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

Heme oxygenase is a mammalian enzyme that converts heme to biliverdin and carbon monoxide. Carbon monoxide activates soluble guanylate cyclase and relaxes vascular smooth muscle, and it has been implicated as a potential neuromessenger. The regulatory functions of endogenous carbon monoxide on hemodynamics are not known. Zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) inhibits heme oxygenase in rats and thus permits assessment of the hemodynamic response to inhibition of endogenous carbon monoxide synthesis. In chronically instrumented, awake male Sprague-Dawley rats, ZnDPBG (45 mumol/kg IP) increased mean arterial pressure (19 +/- 2%, P < .05) and total peripheral resistance (47 +/- 4%, P < .05), decreased cardiac output (-16 +/- 2%, P < .05), but did not affect heart rate. Another heme oxygenase inhibitor, zinc protoporphyrin IX (45 mumol/kg IP), also increased arterial pressure (17 +/- 5%, P < .05), with no effect on heart rate. In contrast, neither the nonmetallic deuteroporphyrin 2,4-bis glycol (45 mumol/kg IP) nor bilverdin (45 mumol/kg IP) had any effect on blood pressure or heart rate. These findings suggest that ZnDPBG and zinc protoporphyrin IX increase arterial pressure by inhibiting heme oxygenase activity. After pretreatment with chlorisondamine (5 mg/kg IP) or prazosin (5 mg/kg IP) to inhibit autonomic ganglionic or alpha 1-adrenoceptor functions, respectively, ZnDPBG did not affect arterial pressure or heart rate. This suggests that ZnDPBG-induced increases in blood pressure rely on autonomic nervous function. We conclude that the pressor response to heme oxygenase inhibitors results from withdrawal of the inhibitory influence of endogenous carbon monoxide on a pressor mechanism mediated by the autonomic nervous system.
Hypertension 1995 Feb
PMID:A heme oxygenase product, presumably carbon monoxide, mediates a vasodepressor function in rats. 784 65

Atrial natriuretic peptide (ANP) specifically stimulates particulate guanylate cyclase, and cyclic guanosine monophosphate (cGMP) has been recognized as its second messenger. Spontaneously hypertensive rats (SHR) have elevated plasma ANP levels, but manifest an exaggerated natriuretic and diuretic response to exogenous ANP when compared to normotensive strains. In isolated glomeruli, the maximal cGMP response to ANP corresponds to a 12- to 14-fold increase over basal levels in normotensive strains (Wistar 13 +/- 2; Wistar-Kyoto 12 +/- 2; Sprague-Dawley 14 +/- 2) while a maximal 33 +/- 3-fold elevation occurs in SHR (P < 0.001). This hyperresponsiveness of cGMP is reproducible in intact glomeruli from SHR from various commercial sources. Furthermore, this abnormality develops early in life, even before hypertension is clearly established, and persists despite pharmacological modulation of blood pressure, indicating that it is a primary event in hypertension. In vitro studies have revealed a higher particulate guanylate cyclase activity in membranes from glomeruli and other tissues from SHR. This increase is not accounted for by different patterns of ANP binding to its receptor subtypes between normotensive and hypertensive strains, as assessed by competitive displacement with C-ANP102-121, an analog which selectively binds to one ANP receptor subtype. The hyperactivity of particulate guanylate cyclase in SHR and its behavior under basal, ligand (ANP), and detergent-enhanced conditions could be attributed either to increased expression or augmented sensitivity of the enzyme. Radiation-inactivation analysis does not evoke a disturbance in the size of regulatory elements normally repressing enzymatic activity, while the expression of particulate guanylate cyclase gene using mutated standard of A- and B-receptors partial cDNAs, quantified by polymerase chain reaction (PCR) transcript titration assay, manifests a selective increase of one guanylate cyclase subtype. Our data suggest that in hypertension, genetic overexpression of the ANP A-receptor subtype is related to the exaggerated biological response to ANP in this disease.
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PMID:Increased cyclic guanosine monophosphate production and overexpression of atrial natriuretic peptide A-receptor mRNA in spontaneously hypertensive rats. 790 Dec 38

