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

Aortic rings from SHR are reported to have a decreased relaxation response to the endothelium-dependent agent acetylcholine compared with rings from WKY rats. Thus, a reduced EDRF (nitric oxide) response could contribute to hypertension. We found that in mesenteric small resistance arteries (200 microns I.D.) taken from 5- to 50-week old rats and mounted in a Mulvany-Halpern myograph, that the concentration-response curves to acetylcholine were similar in range and sensitivity (EC50) in arteries from SHR and WKY rats at the same age. Similarly, in small resistance arteries from human buttock skin, the relaxation to acetylcholine was not different between vessels from normotensive volunteers (mean BP = 95.2 +/- 1.5 mm Hg) and patients with untreated essential hypertension (mean BP = 116.5 +/- 2.5 mm Hg). In rabbits with chronic renovascular hypertension (cellophane renal wrap), acetylcholine and adenosine infusions into the lower abdominal aorta caused falls in hindquarter resistance that were enhanced in range, but with no change in sensitivity compared with normotensive rabbits. In normotensive rabbits, nitric oxide synthase inhibition with N omega-nitro-L-arginine infusion caused a rise in blood pressure, fall in hindquarter conductance and blockade of the acetylcholine responses. These experiments suggest that at the level of resistance arteries in vivo and in vitro, a defect in the receptor-stimulated response to EDRF associated with hypertension could not be detected. Apparently, basal nitric oxide is important in resting vasodilator tone, but its role in chronic hypertension is still unclear.
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PMID:Release of endothelium-derived relaxing factor from resistance arteries in hypertension. 137 18

Nitric oxide (NO) and atrial natriuretic factor (ANF) cause vascular relaxation by generating cyclic guanosine monophosphate (cGMP) via activation of the soluble and particulate guanylate cyclases, respectively. The chronic effects of NG-nitro-L-arginine methyl ester (L-NAME), an L-arginine antagonist and NO synthase inhibitor, on the blood pressure and plasma and aortic cGMP levels of rats were tested. Wistar rats (n = 10 per group) were given doses of L-NAME (0, 1, 5, 10, 20, 50, and 100 mg/kg.d) by gavage twice a day for 4 wk. Chronic L-NAME induced a time- and dose-dependent increase in blood pressure. The total heart weight/body weight ratio did not change in any group, despite the hypertension. The plasma levels of cGMP did not change significantly in any group, and were correlated with the plasma ANF levels (r = 0.51, P less than 0.0001). Aortic cGMP decreased in negative correlation with increasing L-NAME from 0 to 10 mg/kg.d, culminating in a 10-fold drop arterial wall cGMP. The aortic cGMP content of rats in the four highest dose groups (from 10 to 100 mg/d) tended to increase slightly and was positively correlated with endogenous ANF (r = 0.48, P less than 0.002, n = 40). Intravenous L-arginine decreased arterial blood pressure and reversed the decline in aortic cGMP. Exogenous ANF and sodium nitroprusside both significantly increased aortic cGMP. Neither the arterial wall concentrations of cGMP-dependent kinase nor cAMP was changed by L-NAME. Thus, chronic blockade of NO synthase with L-NAME induces a dose-dependent increase in blood pressure and decrease in aortic cGMP. The in vivo basal aortic cGMP seems to be mainly dependent on NO synthase: soluble guanylate cyclase activity and to a minor extent on particulate guanylate cyclase activity.
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PMID:Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxide synthase. 137 15

1. In addition to metabolic and neurohumoral factors endothelium-derived autacoids like the nitric oxide radical NO and prostacyclin are effective regulators of vascular tone and thus tissue perfusion. NO is produced in endothelial cells from L-arginine by a Ca2+/calmodulin-dependent enzyme NO synthase. In addition, the NO radical is ultimately cleaved from all nitrovasodilators and resembles their vasoactive and antiaggregatory principle, which is used under pathological conditions as substitution therapy for impaired endothelial function and autacoid production. Impaired endothelium-dependent vasomotor control has been documented in hypercholesterolaemia, atheromatosis, diabetes, hypertension, and in reperfusion damage. L-arginine supplementation is effective in a few instances.
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PMID:Clinical relevance of endothelium-derived relaxing factor (EDRF). 163 78

