Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016382 (flushing)
 6,387 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute cardiovascular and renal effects of 25 micrograms IV human calcitonin gene-related peptide (hCGRP) have been studied in four normotensive and untreated subjects, in the absence and the presence of indomethacin, a prostaglandin synthesis-blocking agent. Intravenous infusion of hCGRP, alone, caused a transient but significant increase in heart rate (HR), hypotension, and facial flushing. Along with these effects, a positive inotropic action of hCGRP was documented by a noninvasive poligraphy. Furthermore, a significant increase in the catecholamines (norepinephrine and epinephrine), in the cyclic nucleotide (cyclic AMP and cyclic GMP) plasma levels, and a small decrease in total calcium with no change in inorganic phosphorus serum levels, occurred. Also acute renal hCGRP induced effects were observed, as a significant increase in urinary volume and in the urinary calcium, sodium, potassium, and chloride excretion. Indomethacin did not affect all the cardiovascular, metabolic, and renal hCGRP-induced effects. These results are in agreement with the hypothesis that hCGRP acts on the heart, vessels, and kidney, directly or indirectly, by the mediation of other vasodilating agents or systems excluding the prostaglandin system.
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PMID:Acute cardiovascular and renal effects of human calcitonin gene-related peptide. 278 56

Mn++ complexed to DPDP (N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphate) generic name: mangafodipir), abbreviated MnDPDP, acts as an effective contrast enhancing agent for liver MRI. In clinical trials, a commonly reported side effect after i.v. administration of MnDPDP was facial flushing, most probably due to peripheral vasodilation. The present study was conducted to address possible mechanisms to explain the flushing effect. Nitric oxide is known to be stabilized in the presence of both uncomplexed and complexed Mn++ and this stabilization is probably due to the superoxide-scavenging properties of Mn++. The present study has demonstrated that both MnDPDP and MnCl2 relax phenylephrine precontracted bovine mesenteric artery strips in concentration-dependent manner. It was also found that a concentration of 10 microM MnDPDP, MnEDTA or MnCl2 gave approximately the same relaxation response as 0.1 microM acetylcholine. DPDP and EDTA had no appreciable intrinsic relaxation potential Mn(++)-induced relaxation was abolished when the endothelial layer was removed from the arteries. In addition, the Mn(++)-induced relaxation was attenuated by the nitric oxide synthase inhibitor N-nitro-arginine and the putative superoxide anion generator 6-anilino-5,8-quinolinedione, but not by the cyclooxygenase inhibitor indomethacin. Both N-nitro-arginine and 6-anilino-5,8-quinolinedione were found to induce an endothelium-dependent constriction of the bovine mesenteric artery strips. An approximately 2-fold increase in the intracellular concentration of cyclic GMP was detected after the addition of 10 microM MnDPDP or 0.1 microM acetylcholine. The increase in cyclic GMP coincided with the onset of relaxation and was effectively abolished by pretreatment with N-nitro-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mangafodipir (MnDPDP)-and MnCl2-induced endothelium-dependent relaxation in bovine mesenteric arteries. 796 75

Erectile dysfunction may have psychological as well as a variety of organic causes. This necessitates in each case a careful medical evaluation. Various commonly used drugs, as well as alcohol and narcotics, may interfere with erection and should, whenever possible, be discontinued before starting treatment. Organic diseases should be identified and, if feasible, specially treated. In the remaining majority of afflicted men, psychological treatment and partner counseling may produce an improvement, but ultimately what is necessary remains an effective and safe medication. The drug, Sildenafil, introduces a new therapeutic principle. During sexual nerve stimulation, nitric oxide (NO) is released from nerves into the cells of the penile erectile bodies. NO activates in turn its "second messenger", the substance cyclic GMP, and the latter induces the vasorelaxation and blood filling of the erectile bodies. Orally administered Sildenafil competitively inhibits phosphodiesterase type 5, which physiologically inactivates cyclic GMP in the erectile bodies. Thus, Sildenafil increases in men with erectile dysfunction the NO-stimulated cyclic GMP concentration and, thereby, improves erection. This new therapy is attractive because 1. Sildenafil is the first pill (for oral use) with established efficacy that benefits most men with insufficient erection; 2. compared with previous therapeutic approaches (such as drug injections in the penis, instillations into the urinary duct, vacuum pumps or even prostheses), Sildenafil is at least as effective, is easy to take and appears well tolerated with no risk of a prolonged erection; 3. remarkably, this medication stimulates erection only during sexual arousal and, thus, has a rather "natural" effect, and 4. side effects (including headache, facial flushing and dyspepsia or epigastric discomfort) were mostly of mild degree and transient, so that only 4% of men interrupted treatment for this reason. Sildenafil does not need to be taken daily, but may be taken, when needed, 1 hour before a planned sexual activity. The new pill has the potential to enliven the boys "wunder horn" with fresh sound.
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PMID:[New principle in therapy of erectile dysfunction: sildenafil]. 965 82

