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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By the term "insulin resistance" we understand the attenuation of insulin-stimulated glucose uptake, which is mainly due to attenuated glycogen synthesis in skeletal muscle and is partially compensated with regard to plasma glucose homeostasis by hyperinsulinemia. Other mechanisms of insulin are either not attenuated or are less so and may contribute via hyperinsulinemia to the prevalence of hypertension, obesity, dyslipoproteinemia and type-II diabetes. At the level of insulin receptors, resistance can be due to muscle-specific, preferential expression of the low-affinity B-isoform of the insulin receptors. In rare cases of extreme resistance, it can also be due to several mutations at the insulin receptor gene or due to insulin-receptor autoantibodies. At the postreceptor level, the translocation and or expression of the insulin-responsive glucose carrier GluT-4 can be down-regulated via the hexosamine pathway by hyperglycemia plus hyperinsulinemia. Furthermore, Glut-4 can be inhibited and/or down-regulated by sustained insulin deficiency, partially via c-AMP-dependent pathways. Additionally, the insulin-induced glycogen synthesis in skeletal muscle can be attenuated by the endogenous peptides amylin and calcitonin-gene-related peptide, and by modulations of endothelial function, perfusion and capillary recruitment in the microcirculation of skeletal muscle. Epidemiological data indicate a genetic predisposition for insulin resistance. However, among the many mechanisms potentially contributing to the complex syndrome of insulin resistance, no specific localization of that predisposition can be proposed at present.
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PMID:[The mechanisms of insulin resistance]. 153 3

The experimental evidence supporting a direct role for hyperinsulinemia as a cause of insulin resistance remains equivocal. Amylin, an islet beta-cell peptide cosecreted with insulin in response to nutrient stimuli, causes insulin resistance when infused into intact animals or applied to isolated skeletal muscles. We compared measures of amylin and insulin gene expression between control and genetically obese, insulin-resistant Lister Albany/NIH-(LA/N-cp) rats. Pancreatic amylin messenger RNA levels were increased 7.8 +/- 0.7-fold (mean +/- SEM), and plasma amylin-like immunoreactive material was increased 10.9 +/- 1.1-fold (LA/N-lean, 14 +/- 4 pM; LA/N-cp, 153 +/- 16 pM; p less than 0.0001) in obese rats. Pancreatic insulin I mRNA levels were increased 7.4 +/- 0.5-fold, and plasma insulin levels 20.0 +/- 5.0-fold, in these rats (LA/N-lean, 308 +/- 84 pM; LA/N-cp 6,120 +/- 1,540 pM; p less than 0.0001). The EC50 for insulin-stimulated incorporation of glucose into glycogen was about fourfold higher in muscles isolated from obese rats. The present results, coupled with previous observations, support the hypothesis that hyperamylinemia, rather than hyperinsulinemia per se, could have directly caused the insulin resistance in the obese LA/N-cp rats. Hyperamylinemia needs to be considered in future experimental studies probing the relation between hyperinsulinemia and insulin resistance.
Hypertension 1992 Jan
PMID:Hyperamylinemia, hyperinsulinemia, and insulin resistance in genetically obese LA/N-cp rats. 173 Apr 46

Although insulin resistance and hypertension are commonly associated, the underlying cause for this association remains unknown. Plasma concentrations of the recently described hormone amylin, which is cosecreted with insulin by the pancreatic beta cell, are reported to be elevated in various states of insulin resistance, including hypertension and obesity. Preliminary studies by our group have suggested that there are amylin binding sites in the kidney. In nine healthy humans an infusion of human amylin that resulted in steady state plasma amylin levels in the subnanomolar range led to significant increases in plasma renin and aldosterone concentrations. These changes occurred in the absence of significant changes in plasma electrolytes, catecholamines, vasopressin, total renin, or osmolality. Diastolic pressure at 30 minutes and plasma glucose at 60 minutes rose modestly. Since amylin has both metabolic and renal actions, this peptide may be an important link between hypertension, insulin resistance, and the renin-angiotensin system.
Hypertension 1995 Sep
PMID:Amylin stimulates plasma renin concentration in humans. 764 82

