Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe renovascular hypertension was produced in rats by complete aortic ligation between the origin of the renal arteries. Six days after coarctation, a carotid cannula was implanted and mean arterial blood pressure (MABP) and plasma renin activity (PRA) were determined. Subsequently, indomethacin (5 mg/kg in oil) or vehicle was administered subcutaneously three times in the following 24-hour period. On day 7, MABP and PRA were again determined. Indomethacin reduced MABP from 179.0 +/- 6.7 to 156.5 +/- 8.8 mm Hg (P less than 0.002, n = 11) and PRA from 21.2 +/- 7.3 to 9.3 +/- 2.9 ng AI/ml per hr (P less than 0.045, n = 10), whereas vehicle treatment did not alter either MABP or PRA (n = 6). There was a significant association between the decrease in MABP and the percentage decrease in PRA following indomethacin treatment (r = 0.766, P less than 0.016). A similar study was performed in aortic ligated rats in which the left kidney was removed at the time of ligation. In these animals, 6 days after surgery, MABP and PRA were 128.0 +/- 5.9 mm Hg and 0.11 +/- 0.06 ng AI/ml per hr (n = 6), respectively, and indomethacin had no effect on either MABP or PRA. These data provide evidence that the prostaglandin system is involved in the release of renin and in the pathogenesis of elevated blood pressure in this model of renin-dependent hypertension.
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PMID:Indomethacin decreases arterial blood pressure and plasma renin activity in rats with aortic ligation. 701 65

Kallikrein is present in the renal tubule near the macula densa, and it has recently been shown to activate inactive renin in human plasma. We recently showed that kallikrein was a potent stimulus of renin release and increased renin secretion in a dose-dependent fashion. To study its effect on renal renin release, we superfused rat renal cortical slices with purified rat urinary kallikrein. Kallikrein-stimulated renin release was completely abolished by trasylol and by amiloride, but was not affected by soybean trypsin inhibitor. Indomethacin did not block kallikrein action, indicating that kallikrein's effect is not mediated via kinin generation and prostaglandins. Kallikrein-stimulated renin release was not blocked by propranolol, trasylol did not block isoproterenol, and dibutyryl cyclic AMP stimulated renin release, indicating that kallikrein may not play a role in the beta-adrenergic mechanism of renin release. There was no demonstrable acid-activatable or kallikrein activatable renin in the superfusate, suggesting that all of the renin release was in the active form. Cathepsin D and plasmin also stimulated renin release from kidney slices in pH 6.0 buffer, whereas trypsin and pepsin did not. Our results support the hypothesis that kallikrein may play a role in the secretion of renin by the kidney. Other proteases can also release renin from the kidney.
Hypertension
PMID:Direct action of kallikrein and other proteases on the renin-angiotensin system. 702 11

The possibility that 6-keto-prostaglandin E1 (6-keto-PGE1) affects renin release was studied using rabbit renal cortical slices, a preparation that eliminates hemodynamic, neural, and blood-borne factors that might influence renin release. The medium used for incubating the slices was collected for renin assay at the end of each of four successive 20-minute periods. Test agents were added only once, at the beginning of Period 3 (experimental period). Between Periods 3 an 4 (recovery period), the medium was aspirated and the slices rinsed with Krebs solution before replacing the medium. Renin release did not change in vehicle-treated slices. Unlike the PGI2-induced changes, the effects of 6-keto-PGE1 on renin release were sustained in Period 4. Indomethacin potentiated renin stimulation induced by 10 microM concentrations of PGI2 and 6-keto-PGE1 in Period 3 and by 6-keto-PGE1 in Period 4. Using platelet antiaggregatory activity as an index of stability, we found that PGI2 was largely inactivated within 10 minutes under the conditions used for incubating the slices (pH 7.4, 37 degrees C), while 6-keto-PGE1 was stable. The results lend further support to the concept that 6-keto PgE1 is capable of releasing renin through a direct action.
Hypertension
PMID:Prostaglandin-related renin release from rabbit renal cortical slices. 704 Feb 43

