Expression of three forms of nitric oxide synthase in peripheral nerve regeneration

Nitric oxide (NO) is a short-lived molecule with messenger and cytotoxic functions in nervous, cardiovascular, and immune systems. Nitric oxide synthase (NOS), the enzyme responsible for NO synthesis, exists in three different forms: the neuronal (nNOS), present in discrete neuronal populations; the endothelial (eNOS), present in vascular endotheliun, and the inducible isoform (iNOS), expressed in various cell types when activated, including macrophages and glial cells. In this study, we have investigated the possible involvement of NO in Wallerian degeneration and the subsequent regeneration occurring after sciatic nerve ligature, using histochemistry and immunocytochemistry for the three NOS isoforms, at different postinjury periods. Two days after lesion, the three NOS isoforms are overexpressed, reaching their greatest expression during the second week. nNOS is upregulated in dorsal root ganglion neurons, centrifugally transported and accumulated in growing axons. eNOS is overexpressed in vasa nervorum of the distal stump and around ligature, and iNOS is induced in recruited macrophages. These findings indicate that different cellular sources contribute to maintain high levels of NO at the lesion site. The parallelism between NOS inductions and well-known repair phenomena suggests that NO, acting in different ways, may exert a beneficial effect on nerve regeneration.     

Extrinsic denervation increases myenteric nitric oxide synthase-containing neurons and inhibitory neuromuscular transmission in guinea pig

Enteric nerves can function normally without connections with the central nervous system. A contributing component of the functional autonomy exhibited by enteric nerves is their plasticity. In the present study, the number of nitric oxide synthase-immunoreactive (NOS-ir) myenteric neurons and inhibitory neuromuscular transmission were studied in extrinsically denervated ileal segments. Segments of ileum were extrinsically denervated by crushing the mesenteric blood vessels supplying a loop of ileum in anesthetized guinea pigs. Some unoperated animals were treated with capsaicin or 6-hydroxydopamine (6-OHDA) to disrupt primary afferent and sympathetic nerves, respectively. NOS-ir was localized using indirect immunofluorescence. Nerve-mediated relaxations of longitudinal muscle were studied in vitro using standard methods. At 7 weeks after extrinsic denervation there was a 93% increase in the number of NOS-ir myenteric neurons. The number of neurons containing detectable vasoactive intestinal peptide-ir neurons was not changed after extrinsic denervation. Neurogenic relaxations caused by 10, 20 and 50 Hz transmural stimulation were larger in extrinsically-denervated tissues compared to control tissues. The NOS antagonist, nitro-L-arginine (300 microM) inhibited neurogenic relaxations in control and extrinsically-denervated tissues. Capsaicin- but not 6-OHDA-treatment mimicked the effects of extrinsic denervation on NOS-ir and neurogenic relaxations of the longitudinal muscle. Active or passive properties of the longitudinal muscle were unaffected by extrinsic denervation. These data indicate that extrinsic denervation is associated with an increase in the number of myenteric neurons expressing detectable NOS-ir and potentiation of inhibitory transmission to longitudinal muscle. This effect is due to loss of extrinsic sensory nerves.     

The role nitric oxide and other neurotransmitter in canine penile erection

The role on nitric oxide and its relative factors (cGMP, cAMP, methylene blue) was studied in canine erection induced by stimulating pelvic nerves, and the effect of cholinergic neuroeffectors and the sinusoidal endothelium was also observed in this experiment. The results indicate that intracavernous injection of nitric oxide can evoke a penile tumescence, which is similar to that of the neurostimulation. The results also suggest that the cholinergic nerves and the sinusoidal endothelium are involved in erection, and the effect of the former must depend on mediation of the latter. The study supports that cholinergic and nonadrenergic noncholinergic (NANC) neuroeffectors take part in penile erection, and nitric oxide may be one of chief NANC neurotransmitters.     

Dietary fish oil enhances macrophage production of nitric oxide

Melanotic neuroectodermal tumor of infancy (MNTI) is a rare but well-documented lesion of neuroectodermal derivation. Maturation of the neural elements has been reported only occasionally. We report a case of MNTI of the maxilla showing maturation of neural elements to ganglionic cells.     

