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)

The exact mechanisms by which NO mediates its neuromodulatory effects within the central control of cardiovascular functions are still unclear. Both excitatory and inhibitory actions of NO in different regions of the brainstem have been reported, and that it could be caused by direct actions of NO on neurones and/or by NO-mediated changes in local cerebral blood flow. Microinjection studies suggest that direct modulation of neuronal activity by NO through cyclic 3'-5' guanosine monophosphate (cGMP)-dependent mechanisms predominates. In contrast, endogenous NO produces. only minor changes in local cerebral blood flow, and potentiation of NO-dependent vasodilation with an inhibitor of phosphodiesterase V (PDE5i) has no significant effect on sympathetic activity. Activation of the NO-system in the lower brain stem modulates various central and reflex-activated neuronal pathways. To a large extent, this appears to be mediated by NO-induced GABA- and glutamate-release within the ventrolateral medulla (VLM) and the nucleus of the solitary tract (NTS). In addition, NO has been shown to reduce local generation of angiotensin II (AII) in all areas. Recent studies suggest that the NO-mediated modulation of autonomic function is severely impaired in cardiovascular diseases. Possibly in conjunction with AII, which triggers and promotes superoxide radical generation, chronic oxidative stress (COS) could act as a key mediator of this process. Evidence supporting this hypothesis comes from studies on pigs that were chronically treated with organic nitrates to pharmacologically induce COS. In these animals, microinjection of superoxide dismutase into the rostral VLM (RVLM) diminished sympathetic activity by up to 70%, whereas peroxynitrite, a key mediator of NO-related oxidative stress, had excitotoxic effects. Antagonism of neuronal COS may therefore represent a novel approach to counteract neurohumoral activation in diseases such hypertension, obesity and heart failure.
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PMID:Mechanisms of action of nitric oxide in the brain stem: role of oxidative stress. 1214 34

The incidence of erectile dysfunction (ED), defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance, increases with age and with risk factors for vascular disease, including smoking, diabetes and hypertension. Penile erection results from an arousal-induced synthesis of nitric oxide (NO) in nonadrenergic-noncholinergic nerves (NANC), endothelial cells and cavernosal smooth muscle cells (SMCs). Vasodilation and relaxation of cavernosal SMCs engorges the corpora cavernosa with blood at arterial pressure. The subcellular mechanism by which tumescence occurs involves NO-induced activation of soluble guanylate cyclase, increased cyclic guanosine monophosphate (cGMP) levels and activation of cGMP-dependent protein kinase (PKG). PKG phosphorylates numerous ion channels and pumps, each promoting a reduction in cytosolic calcium. In particular, PKG activates high-conductance Ca2+(-)sensitive K+ (BKCa) channels, which hyperpolarize the arterial and cavernosal SMC membranes, causing relaxation. This mechanism appears to be compromised with age and with vascular disease, leading to ED. Thus, increasing cavernosal nitric oxide synthase (NOS) expression, cGMP levels and/or BKCa channel expression is an effective therapy for experimental ED. Future therapies may involve augmenting K+ channel expression by gene transfer or increasing channel function through the use of Type 5 phosphodiesterase (Type 5 PDE) inhibitors or phosphatase inhibitors.
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PMID:Potassium channels and erectile dysfunction. 1237 24

Sildenafil inhibits cGMP breakdown by phosphodiesterase 5. In vitro, increased cGMP levels inhibit cAMP breakdown by phosphodiesterase 3. It is uncertain, however, whether sildenafil increases biological effects of interventions increasing cAMP levels in vivo. The objective of the present study in 40 healthy male volunteers was to determine the existence and extent of interactions with sildenafil and vasodilators acting via cGMP or cAMP or independently from these mediators on the arterial tone of the human forearm. Forearm blood flow (FBF) responses (plethysmography) to brachial artery infusions of 3 doses each of nitroglycerin, which increases cGMP levels; of isoprenaline and milrinone, which increase cAMP levels; and of verapamil as a control were assessed at baseline and 80 minutes after 50 mg oral sildenafil in 10 volunteers each. Sildenafil increased FBF (2.5+/-0.1 to 3.5+/-0.2 mL/min per 100 mL, P<0.001; n=40). At equipotent vasodilator dosages, sildenafil increased FBF from 7.5+/-1.0 to 9.8+/-1.2 mL/min per 100 mL for nitroglycerin, from 8.3+/-1.0 to 10.4+/-1.4 mL/min per 100 mL for isoprenaline, and from 8.1+/-1.0 to 10.3+/-1.2 mL/min per 100 mL for milrinone and slightly decreased FBF from 7.7+/-1.3 to 7.1+/-1.2 mL/min per 100 mL for verapamil. ANOVA for repeated measures revealed a significant interaction between sildenafil and the type of vasodilator on FBF (P<0.01). The responses of FBF to nitroglycerin, milrinone, and isoprenaline after sildenafil were similarly increased compared with the response to verapamil (P<0.01). Sildenafil markedly enhanced the arterial vasodilator response to nitroglycerin, milrinone, and isoprenaline. The response to milrinone and isoprenaline is compatible with an interaction between cGMP and phosphodiesterase 3 or an enhancement of the NO component of cAMP-mediated vasodilation, and raises the possibility of enhanced biological effects of interventions leading to increases of cAMP in the presence of sildenafil.
Hypertension 2002 Nov
PMID:Interaction of sildenafil with cAMP-mediated vasodilation in vivo. 1262 68