The prostaglandins are potent vasoactive fatty acids that are ubiquitously distributed throughout the body. It is now well established that the prostaglandins participate in a variety of pathophysiological processes such as inflammation, burns, renal aspects of hypertension, peptic ulcer disease, diarrhea, skin conditions, vasomotor dysfunctions, platelet abnormalities, dysmenorrhea, fever, and shock. We have previously shown that the prostaglandins appeared to be elevated and were related to the circulatory dysfunction in canine and baboon endotoxin shock. In addition, our studies demonstrated that indomethacin, a prostaglandin synthetase inhibitor, not only inhibited the prostaglandin release and improved the hemodynamic derangements, but also significantly improved the survival. Indomethacin clearly improved the survival in baboon endotoxin shock even when administered after shock had occurred. Since the previous studies were in endotoxin models, the next logical step was to determine the effects of indomethacin in a clinically-relevant rat sepsis model. Two hundred sixty-six male rats (250-500 g) were randomly allocated to saline treated controls or to indomethacin treatment. A pure suspension of live E. Coli organisms (225 X 10(10)/rat) were injected i.p. to each rat. Treatment was introduced at three hours when all blood cultures were positive. Groups were divided into gentamicin (4 mg/kg/rat) alone, gentamicin and indomethacin (3 mg/kg), or indomethacin alone in addition to the saline treated controls. Results showed that indomethacin in combination with gentamicin significantly (p = 0.05) improved the survival at 24 (90%) and 48 hours (90%), when compared with saline treated controls (65%, 45%) and with gentamicin (40%, 40%). Indomethacin alone significantly (p = 0.01) improved the survival. Conclusions are that (i) therapeutic doses of indomethacin or gentamycin clearly improved the survival in a clinically relevant rat sepsis model; (ii) the exact mechanism of protection with indomethacin is unknown; and (iii) indomethacin should be considered for use in human clinical sepsis.
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PMID:The role of prostaglandins in sepsis. 704 14

Pulmonary edema which develops during acute myocardial infarction is generally believed to result solely from pulmonary microvascular hypertension. However, patient with myocardial infarction and pulmonary edema occasionally are found to have normal pulmonary wedge pressure. We report data indicating that pulmonary edema develops after coronary artery ligation despite stable microvascular pressure. Four groups of open-chest dogs were studied: (1) nine dogs with left anterior descending coronary artery ligation, (2) seven dogs with sham coronary ligation, (3) seven dogs ligated after beginning an infusion of indomethacin (5 mg/kg per hr), and (4) five dogs ligated after an infusion of the drug's vehicle was begun. Extravascular lung water and pulmonary blood volume were measured at hourly intervals during the 2 hours before and after coronary ligation or sham ligation. Gravimetric lung water was measured immediately thereafter. Changes of net pulmonary intravascular driving force (the difference of microvascular hydrostatic and oncotic pressure) after ligation or sham ligation were small and comparable in all groups. Pulmonary blood volume did not change in any group. Pulmonary extravascular water volume remained constant in the sham group but rose significantly in the ligated group. Gravimetric lung water also was significantly higher in the latter group. We interpret these results to indicate that factors other than microvascular pressure can mediate the formation of these results to indicated that factors other than microvascular pressure can mediate the formation of edema during acute myocardial infarction; increased pulmonary microvascular permeability may be responsible. Indomethacin infusion blocked the formation of edema after coronary ligation, even though net microvascular driving force was highest in this group. Infusion of the vehicle alone did not prevent edema. The mechanism by which indomethacin exerts this protective effect is unclear but is probably a result of its inhibition of cyclo-oxygenase or cyclic nucleotide phosphodiesterase.
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PMID:Non-hydrostatic pulmonary edema after coronary artery ligation in dogs. Protective effect of indomethacin. 705 61

Acute pulmonary artery hypertension and an increased plasma concentration of thromboxane B2 (TXB2), the stable metabolite of the potent vasoconstrictor thromboxane A2, occur within minutes of the onset of venovenous (VV) partial bypass in the awake sheep. To search for systemic vasoconstriction, we assessed systemic blood flow distribution by radioactive microspheres and correlated the changes to alterations in plasma TXB2 and 6-keto-F1 alpha concentration. In 10 control sheep mean plasma TXB2 concentration increased from 0.39 ng/ml prebypass to about 1.1 ng/ml at 8 and 16 min of bypass. Despite marked pulmonary vasoconstriction with a threefold elevated resistance, the blood flow to the heart, brain, and kidney were unchanged at 8 and 16 min of bypass. However, hepatic vascular resistance increased twofold at 8 min of bypass. Indomethacin treatment (10 mg/kg) of six sheep blocked the increase of both pulmonary and hepatic vascular resistance as well as reduced TXB2 levels below 0.1 ng/ml. Thus VV bypass induces transient and selective vasoconstriction of the lung and liver mediated by vasoconstrictor eicosanoids.
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PMID:Effect of lung thromboxane generation on regional blood flow during sheep bypass. 706 6