Visualisation of nitric oxide released by nerve stimulation

We have visualised nitric oxide (NO) released from the electrically stimulated myenteric plexus and hypogastric nerve. NO was visualised by a reaction with luminol and hydrogen peroxide to generate photons which were counted using a microscope coupled to a photon counting camera. Electrical stimulation of the tissues induced an increase in photon counts which was frequency-dependent and prevented by inhibition of the NO synthase or by tetrodotoxin. The light emitted during nerve stimulation was not only observed at the nerve terminals but also at the axon and soma. Our results indicate that NO released from the whole nerve cell may affect target cells surrounding all parts of the nitrergic neuron. Thus, NO functions as a unique mechanism of synaptic and non-synaptic communication in the nervous system.     

Treatment of septic shock in rats with nitric oxide synthase inhibitors and inhaled nitric oxide

OBJECTIVE: To evaluate the effect of treatment with a combination of nitric oxide synthase inhibitors and inhaled nitric oxide on systemic hypotension during sepsis. DESIGN: Prospective, randomized, controlled study on anesthetized animals. SETTING: A cardiopulmonary research laboratory. SUBJECTS: Forty-seven male adult Sprague-Dawley rats. INTERVENTIONS: Animals were anesthetized, mechanically ventilated with room air, and randomized into six groups: a) the control group (C, n=6) received normal saline infusion; b) the endotoxin-treated group received 100 mg/kg i.v. of Escherichia coli lipopolysaccharide (LPS, n=9); c) the third group received LPS, and 1 hr later the animals were treated with 100 mg/kg i.v. Nw-nitro-L-arginine (LNA, n=9); d) the fourth group received LPS, and after 1 hr, the animals were treated with 100 mg/kg i.v. aminoguanidine (AG, n=9); e) the fifth group received LPS and 1 hr later was treated with LNA plus 1 ppm inhaled nitric oxide (LNA+NO, n=7); f) the sixth group received LPS and 1 hr later was treated with aminoguanidine plus inhaled NO (AG+NO, n=7). Inhaled NO was administered continuously until the end of the experiment. MEASUREMENTS AND MAIN RESULTS: Systemic mean blood pressure (MAP) was monitored through a catheter in the carotid artery. Mean exhaled NO (ENO) was measured before LPS (T0) and every 30 mins thereafter for 5 hrs. Arterial blood gases and pH were measured every 30 mins for the first 2 hrs and then every hour. No attempt was made to regulate the animal body temperature. All the rats became equally hypothermic (28.9+/-1.2 degrees C [SEM]) at the end of the experiment. In the control group, blood pressure and pH remained stable for the duration of the experiment, however, ENO increased gradually from 1.3+/-0.7 to 17.6+/-3.1 ppb after 5 hrs (p< .05). In the LPS treated rats, MAP decreased in the first 30 mins and then remained stable for 5 hrs. The decrease in MAP was associated with a gradual increase in ENO, which was significant after 180 mins (58.9+/-16.6 ppb) and reached 95.3+/-27.5 ppb after 5 hrs (p< .05). LNA and AG prevented the increase in ENO after LPS to the level in the control group. AG caused a partial reversal of systemic hypotension, which lasted for the duration of the experiment. LNA reversed systemic hypotension almost completely but only transiently for 1 hr, and caused severe metabolic acidosis in all animals. The co-administration of NO with AG had no added benefits on MAP and pH. In contrast, NO inhalation increased the duration of the reversal in MAP after LNA, alleviated the degree of acidosis, and decreased the mortality rate (from 55% to 29%). CONCLUSIONS: In this animal model, LPS-induced hypotension was alleviated slightly and durably after AG, but only transiently after LNA. Furthermore, co-administration of NO with AG had no added benefits but alleviated the severity of metabolic acidosis and mortality after LNA. We conclude that nitric oxide synthase (NOS) inhibitors, given as a single large bolus in the early phase of sepsis, can exhibit some beneficial effects. Administration of inhaled NO with NOS inhibitors provided more benefits in some conditions and therefore may be a useful therapeutic combination in sepsis. NO production in sepsis does not seem to be a primary cause of systemic hypotension. Other factors are likely to have a major role.     