The vascular endothelium plays an essential role in regulating the contractility of the adjacent smooth muscle cell through its secretory and metabolic properties. One of these well known properties is the conversion of angiotensin I into angiotensin II. But the endothelium also secretes at least three compounds able to diffuse to the smooth muscle cell and exerting a paracrine action: these are the prostacyclin (PGI2), the endothelium derived relaxing factor (EDRF) and the endothelin 1. The secretion of these different vasoactive compounds by endothelial cells is triggered by mechanical events, such as the shear stress, or by the effect of several humoral factors locally released, for example from platelets. The compound NO (nitric oxide) is produced by the endothelial enzyme NO synthase from its precursor L-arginine, and is responsible for the vasodilatory and antiplatelets properties of EDRF. NO, by activating the soluble guanylate cyclase in the smooth muscle cell, is responsible for the endothelium dependent vasodilatation. We observed in an isolated perfused rat kidney that the compound L-NAME (NG-monomethyl-L-arginine methyl ester), a competitive inhibitor of NO synthase blocking the production of NO, induces renal vasoconstriction and inhibits renin release. This suggests that not only the renal vasoconstriction but also the renal vasodilatation are active processes, permanently regulated by vasoactive compounds such as EDRF. It seems also that EDRF plays an important role in maintaining the secretion of renin. It can be hypothetized that an abnormality in the release or fate of EDRF might perhaps contribute to high blood pressure, by both a direct effect on the vascular tone and an indirect effect on the release of renin, which in turn regulates also the renal and systemic hemodynamics.
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PMID:[Control of vascular tone by the endothelium: the coupling active vasodilation in the kidney to renin secretion]. 163 4

We studied whether inhibition of angiotensin converting enzyme stimulates the formation of nitric oxide and prostacyclin in cultured human and bovine endothelial cells by an enhanced accumulation of endothelium-derived bradykinin. Nitric oxide formation was assessed in terms of intracellular cyclic GMP accumulation, prostacyclin release by a specific radioimmunoassay. Inhibition of angiotensin converting enzyme by ramiprilat dose- and time-dependently increased the formation of nitric oxide and prostacyclin. These increases, peaking within 10 minutes, were maintained for at least 60 minutes. The ramiprilat-induced cyclic GMP increase was completely abolished by the stereospecific inhibitor of nitric oxide synthase, NG-nitro-L-arginine. The B2-kinin receptor antagonist, Hoe 140 (0.1 microM), markedly attenuated the cyclic GMP accumulation and abolished the increase in prostacyclin release. The supernatant of endothelial cells, incubated with ramiprilat (0.3 microM) for 15 minutes, elicited a significant nitric oxide release (as assessed by a guanylyl cyclase assay) in untreated endothelial cells used as detector tissue. Preincubation of the detector cells with Hoe 140 completely abolished this nitric oxide release. These data indicate that cultured endothelial cells from different species are capable of producing and releasing bradykinin into the extracellular space in amounts that lead to a sustained stimulation of nitric oxide and prostacyclin formation, provided that bradykinin degradation is prevented by angiotensin converting enzyme inhibition. Thus, the protective effect of angiotensin converting enzyme inhibitors observed on endothelial vasomotor function in hypertension may be explained by the local accumulation of endothelium-derived bradykinin that acts in an autocrine and paracrine manner as potent stimulus for endothelial autacoid formation.
Hypertension 1991 Oct
PMID:Ramiprilat enhances endothelial autacoid formation by inhibiting breakdown of endothelium-derived bradykinin. 165 53

