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)

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

To investigate the possible relationship of hypertension and the N-terminus of the atrial natriuretic factor (ANF) prohormone which contains two peptides [i.e. pro ANF-(1-30) and pro-ANF-(31-67)] with blood pressure-lowering effects, we examined the circulating levels of the N-terminus of the ANF prohormone in three patients with pheochromocytomas before surgery, during an increase in their blood pressure with surgical manipulation of their tumors, and after surgery when their blood pressures returned to normal. The circulating levels of the whole N-terminus [amino acids 1-98; pro-ANF-(1-98)] and pro-ANF-(31-67) from the midportion of the N-terminus of the ANF prohormone were increased 2-fold in patients with both extraadrenal and intraadrenal pheochromocytomas. In both the intraadrenal and extraadrenal patients N-terminus [pro-ANF-(1-98)] and pro-ANF-(31-67) circulating levels increased further during surgical manipulation and returned to normal after surgical removal of their respective tumors. Each of these pheochromocytomas was found to have pro-ANF-(1-30) and -(31-67)-binding sites that were functional, since they could enhance the guanylate cyclase-cGMP system 2-fold in these pheochromocytomas. The entire 126 amino acids of the prohormone were present within each of the pheochromocytomas, since both the whole N-terminus and C-terminus (i.e. ANF) of the prohormone were present. Examination of the pheochromocytomas by electron microscopy revealed electron-dense granules similar to those in the heart, which have been associated with the synthesis and storage of the ANF prohormone. We conclude that 1) the whole N-terminus [pro-ANF-(1-98)] and pro-ANF-(31-67) of the ANF prohormone circulate at higher concentrations in persons with pheochromocytomas and return to normal with removal of the tumors; 2) pheochromocytomas contain specific binding sites for pro-ANF-(1-30) and -(31-67); 3) these binding sites are functional, since pro-ANF-(1-30) and -(31-67) could enhance the enzyme guanylate cyclase within these tumors; and 4) the entire 126 amino acids of the ANF prohormone are present within these tumors, which have electron-dense granules associated with polypeptide hormone synthesis, suggesting that the ANF prohormone is being synthesized within the pheochromocytomas.
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PMID:Increased circulating concentration of the N-terminus of the atrial natriuretic factor prohormone in persons with pheochromocytomas. 197 56

Endothelium-dependent relaxation of carotid arteries and changes in levels of cyclic (c)GMP between stroke-prone spontaneously hypertensive (SHRSP) and Wistar-Kyoto (WKY) rats have been compared. The concentration-response curve for acetylcholine (ACh)-induced relaxation was shifted to the right in carotid arteries from SHRSP. Relaxation responses produced by calcimycin (A 23187) and melittin, both endothelium-dependent agents, were depressed in carotid arteries from SHRSP. Relaxation responses produced by sodium nitroprusside and 8-Br-cGMP were similar to those in strips from WKY. ACh-induced production of cGMP was significantly decreased in carotid arteries from SHRSP when compared with the level for similarly treated strips from WKY. These results suggest that functional changes in endothelium, but not guanylate cyclase activity or cGMP sensitivity in the carotid arteries, may occur in hypertension. Thus, impaired endothelium-dependent relaxation in SHRSP may play an important role in hypertensive vascular diseases such as stroke.
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PMID:Impairment of endothelium-dependent relaxation and changes in levels of cyclic GMP in carotid arteries from stroke-prone spontaneously hypertensive rats. 198 99

This paper review the actual knowledges about the physiological role of nitric oxide, sintetized from amino acid L-arginine. The nitric oxide sintetized in the vascular endothelium has a fundamental role in vascular tone, blood flow and arterial pressure control, acting stimulating guanylate cyclase on vascular smooth muscle. Nitric oxide could be considered the endogenous nitrovasodilator. Its action on the cardiovascular system are imitated by nitroglycerine, sodium nitroprusside and related compounds. Probably the disturbance in the synthesis or release of nitric oxide may be involved in the pathophysiology of hypertension, vasospasm and atherosclerosis. Recently has been shown that nitric oxide synthesis from L-arginine also occurs in other different cells like macrophages, central nervous system, liver, neutrophils, adrenal glands, playing different biological effects. Changes in nitric oxide synthesis or action in those systems, could be related to different pathological disorders as inflammation, atherosclerosis and cancer. The found of a substance as simple as nitric oxide, let suppose that we are in the presence of a biological mediator with a very early evolutionary origin, probably widespread in all the animal kingdom, and which represents the universal transduction system for activation of the soluble guanylate cyclase enzyme.
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PMID:[Nitric oxide: from endogenous vasodilator to biologic mediator]. 209 54

