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)

We report the case of a six-day-old male infant exposed in utero to a prostaglandin synthetase inhibitor, who presented pulmonary arterial hypertension, tricuspid insufficiency, and electrocardiographic signs of diffuse myocardial ischemia. The necropsy showed organizing infarction of the anterior and posterior right papillary muscles (probably occurred in utero) with complete rupture of the former, besides abnormal muscularization of the intraacinar pulmonary arterioles (persistent fetal circulation of the newborn). The authors suggest a possible relation between the myocardial ischemic and pulmonary hypertensive lesions since the prostaglandin synthetase inhibitor can induce precocious pulmonary arteriolar muscularization and constriction of the arterial duct, leading to right ventricular overload, thus facilitating the occurrence of papillary and subendocardial ischemia.
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PMID:Post-ischemic rupture of the anterior papillary muscle of the right ventricle associated with persistent pulmonary hypertension of the newborn: a case report. 162 31

Flavodilol, a new antihypertensive drug, was evaluated in a variety of test systems for better understanding of its biologic properties and the nature of its mechanism of action. Oral administration of the drug to spontaneously hypertensive rats (SHR) lowered arterial blood pressure (ABP) in a dose-related manner, and doses greater than 35 mg/kg increased duration but not magnitude of the response. In contrast, oral administration of flavodilol to normotensive rats did not significantly alter ABP at 35 mg/kg, although larger doses of 75 or 150 mg/kg significantly lowered ABP. In rats with DOCA/salt hypertension, flavodilol effectively lowered ABP to a degree similar to that observed in SHR. At antihypertensive doses, flavodilol did not alter blood pressure responses to a 90 degrees head-up tilt in SHR and did not influence cardiac output in conscious SHR. In addition, flavodilol did not appear to manifest its antihypertensive activity through an interaction with beta-adrenoceptors, dopamine (DA) receptors or prostaglandin synthetase. Daily oral administration of flavodilol to SHR for 4 days resulted in augmented vasopressor responses to exogenously administered epinephrine (EPI) or norepinephrine (NE) and attenuated responses to exogenously administered tyramine. In addition, flavodilol treatment attenuated in a dose-related manner ABP and heart rate (HR) responses of pithed SHR to electrical stimulation of sympathetic nerves. We conclude that flavodilol is an effective antihypertensive drug which decreases the release of NE from postganglionic sympathetic nerves, resulting in attenuation of peripheral noradrenergic function.
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PMID:Flavodilol: a new antihypertensive agent. 247 4

Recent clinical studies have reported a significant reduction in the incidence of pregnancy-induced hypertension after the ingestion of low-dose aspirin. The effect of 80 mg of acetylsalicylic acid on vascular sensitivity to exogenous angiotensin II (Hypertensin, Ciba-Geigy Limited, Basel, Switzerland) was examined in 13 normotensive pregnant patients. The effective pressor dose before treatment (17.4 +/- 2.2 ng/kg/min) (mean +/- SE) was significantly less (p less than 0.001) than that after treatment (35.1 +/- 4.2 ng/kg/min). Low-dose aspirin therapy resulted in an enhancement of the pregnancy-acquired refractoriness to angiotensin II. It can be speculated that prostaglandin synthetase inhibitors at a low dose may alter the thromboxane A2/prostacyclin ratio in favor of the latter.
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PMID:Effect of low-dose aspirin on angiotensin II pressor response in human pregnancy. 379 52

The effects of propranolol on angiotensin II (AII) enhancement of sympathetic nerve transmission were investigated in the in situ blood-perfused mesenteric vascular bed of the rat. Angiotensin II in subpressor concentrations (3 ng/ml) potentiated the vasoconstrictor responses to both sympathetic nerve stimulation (NS) and exogenous norepinephrine (NE). The dl-propranolol had no effect on the basal vasoconstrictor responses to NS and NE, yet inhibited the AII-enhanced vasoconstrictor responses to NS by 47% (p less than 0.05) and 81% (p less than 0.001) at 100 and 300 ng/ml respectively. In contrast, the potentiation of NE responses by AII was unaffected by propranolol. A similar blockade of AII enhancement of NS was observed with the d-isomer of propranolol. Dibucaine (300 ng/ml), a local anesthetic, failed to alter the basal or AII-enhanced responses to either NS or NE. Indomethacin, a prostaglandin synthetase inhibitor (5 mg/kg, s.c.), abolished the inhibitory effect of dl-propranolol on AII enhancement of NS. Prostaglandin E2 (PGE2), but not prostaglandin I2, (3 ng/ml) inhibited AII enhancement of NS without altering the basal response to NS or NE in indomethacin-pretreated animals. Intraarterial infusions of dl-propranolol, d-propranolol, AII, and dl-propranolol-plus-AII into the superior mesenteric artery increased mesenteric venous PGE2 concentrations from 216 +/- 33 to 355 +/- 33 (p less than 0.01), 328 +/- 44 (p less than 0.05), 325 +/- 27 (p less than 0.02), and 407 +/- 44 pg/ml (p less than 0.01) respectively. We conclude that propranolol antagonizes AII enhancement of NS by increasing prostaglandin levels in vascular tissue. Furthermore, these findings suggest that propranolol may exert its antihypertensive effect through the release of prostaglandins when used in therapeutic doses in excess of those required for beta-adrenergic blockade.
Hypertension
PMID:A possible antihypertensive mechanism of propranolol: antagonism of angiotensin II enhancement of sympathetic nerve transmission through prostaglandins. 625 59