Of the four endogenous members of the natriuretic peptide family, only atrial natriuretic peptide has been demonstrated to have neuromodulatory effects. This study compares the neuromodulatory effects of atrial natriuretic peptide and a recently identified natriuretic peptide, C-type natriuretic peptide, in the rabbit isolated vas deferens. The ability of these peptides to alter cyclic nucleotide concentrations was assessed to determine the potential contribution of either cyclic AMP or cyclic GMP to the observed responses. The central hypothesis tested was that C-type natriuretic peptide modulates neurotransmission via an interaction with a guanylyl cyclase. C-type natriuretic peptide inhibited both purinergic and adrenergic neurotransmission in a concentration-dependent manner but failed to alter either cyclic GMP or cyclic AMP concentrations. Maximal inhibitory effects of C-type natriuretic peptide averaged 35 +/- 4% for purinergic and 49 +/- 7% for adrenergic neurotransmission. Atrial natriuretic peptide not only attenuated both purinergic and adrenergic neurotransmission but also increased cyclic GMP concentrations. C-type natriuretic peptide probably inhibited the release of the neurotransmitters because it failed to alter contractions to exogenously administered norepinephrine or ATP, the two putative neurotransmitters. These results suggest that the C-type natriuretic peptide receptor, guanylyl cyclase B, is not present in rabbit vas deferens and that C-type natriuretic peptide suppresses peripheral sympathetic neurotransmission independently of guanylyl cyclase activation.
Hypertension 1994 Jan
PMID:C-type natriuretic peptide neuromodulates independently of guanylyl cyclase activation. 790 55

We investigated the role of nitric oxide on rapid (25- and 40-minute) baroreceptor resetting during the onset of acute hypertension in rats treated with NG-nitro-L-arginine, an inhibitor of nitric oxide synthesis, and methylene blue, an inhibitor of guanylate cyclase. The effect of treatment with glibenclamide, an ATP-dependent K+ channel blocker, was also investigated. Arterial hypertension was provoked in a ramp progression by the drug NG-nitro-L-arginine alone or in association with aortic coarctation. Whole aortic nerve activity and carotid pressure were recorded in the anesthetized rats. The extent of rapid resetting was evaluated by means of the ratio (delta Systolic Threshold Pressure/delta Control Diastolic Pressure) x 100 as well as by the extent of displacement of the pressure-nerve activity curve defined by the ratio (delta Mean Arterial Pressure at 50% of maximum activity/delta Mean Arterial Pressure) x 100. All groups gave the same increase in mean arterial pressure at 25 and 40 minutes after the onset of hypertension. A greater extent of resetting to hypertensive levels was observed in the treated groups compared with coarctation alone. At 40 minutes after the onset of hypertension, the coarctation and nitro-L-arginine groups exhibited a further increase in the extent of resetting. The rats submitted to glibenclamide plus coarctation presented a slight but significant decrease in gain. These findings suggest that an active L-arginine-nitric oxide-cyclic GMP pathway blunts rapid resetting during the onset of hypertension. In addition, they also indicate that ATP-dependent K+ channels can also modulate rapid resetting of the baroreceptors to hypertensive levels.
Hypertension 1994 Jan
PMID:Blockers of the L-arginine-nitric oxide-cyclic GMP pathway facilitate baroreceptor resetting. 790 58

Nitric oxide is widely distributed in the body. It has an important role in the regulation of the circulation and as yet, ill-defined roles in nervous and immune systems. It is derived from L-arginine from a reaction catalysed by a constitutive intracellular enzyme, nitric oxide synthase. It is recognised as the endogenous nitrovasodilator whose action is mimicked by all exogenous nitrovasodilators. After production in the vascular endothelial cell, it diffuses to the smooth muscle cell where it activates the enzyme guanylate cyclase which leads to an increase in cyclic GMP and thence to muscle relaxation. The duration of its action is brief, a few seconds. Disorders of NO metabolism underlie many disease states including endotoxic shock in which prolonged production of nitric oxide may be induced by cytokines. Deficiencies in endogenous production may account for hypertension in various disease states including atherosclerosis and chronic renal failure. NO therapy been used experimentally to successfully treat idiopathic pulmonary hypertension and pulmonary hypertension associated with cardiac and respiratory diseases. However, the long-term benefits have yet to be studied. Administration of NO requires the use of a device to monitor the concentrations of both NO and of NO2. The latter is a noxious agent and a time-related product of the reaction between NO and O2 and is a possible contaminant of preparations of NO. Precautions must be taken to prevent contamination of the work-place atmosphere with NO and NO2. These include gas scavenging and the use of a leak-free system for spontaneous and mechanical ventilation. Using NO in its gaseous form, clinicians have at long last been provided with the means to treat pulmonary hypertension without adversely causing systemic hypotension. The therapy is most suited to short-term use in mechanically ventilated patients. Safe practical long-term NO therapy must await the development of agents which release NO from aerosol preparations.
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PMID:The role of nitric oxide (formerly endothelium-derived relaxing factor-EDRF) in vasodilatation and vasodilator therapy. 812 32

