Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study examined the effect of short-term streptozotocin-induced diabetes in rats on the response of cremaster muscle arterioles to angiotensin II (ANG II) and vasodilatory prostaglandins. Topically applied ANG II (10(-10) to 10(-6) M) caused significantly greater vasoconstriction of third-order arterioles in diabetic animals in comparison with controls. For example, in response to 10(-6) M ANG II arterioles of the diabetic animals constricted to 43 +/- 10% of basal diameter compared with controls' 67 +/- 6% (P less than 0.05). Furthermore, the magnitude of the secondary vasodilatation after ANG II-induced constriction was decreased in diabetic animals (108 +/- 4 and 131 +/- 9%, P less than 0.025). Cyclooxygenase inhibition resulted in marked arteriolar constriction, with this effect being less evident in diabetic animals. In response to indomethacin (2.8 x 10(-5) M), arterioles of the diabetic animals constricted to 84 +/- 7% of basal diameter compared with 56 +/- 4% in controls (P less than 0.01). Arterioles of the diabetic animals were less responsive to exogenous prostaglandin I2 (PGI2) and PGE2 (10(-12) to 10(-6) M) despite evidence of increased in vitro PGI2 production. The data demonstrate potentiation of the vasoconstrictor response and a diminution of the secondary vasodilator response to ANG II in experimental diabetes. These alterations may be due, in part, to decreased responsiveness of skeletal muscle arterioles to vasodilatory prostaglandins.
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PMID:Altered microvascular reactivity in streptozotocin-induced diabetes in rats. 253 51

Numerous abnormalities in the renin-angiotensin system have been described in diabetes mellitus. Plasma renin activity (PRA) has been noted to be low, normal, and high in diabetic patients; these variable results may be explained by differences in patient selection and standardization of study conditions. We evaluated PRA and inactive renin responses in Type II normotensive (n = 7) and hypertensive (n = 12) diabetic patients specifically selected for no or minimal evidence (background retinopathy) for microvascular complications. Patients were studied in a metabolic ward after 7 days on a constant low sodium (20 meq/day) and 7 days on a high sodium (250 meq/day) diet. Nondiabetic control subjects (n = 7) were evaluated under similar conditions. On low sodium intake, mean PRA levels were significantly reduced in the hypertensive diabetic group, but were not different between the control and normotensive diabetic groups. Hypertensive diabetic patients on high sodium intake also had greater reductions in PRA responses compared with the other study groups. In general, diabetic subjects on high sodium intake excreted less sodium and had more cumulative sodium retention than control subjects. Levels of inactive renin were not significantly different between the normotensive and hypertensive diabetic patients and were comparable with the levels in control subjects. Inactive renin levels changed in a similar direction and magnitude as PRA in response to sodium intake and posture in the three study groups. Infusion of angiotensin II led to comparable reductions in PRA in both diabetic groups and in the control group, suggesting an intact short feedback loop control.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renin regulation in type II diabetes mellitus: influence of dietary sodium. 264 16

Contrary to popular belief, the primary directive for the release of renin is not the preservation of circulatory homeostasis, since activation of this hormonal system in patients with chronic heart failure results in deleterious rather than beneficial effects on cardiac performance. Instead, renin appears to be released by the kidneys to maintain glomerular filtration rate when renal perfusion pressure is reduced. The renin-angiotensin system carries out this beneficial action by exerting a constrictor action on the efferent arteriole. In doing so, renal blood flow declines, but filtration fraction increases and thus, glomerular hydraulic filtration pressure (and renal function) is preserved, despite severe renal hypoperfusion. When the formation of angiotensin II is inhibited during converting-enzyme inhibition, the beneficial action of this hormone on the efferent arteriole is lost, and renal function may deteriorate. This sequence of events is most likely to be seen when four risk factors are present: hyponatremia; high-dose diuretic therapy; diabetes mellitus; and the use of long-acting converting-enzyme inhibitors. In randomized studies, renal insufficiency developed more frequently with enalapril and lisinopril than with captopril. This risk of worsening azotemia is particularly high in patients with the most severe (class IV) heart failure.
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PMID:Identification of risk factors predisposing to the development of functional renal insufficiency during treatment with converting-enzyme inhibitors in chronic heart failure. 267 Feb 21