Phosphodiesterases are enzymes that catalyze the degradation of the cyclic nucleotides, cyclic AMP and cyclic GMP, to the corresponding 5' nucleotide monophosphates. Ten different phosphodiesterase families have been described to date. These enzymes exist as homodimers and there is structural similarity between the different families. However, they differ in several respects like selectivity for cyclic nucleotides, sensitivity for inhibitors and activators, physiological roles and tissue distribution. Interest in these enzymes has increased tremendously, both within the medical community and in the general public as a consequence of sildenafil (Viagra), the medication recently introduced for the treatment of erectile dysfunction. Sildenafil mediates its effects by inhibiting phosphodiesterase 5. Some biochemical and molecular biological aspects of this enzyme are presented here. To achieve satisfactory erection, normal penile innervation is required. Nitrogen monoxide, the transmitter substance in these nerves, activates guanylyl cyclase, thereby increasing cyclic GMP production. The increased levels of cyclic GMP cause relaxation of smooth muscles in penile vessels and this leads to an erection. Erection is dependent on elevated levels of cyclic GMP and sildenafil mediates its effects by inhibiting the degradation of cyclic GMP. Other functions that are mediated by the phosphodiesterases explain visual disturbances, flushing and decreased blood pressure that are some of the side effects seen with sildenafil treatment. Furthermore, the potentially fatal consequence of combining sildenafil and nitrovasodilators is discussed.
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PMID:[Phosphodiesterase 5--the enzyme inhibited by sildenafil (Viagra)]. 1021 Sep 55

Raising intracellular cAMP or cGMP concentrations protects lungs from ischemia-reperfusion injury. These nucleotides are catabolized by a number of distinct phosphodiesterase (PDE) isoenzyme subfamilies. We examined the ability of PDE inhibitors of differing selectivities to protect lungs from the effects of prolonged hypothermic storage. Rat lungs were perfused with bicarbonate buffer mixed with rat blood (4:1 vol/vol, 37 degrees C), ventilated, and vascular resistance, airway compliance, and resistance, and gas exchange measured. Lungs were then flushed with, and immersed in, St. Thomas' Hospital Solution (STH) (4 degrees C) or STH containing rolipram, milrinone, zaprinast, or theophylline. After 8 h storage, function was reassessed during 40 min reperfusion. Lungs stored in STH containing rolipram or theophylline had improved function on reperfusion. After 40 min reperfusion, pulmonary compliance (Cstat) was 0.07 +/- 0.01 ml/cm H(2)O in lungs stored in STH alone. Adding rolipram (100 microM) or theophylline (3,000 microM) to the STH used for flushing and storage improved Cstat after reperfusion to 0.17 +/- 0.02 ml/cm H(2)O (p < 0.05) and 0.17 +/- 0.02 ml/cm H(2)O (p < 0. 05), respectively. Theophylline also improved the increase in perfusate PO(2) on transit through the lung after storage to 25.16 +/- 2.33 compared with 4.72 +/- 2.18 mm Hg in lungs stored in STH alone (p < 0.05). Of the selective PDE inhibitors tested, rolipram (type IV inhibitor) was most effective. However, the nonselective agent, theophylline, provided the best protection of function after storage and reperfusion of rat lungs.
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PMID:Comparison of phosphodiesterase inhibitors of differing isoenzyme selectivity added to St. Thomas' hospital cardioplegic solution used for hypothermic preservation of rat lungs. 1098 94