The effects of cilazaprilat were assessed on endothelium-dependent relaxations and contractions in isolated canine arteries. In coronary arteries incubated with indomethacin, cilazaprilat potentiated endothelium-dependent relaxations to bradykinin. In superfusion-perfusion bioassay studies with femoral arteries, cilazaprilat augmented the release of nonprostanoid endothelium-derived relaxing factors caused by bradykinin. To verify whether this effect was solely due to inhibition of the converting enzyme, the effects of cilazaprilat on responses to a variety of endothelium-dependent vasoactive agents were assessed. Endothelium-dependent relaxations to acetylcholine, thrombin, and vasopressin were not altered significantly by cilazaprilat. However, those induced by ADP and aggregating platelets were enhanced significantly by the compound. Endothelium-dependent relaxations to ADP-beta-S were augmented significantly but to a lesser extent. Furthermore, in the presence of the nitric oxide synthase antagonist NG-nitro-L-arginine, ADP-beta-S still caused small relaxations that were possibly mediated by endothelium-derived hyperpolarizing factor. These relaxations were augmented by cilazaprilat. Thus, the augmentation of purinergic relaxations may involve an increased production of endothelium-derived relaxing factors in addition to the protection of ADP from breakdown. Cilazaprilat did not affect endothelium-dependent contractions to acetylcholine or the calcium ionophore A23187 in canine basilar arteries, previously shown to be mediated by superoxide anions. Thus, cilazaprilat is not a scavenger of superoxide anion. Because this agent potentiates endothelium-dependent relaxations to bradykinin, ADP, and aggregating platelets, the present study suggests that, in addition to the lowering of plasmatic levels of angiotensin II, the antihypertensive and cardioprotective effects of cilazaprilat are mediated through an increased production of endothelium-derived relaxing factors.
Hypertension 1991 Oct
PMID:Effects of the converting enzyme inhibitor cilazaprilat on endothelium-dependent responses. 191 98

Nitric oxide first captured the interest of biologists when this inorganic molecule was found to activate cytosolic guanylate cyclase and stimulate cyclic guanosine monophosphate (GMP) formation in mammalian cells. Further studies led to the finding that nitric oxide causes vascular smooth muscle relaxation and inhibition of platelet aggregation by mechanisms involving cyclic GMP and that several clinically used nitrovasodilators owe their biological actions to nitric oxide. Nitric oxide possesses physicochemical and pharmacological properties that make it an ideal candidate for a short-term regulator or modulator of vascular smooth muscle tone and platelet function. Nitric oxide is synthesized by various mammalian tissues including vascular endothelium, macrophages, neutrophils, hepatic Kupffer cells, adrenal tissue, cerebellum, and other tissues. Nitric oxide is synthesized from endogenous L-arginine by a nitric oxide synthase system that possesses different cofactor requirements in different cell types. The nitric oxide formed diffuses out of its cells of origin and into nearby target cells, where it binds to the heme group of cytosolic guanylate cyclase and thereby causes enzyme activation. This interaction represents a novel and widespread signal transduction mechanism that links extracellular stimuli to the biosynthesis of cyclic GMP in nearby target cells. The small molecular size and lipophilic nature of nitric oxide enable communication with nearby cells containing cytosolic guanylate cyclase. The extent of transcellular communication is limited by the short half-life of nitric oxide, thereby ensuring a localized response. Labile nitric oxide-generating molecules such as S-nitrosothiols may be involved as precursors or effectors. Further research will provide a deeper understanding of the biology of nitric oxide and the nature of associated pathophysiological states.
Hypertension 1990 Nov
PMID:Nitric oxide. A novel signal transduction mechanism for transcellular communication. 197 98