Calcitonin gene-related peptide (CGRP), a 37 amino acid peptide resulting from the specific maturation processes of calcitonin gene products, was discovered in 1982. Its messenger RNA was isolated from a calcitonin cancer in rats similar to the human thyroid medullary carcinoma. CGRP is closely related to calcitonin and amylin, and to a lesser extent, to the region coding for the alpha chains of relaxins, insulin and insulin growth factors. In thyroid C cells, calcitonin itself is the major gene product, but CGRP is predominant in the central and peripheral nervous system. CGRP is found in most all tissues and is considered to be a neuromediator of particular importance in the cardiovascular system. CGRP is a powerful endogenous vasodilator in man; plasma concentrations of 56 pmol/l (slightly above physiological levels) provoke flush, hypotension and secondary catecholamine release and subsequent tachycardia. Intravenous injections lead to systemic vasodilatation and redistribution of blood flow to the skin, the brain, and probably the splanchnic territory. It has been suggested that CGRP plays a role in blood pressure modulation in certain pathological conditions. CGRP level is decreased in hypertension and increased in septic shock. In patients with terminal renal failure, CGRP is correlated with excess volaemia. It could affect blood pressure by redistributing blood flow, interacting with the renin-angiotensin system or by inhibiting aldosterone secretion. CGRP may also play a role in modulating cutaneous vascular constriction in Raynaud's syndrome and cerebral vascularization in patients with migraine or meningeal hemorrhage subsequent to rupture of cerebral aneurisms. CGRP increases arterial flow in the cavernous body. Coronarian vascular tone and cardiac performance (positive chronotrope and inotrope effects) are improved. CGRP has also been studied in connection with glucose metabolism and may have other endocrine effects. Finally, CGRP increases electrolyte and water flow in the colon and its bronchoconstrictor effect could be implicated in asthma. The clinical significance of plasma CGRP is not yet known although it may be a marker of poor prognosis in thyroid medullary cancer. Recent studies suggest that CGRP could be a useful therapeutic agent in severe Raynaud syndrome, impotency, ischaemic neurological lesions due to ruptured aneurisms and in severe heart failure.
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PMID:[Calcitonin gene-related peptide (CGRP)]. 817 60

Isolation of calcitonin mRNA initiated studies on the multigene complex encoding a family of peptides: calcitonin, its terminal flanking peptides, calcitonin gene-related peptide (CGRP), and amylin. CGRP is expressed in alpha- and beta-forms that vary by one and three amino acids in rat and humans, respectively. Both alpha- and beta-CGRP are very similar in their biologic activities, therefore the role of duplicating the calcitonin/CGRP gene is unclear. CGRP behaves principally as a regulatory neuropeptide acting locally through interaction with target organ receptors that are either cyclic-AMP dependent, or capable of activating KATP channels of vascular smooth muscle. The dense distribution of CGRP-rich structures and the expression of mRNA in the central nervous system suggests that CGRP has a neuromodulator or neurotransmitter role not limited to vasoregulatory effects only, but like calcitonin, extends its action to physiologic, metabolic, and behavioral functions. Activation of perivascular sensory nerves stimulates the release of neuropeptides, including CGRP, which exerts a potent vasodilatory effect on venous and arterial vasculature. The increased levels of CGRP-like immunoreactivity were observed in volume overload states, in heart failure and myocardial infarction, and in some forms of hypertension. The beneficial effect of CGRP infusions was demonstrated in patients with congestive heart failure and also in subjects with neurological deficits after surgical treatment of subarachnoid hemorrhage. On the other hand, there are experimental studies on the inhibition of increased CGRP activity, in septic and shock conditions, in which the vascular hyperrelaxation could have deleterious effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcitonin gene-related peptide and regulation of human cardiovascular homeostasis. 839 Feb 69