Atrial natriuretic peptide is an important peptide hormone of cardiac origin that functions to regulate cardiac preload via the regulation of sodium excretion. This natriuretic action occurs through activation of the particulate guanylyl cyclase-linked natriuretic peptide-A receptor. HS-142-1 is a newly discovered antagonist of the natriuretic peptide-A receptor that permits insight into the functional role of atrial natriuretic peptide in cardiorenal homeostasis. The first objective of this study was to define for the first time the intrarenal action of HS-142-1 on exogenous atrial natriuretic peptide-mediated natriuresis in anesthetized normal dogs. In group 1 (n = 6), which received intravenous atrial natriuretic peptide at 100 ng/kg per minute, intrarenal HS-142-1 (0.5 mg/kg bolus) attenuated atrial natriuretic peptide-induced increases in glomerular filtration rate, urine flow, sodium excretion, and renal cyclic GMP generation and decreases in distal tubular sodium reabsorption. The second objective was to determine whether endogenous atrial natriuretic peptide participates in the regulation of basal sodium excretion. In group 2 (n = 6), intrarenal HS-142-1 alone decreased both absolute and fractional sodium excretion and renal cyclic GMP generation and increased distal tubular sodium reabsorption. These studies demonstrate that HS-142-1 markedly attenuates exogenous atrial natriuretic peptide-mediated natriuresis via enhancement of distal tubular reabsorption and blunting of increases in glomerular filtration rate. Second, the current studies support a functional role for endogenous atrial natriuretic peptide in the regulation of basal sodium excretion.
Hypertension 1994 May
PMID:Modulation of exogenous and endogenous atrial natriuretic peptide by a receptor inhibitor. 817 70

Deendothelialized rings of rabbit aorta relax after exposure to UV light because of release of a relaxing factor that is similar if not identical to nitric oxide. We tested the hypothesis that production of the photo-induced relaxing factor is impaired in a rat model of genetic hypertension. Thoracic aortas were removed from adult Wistar-Kyoto rats and stroke-prone spontaneously hypertensive rats. The vessels were cut into rings, denuded of endothelium, and placed in a muscle bath for isometric force measurement. Rings were contracted with phenylephrine, and relaxation was measured after exposure to UV light. Aortic rings from stroke-prone spontaneously hypertensive rats relaxed to a greater extent after exposure to UV light than did rings from Wistar-Kyoto rats. An inhibitor of nitric oxide synthase (N omega-nitro-L-arginine) greatly potentiated the relaxation responses to light in both strains, and these enhanced relaxations were attenuated by tetraethylammonium chloride, potassium chloride, ouabain, or inhibitors of guanylate cyclase. These results suggest that UV irradiation induces relaxation in aortic smooth muscle that is greater in hypertensive than normotensive rats and is greatly enhanced after addition of inhibitors of nitric oxide production. Thus, the unidentified photo-induced relaxing factor is not solely nitric oxide but may also represent either a hyperpolarizing factor, because depolarization blocks the responses entirely, or possibly smooth muscle guanylate cyclase that might itself be photoactivable.
Hypertension 1994 Jun
PMID:A photoactivable source of relaxing factor in genetic hypertension. 820 24

We examined the hypothesis that dilatation of the basilar artery in response to activation of ATP-sensitive potassium channels is impaired in stroke-prone spontaneously hypertensive rats (SHRSP). Changes in basilar artery diameter in response to aprikalim, a direct activator of ATP-sensitive potassium channels, were measured in anesthetized SHRSP and normotensive Wistar-Kyoto (WKY) rats through a cranial window. Topical application of aprikalim increased basilar artery diameter in WKY rats. Glibenclamide, a selective inhibitor of ATP-sensitive potassium channels, abolished aprikalim-induced vasodilatation. Thus, ATP-sensitive potassium channels are functional in the basilar artery of WKY rats in vivo. Aprikalim (10(-6) mol/L) dilated the basilar artery by 31 +/- 5% (mean +/- SEM) in WKY rats but only 5 +/- 1% in SHRSP. The concentration-response curve to aprikalim in SHRSP was significantly shifted to the right, but the response to the highest concentration of aprikalim (10(-5.5) mol/L) was similar in SHRSP and WKY rats. Vasodilatation in response to norepinephrine was also impaired in SHRSP. Dilator responses of the basilar artery to forskolin, a direct activator of adenylate cyclase, and nitroprusside, a direct activator of guanylate cyclase, were normal in SHRSP. The findings suggest that dilatation of the basilar artery in response to direct activation of ATP-sensitive potassium channels is impaired in SHRSP compared with WKY rats in vivo.
Hypertension 1993 Nov
PMID:ATP-sensitive potassium channels in the basilar artery during chronic hypertension. 822 27