To determine whether prostaglandins contribute to the depressor response to the converting enzyme inhibitor, captopril, we measured the plasma prostaglandin levels by radioimmunoassy before and after captopril administration, and then examined the effect of prostaglandin synthetase inhibition on captopril's antihypertensive effect. When a single oral captopril dose (25-100 mg) was given to 31 sodium-restricted patients with essential hypertension, the levels of the stable transformation product of prostacyclin remained unmeasurable and that of thromboxane A2 did not change, while the metabolite of PGE2 (PGE-M) increased by 53% (34 +/- 4pg/ml pre-captopril, 52 +/- 5 pg/ml after; p less than 0.001). As expected, blood pressure (BP) and angiotension II (AII levels fell, and kinin levels rose (all changes p less than 0.001). We then blocked prostaglandin synthesis in 18 of these subjects for 24 hours with either indomethacin (n = 10) or aspirin (n = 8) before repeating the captopril dose, to assess the importance of these PGE-M increments. The PGE-M responses to captopril were effectively blocked in nine of 10 subjects receiving indomethacin and four of eight receiving aspirin. In these 13 patients, the depressor response to captopril was significantly blunted (-20 +/- 3mm Hg pre-synthetase inhibition vs - 13 +/- 2 mm Hg post; p less than 0.05). When these agents did not block the PGE-M response to captopril, the BP response was also unchanged (-15 +/- 4mm Hg pre, -18 +/- 5mm Hg post). Neither indomethacin nor aspirin changed the AII or kinin responses to captopril. We conclude that the prostaglandins may be important mediators of captopril's antihypertensive effect in the sodium-restricted state.
Hypertension
PMID:Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension. 626 Jun 45

To assess the implication of renal prostaglandins in the pathogenesis of essential hypertension, urinary PGE2 and PGF2 alpha were measured in 22 control subjects (11 males) and in 58 patients (33 males) with borderline and sustained essential hypertension under strictly control conditions. Although the mean PGs urinary excretion in essential hypertension was not significantly different from control subjects, 12% of the patients had very low PGE2 levels comparable to subjects receiving prostaglandin synthetase inhibitors. There was no difference in urinary PGE2 between borderline and sustained essential hypertension. Urinary PGF2 alpha values were also not significantly different in normal subjects and in hypertensive patients, although four patients (2 of each sex) had excessively elevated PGF2 alpha. There was no significant correlation between the two urinary prostaglandins and blood pressure levels, plasma renin activity, urinary volumes and sodium excretion. These results suggest that with the exception of a small percentage of patients, the renal production of PGE2 and PGF2 alpha are comparable in normal and in hypertensive patients; the production rates of these two compounds are also not influenced by the degree or stage of hypertension.
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PMID:Renal prostaglandins in borderline and sustained essential hypertension. 704 32

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

Isolated hypoaldosteronism is found in 75% diabetics where the disease has persisted for 10 or more years. Sporadically it is found in congenital autonomous neuropathy, in acute glomerulonephritis, in gouty kidney, tubulointerstitial nephritis, after transplantation of the kidney, on mytomycin etc. During dynamic testing of the response of plasma renin activity and aldosterone to the administration of furosemide and a vertical position in diabetics a significantly reduced response was recorded as compared with non-diabetic hypertonic subjects. In 18.3% no response was observed (decompensated form of IHH). Diabetic hypertonics behaved like control hypertonics on long-term beta-blocker treatment. In the decompensated form of IHH after administration of drugs interfering with the activity of SNS-RAAS activity (ACEI, spirolactone etc.) a hyperkalaemic crisis may develop which threatens the patient with acidosis, dehydration, myoplegia, muscular spasms, however, in particular with fatal disorders of the cardiac rhythm. A similar effect may be exerted also by blockers of prostaglandin synthetase (non-steroid antirheumatics) and other drugs. The cause of IHH in diabetics is the coincidence of several pathogenic factors: 1. hypersecretion of ANF with hyperosmolar hyperglycaemic hypervolaemia and hyperfiltration already at the onset of DN, 2. early development of autonomous neuropathy of the sympathetic nerve, 3. reduced renin and prostaglandin formation already in the early stages of DN, 4. reduced extrarenal isorenin formation, 5. reduced conversion of prorenin into active renin, 6. reduced reactivity of the zona glomerulosa to AII, hyperkalaemia and ACTH for its functional reconstruction as a result of periodic activation of contraregulative hormones by fluctuations of the blood sugar level in diabetic patients, 7. reduced response of the distal renal tubule to aldosterone because of tubulointerstitial changes. IHH is thus another serious but rarely diagnosed late complication of diabetes which depends only partly on the stage of DN. It must be, however, diagnosed and respected with regard to the selection of drugs for the treatment of arterial hypertension and the syndrome of insulin resistance and the 5H syndrome resp., i.e. the association of hyperinsulinism which compensates insulin resistance with hyperglycaemia (NIDDM), hypertension, hyperlipoproteinaemia and hirsutism in women (so-called Stein-Leventhal syndrome).
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PMID:[Diabetic nephropathy and isolated hyporeninemic hypoaldosteronism]. 892 9

