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)

Guanylate cyclase-A, the receptor for atrial natriuretic factor, contains a protein kinase-like domain and a catalytic domain in the intracellular region. To investigate the active site (the catalytic cavity) of guanylate cyclase-A, we amplified the catalytic domain plus three amino acids from the kinase-like domain of guanylate cyclase-A (GC-c) with polymerase chain reaction (PCR) and expressed it in Escherichia coli. During the screening of the PCR-cloned gene products with guanylate cyclase assay, a mutant that lacks enzyme activity was identified. Results of cDNA sequencing revealed that Leu 817 was replaced by an Arg residue in the mutated protein. The mutated GC-c bound to GTP-agarose as well as the wild-type protein, indicating that the binding capability of mutated GC-c to GTP is not significantly affected by the Arg substitution. Gel-filtration column chromatography showed that, like the wild-type GC-c, the mutated protein also formed a high-molecular-weight complex. Since mutation of Leu 817 to Arg abolishes the catalytic activity, Leu 817 is likely located near the active site of guanylate cyclase-A. These results demonstrate that the carboxyl fragment of guanylate cyclase-A is an ideal system for studying the active site of guanylate cyclase-A.
Hypertension 1995 Apr
PMID:Mutational inactivation of the catalytic domain of guanylate cyclase-A receptor. 772 18

To directly assess insulin-related venomotor changes objectively and quantitatively, we used a modified ultrasonographic technique to measure venous diameter. Ten healthy men and women were studied by use of an Acuson 128 XP ultrasonograph with a linear 7.5-MHz ultrasonographic transducer (sensitivity, +/- 0.1 mm). Venous diameter was measured with the arm kept at 30 degrees elevation and with a pneumatic cuff above the elbow inflated at 40 mm Hg for the last 2 minutes of each 5-minute observation period. Norepinephrine was infused at incremental concentrations of 12.5, 25, 50, and 100 ng/min (75, 150, 300, and 600 pmol/min, respectively) for 5 minutes each. Maximal venoconstriction was achieved by the dose of 100 ng/min norepinephrine, which was then combined with insulin doses of 8, 16, 24, and 32 microU/min (60, 120, 180, and 230 fmol/min, respectively) for 5 minutes each. In six different subjects, methylene blue, an inhibitor of guanylate cyclase, was infused simultaneously with 32 microU/min insulin and 100 ng/min norepinephrine. Mean resting diameter of the vein (1.8 +/- 0.6 mm [mean +/- SD]) increased (to 3.0 +/- 1.0 mm) after cuff inflation. Incremental doses of norepinephrine caused highly reproducible dose-dependent decrease in venous diameter (to 1.8 +/- 0.6 mm, P < .001). Incremental doses of insulin, when combined with the maximum dose of norepinephrine, caused highly reproducible dose-dependent increases in mean venous diameter (P < .001) compared with norepinephrine alone. Methylene blue, which had no independent effect on venous diameter, inhibited the venodilator effect of insulin (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Apr
PMID:Insulin attenuates norepinephrine-induced venoconstriction. An ultrasonographic study. 772 32

We analyzed mechanisms underlying neurogenic vasodilatation in dog and Japanese monkey renal arteries. Isometric mechanical responses of the arterial strip to nerve stimulation by nicotine were recorded. Nicotine-induced contractions were abolished by hexamethonium and potentiated by NG-nitro-L-arginine, a nitric oxide synthase inhibitor. The potentiating effect was reversed by L-arginine. NG-Nitro-L-arginine did not potentiate the contraction caused by norepinephrine. The nicotine-induced contraction was reversed to a relaxation by prazosin. The relaxation was not influenced by indomethacin, timolol, or atropine but was abolished by NG-nitro-L-arginine, methylene blue (a guanylate cyclase inhibitor), oxyhemoglobin (a nitric oxide scavenger), and hexamethonium. In the strips treated with NG-nitro-L-arginine, the nicotine-induced relaxation was restored by L-arginine. Histochemical study demonstrated perivascular nerves containing NADPH diaphorase and nitric oxide synthase immunoreactivity in dog and monkey arteries. We conclude that renal arteries are innervated by nitric oxide-mediated vasodilator and adrenergic vasoconstrictor nerves, and depression of the vasodilator nerve function by nitric oxide synthase inhibition potentiates the contraction caused by adrenergic nerve excitation.
Hypertension 1995 May
PMID:Nitroxidergic innervation in dog and monkey renal arteries. 773 21

Recent investigations have suggested that the vascular endothelium is an active participant in the regulation of arterial tone and blood flow. In a state of health, the endothelium contributes to hemodynamic equilibrium; however, it rapidly becomes dysfunctional in hypercholesterolemia and diabetes mellitus or with exposure to the stress of hypertension or long-term smoking. Among the deficits observed during endothelial dysfunction is a reduction in the synthesis and release or an excessive degradation of EDRF. This potent vasorelaxant is derived from the amino acid L-arginine and has been characterized as NO or a closely related substance. EDRF relaxes vascular smooth muscle by activating guanylate cyclase. A deficiency in the activity of EDRF may be the mechanism of diminished coronary vasodilation in patients with ischemic heart disease. Organic nitrates, which are metabolized to NO or S-nitrosothiol at the cellular level, are often used in the management of myocardial ischemia; they also induce vasodilation by activating guanylate cyclase. The similarities between organic nitrates and endogenous EDRF and their interactions are discussed in this review.
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PMID:Endothelium, coronary vasodilation, and organic nitrates. 783 12

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

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

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


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