Biochemical, cytochemical and immunological methods were used to compare the metabolic and neuroendocrine properties of the subfornical organ (SFO) with the hypothalamo-neurohypophysial system (HNS) in the rat. The SFO resembles the HNS in that both have (a) increased label incorporation into RNA during dehydration; (b) an intense reaction for glucose-6-phosphate dehydrogenase; (c) NADPH-diaphorase and the Type I pathway for hydrogen utilization from NADPH, presumably as part of the mixed-function oxidase system for the metabolism of endogenous substrates and xenobiotics; (d) immunoreactive vasopressin and oxytocin. Gel filtration of extracts of the SFO area using Sephadex G-25 chromatography resulted in immunoreactive peaks for both AVP and OT which were similar to synthetic hormones. One other fraction in the SFO extract, containing a substance(s) of higher molecular weight than AVP, was detected using the antiserum for AVP. The concentration of immunoreactive AVP in the SFO area was increased after colchicine, decreased by hypophysectomy, and unaltered by: (a) infusion (4.6 pg/min for 3 hr) or injection (1 or 6 ng) of AVP into the lateral cerebroventricle; (b) dehydration; (c) renin administered intracerebroventricularly; (d) pinealectomy; or (e) hypertension in the spontaneously hypertensive rat. In conclusion, cells in the SFO have specialized metabolic and neuroendocrine properties similar to the HNS. It can be inferred from these biochemical specializations that the SFO has metabolic and secretory activities.
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PMID:The subfornical organ: biochemical and neuroendocrine comparisons with the hypothalamo-neurohypophysial system. 402 8

To explore the relationship between insulin resistance and hypertension, we examined whether acute induction of hypertension can engender insulin resistance. For this purpose we measured rates of insulin-mediated glucose uptake in awake unstressed rats with the euglycemic hyperinsulinemic (12 microns.kg-1.min-1) clamp technique during infusions of saline alone or after induction of hypertension by bolus administration of NG-monomethyl-L-arginine (L-NMMA, 30 and 15 mg/kg), a competitive inhibitor of nitric oxide synthase. Arterial pressure was approximately 20% greater with L-NMMA bolus than with saline alone. Isotopically determined steady-state rates of glucose uptake were 36 +/- 1 mg.kg-1.min-1 during saline alone and 26 +/- 2 and 19 +/- 1 mg.kg-1.min-1 with low- and high-dose L-NMMA (P < 0.001 vs. saline), respectively. To rule out that insulin resistance induced by L-NMMA was adrenergically mediated, clamp studies were repeated with alpha- and beta-blockade. Rates of glucose uptake remained approximately 20% below those observed with saline alone (P < 0.001). A significant inverse correlation was observed between the height of the blood pressure and the rate of glucose uptake (r = 0.32, P = 0.04). In conclusion, acute induction of hypertension with L-NMMA can cause marked insulin resistance. We postulate that reduced skeletal muscle perfusion and/or sympathetic nervous system activation may contribute to insulin resistance induced by L-NMMA.
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PMID:Insulin resistance after hypertension induced by the nitric oxide synthesis inhibitor L-NMMA in rats. 876 92

Ingestion of a high-salt diet has previously been shown to suppress the endogenous influence of nitric oxide (NO) on arteriolar tone in hypertension-resistant, salt-resistant Dahl (SR/Jr) rats. Because luminal blood flow can be an important stimulus for endothelial NO release, this study was undertaken to determine whether high salt intake can also lead to a deficit in the direct flow-dependent regulation of arteriolar diameter. The spinotrapezius muscle microvasculature was studied by in vivo microscopy in SR/Jr rats fed low (0.45%)- or high (7%)-salt diets for 2 wk, and arcade arteriole responses to increased luminal flow (via parallel vessel occlusion) were studied in both dietary groups. There was no significant difference between groups in arterial pressure or in resting arteriolar diameters, volume flows, or wall shear rates. In low-salt SR/Jr, a 36% increase in luminal flow produced an average arteriolar dilation of 38% that was significantly reduced by the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). In high-salt SR/Jr, a similar flow increase produced an average dilation of only 16% (P < 0.05 vs. low-salt SR/Jr), and this response was unaffected by L-NMMA. Inhibition of cyclooxygenase activity with meclofenamate had no effect on this response in either group. These findings suggest that NO release mediates a portion of flow-dependent arteriolar dilation in rat spinotrapezius muscle and that high salt intake, in the absence of hypertension, can attenuate this response via a suppression of NO activity.
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PMID:Flow-dependent arteriolar dilation in normotensive rats fed low- or high-salt diets. 748 74


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