In the kidney, prostanoids play a role as vasoactive and immunomodulatory mediators. One of the main biosynthetic enzymes, the inducible cyclooxygenase-2 (EC 1.14.99.1, Cox-2), has been recognized as a target of glucocorticoids. Therefore, we investigated whether the physiologically active corticosteroid aldosterone in the kidney might also interfere with prostaglandin (PG) synthesis. In two cell types, an epithelial cell line of tubular origin (MDCK) and rat renal mesangial cells, PGE2, release, Cox activity and Cox mRNA expression were determined after stimulation with phorbol ester and IL-1 beta, respectively. An increase in PGE2 release and Cox activity was observed, which correlated with an increase in Cox-2 mRNA expression. In MDCK cells, both dexamethasone and aldosterone were equally effective, suppressing all parameters measured by approximately 60%. A similar effect of aldosterone was also seen in mesangial cells, whereas dexamethasone was far more potent (> 90% inhibition at 10(-6) M). Whole cell binding assays showed the same number of receptors for aldosterone in both cell types (approximately 70,000 receptors/cell) but more than ten times higher receptor numbers for dexamethasone in mesangial cells than in MDCK cells (90,000 vs. 6000 receptors/cell). Receptor affinities of the corticosteroids were comparable. Thus, interaction of the corticosteroids with their cognate receptors was not sufficient to explain their different potencies but indicated the involvement of more complex regulatory mechanisms. Pathophysiologically, inhibition of PGE2 synthesis by aldosterone may play a role in the induction of hypertension by high concentrations of aldosterone.
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PMID:Interference of corticosteroids with prostaglandin E2 synthesis at the level of cyclooxygenase-2 mRNA expression in kidney cells. 893 52

Prostaglandins contribute to the regulation of renin synthesis and secretion. We tested the hypothesis that the inducible isoform of prostaglandin G/H synthase, cyclooxygenase-2, contributes to the stimulation of renin synthesis in renovascular hypertension. The expression of cyclooxygenase-2 and renin was investigated in the kidneys of rats with two-kidney, one-clip renovascular hypertension or sham operation. Systolic blood pressure was increased 2 weeks after clipping (153+/-7 versus 112+/-4 mmHg in controls, n=6 each, P<.05) and continued to rise until 4 weeks. Cyclooxygenase-2 mRNA levels were increased in clipped kidneys but remained unchanged or slightly decreased in nonclipped kidneys. Cyclooxygenase-2 protein was expressed mainly in the macula densa and occasionally in distal tubular cells not associated with the macula densa. Two weeks after clipping, the percentage of juxtaglomerular apparatus staining positive for cyclooxygenase-2 was 27.8+/-3.6 in clipped kidneys, 3.1+/-0.4 in contralateral kidneys, and 8.0+/-1.3 in controls; the percentages for immunoreactive renin staining in the afferent arteriole were 33.6+/-2 in clipped kidneys, 1.9+/-0.5 in contralateral kidneys, and 12.4+/-4.0 in controls, respectively. Similar parallel changes in renin and cyclooxygenase-2 staining were observed 4 weeks after clipping. The percentage of cyclooxygenase-2-positive juxtaglomerular apparatus correlated positively with the percentage that was renin positive (r=0.78, P<.05). Double immunostaining showed coexpression of cyclooxygenase-2 and renin protein in the same juxtaglomerular apparatus. Our data are consistent with a role for macula densa cyclooxygenase-2 in the regulation of renin in renovascular hypertension.
Hypertension 1998 Jan
PMID:Coordinate expression of cyclooxygenase-2 and renin in the rat kidney in renovascular hypertension. 945 3


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