Intraventricular injection of bradykinin produced a dose-dependent increase in the mean arterial blood pressure of conscious rats. With 5 nmol of bradykinin, a dual pressor response was observed, which was associated with a biphasic behavioral change. With repeated hourly injections of bradykinin, tachyphylaxis developed to the pressor and central nervous system (CNS) stimulating effect. Indomethacin, given intraventricularly, reduced the hypertension and the behavioral excitation caused by bradykinin in a dose-dependent manner. When prostaglandin E2 was injected into the cerebral ventricles, it induced hypertension and behavioral sedation similar to the secondary response to bradykinin. These results suggest that bradykinin has a dual action on the CNS, and this is mediated by prostaglandin-related systems in the brain.
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PMID:Relationship between central actions of bradykinin and prostaglandins in the conscious rat. 707 Jun 2

In 6-week old spontaneously hypertensive rats (SHR), indomethacin (5 mg/kg i.v.) and pinane-thromboxane A2 (PTA2) (50 micrograms/kg per h i.v.) a thromboxane A2 (TXA2) antagonist as well as a TXA2 synthetase inhibitor, resulted in natriuresis accompanied by an increase in p-aminohippuric acid and inulin clearances. Indomethacin acted as an antidiuretic in 6 week Wistar-Kyoto rats (WKY). PTA2 did not alter renal functions in either 6 week WKY and 18 week SHR. Basal urinary excretion of TXB2 (UTXB2V) was greater in 6 week SHR than in 6 week WKY and 18 week SHR, and that of 6-keto-PGF1 alpha (U6-keto-PGF1 alpha V) did not differ among these strains. Thus, U6-keto-PGF1 alpha V/UTXB2V was lower in the 6 week SHR. Basal urinary excretion of PGE (UPGEV) was much greater in 18 week SHR than in the 2 other groups. In the 6 week SHR, PTA2 decreased UTXB2V and increased U6-keto-PGF1 alpha V without affecting UPGEV, and indomethacin reduced UTXB2V more markedly than did U6-keto-PGF1 alpha V and UPGEV. Thus, both PTA2 and indomethacin increased U6-keto-PGF1 alpha V/UTXB2V in the 6 week SHR. These findings indicate that a disequilibrium in the biosynthesis of vasoconstrictive TXA2 and of vasodilator PGI2 may be involved in water and sodium retention in SHR during the developmental phase of hypertension.
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PMID:Renal effects of pinane-thromboxane A2 and indomethacin in saline volume-expanded spontaneously hypertensive rats. 715 63

Intravenous urography is the standard screening test for renovascular hypertension but there is a significant incidence of false negative and false positive results. In an attempt to improve the detection rate, indomethacin was administered orally to nine patients with renal artery stenosis (proven by arteriography and by divided ureteric function studies) before rapid-series intravenous urography. This urogram was compared independently by two observers with prior similar-series urograms. Indomethacin did not alter diagnostic accuracy.
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PMID:Does inhibition of prostaglandin synthesis increase the diagnostic accuracy of the intravenous urogram in renal artery stenosis? 724 20

Two siblings are described with hypertension, hyperreninism, hyperaldosteronism and hypokalemia. Propranolol therapy lowered blood pressure markedly, but failed to normalize serum potassium. Indomethacin orally decreased blood pressure and normalized all biochemical abnormalities. We suggest that in these patients there exists a renin-dependent hypertension in combination with a state of hyperprostaglandinism. It is likely from our studies in these 2 patients, that the state of hyperprostaglandinism is secondary to a hypertension with increased sympathetic tone.
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PMID:Effect of indomethacin in two siblings with a renin-dependent hypertension, hyperaldosteronism and hypokalemia. 735 42


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