indomethacin-treated rats, in the absence of indomethacin in vitro, led to an eventual return of [3H]dThd incorporation into DNA, iPGE, and mucosal cAMP to control values. Conversely, inclusion of indomethacin (0.25 mM) in the incubations (6 h) of coAddress all correspondence to Dr. Frederick R. DeRubertis.Received for publication 1 April 1983 and in revised form 28 June 1983. lonic segments from indomethacin-treated rats resulted in persistent suppression of iPGE and mucosal cAMP, as well as persistent enhancement of [3H]dThd incorporation into mucosal DNA. However, incubation of colonic segments from control rats (no in vivo drug exposure) with indomethacin or aspirin in vitro for periods up to 24 h failed to alter DNA synthesis, despite marked reduction in media iPGE and lower mucosal cAMP. The latter observations suggested that additional in vivo factors initiated the enhancement of DNA synthesis in indomethacin-or aspirin-treated rats. Exogenous PGE2, D2, I2, or F2a, each of which increased the endogenous mucosal cAMP content of incubated colonic segments from control, indomethacin-or aspirin-treated rats, all suppressed [3H]dThd incorporation into mucosal DNA in vitro. Dibutyryl cAMP, but not dibutyryl cGMP, had an analogous suppressive effect on in vitro [3H]dThd incorporation into DNA. Thus, the present observations are consistent with an inhibitory action of endogenous colonic PG synthesis on the proliferative activity of colonic epithelium. This action may be mediated through cAMP. INTRODUCTIONThe colon is an active site of prostaglandin (PG)' synthesis (1, 2). There is evidence that PG may modulate coloni...

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“…iPGE content was assessed as previously reported (2,14,15 Extraction and assay of DNA. DNA content of the colonic mucosa was extracted as previously described (6).…”

Section: Methodsmentioning

confidence: 99%

Role of local prostaglandin synthesis in the modulation of proliferative activity of rat colonic epithelium.

Craven¹,

Saito²,

DeRubertis³

1983

J. Clin. Invest.

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“…In this respect, recent studies have shown that calcium enhances prostaglandin synthesis. 33 " 35 The purposes of the present study therefore were 1) to determine the cardiovascular mechanisms of the pressor response to acute hypercalcemia in the conscious rat and 2) to evaluate a possible enhancing and vasoconstrictive role for angiotensin II, catecholamines, and vasopressin; a possible attenuating and vasodilative role for prostaglandins and parathyroid hormone; and the role of cellular calcium uptake in the pressor response.…”

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Mechanism of acute hypercalcemic hypertension in the conscious rat.

Berl¹,

Levi²,

Ellis³

et al. 1985

Hypertension

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SUMMARY Acute hypercalcemia in the conscious, unanesthetized rat, achieved by a 30-minute infusion of CaCl 2 (serum calcium level, 12.8 ± 0.6 mg/dl) resulted in significant elevation of mean arterial pressure (from 112 ± 2 mm Hg to 129 ± 3 mm Hg, p < 0.001). This pressor response was associated with a significant increase in systemic vascular resistance, from 0.45 ± 0.02 mm Hg/(ml/min)/kg body weight to 0.50 ± 0.02 mm Hg/(ml/min)/kg body weight (p < 0.05), but it caused no alteration in cardiac index. The pressor response to acute hypercalcemia does not appear to be mediated by vasopressor hormones or attenuated by vasodepressor hormones since inhibition of the renin-angiotensin system (nephrectomy), catecholamines (central and peripheral 6-hydroxydopamine), vasopressin (vascular antagonist), prostaglandins (indomethacin), and parathyroid hormone (parathyroidectomy) did not significantly alter the pressor response to infusion of CaCI 2 in spite of similar serum calcium levels in all groups of animals. Rather, the pressor response to acute hypercalcemia seems to be mediated by a direct action of calcium ion on smooth muscle and perhaps myocardial cell contractility, since pretreatment with the calcium channel blockers verapamil or nifedipine blocked the pressor response to acute hypercalcemia. (Hypertension 7: 923-930, 1985)