Hypertension is an important risk factor in the progression of renal failure, particularly in patients with pre-existing glomerulopathies such as diabetes and chronic glomerulonephritis. The mechanisms involved in hypertensive glomerular injury are currently unclear and cannot be studied in humans because of the constraints of human experimentation. However, recent animal studies have elucidated mechanisms which may explain the variable relationship between systemic hypertension and glomerular injury. Experimentally, at similar levels of systemic hypertension, glomerular injury only develops when preglomerular resistances are ineffective, thus allowing the development of glomerular hypertension. The mechanisms by which the haemodynamic stress of elevated intracapillary pressures and flows lead to progressive glomerular damage are at present unknown. Endothelial cell injury, increased mesangial traffic and/or trapping of macromolecules and epithelial cell injury appear to occur early, followed by in situ inflammatory and microthrombotic mechanisms. The intrarenal renin-angiotensin system appears to play an important role in the pathogenesis of progressive glomerular injury. Haemodynamically, angiotensin II (Ang II) has a relatively greater vasoconstrictive effect on efferent than on afferent arterioles. In addition, Ang II decreases the glomerular ultrafiltration coefficient. These combined effects result in increased intraglomerular capillary pressures. Angiotensin II increases the uptake and decreases the egress of circulating macromolecules in the glomerular mesangium and fosters mesangial cell mitogenesis. Thus, inhibition of Ang II generation may explain why angiotensin converting enzyme (ACE) inhibitors may be effective in arresting or slowing the progression of renal failure in experimental animals and in man.
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PMID:Possible mechanism for the renoprotective effect of angiotensin converting enzyme inhibitors. 269 55

Streptozotocin-induced diabetic rats showed a significant lowering in both PRA (-31%) and basal plasma aldosterone concentration (-59%), coupled with a notable atrophy of the zona glomerulosa (-30%) and its parenchymal cells (-36%). Kalaemia and the blood level of ACTH were not affected. Insulin infusion reversed all the streptozotocin-evoked effects. Analogous, though less conspicuous, changes were induced by experimental diabetes also in rats whose hypothalamo-hypophyseal-adrenal axis and renin-angiotensin system had been pharmacologically interrupted by the simultaneous administration of dexamethasone-captopril and maintenance doses of ACTH-angiotensin II: the drops in the basal plasma aldosterone concentration and in the volume of zona glomerulosa and its cells ranged from -20% to -22%. In these animals, experimental diabetes significantly depressed the aldosterone response to the acute stimulation with angiotensin II (-55%), potassium (-50%), and ACTH (-43%). These findings indicate that the well known impairment of renin release may only partially account for the antiadrenoglomerulotrophic effect of experimental diabetes in rats. The hypothesis is advanced that the chronic lack of insulin may directly depress both the growth of the zona glomerulosa and the newly synthesis of some enzymes of aldosterone synthesis.
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PMID:Zona glomerulosa morphology and function in streptozotocin-induced diabetic rats. 284 Feb 71