Methylene blue (MB) is a soluble guanylate cyclase inhibitor, and known as an endothelium-derived relaxing factor (EDRF) inhibitor in vitro. In the present study, it was demonstrated that intravenous administration of MB caused a dose-dependent hypertensive effect in rats. The hypertensive responses to the higher doses (10 and 20 mg/kg) of MB was followed by a reflex hypotension which did not appear in pithed rats. Noradrenaline depletion by reserpine pretreatment did not inhibit MB-induced hypertension, but abolished the hypotensive response. Both hypertensive and hypotensive phases were not altered by indometacin. These results may suggest that in vivo guanylate cyclase inhibition leads to an increase in blood pressure; prostaglandins and noradrenaline release from sympathetic nerve endings do not contribute to MB-induced hypertension and it may be due in part to the inhibition of EDRF.
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PMID:Effect of methylene blue on blood pressure in rats. 848 67

Ten years ago, the term "oxidative stress" (sigma -O2) was created to define oxidative damage inflicted to the organism. This definition brings together processes involving reactive oxygen species production and action such as free radical production during univalent reduction of oxygen within mitochondria, activation of NADPH-dependent oxidase system on the membrane surface of neutrophils, flavoprotein-catalyzed redox cycling of xenobiotics and exposure to chemical and physical agents in the environment. Since the discovery of the nitric oxide biosynthetic pathway, the deleterious effects of uncontrolled nitric oxide generation are generally classified as oxidative stress. Indeed, products of the reaction of NO and superoxide lead to oxidants such as peroxinitrite, nitrogen dioxide and hydroxyl radical, which are involved in mechanisms of cell-mediated immune reactions and defence of the intracellular environment against microbiol invasion. However NO can also regulate many biological reactions and signal transduction pathways that lead to a variety of physiological responses such as blood pressure, neurotransmission, platelet aggregation, endothelin generation or smooth muscle cell proliferation. Then the uncontrolled NO production can lead to a variety of physiological and pathophysiological responses similar to a Nitric Oxide Stress: activation of guanylate cyclase and production of cGMP: overstimulation of the inducible L-arginine to L-citrulline and NO pathway by bactericidal endotoxins and cytokines has been shown to promote undesired increases in vasodilatation, which may account for hypotension in septic shock and cytokine therapy. stimulation of auto-ADP-ribosylation and modification of SH-groups of glyceraldehyde-3-phosphate dehydrogenase in a cGMP-independent mechanism: by this way, NO in excess can strongly inhibits this important glycolytic enzyme and reduce the cellular energy production. inhibition of ribonucleotide reductase: extensive inhibition of this key enzyme in DNA synthesis in the presence of large amounts of NO could lead to important antiproliferative effects; inhibition of cytochrome P450-dependent metabolism: in Kupffer cells and hepatocytes, LPS-induced overproduction of NO has been shown to inhibit cytochrome P450-dependent metabolism and to mediate the suppression of hepatic metabolism. Moreover, NO synthetized in the peripheral nervous system is known to mediate nonadrenergic noncholinergic (NANC) neurotransmission. Overstimulation of NO synthases might therefore contribute to pathophysiological states such as: gastrointestinal motility, reflux oesophagitis, asthma, adult respiratory distress syndrome (ARDS) and chronic pulmonary artery hypertension. To these NO-mediated biological functions, one could add the biological effects of NO-derivatives such as N-nitrosocompounds, which act as carcinogenic agents, or C-nitrosocompound which were recently used as "zinc-ejecting" agents to inhibit HIV-1 infectivity of human T-lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Does nitric oxide stress exist?]. 852 Oct 87


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