Long-term cardiovascular role of nitric oxide in conscious rats

Twenty-eight non-allergic subjects suffering from mono- and bilateral chronic nasal respiratory obstruction underwent investigation employing routine semeiological examination. The real cause of the obstruction, however, was not ascertained. The subjects underwent nasal endoscopy employing rigid fiberoptics and, on the grounds of the findings, a cat scan of the nasal fossae in coronal projection, was made. The results of the study revealed involvement of the middle meatal area in 63% of bilateral nasal obstructions (B.N.O.) and in 77.7% of the monolateral obstructions (M.N.O.). Choanal pathology was evident in 21% of the B.N.O., while isolated upper and posterior deviations of the septum were present in 23.6% of the B.N.O. and in 22.5% of the M.N.O. Meatal involvement was due to the presence of anatomic changes of the middle turbinate (m.t.) such as concha bullosa, paradoxical deviation of the m.t. and of the uncinate process. Moreover, small "mucosal polyps" were also noticed in this meatal area. Cat scans, performed on 18 of these 28 patients, confirmed and defined meatal alterations found with endoscopy in 16 cases. In the remaining 2 cases, cat scans showed a thickening of the mucosal+bony tissues of the m.t. The Authors did not consider CT necessary in 10 subjects in that endoscopy sufficed in explaining obstruction symptoms.     

Oxytocin increases nitric oxide production in the paraventricular nucleus of the hypothalamus of male rats: correlation with penile erection and yawning

Dog collars made of PVC plastic impregnated with the pyrethroid insecticide deltamethrin at 40 mg/g were investigated for their protective efficacy against phlebotomine sandflies. Collared dogs were kept separately (two untreated control dogs lived together) in outdoor enclosures, each with a kennel, in the Cévennes, southern France. To measure sandfly mortality and anti-feeding effects due to the deltamethrin-impregnated collars worn continuously by the dogs for up to 8 months, each dog was periodically sedated and exposed for 2h to 150-200 laboratory-reared Phlebotomus perniciosus females (plus c. 25 males) inside a net (1.2 m square, 1.8 m high) indoors. After dogs were removed from the nets, allowed to recover and returned to their kennels, any dead sandflies were collected from inside the net and counted. Surviving flies were kept overnight, then scored according to whether they were still alive or dead, unfed or blood-fed. From tests 2, 3, 4, 13, 20, 26 and 34 weeks after the dogs began wearing collars, the overall numbers of blood-fed female sandflies recaptured were 75 from two dogs with collars, compared with 1911 from two collarless dogs. Thus, for every 100 flies which fed on collarless dogs, only 4 fed on collared dogs, i.e. the collars protected dogs from 96% of the bites and this activity was maintained for up to 34 weeks. During the same period, the percentage of recaptured female sandflies that had fed on collared dogs was 0-12% compared to 55-95% on collarless dogs. Immediately after dogs were taken out of the nets, 21-60% of flies confined with the collared dogs were found dead, compared to 0-12% with the controls. It is concluded that, at least in the Mediterranean subregion, this insecticidal collar would protect a dog from the majority of sandfly bites and retain a killing effect for a complete sandfly season. Moreover, it seems likely that the use of collars on all dogs in a focus of Leishmania infantum would reduce contact between sandfly vectors and canine reservoir hosts sufficiently to diminish the risk of infection for humans as well as dogs.     

Down-regulation of neuronal nitric oxide synthase by nitric oxide after oxygen-glucose deprivation in rat forebrain slices

The precise role that nitric oxide (NO) plays in the mechanisms of ischemic brain damage remains to be established. The expression of the inducible isoform (iNOS) of NO synthase (NOS) has been demonstrated not only in blood and glial cells using in vivo models of brain ischemia-reperfusion but also in neurons in rat forebrain slices exposed to oxygen-glucose deprivation (OGD). We have used this experimental model to study the effect of OGD on the neuronal isoform of NOS (nNOS) and iNOS. In OGD-exposed rat forebrain slices, a decrease in the calcium-dependent NOS activity was found 180 min after the OGD period, which was parallel to the increase during this period in calcium-independent NOS activity. Both dexamethasone and cycloheximide, which completely inhibited the induction of the calcium-independent NOS activity, caused a 40-70% recovery in calcium-dependent NOS activity when compared with slices collected immediately after OGD. The NO scavenger oxyhemoglobin produced complete recovery of calcium-dependent NOS activity, suggesting that NO formed after OGD is responsible for this down-regulation. Consistently, exposure to the NO donor (Z)-1-[(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-iu m-1,2-diolate (DETA-NONOate) for 180 min caused a decrease in the calcium-dependent NOS activity present in control rat forebrain slices. Furthermore, OGD and DETA-NONOate caused a decrease in level of both nNOS mRNA and protein. In summary, our results indicate that iNOS expression down-regulates nNOS activity in rat brain slices exposed to OGD. These studies suggest important and complex interactions between NOS isoforms, the elucidation of which may provide further insights into the physiological and pathophysiological events that occur during and after cerebral ischemia.     