The comparative effects of lisinopril, a third generation angiotensin converting enzyme (ACE) inhibitor, on components of the renin-angiotensin system were assessed in normal and in an animal model of diabetes-related hypertension, the streptozotocin-diabetic rat. Two weeks after injection of streptozotocin the mean systolic blood pressure of diabetic rats was elevated 11% above that of normal rats. This effect was prevented by daily injection of insulin. The mean serum ACE activity was elevated 71% above that of normal rats. Lisinopril reduced systolic blood pressure and inhibited serum ACE activity in both normal and diabetic rats in a dose-response fashion. In normal rats maximum inhibition of blood pressure occurred at a mean dose of 1.0 mg/kg and in the diabetic rat at a mean dose of 5.0 mg/kg. At a mean dose of 5 mg/kg, ACE was inhibited by 100 and 92% in normal and diabetic rats, respectively. Plasma renin activity (PRA) increased sharply in both groups of rats treated with the lower doses of lisinopril, only to decrease at the 5 mg/kg level. At 20 mg/kg, PRA continued to decline in normal animals, but not in diabetic rats. Formation of angiotensin II (Ang II) in both normal and diabetic rats was maximally inhibited at doses of 1.0 and 0.1 mg/kg of lisinopril, respectively without a significantly greater effect at the higher doses of the drug. In separate experiments the effects of chronic treatment with lisinopril at two dosage levels on various physiological parameters of streptozotocin-diabetic rats were compared with the effects of another hypotensive agent, hydralazine, an arteriolar vasodilator.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of the angiotensin converting enzyme inhibitor, lisinopril, on normal and diabetic rats. 284 85

Hypertension in diabetic patients is more common than in controls, contributes substantially to their increased cardiovascular morbidity and mortality, and should be treated as accurately as diabetes mellitus itself. After appropriate exclusion of secondary forms, the first therapeutic step consists of reduction of overweight, salt intake, and smoking; the omission of interfering drugs; and adequate instruction. Step 2 has usually been the prescription of a diuretic drug, in spite of its known side effects on carbohydrate and lipid metabolism. A new possible alternative may be a calcium antagonist. Results in 10 hypertensive diabetic persons suggest that at a dose that normalizes blood pressure, neither carbohydrate nor lipid metabolism is altered, uric acid decreases, the exaggerated cardiovascular reactivity toward norepinephrine becomes normal, and the pressor dose for angiotensin II tends to rise. Body weight, blood volume, exchangeable sodium, as well as plasma and urinary sodium, potassium, and creatinine levels were unchanged. The third therapeutic step is the addition of a cardioselective beta blocker in a moderate dose. This avoids the disadvantages of beta 2-adrenergic blockade such as decreased insulin output, prolonged hypoglycemia, diminished glucagon secretion, and increased vasospasticity during hypoglycemic states, as well as aggravation of peripheral vascular disease. Alternatives are other sympatholytics with their known tendency to cause or increase orthostatic and sexual problems or, again, a calcium antagonist. In step 4, a hydralazine-type drug or prazosine is added. The fifth step, which adds minoxidil or captopril to the previous drugs, should only be taken after a specialist reevaluates the overall situation.
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PMID:Antihypertensive therapy in diabetic patients. 286 38

Despite a dramatic fall in renal blood flow, glomerular filtration rate is usually preserved in patients with congestive heart failure until the terminal stages of the disease. This maintenance of renal function appears to be achieved in part by the synthesis of two vasoactive factors within the kidney--angiotensin II and prostaglandins--which are rapidly released whenever renal perfusion is compromised or sympathetic nerve traffic to the kidneys is increased. Although these two hormonal systems exert opposite effects on systemic and renal blood flow and sodium and water excretion, both act to preserve glomerular filtration rate: prostaglandins by a vasodilator action exerted primarily on the afferent arteriole and angiotensin II by a vasoconstrictor effect on the efferent arteriole. Consequently, when the synthesis of these hormones is experimentally blocked, renal function deteriorates, especially in subjects with marked renal hypoperfusion and sodium depletion; these two factors interact to determine the importance of intrarenal hormonal release in the modulation of renal function. Clinically, four specific factors have been identified that predispose patients with heart failure to the development of functional renal insufficiency after treatment with converting-enzyme or cyclo-oxygenase inhibitors: (1) marked renal hypoperfusion, (2) vigorous diuretic therapy, (3) diabetes mellitus, and (4) intensity of hormonal inhibition within the kidney. This last risk factor may provide the basis for differentiating among enzyme-inhibitory drugs and suggests that renal insufficiency in low-output states may be minimized by the development of therapeutic agents that block hormonal synthesis selectively at sites that are critical to the disease process but spare the homeostatic tissue-based enzyme systems that exist within the kidney.
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PMID:Interaction of prostaglandins and angiotensin II in the modulation of renal function in congestive heart failure. 296 29