Amylin is a recently discovered peptide hormone composed of 37 amino acids that is cosecreted with insulin by pancreatic beta cells. Amylin has been reported to be present in increased amounts in insulin-resistant subjects who are hyper-insulinemic. Because blacks and whites differ in the prevalence of both hypertension and diabetes, we examined amylin levels in 77 individuals; 42 were black (11 hypertensive and 31 normotensive) and 35 were white (10 hypertensive and 25 normotensive) individuals who were either healthy control subjects or hypertensive subjects not receiving antihypertensive medication. Plasma amylin concentrations were measured in two separate monoclonal antibody-based immunofluorescent sandwich-type assays. The F002-2 capture antibody binds amylin plus at least two additional amylin-like peptides, and the F024-4 capture antibody detectably binds only the amylin peptide. There was a significant race-by-diagnosis interaction for levels of amylin immunoreactivity during a 2-hour glucose tolerance test (P<.005 for F002-2 antibody and P<.05 for F024-4 antibody). Highest levels were found in black hypertensive subjects. The results appear to fit with previously observed differences in metabolic status between blacks and whites and with the association between hypertension and alterations in metabolic status.
Hypertension 1996 Jun
PMID:Effect of race and hypertension on plasma amylin concentrations. 864 35

125I-labeled rat amylin binds to specific sites in the cortex of rat kidney, which can be distinguished from those for 125I-labeled salmon calcitonin (sCT) and 125I-labeled rat alpha-calcitonin gene-related peptide (alpha-CGRP) on the basis of regional distribution. These sites have a high affinity (approximately 1 nM) for amylin, and 125I-amylin binding is potently inhibited by the peptide antagonists AC413 and sCT-(8-32), whereas CGRP-(8-37) is a poor inhibitor of binding. Furthermore, incubation with guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) inhibits 125I-amylin binding by > 90%, indicating that binding is dependent on coupling to G proteins. In renal cortex, amylin stimulated adenylyl cyclase activity three- to fourfold, and this was inhibited by AC413 and sCT-(8-32) but not by CGRP-(8-37). Amylin activated plasma renin twofold, and this was blunted by prior administration of AC413 but not CGRP-(8-37). We speculate that amylin may play an important role in renal physiology and that in states of hyperamylinemia, as found in obesity and the insulin resistance syndrome, this peptide may be involved in the genesis and development of hypertension.
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PMID:Amylin binding in rat renal cortex, stimulation of adenylyl cyclase, and activation of plasma renin. 877 89

Human adrenomedullin, a novel hypotensive peptide, contains a six-member ring structure similar to that found in calcitonin gene-related peptide and pancreatic amylin. Unlike the full-sequence peptide, human adrenomedullin-(15-22) [hADM-(15-22)], which contains the ring structure, increases systemic arterial pressure in the rat but not the cat. We undertook the present study to investigate the mechanism by which hADM-(15-22) increases systemic arterial pressure in the rat. Injection of hADM-(15-22) in doses of 10 to 300 nmol/kg i.v. increased systemic arterial pressure in a dose-dependent manner and was threefold less potent than norepinephrine when doses were compared on a nanomole basis. However, the ring structures of human calcitonin gene-related peptide and human amylin, human calcitonin gene-related peptide-(1-8) and human amylin-(1-8), respectively, had no significant effect on systemic arterial pressure in the rat. Pressor responses to hADM-(15-22) were reduced significantly after administration of phentolamine or reserpine. Responses to hADM-(15-22) were not altered by the angiotensin type 1 blocking agent DuP 753 or the endothelin-A/endothelin-B receptor blocking agent bosentan, and responses to hADM-(15-22) and the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) were reduced after bilateral adrenalectomy. Pressor responses to DMPP were reduced by hexamethonium, whereas the nicotinic blocking agent had no effect on the pressor response to hADM-(15-22). These data suggest that increases in systemic arterial pressure in response to hADM-(15-22) in the rat are mediated by the activation of alpha-adrenergic receptors by catecholamines released from the adrenal medulla. The present data suggest that hADM-(15-22) releases catecholamines from the adrenal medulla by a noncholinergic mechanism.
Hypertension 1996 Dec
PMID:Catecholamine release mediates pressor effects of adrenomedullin-(15-22) in the rat. 895 94