Impact of surgery on nitric oxide in rats: evidence for activation of inducible nitric oxide synthase

We investigated the effect of euvolemic surgical preparation, on chemical indices of activity of the nitric oxide (NO) system, in anesthetized, acutely prepared rats. The urinary excretion of NO2+NO3 (UNOXV) and cGMP (UcGMPV) increased progressively during the experiment. Pretreatment with aminoguanidine or dexamethasone, inhibitors of inducible NO synthase (iNOS), prevented the increase in UNOXV and UcGMPV but had no impact on mean arterial pressure (BP), renal vascular resistance (RVR) or GFR. Since these variables did not change in the conscious rat, the increased UNOXV results from some aspect of the acute surgical preparation. When acutely prepared rats received L-NAME, a non-specific NOS inhibitor, BP and RVR increased but paradoxical increases in UNOXV and UcGMPV were also seen. Nonselective NOS inhibition (+L-NAME) was fatal in 50% of acutely prepared rats, causing cardiac contracture. The same dose of L-NAME produced no deaths in either conscious chronically catheterized rats or in acutely prepared rats, previously subjected to sterile surgery and acute L-NAME in the conscious state. These data indicate that acute, nonsterile surgery induces expression of iNOS, but that the additional NO generated has no obvious cardiovascular/renal actions. Acute UNOXV and UcGMPV do not predict total NO production, or "hemodynamically active" NO. Generalized NO inhibition in rats acutely stressed by surgery/anesthesia can be fatal.     

A vitamin E-deficient diet affects nerve regeneration in rats

BLAST searches of 61 equine microsatellite sequences revealed two related families of retroposons. The first family included seven markers, all of which showed significant homology to the Equine Repetitive Element-1 (ERE-1) Short Interspersed Nucleotide Element (SINE) sequence. Length of homology ranged from 76 to 171 bases with identities to the ERE-1 consensus sequence ranging from 71% to 83%. The second family referred to as Equine Repetitive Element-2 (ERE-2) has a consensus sequence that showed homology to ERE-1 over approximately 60 bases. These 60 bases comprised subunit I. Sequence comparisons for the two retroposons led to the identification of a subunit II, subunit III, as well as the tRNAser subunit. The subunit structure of ERE-1 was tRNAser-I-II. By contrast, the subunit structure of ERE-2 was I-III-III. The nine markers related to ERE-2 showed homology lengths ranging from 84 to 163 bases with identities ranging from 75% to 99%. In addition to being present in microsatellites, ERE-2 appeared in three separate equine genes. It occurred in an intron of DNA-PK, in an untranslated region as well as in the promoter of PGHS, and in the coding region of PAM. The amino acids corresponding to the ERE-2 sequence in PAM were not present in the human or mouse PAM homologs. These amino acids associated with the ERE-2 sequence were present on the cytosolic side of the transmembrane domain of the PAM enzyme. Microsatellite markers in the ERE-1 and ERE-2 families were found throughout the genus equus and also for rhinoceros, indicating that the appearance of both retroposons predates the divergence of equids from the other perissodactyls. The markers did not amplify in human or bovine DNA. This indicated that ERE-1 and ERE-2 are, at least, perissodactyl specific.     

Nonselective nerve fibre damage in peripheral nerves after experimental thermocoagulation