The effect of E-series prostaglandins (PGE) on hormone-stimulated glycogenolysis was studied in isolated rat hepatocytes. As previously reported, the physiologically active analogue 16,16-dimethyl-PGE2 inhibited glucagon-stimulated glycogenolysis. This effect could be reproduced by repetitive addition of PGE2 to compensate for PGE2 catabolism. In contrast, glycogenolysis stimulated by N6,O2'-dibutyryladenosine-3',5'-cyclic monophosphate (dibutyryl-cAMP) was unaffected by either PGE2 or 16,16-dimethyl-PGE2 (rate of glycogenolysis with 0.34 microM dibutyryl-cAMP plus 1.7 microM 16,16-dimethyl-PGE2 = 99 +/- 6% of rate with 0.34 microM dibutyryl-cAMP alone; mean +/- SEM, N = 5). Similarly, glycogenolysis stimulated by 8-bromoadenosine-3',5'-cyclic monophosphate was not inhibited by PGE2 or 16,16-dimethyl-PGE2. Epinephrine-stimulated glycogenolysis was inhibited by 16,16-dimethyl-PGE2 in a dose-dependent manner. PGE inhibited the cAMP-independent stimulation of glycogenolysis resulting from phenylephrine or angiotensin II exposure (rate of glycogenolysis with 8 microM phenylephrine + 1.7 microM 16,16-dimethyl-PGE2 = 65 +/- 10% of rate with 8 microM phenylephrine alone, N = 4, P less than 0.05; 4.9 microM angiotensin II + 1.7 microM 16,16-dimethyl-PGE2 = 75 +/- 7% of rate with 4.9 microM angiotensin II alone, N = 4, P less than 0.05). Glycogenolysis stimulated by the calcium ionophore A23187 was also inhibited by PGE (rate of glycogenolysis with 0.55 micrograms/ml A23187 + 1.7 microM 16,16-dimethyl-PGE2 = 83 +/- 5% of rate with 0.55 micrograms/ml A23187 alone, N = 7, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1985 Mar
PMID:Effect of E-series prostaglandins on cyclic AMP-dependent and -independent hormone-stimulated glycogenolysis in hepatocytes. 298 82

offlated hypoaldosteronism with or without hyperkalemia in patients with diabetes mellitus has been shown to exist occasionally without hyporeninemia. To assess in detail the adrenal function in this disorder, the responses of plasma aldosterone (PA) and its precursor steroids to angiotensin II (AII) infusion and adrenocorticotropic hormone (ACTH) injection were studied in seven patients with asymptomatic normoreninemic hypoaldosteronism (ANH) and 11 age-matched normal subjects. The ANH diabetic patients had, by definition, a low PA level after furosemide (80 mg orally) plus upright posture (4 hours) stimulation, low PA and high plasma renin activity (PRA) increases after the stimulation (a low delta PA/delta PRA ratio), and normokalemia. Plasma inactive renin and the inactive renin/total renin ration were similar in the ANH diabetic patients and in the normal subjects. Under the pre-AII condition, plasma DOC and corticosterone levels tended to be low, and the plasma 18-OHB and PA levels were low in the ANH diabetic patients compared with the normal subjects. The ratio of plasma 18-OHB to PA was similar in the two groups. All infusion produced no increases in plasma 18-OHB and PA in the ANH diabetic patients, whereas the infusion caused dose-dependent increases in these steroids in the normal subjects. Plasma DOC and corticosterone levels remained unchanged during AII infusion in the two groups. ACTH injection produced appropriate PA increases relative to the basal PA in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Unresponsiveness of plasma mineralocorticoids to angiotensin II in diabetic patients with asymptomatic normoreninemic hypoaldosteronism. 298 80


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