In Germany, some 4-6 million men, including 1.2 million diabetics, suffer from erectile dysfunction (ED). Various other diseases including heart disease, hypertension, arteriosclerosis, hyperlipidemia, endocrine disorders, chronic renal insufficiency, prior radical prostatectomy, neurological diseases, trauma and the abuse of alcohol, tobacco, and side effects of medications, are frequently associated with ED. Medical history, clinical examination, routine blood chemistry and sexual hormone levels may help clarify the etiology of ED. Normally, relaxation of the smooth muscles of the corpus cavernosum--mediated by cGMP and cAMP--together with dilatation of penile arteries and occlusion of venous outflow, results in an erection. The oral type V phosphodiesterase inhibitor, Sildenafil, or prostaglandin E1 injection elevates the cGMP and cAMP levels, respectively. Other therapeutic options include mechanical aids, surgery, hormone replacement or sublingual apomorphine. Since 1998, Sildenafil, an effective, simple and safe oral treatment, has been available.
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PMID:[Erectile dysfunction. An important manifestation of autonomic diabetic neuropathy]. 1253 21

Calcium channel antagonists are used primarily for the treatment of hypertension and tachyarrhythmias. Overdose of calcium channel antagonists can be lethal. Calcium channel antagonists act at the L-type calcium channels primarily in cardiac and vascular smooth muscle preventing calcium influx into cells with resultant decreases in vascular tone and cardiac inotropy and chronotropy. The L-type calcium channel is a complex structure and is thus affected by a large number of structurally diverse antagonists. In the setting of overdose, patients may experience vasodilatation and bradycardia leading to a shock state. Patients may also be hyperglycaemic and acidotic due to the blockade of L-type calcium channels in the pancreatic islet cells that affect insulin secretion. Aggressive therapy is warranted in the setting of toxicity. Gut decontamination with charcoal, or whole bowel irrigation or multiple-dose charcoal in the setting of extended-release products is indicated. Specific antidotes include calcium salts, glucagon and insulin. Calcium salts may be given in bolus doses or may be employed as a continuous infusion. Care should be exercised to avoid the administration of calcium in the setting of concomitant digoxin toxicity. Insulin administration has been used effectively to increase cardiac inotropy and survival. The likely mechanism involves a shift to carbohydrate metabolism in the setting of decreased availability of carbohydrates due to decreased insulin secretion secondary to blockade of calcium channels in pancreatic islet cells. Glucose should be administered as well to maintain euglycaemia. Supportive care including the use of phosphodiesterase inhibitors, adrenergic agents, cardiac pacing, balloon pump or extracorporeal bypass is frequently indicated if antidotal therapy is not effective. Careful evaluation of asymptomatic patients, including and electrocardiogram and a period of observation, is indicated. Patients ingesting a nonsustained-release product should be observed in a monitored setting for 12 hours, while those who ingest a sustained-release preparation should be observed for no less than 24 hours. Charcoal should be given to the asymptomatic patient with a history of calcium channel antagonist overdose.
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PMID:Management of calcium channel antagonist overdose. 1253 24

Sildenafil is the first oral therapeutic agent for erectile dysfunction. Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase (PDE-5). Penile erection involves relaxation of the corpus cavernosum, an event mediated by NO and cGMP. The biological actions of cGMP are terminated by phosphodiesterase enzymes and PDE-5 is the major cGMP metabolising enzyme in this tissue. Sildenafil is relatively safe compared to erection injectables because it does not relax on isolated human corpus cavernosum, and does not cause priapism. Due to the tendency of abuse of sildenafil, its adverse cardiovascular associations with myocardial infaraction, ventricular arrhythmia and hypertension need to be alerted.
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PMID:[Mode of action of sildenafil]. 1256

It is established that dietary protein restriction of pregnant rats results in their offspring developing hypertension. However, to date no studies have investigated peripheral vascular function of offspring using the low protein model. Therefore, the aim of the study was to assess isolated resistance artery function from adult male offspring of control (C, 18% casein) and protein-restricted (PR, 9% casein) pregnant dams at two different ages. The birthweight of PR offspring did not significantly differ from that of C offspring. Systolic blood pressure was significantly elevated in PR compared with C (p < 0.05). Maximal vascular contraction to phenylephrine and the thromboxane analog U46619 were similar in C and PR offspring at postnatal d 87 and 164. Relaxation induced by the endothelium-dependent vasodilators acetylcholine or bradykinin was significantly reduced in the PR group (p < 0.05). Relaxation to the endothelium-independent vasodilator sodium nitroprusside and phosphodiesterase type 3 inhibitor cilostamide was less in the PR offspring compared with C (p < 0.01). Dietary protein restriction in pregnancy induces hypertension and vascular dysfunction in male offspring. Abnormalities in the nitric oxide-cGMP pathway may explain the defect in endothelium-dependent and -independent relaxation. Reduced vasodilation may be a potential mechanism underlying the elevated systolic blood pressure observed in this model.
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PMID:Dietary protein restriction in pregnancy induces hypertension and vascular defects in rat male offspring. 1264 17

Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary vasculature leading to vasoconstriction and remodeling of the pulmonary arteries. The resulting increase in the right ventricular afterload leads to right ventricular failure and death. The treatment options are limited, expensive and associated with significant side effects. The nitric oxide (NO) pathway in the pulmonary circulation provides several targets for the development of new therapies for this disease. However, the NO pathway is modulated at multiple levels including transcription and expression of the NO synthase gene, regulation of the NO synthase activity, regulation of the production of cyclic guanomonophosphate (cGMP) by phosphodiesterases, postsynthetic oxidation of NO, etc. This makes the study of the role of the NO pathway very difficult, unless one uses multiple complementary techniques. Furthermore, there are significant differences between the pulmonary and the systemic circulation which make extrapolation of data from one circulation to the other very difficult. In addition, the role of NO in the development of pulmonary hypertension varies among different models of the disease. This paper reviews the role of the NO pathway in both the healthy and diseased pulmonary circulation and in several animal models and human forms of the disease. It focuses on the role of recent therapies that target the NO pathway, including L-Arginine, inhaled NO, the phosphodiesterase inhibitor sildenafil and gene therapy.
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PMID:The role of the NO axis and its therapeutic implications in pulmonary arterial hypertension. 1265 55

Numerous attempts have been made to develop strategies for regulating the intracellular cyclic AMP signal pharmacologically, with an intention to establish either new medical therapeutic methods or experimental tools. In the past decades, many pharmacological reagents have been identified that regulate this pathway at the level of the receptor. G protein, adenylyl cyclase, cyclic AMP, protein kinase A and phosphodiesterase. Since the cloning of adenylyl cyclase isoforms during the 1990s, investigators including ourselves have tried to find reagents that regulate the activity of this enzyme directly in an isoform-dependent manner. The ultimate goal of developing such reagents would be to regulate the cyclic AMP signal in an organ-dependent manner. Ourselves and other workers have reported that such reagents may vary from a simple cation to kinases. In a more recent study, using the results from crystallographic studies and computer-assisted drug design programs, we have identified subtype-selective regulators of adenylyl cyclase. Such regulators are mostly based upon forskolin, a diterpene compound obtained from Coleus forskolii, that acts directly on adenylyl cyclase to increase the intracellular levels of cyclic AMP. Similarly, novel reagents have been identified that inhibit a specific adenylyl cyclase isoform (e.g. type 5 adenylyl cyclase). Such reagents would potentially provide a new therapeutic strategy to treat hypertension, for example, as well as methods to selectively stimulate or inhibit this adenylyl cyclase isoform, which may be reminiscent of overexpression or knocking out of the cardiac adenylyl cyclase isoform by the use of a pharmacological method.
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PMID:Isoform-targeted regulation of cardiac adenylyl cyclase. 1268 88

Smoking is associated with endothelial dysfunction. The purpose of this study was to determine the effect of sildenafil, an inhibitor of phosphodiesterase type 5 (PDE5), on endothelial function in smokers. We evaluated the forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium-independent vasodilator, before and after oral sildenafil administration (100 mg) with a strain-gauge plethysmograph in 10 young healthy male smokers and 10 young healthy male nonsmokers. FBF response to ACh was lower in smokers than in nonsmokers. The vasodilatory effects of SNP were similar in both groups. Sildenafil increased the FBF response to ACh from 9.3+/-2.0 to 12.5+/-3.5 mL/min per 100 mL tissue in smokers and from 12.6+/-5.6 to 19.6+/-8.4 mL/min per 100 mL tissue in nonsmokers, and it increased the response to SNP from 13.3+/-3.9 to 15.1+/-4.3 mL/min per 100 mL tissue in smokers and from 14.8+/-5.2 to 18.4+/-6.0 mL/min/100 mL tissue in nonsmokers (P<0.05 for all). The ratio of maximal ACh-stimulated FBF expressed as a ratio of maximal SNP-stimulated FBF significantly increased after administration of sildenafil in both groups. Infusion of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, abolished sildenafil-induced augmentation of the FBF response to ACh in both groups. The findings suggest that endothelial function is impaired in smokers compared with that in nonsmokers, that inhibition of PDE5 by sildenafil significantly increases nitric oxide-mediated vasodilation, and that the activities of PDE5 in smokers and nonsmokers may be similar.
Hypertension 2003 May
PMID:PDE5 inhibitor sildenafil citrate augments endothelium-dependent vasodilation in smokers. 1269 18


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