BACKGROUND: The insoluble material in supersaturated bile is prerequisite for the formation of gallstones. We therefore studied the biliary precipitable and soluble cholesterol and noncholesterol sterols, including the cholesterol precursor sterols (including lanosterol and lathosterols), and the plant sterols campesterol and sitosterol, and cholestanol, which usually reflect cholesterol synthesis and absorption, respectively, before and after a 6-month treatment with ursodeoxycholic acid (UCDA), 15.4 +/- 4 mg/kg/day (standard error of the mean) or simvastatin (40 mg/day) in 21 patients with cholesterol gallstones, to obtain further information about the factors contributing to the formation of gallstones. METHODS: The sediment and supernatant fractions of duodenal bile samples were separated by ultracentrifugation and analyzed with gas-liquid chromatography. RESULTS: At the base line (n = 21) 50% +/- 3% of biliary cholesterol and a variable amount of the noncholesterol sterols (from 14% of lanosterol to 62% of cholestanol) were in the sediment fraction. The pattern of the noncholesterol sterols in the sediment resembled that of gallstones described previously. At base line body mass index was positively related to the percentage of precipitable cholesterol in bile (r = 0.46, P < 0.05), and the serum sitosterol proportion negatively related to the molar percentage of biliary cholesterol and positively to that of bile acids (r = -0.46 and r = 0.50, P < 0.05 for both). UDCA decreased the precipitable percentage of cholesterol from 46% to 31% (P < 0.03) and simvastatin from 57% to 42% (P = 0.05). Both drugs also decreased the precipitable percentages of lathosterols and cholestanol while increasing that of lanosterol. In relation to cholesterol, the sediment to supernatant ratios of all methylsterols were increased, whereas those of polar lathosterols tended to decrease during UDCA treatment. CONCLUSIONS: Patients with high body mass index have more precipitable cholesterol in their bile. Although both UDCA and simvastatin decreased the precipitable cholesterol, the bile still contained one-third of its cholesterol in the sedimentable form.     

Anandamide amidase inhibition enhances anandamide-stimulated nitric oxide release in invertebrate neural tissues

Anandamide, an endogenous cannabinoid signaling molecule, in a concentration dependent manner, initiates the release of nitric oxide (NO) from leech and mussel ganglia. SR 141716A, a cannabinoid antagonist, blocks the anandamide stimulated release of NO from these tissues. Methyl arachidonyl fluorophosphonate (MAFP), a specific anandamide amidase inhibitor, when administered to either ganglia with anandamide (10-6 M) did not increase the peak level of NO release but did significantly extend NO release from 12 to 18 min (P<0.05). Lower levels of anandamide (10-8 and 10-7 M) do not stimulate the release of significant amounts of NO from these tissues. However, in the presence of MAFP (2.5 nM), the lower anandamide concentrations were able to release significant peak amounts of NO. In mussel neural tissues, the peak NO release increased from 2.2+/-1.3 nM to 8.6+/-2.1 nM. Taken together, the results indirectly demonstrate the presence of anandamide amidase in these tissues, suggesting that the enzyme may serve as an endogenous regulator of anandamide action.     

Endothelin enhances lipopolysaccharide-induced expression of inducible nitric oxide synthase in rat glial cells

Lipopolysaccharide is known to stimulate production of nitrite via expression of inducible nitric oxide (NO) synthase in not only macrophages but also glial cells. We found that in glial cell cultures lipopolysaccharide-stimulated inducible NO synthase expression and nitrite accumulation were synergistically enhanced by pretreatment with endothelin, whereas endothelin itself did not induce these responses. Pretreatment with endothelin-1, endothelin-3, and the selective endothelin type B (ETB) receptor agonist IRL 1620 caused the same effect with similar potencies, suggesting that the synergism was mediated via the endothelin ETB receptor. A protein kinase C inhibitor, calphostin C, suppressed endothelin-3-enhanced inducible NO synthase expression. Pretreatment with either endothelin-3 or phorbol ester enhanced lipopolysaccharide-induced production of tumor necrosis factor-alpha (TNF-alpha). Simultaneous addition of TNF-alpha increased lipopolysaccharide-stimulated inducible NO synthase expression. These results suggest that the increase in inducible NO synthase expression by endothelin was due to the elevated TNF-alpha production via protein kinase C. Our findings present the possibility that endothelin is implicated in neurotoxicity via enhancement of inducible NO synthase expression.     

Inhibition of nitric oxide synthesis enhances the expression of inducible nitric oxide synthase mRNA and protein in a model of chronic liver inflammation

In septic shock the inhibition of inducible nitric oxide synthase (iNOS) could be of therapeutic value. However, side effects have to be investigated. Therefore we studied the effects of chronic NOS inhibition on the level of iNOS expression in a model of chronic liver inflammation induced by Corynebacterium parvum (C. parvum) which causes sustained iNOS expression in the liver. NOS inhibitors decreased the rise in plasma levels and urinary excretion of nitrite/nitrate by about 50%; however, iNOS mRNA and protein were increased to 200% and 150%, respectively. Thus chronic inhibition of NOS can result in an increase in iNOS mRNA level and protein under conditions when iNOS is expressed. This could result in an overproduction of NO upon removal of the NOS-inhibitor.     