The treatment of erectile dysfunction (ED) has been revolutionised by new agents to inhibit the enzyme PDE5. The scientific basis of this treatment of ED includes relaxation of the corpus cavernosum smooth muscle tissue by inhibition of PDE5 that breaks down cGMP, the key pathway for the production of erectile function in humans. Many clinical studies, both pre- and post-marketing, have demonstrated the clinical efficacy and safety of sildenafil (Viagra, Pfizer) - the first approved selective PDE inhibitor for the treatment of ED. Sildenafil is inhibitory of PDE5 at a rate tenfold higher than for the next PDE (PDE6), which produces visual changes through the retinal rods. Its clinical effectiveness has been well documented in the majority of men with ED irrespective of aetiology. The aetiology of ED, also, does not appear to effect the function of sildenafil in relaxing corpus cavernosum smooth muscle tissue. Adverse events are usually associated with the vascular changes from PDE5 inhibition. These include headache and flushing. Each of these adverse events, however, declines with medication use. With the use of sildenafil, it has been clearly, clinically demonstrated that the selective inhibition of PDE5 is an appropriate, effective, safe method for the treatment of ED of all aetiologies and severities.
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PMID:Long-term use of sildenafil. 1261 92

The discovery that inhibition of phosphodiesterase-5 (PDE5) reduces the degradation of cGMP, allowing erectile function to occur by relaxation of penile smooth muscle, represents a revolutionary approach or the treatment of erectile dysfunction (ED). Three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) are clinically available at this time, and extensive drug design efforts are registered for finding agents with a better activity, enhanced selectivity and reduced side effects. Many classes of such compounds have been reported, belonging to diverse chemical entities. The drug design has been very much facilitated after the report of the X-ray crystal structure of the PDE5 catalytic domain in complex with the three clinically used derivatives. PDE5 inhibitor therapy, has been found to be effective in special clinical populations, such as those with prostate cancer, diabetes, and cardiovascular disease. The duration of action of sildenafil and vardenafil is of about 4 hours, whereas that of tadalafil is of about 36 hours, and the overall safety of the treatments is good. There is a risk of hypotension if nitrates are given concurrently with the PDE5 inhibitors. Common side-effects include headache, facial flushing, nasal congestion, dyspepsia and transient visual impairment. There are pharmacological interactions between these drugs and other medications metabolized by the cytochrome P450 (P3A4 isoform), such as the azole antifungals, erythromycin and the HIV protease inhibitors.
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PMID:Phosphodiesterase 5 inhibitors--drug design and differentiation based on selectivity, pharmacokinetic and efficacy profiles. 1701 39

Vardenafil is a selective phosphodiesterase-5 inhibitor approved for the treatment of erectile dysfunction. It was found to be effective in a high percentage of patients and a broad spectrum of underlying conditions. It potentiates the increase in intracellular cGMP in the corpora cavernosa in response to sexual stimuli, resulting in enhanced and prolonged erections. The overall tolerability and safety profile is acceptable, with headache, flushing, rhinitis and dyspepsia being the major reported side effects. Importantly, tolerability and safety in cardiovascular patients seems to be good with no significant increase in cardiovascular events that could be directly attributed to the pharmacologic agent. Only mild blood-pressure lowering effects were observed in healthy individuals, as well as hypertensive patients on multiple antihypertensive agents. However, special caution is mandatory if vardenafil is administered in combination with alpha-blockers, as significant hypotension might occur. Importantly, any drug serving as a nitric oxide donor is contraindicated in combination with vardenafil.
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PMID:Vardenafil: a selective inhibitor of phosphodiesterase-5 for the treatment of erectile dysfunction. 1747 42