The syndrome of insulin resistance comprises the following H-phenomena: 1. Hyperinsulinism compensating the inborn postreceptor insulin resistance, 2. Hyperglycaemia-non-insulin-dependent diabetes mellitus, 3. Hyperlipoproteinaemia with android obesity, 4. Hypertension, 5. Hirsutism with the syndrome of polycystic ovaries as a manifestation of a hyperandrogenic situation in the female organism. Molecular syndromes of this syndrome of insulin resistance are obscure. They are the subject of intensive studies because H-phenomena are an aggregation of the main risk factors of atherogenesis. Recently attention is focused also on amylin--a 37 amino acid peptide with a 50% homologous amino acid sequence with a calcitonin-gene--related peptide (CGRP), which is the product of a gene made up of three introns on the 12th chromosome. Amylin acts in the beta-cells of the pancreas as a co-secretion of insulin. If in excess, it is deposited in the form of an amyloid in the beta-cells. In the early stage of NIDDM it alters the physiological response of the beta-cell to glycaemic stimuli and food, in later stages of the disease, after accumulation, it causes apoptosis of the beta-cell and reduces thus the secretory capacity of the Langerhans islets. It is excreted in the urine and thus, if the glomerular filtration is reduced, it cumulates in the blood stream and thus enhances insulin resistance already in the early stages of chronic renal insufficiency, or in diabetic nephropathy. In type II diabetes similarly as insulin levels also amylin levels are elevated, while in type I diabetes with early autoimmune destruction of the beta-cells the insulin and amylin levels are reduced or even zero. Amylin reduces in the muscle, probably by inhibition of glycogen synthase, the insulin stimulated non-oxidative utilization of glucose into muscle glycogen and conversely by stimulation of phosphorylase it stimulates glycogenolysis and thus also lactate production and gluconeogenesis in the liver which all are anti-insulin effects which intensify the insulin resistance of the main target tissues. Amylin, similarly as CGRP or calcitonin, reduces Ca blood levels and has a vasodilatating effect; it reduces the BP but in different minimal and maximal doses and by a different mechanism and via special receptors because the link of amylin to calcitonin receptors is 100 times lower and does not produce a rise of cAMP in the target cell. The effect on the enhancement of insulin resistance in muscle was proved also by direct measurements using an hyperinsulinaemic euglycaemic clamp. After prolongation of the clamp to more than two hours the effect on insulin resistance disappeared, although the hypocalcinaemic effect persisted. Amylin is able by its biological action to modify the secretion as well as the effectiveness of insulin to pathological values. These two characteristics are typical for impaired glucose tolerance in type II diabetes. Studies are under way to find out whether the effect of amylin is involved directly also in the pathogenesis of the other H-phenomena or only via accentuation of hyperinsulinism. In any case amylin is a new link the role of which in the pathogenesis of NIDDM and the syndrome of insulin resistance awaits evaluation. Due to its effect on gastric evacuation it participates also in the postprandial glycaemic control in particular in type I diabetes where it it begins to be used in therapy. Perhaps it will be possible to administer it in these patients along with insulin to improve diabetes compensation.
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PMID:[Amylin as an additional possible pathogenic factor in NIDDM and the insulin resistance syndrome]. 896 27

In autoradiographic studies in anesthetized rats, 125I-labeled amylin binding was associated with proximal convoluted tubules but not distal tubules, interstitium, or glomeruli in the renal cortex. Split-drop micropuncture experiments showed that perfusion of the peritubular capillaries with amylin (10(-9) M) stimulated proximal tubular fluid absorption by 28%. This effect was inhibited by luminal addition of ethylisopropylamiloride, indicating mediation by a brush-border Na+/H+ exchanger. Intravenous infusion of an amylin binding antagonist, AC-187, reduced proximal fluid reabsorption (22%) in anesthetized rats, indicating a role for endogenous amylin in salt homeostasis. In primary cultures of rat proximal tubule cells, amylin (10(-7) M) stimulated proliferation with a potency equal to epidermal growth factor. Peptide antagonists (AC-187, AC-413, and AC-512) of the amylin binding sites in the renal cortex blocked the mitogenic action of amylin. We conclude that amylin acts on renal proximal tubules to promote sodium and water reabsorption and cell proliferation. These novel actions may have implications for the development of hypertension for example in non-insulin-dependent diabetes mellitus and obesity in which hyperamylinemia has been observed.
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PMID:Amylin stimulates proximal tubular sodium transport and cell proliferation in the rat kidney. 903 44


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