Tyrosine hydroxylase- and nitric oxide synthase-immunoreactive nerve fibers in mitral valve of young adult and aged Fischer 344 rats

Using confocal fluorescence microscopy we studied, in whole mounts of heart mitral valves of young adult and aged Fischer 344 rats, the distribution of nerves containing the catecholamine marker tyrosine hydroxylase (TH) or the synthetic enzyme marker for nitric oxide, nitric oxide synthase (NOS). TH-IR was localized in two separate nerve plexuses which do not intermingle. The 'major' plexus arose from the annulus region, traversed the basal zone of the valve, and ramified in the intermediate zone to form a dense network of fine fibers. The 'minor' plexus was restricted to the distal zone and originated from bundles that ascended the chordae tendineae to enter the valve cusp. A concentric zone located between the major and minor plexuses was devoid of TH-IR nerve fibers. Both plexuses demonstrated (i) nerves that contained numerous varicosities along the length of each fiber, (ii) many terminal axons and (iii) different shaped terminal axon endings. With age, the density of TH-IR innervation in the mitral valve was markedly reduced; and nerve fibers of the minor plexus were limited to the chordae tendinae, without extending into the valve cusp itself. NOS-IR fibers in the mitral valve formed a loose network that extended from the annulus to more than halfway down the cusp. The varicose beads of the terminal NOS-IR axons appeared to become progressively smaller and less intensely fluorescent until they disappeared at the terminal endings, which showed no specializations. No NOS-IR fibers were observed in the distal zone of the valve leaflet or in the chordae. In the aged mitral valve, the density of NOS-IR nerves was decreased, as compared with NOS-IR innervation in the young adult valve. The existence of TH and NOS as well as other signal molecule markers in heart valve nerves and the disparate patterns of their distribution and localization provide evidence supporting the theory that heart valve nerves form a complex reflexogenic control system in the mitral heart valve. In summary, two distinct neural architectures are described for TH-IR and NOS-IR valve nerves, respectively. The former are believed to be axons dedicated to sympathetic motor functions. The NOS-IR valve nerves may have sensory and/or postganglionic parasympathetic motor functions. An implication of these findings is that different, but perhaps related, valve functions may be mediated by separate, dedicated circuits.     

Prevention by morphine of N-methyl-D-aspartic acid-induced penile erection and yawning: involvement of nitric oxide

A role for catecholamines in the regulation of the blood neutrophilia induced by intravenous (i.v.) injection of lipopolysaccharide (LPS; 250 micrograms/kg) was examined in Wistar rats by means of surgical adrenalectomy or pretreatment with adrenergic and dopaminergic antagonists into naive animals. Treatment of animals with a single dose (250 micrograms/kg) of LPS caused a dramatic increase in the number of circulating neutrophils concomitant with a decrease in the number of these cells in the bone marrow. These effects were partially reversed when catecholamine stores were depleted with reserpine. It was found that neither adrenalectomy nor pretreatment with the dopaminergic antagonists, chlorpromazine and pimozide, affected the changes in neutrophil counts induced by LPS. The injection of the alpha 1/alpha 2-adrenoceptor antagonist, phentolamine, and the selective alpha 1-adrenoceptor antagonist, prazosin, significantly decreased blood neutrophilia induced by LPS. However, neither the selective alpha 2-adrenoceptor antagonist, yohimbine, nor the beta-adrenoceptor antagonist, propranolol, had any effect on LPS response. Taken together, these findings support the hypothesis that the catecholamine norepinephrine plays a role in the regulation of the LPS-induced neutrophilia through activation of alpha 1-adrenoceptors.     

Expression of peptides, nitric oxide synthase and NPY receptor in trigeminal and nodose ganglia after nerve lesions

Infective endocarditis, especially when it involves prosthetic valves, is a serious, often fatal illness. Although antibiotics are essential in management, surgery is required in many patients who develop even incipient heart failure and structural complications. Early identification and referral results in improved mortality and morbidity rates, and there is evidence that surgery should play a larger role in managing infective endocarditis. Patients with intracardiac pacemakers and cardioverting devices represent a growing reservoir of patients with the potential to develop endocarditis.