We reported that dexamethasone treatment of rabbits causes a reduction in renal vasoconstrictor responses to prostaglandin F2 alpha and U46619, an agonist at the thromboxane-endoperoxide receptor, but not to phenylephrine. The purpose of this study was to examine if dexamethasone treatment can affect the renal vasodilatory responses to prostacyclin (PGI2) and prostaglandin E2 (PGE2) in isolated Krebs-perfused kidneys constricted with phenylephrine. In kidneys from dexamethasone-treated rabbits, the vasodilatory response to PGI2 was reduced by 57%, whereas that to PGE2 was converted to a vasoconstrictor response. This effect of dexamethasone appears to be specific in that the renal vasodilatory responses to forskolin and to sodium nitroprusside were not affected by the steroid. Contrasting with the inhibitory effect of dexamethasone on prostanoid-induced renal vasodilation, treatment with dexamethasone augmented the renal vasodilatory response to arachidonic acid; for example, arachidonic acid, at 10 micrograms decreased perfusion pressure by 24.8 +/- 5.4 and 49.0 +/- 5.6 mm Hg in kidneys from vehicle- and dexamethasone-treated rabbits, respectively. The enhanced vasodilatory effect of arachidonic acid could not be attributed to increased renal formation of PGE2 and PGI2. In conclusion, dexamethasone interferes with prostanoid-mediated renal vasodilation, which is not associated with an impairment in renal responsiveness to direct activators of adenylate cyclase and guanylate cyclase. The reciprocal effect of dexamethasone on the renal vascular responses to arachidonic acid and vasodilatory prostanoids are indicative of a previously unrecognized influence of glucocorticoids on the renal arachidonate-prostaglandin system.
Hypertension 1990 Feb
PMID:Reciprocal effects of dexamethasone on vasodilatory responses to arachidonic acid and prostanoids in the isolated perfused rabbit kidney. 210 68

Acute coadministrations of an inhibitor of endopeptidase 24.11 (thiorphan) and a ligand (SC-46542) selective for the non-guanylate cyclase-linked atriopeptin binding sites increases urinary sodium excretion to a greater degree in conscious spontaneously hypertensive rats than in normotensive Wistar-Kyoto rats. In the present study, we examined the effects of chronic 10-day intravenous infusions of SC-46542 (des[Phe106,Gly107,Ala115,Gln116] atriopeptin-(103-126] (0.1 mg/kg/hr), thiorphan (1.5 mg/kg/hr), and atriopeptin-(103-126) (100 ng/hr) alone or in combination on direct recording of mean arterial pressure in conscious spontaneously hypertensive rats. During an 11-day time-control infusion of isotonic saline vehicle (100 microliters/hr), mean arterial pressure remained stable. Chronic infusion of atriopeptin-(103-126) decreased mean arterial pressure progressively over the first 3 days; then mean arterial pressure progressively rose to control level over the following 3 days and remained at control level for the remainder of the experiment. Similarly, coinfusions of atriopeptin-(103-126) and SC-46542 or thiorphan, SC-46542 and thiorphan, or the triple infusion of atriopeptin-(103-126), SC-46542, and thiorphan had only transient effects on mean arterial pressure during 10-day infusions. SC-46542 alone had no effect on mean arterial pressure. Similarly, thiorphan alone had no effect on mean arterial pressure except at doses that blocked the acute pressor response to angiotensin I. Chronic infusions of atriopeptin-(103-126), SC-46542, and thiorphan alone or in combination are not effective long-term treatments for hypertension in spontaneously hypertensive rats.
Hypertension 1990 Dec
PMID:Chronic atriopeptin regulation of arterial pressure in conscious hypertensive rats. 214 72

In order to investigate the involvement of endothelium-derived vasoactive substances in deoxycorticosterone acetate (DOCA)-salt hypertension, the responses to noradrenaline, acetylcholine, sodium nitroprusside and papaverine were studied in the absence and presence of indomethacin. Noradrenaline was equally effective in evoking a constrictor response of aorta, with or without endothelium, isolated from DOCA-salt hypertensive rats, while in controls, noradrenaline induced higher submaximal responses in rubbed than in unrubbed preparations. A decreased response to acetylcholine, an endothelium-dependent vasodilator, was observed in aorta with endothelium which had been precontracted with noradrenaline isolated from hypertensive rats. The relaxant response was lost after removal of the endothelium in both control and DOCA-salt hypertensive groups. The response to sodium nitroprusside, an endothelium-independent agent, in aorta isolated from hypertensive rats as well as the response to papaverine, an agent partially dependent on the endothelium, was not altered. Indomethacin treatment altered the response to noradrenaline only in unrubbed aorta of hypertensive rats. In these preparations, a biphasic response to noradrenaline was observed. At lower concentrations noradrenaline induced the characteristic constrictor response, while at higher concentrations a relaxant response was obtained that was abolished by methylene blue, a guanylate cyclase inhibitor. This could indicate that noradrenaline induced the release of endothelium-derived relaxing factor (EDRF) in aorta of hypertensive rats. Furthermore, indomethacin treatment restored the decreased response to acetylcholine in aorta isolated from DOCA-salt hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Indirect evidence for an endothelium-derived contracting factor release in aorta of deoxycorticosterone acetate-salt hypertensive rats. 215 57

