Dilated cardiomyopathy in cats: survey of veterinary cardiologists and retrospective evaluation of a possible association with diet.

INTRODUCTION/OBJECTIVES: The objectives were to conduct a survey of cardiologists on their recent experiences with cats that have dilated cardiomyopathy (DCM) and to retrospectively review individual cases of feline DCM. ANIMALS, MATERIALS AND METHODS: Part one: A survey was distributed to cardiologists with questions regarding caseload and clinical management of cats with DCM diagnosed over the past two years. Part two: Cardiologists completing the survey were invited to submit data from cats recently diagnosed with DCM. Data on signalment, clinical signs, diet, echocardiographic measurements and outcome were recorded. RESULTS: Part one: From 52 completed surveys, many cardiologists responded that measuring and supplementing taurine and recommending a diet change in cats with DCM are common practices. Few (15%) cardiologists reported an increase in the number of feline DCM cases over the past two years, although some had cases that improved even if taurine deficiency was not present. Part two: Twenty of 37 (54%) cats ate low pea/lentil (low PL) diets, and 14/37 (38%) ate high PL diets at the time of diagnosis; three had incomplete diet information. Two of 13 cats (15%) in which taurine was measured had levels below the reference range. After adjusting for other variables, cats eating high PL diets that changed diets after diagnosis had a significantly longer survival time than that of cats eating high PL diets that did not change diets after diagnosis (P = 0.025). CONCLUSIONS: Additional research is warranted to determine whether there could be a possible association between diet and DCM in cats.

Arrhythmogenic right ventricular cardiomyopathy in dogs.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease seen in dogs, cats, and humans. A common entity in Boxers and the related English bulldog, the disease is characterized by fatty or fibrofatty replacement of the myocardium, ventricular arrhythmias, and the potential for syncope or sudden death. In some individuals, concomitant left ventricular involvement results in systolic dysfunction and a progression to congestive heart failure. The clinical and pathological characteristics of ARVC share many similarities in dogs and humans, and Boxers serve as an important spontaneous model of the disease. Although multiple mechanisms have been implicated in the pathogenesis of ARVC, the disease is ultimately considered to be a disorder of the desmosome. Multiple causal genetic mutations have been identified in people, and over 50% of affected humans have an identifiable mutation in desmosomal proteins. To date, only a single genetic mutation has been associated with ARVC in Boxer dogs. Other as-yet-undiscovered genetic mutations and epigenetic modifiers of the disease are likely. Treatment of ARVC in dogs is focused on controlling ventricular arrhythmias and associated clinical signs. This article will review the pathophysiology, clinical diagnosis, treatment, and prognosis of ARVC in the dog.

Echocardiographic assessment of right ventricular systolic function in Boxers with arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVES: To determine whether there are differences in measures of longitudinal right ventricular (RV) systolic function among Boxers with arrhythmogenic right ventricular cardiomyopathy (ARVC) compared with healthy control Boxer dogs. To explore relationships between markers of RV systolic function and age, body weight, gender, arrhythmia frequency, and markers of left ventricular (LV) systolic function in Boxer dogs. ANIMALS: The study included 50 client-owned Boxer dogs. METHODS: This is a retrospective echocardiographic study. Tricuspid annular plane systolic excursion (TAPSE) and pulsed wave tissue Doppler imaging-derived systolic myocardial velocity of the lateral tricuspid annulus (S') were measured in healthy control Boxers (n = 18), Boxers with ARVC and normal LV systolic function (n = 19), and Boxers with ARVC and reduced LV systolic function (n = 13). RESULTS: Tricuspid annular plane systolic excursion (p=0.002) and S' (p=0.001) were significantly different between affected and control groups. Significant correlations were found between measures of left heart size and function and both TAPSE and S'. No correlations were found between RV function parameters and age, gender, or body weight in this fairly homogeneous, single-breed population. Receiver operating characteristic curve analysis revealed that both TAPSE and S' had an area under the curve of 0.77 in distinguishing healthy Boxers from those with ARVC. CONCLUSIONS: Tricuspid annular plane systolic excursion and S' are reduced in Boxers with ARVC. In contrast to prior studies evaluating these parameters in dogs of different breeds and body types, no correlation was found between markers of RV function and body weight in this population of Boxer dogs.

Association between Survival Time and Changes in NT-proBNP in Cats Treated for Congestive Heart Failure.

BACKGROUND: Reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations after treatment have been associated with improved survival in people with congestive heart failure (CHF), but have not been reported in cats with CHF. OBJECTIVES: To evaluate changes in NT-proBNP concentrations in cats with CHF after treatment and determine whether serial NT-proBNP measurements provide prognostic information. ANIMALS: Thirty-one client-owned cats. METHODS: Prospective, observational study in cats with new onset CHF secondary to cardiomyopathy. Concentrations of NT-proBNP were measured within 4 hours of admission to the hospital, on the day of discharge, and at re-evaluation 7-10 days later. RESULTS: Median NT-proBNP concentrations decreased significantly from admission (1,713 pmol/L [range, 160-3,784 pmol/L]) to discharge (902 pmol/L [range, 147-3,223 pmol/L]); P = .005) and from admission to re-evaluation (1,124 pmol/L [range, 111-2,727 pmol/L]; P = .024). Median survival time was 109 days (range, 1-709 days), with 5 cats still alive at the time of analysis. Cats with a larger percent decrease in NT-proBNP from admission to discharge had a longer survival time (P = .048). Cats with evidence of active CHF at the time of re-evaluation (P = .010) and cats whose owners had difficulty administering medications (P = .045) had shorter survival times. CONCLUSIONS AND CLINICAL IMPORTANCE: Cats with a larger percent decrease in NT-proBNP during hospitalization and no evidence of CHF at the time of re-evaluation had longer survival times. Additional studies are needed to determine whether NT-proBNP can help guide treatment in cats with CHF.