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“…Alternatively, calcium ion could directly, independent of AII, mediate the decrement in RBF and GFR in chronic hypercalcemia (19). On the other hand, the vasodilatory renal prostaglandins (PG), whose synthesis in vitro has been shown to be stimulated by calcium ion (20)(21)(22), could have an attenuating effect on the vasoconstrictor activity of AII and calcium ion. The present experiments were therefore performed to (a) assess the systemic and renal hemodynamic effect of chronic hypercalcemia in the conscious rat, and (b) determine the role of PG, AII, and calcium per se in the control of RBF and GFR in such a setting.…”

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Control of Renal Hemodynamics and Glomerular Filtration Rate in Chronic Hypercalcemia

Levi¹,

Ellis²,

Berl³

1983

J. Clin. Invest.

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A B S T R A C T The role of prostaglandins (PG), reninangiotensin system (RAS) and calcium (Ca) in the control of renal hemodynamics and glomerular filtration rate (GFR) in chronic hypercalcemia (serum Ca 12.8 mg%) was studied. Renal blood flow (RBF, 6.39 ml/ min per gram kidney weight [gkw]) and GFR (0.52 ml/min per gkw) were significantly decreased in hypercalcemic rats when compared with normocalcemic rats (7.15, P < 0.001 and 0.74, P < 0.05, respectively). These changes in RBF and GFR occurred independent of any significant alterations in systemic hemodynamics, blood and plasma volume. Inhibition of the renal PG with indomethacin resulted in marked decrements in both RBF (6.39-4.12 ml/min per gkw, P < 0.01) and GFR (0.52-0.19 ml/min per gkw, P < 0.01) in hypercalcemic rats, whereas there was no significant alterations in normocalcemic rats. Inhibition of the RAS with captopril resulted in marked increments in both RBF (6.39-7.35 ml/min per gkw, P < 0.05) and GFR (0.52-0.74 ml/min per gkw, P < 0.05) in hypercalcemic rats. In fact, there was no significant difference from the RBF and GFR of similarly treated normocalcemic rats. Similar results were also obtained with the competitive angiotensin II (AII) antagonist (sarcosyll-isoleucyl5-glycyl8) AII. Since both the renal PG and the RAS are involved in the control of RBF and GFR in hypercalcemia, the role of each is best revealed in the absence of the other. Hence, comparison of the RBF and GFR in the PG-inhibited hypercalcemic rats in the presence of AII (4.12 and 0.19 ml/ min per gkw, respectively) and absence of AII (5.99 and 0.53 ml/min per gkw, P < 0.01 for both) reveals the vasoconstrictive role for All in hypercalcemia. On the other hand, comparison of the RBF and GFR in the AII-inhibited hypercalcemic rats in the presence of PG (7.35 and 0.74 ml/min per gkw, respectively) and absence of PG (5.99 and 0.53 ml/min per gkw, P < 0.01 and P < 0.05, respectively) reveals the vasodilatory role for PG in hypercalcemia. Finally, comparison of the RBF and GFR in both PG-and Allinhibited hypercalcemic rats (5.99 and 0.53 ml/min per gkw, respectively) with similarly treated normocalcemic rats (7.30 and 0.94 ml/min per gkw, P < 0.001 and P < 0.005, respectively) reveals the vasoconstrictive role for Ca in chronic hypercalcemia. Our study therefore demonstrates that in chronic hypercalcemia the RBF and GFR are controlled by an active interplay of the vasoconstrictive effect of AII, the vasodilatory effect of renal PG, and the direct vasoconstrictive effect of Ca, independent of either AII or PG. The sum total of these forces produces a modest but significant decrease in RBF and GFR. INTRODUCTIONThe association of acute and chronic hypercalcemia with decrements in renal blood flow (RBF)' and glomerular filtration rate (GFR) has been widely recognized in both man and experimental animals (1-15). While the mechanisms responsible for the decrement in RBF and GFR have been studied in anesthetized, acutely hypercalcemic animals, there have been no such studies in the setting...

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Renal inner medullary prostaglandin synthesis. A calcium-calmodulin-dependent process suppressed by urea.

Cited by 43 publications

References 34 publications

Role of local prostaglandin synthesis in the modulation of proliferative activity of rat colonic epithelium.

Role of local prostaglandin synthesis in the modulation of proliferative activity of rat colonic epithelium.

Mechanism of acute hypercalcemic hypertension in the conscious rat.

Control of Renal Hemodynamics and Glomerular Filtration Rate in Chronic Hypercalcemia

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