Two subclasses of cyclic guanosine monophosphate (GMP)-specific phosphodiesterases were identified in vascular tissue from several beds. The activity of one subclass (phosphodiesterase IB) was stimulated severalfold by calmodulin and selectively inhibited by the phosphodiesterase inhibitor TCV-3B. The activity of the other subclass (phosphodiesterase IC) was not stimulated by calmodulin and was selectively inhibited by the phosphodiesterase inhibitor M&B 22,948. To assess the involvement of both subclasses in regulating cyclic GMP-dependent responses, the ability of TCV-3B and M&B 22,948 to potentiate the in vitro and in vivo responses to the endogenous guanylate cyclase stimulator atrial natriuretic factor (ANF) was evaluated. Both TCV-3B and M&B 22,948 relaxed isolated rabbit aortic and pulmonary artery rings and also potentiated the relaxant effect of ANF. In addition, both inhibitors produced small increases in urine flow and sodium excretion in anesthetized rats and potentiated the diuretic and natriuretic responses to exogenous ANF. M&B 22,948 (30 micrograms/kg/min) produced a threefold increase in the natriuretic response to simultaneously administered ANF, and TCV-3B (10 micrograms/kg/min) produced a twofold increase in the response to ANF. The results of the present experiments suggest that both the calmodulin-sensitive and calmodulin-insensitive subclasses of cyclic GMP-specific phosphodiesterase play a role in regulating the in vitro and in vivo response to ANF.
Hypertension 1990 May
PMID:Subclasses of cyclic GMP-specific phosphodiesterase and their role in regulating the effects of atrial natriuretic factor. 215 39

The great discovery by Furchgott of the relaxing factor released from the endothelium (EDRF) awakened us to the necessity to reevaluate the functional importance of endothelial cells that have been chemically or physically stimulated. EDRF was first demonstrated to be released by acetylcholine, substance P, bradykinin and calcium ionophore A23187; thereafter, many substances have been found to release EDRF. This factor is quite unstable, is not produced by cyclooxygenase, and is an activator of soluble guanylate cyclase that synthesizes cyclic GMP; its action is suppressed by antioxidants via the superoxide anions produced, potentiated by superoxide dismutase and abolished by methylene blue and oxyhemoglobin. Recently, the role of lipoxygenase products in the production of EDRF was evaluated with new 5-lipoxygenase inhibitors without antioxidant activity. During the last couple of years, the actions and chemical properties of EDRF were verified to be quite similar to those of nitric oxide (NO); therefore, the hypothesis of "EDRF = NO" is widely being accepted. NO is produced from L-arginine via catalysis by an enzyme that is activated by Ca2+. The enzyme activity is inhibited by L-monomethyl arginine and other L-arginine analogs. Chemical and physical stimulations increase intracellular Ca2+ in endothelial cells that seems to be associated with K(+)-channel opening and hyperpolarization. Current interests are directed to the possible roles of NO in the regulation of nerve function. There are evidences suggesting that NO modulates adrenergic nerve function in blood vessels and some brain cell functions regulated by cellular cyclic GMP. Particularly, NO may be a transmitter substance in non-adrenergic, non-cholinergic vasodilator nerves innervating the cerebral arteries. Future investigations will determine the physiological roles of EDRF or NO and its relationships to pathophysiology of vascular dysfunctions, such as vasospasm and those related to hypertension, diabetes, aging, etc., and the extended roles of NO in nerve function, inflammation, immune reactions, etc. would be clarified more extensively by accelerated progress in this field of research.
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PMID:[Endothelium-derived relaxing factor (EDRF)]. 216 93

The effect of glucocorticoids on the atrial natriuretic factor (ANF)-mediated formation of cyclic guanosine monophosphate (cGMP) by intact vascular smooth muscle cells (VSMC) was studied in rats. Cultured VSMC were obtained from the renal arteries of 14-week-old Wistar rats by the explant method. Micromolar concentrations of dexamethasone, given as pretreatment for 48 hours, suppressed the ANF-mediated response. The dexamethasone-induced suppression was detectable at 6 hours and reached a maximum 24 hours after administration in a dose-dependent manner. Inhibitors of protein synthesis blocked this effect of the glucocorticoid. The basal activity of guanylate cyclase in the dexamethasone-treated cells was lower than in the control cells. Other steroids having glucocorticoid action mimicked this suppression of the ANF-mediated response. This suppression was blocked by a glucocorticoid receptor antagonist. The results suggest that glucocorticoids suppress ANF-mediated cGMP formation by VSMC through glucocorticoid type II receptors and the induction of protein synthesis. Suppression of the ANF-mediated response may play a role in glucocorticoid-induced hypertension.
Hypertension 1990 Nov
PMID:Glucocorticoids and atrial natriuretic factor receptors on vascular smooth muscle. 217 62


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