Relationship of plasma N-terminal pro-brain natriuretic peptide concentrations to heart failure classification and cause of respiratory distress in dogs using a 2nd generation ELISA assay.

BACKGROUND: Cardiac biomarkers provide objective data that augments clinical assessment of heart disease (HD). HYPOTHESIS/OBJECTIVES: Determine the utility of plasma N-terminal pro-brain natriuretic peptide concentration [NT-proBNP] measured by a 2nd generation canine ELISA assay to discriminate cardiac from noncardiac respiratory distress and evaluate HD severity. ANIMALS: Client-owned dogs (n = 291). METHODS: Multicenter, cross-sectional, prospective investigation. Medical history, physical examination, echocardiography, and thoracic radiography classified 113 asymptomatic dogs (group 1, n = 39 without HD; group 2, n = 74 with HD), and 178 with respiratory distress (group 3, n = 104 respiratory disease, either with or without concurrent HD; group 4, n = 74 with congestive heart failure [CHF]). HD severity was graded using International Small Animal Cardiac Health Council (ISACHC) and ACVIM Consensus (ACVIM-HD) schemes without knowledge of [NT-proBNP] results. Receiver-operating characteristic curve analysis assessed the capacity of [NT-proBNP] to discriminate between dogs with cardiac and noncardiac respiratory distress. Multivariate general linear models containing key clinical variables tested associations between [NT-proBNP] and HD severity. RESULTS: Plasma [NT-proBNP] (median; IQR) was higher in CHF dogs (5,110; 2,769-8,466 pmol/L) compared to those with noncardiac respiratory distress (1,287; 672-2,704 pmol/L; P < .0001). A cut-off >2,447 pmol/L discriminated CHF from noncardiac respiratory distress (81.1% sensitivity; 73.1% specificity; area under curve, 0.84). A multivariate model comprising left atrial to aortic ratio, heart rate, left ventricular diameter, end-systole, and ACVIM-HD scheme most accurately associated average plasma [NT-proBNP] with HD severity. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma [NT-proBNP] was useful for discriminating CHF from noncardiac respiratory distress. Average plasma [NT-BNP] increased significantly as a function of HD severity using the ACVIM-HD classification scheme.

A randomized study assessing the effect of diet in cats with hypertrophic cardiomyopathy.

BACKGROUND: Diet might influence progression of hypertrophic cardiomyopathy (HCM). OBJECTIVE: To investigate whether diet composition could alter clinical, biochemical, or echocardiographic variables in cats with HCM. ANIMALS: Twenty-nine cats with HCM (International Small Animal Cardiac Health Council stage 1b) examined at a university teaching hospital. METHODS: Randomized, placebo-controlled trial. After physical examination, echocardiogram, and blood collection, cats were randomized to 1 of 3 diets, which varied in carbohydrate and fat content and ingredients. Measurements were repeated after 6 months. RESULTS: There were no significant differences among the 3 groups at baseline. After 6 months, there were no significant changes in the primary endpoints, left ventricular free wall (Group A, P = .760; Group B, P = .475; Group C, P = .066) or interventricular septal thickness in diastole (Group A, P = .528; Group B, P = .221; Group C, P = .097). Group A had significant increases in BUN (P = .008) and cholesterol (P = .021), while Group B had significant increases in BUN (P = .008), cholesterol (P = .007), and triglycerides (P = .005), and significant decreases in NT-proBNP (P = .013) and hs-troponin I (P = .043). Group C had significant decreases in body weight (P = .021), left atrial dimension (P = .035), interventricular septal thickness in systole (P = .038), and liver enzymes (P = .034-.038). CONCLUSIONS AND CLINICAL IMPORTANCE: These data suggest that diet might influence some clinical, biochemical, and echocardiographic variables in cats with HCM.

Association of dilated cardiomyopathy with the striatin mutation genotype in boxer dogs.

BACKGROUND: Myocardial disease in the Boxer dog is characterized by 1 of 2 clinical presentations, dilated cardiomyopathy (DCM) characterized by ventricular systolic dysfunction, dilatation and tachyarrhythmias, and arrhythmogenic right ventricular cardiomyopathy (ARVC) characterized by ventricular tachyarrhythmias, syncope, and sudden death. Boxer ARVC has been associated with a deletion in the striatin gene in some families. HYPOTHESIS/OBJECTIVES: We hypothesized that both presentations represent a single disease, and the development of DCM in the Boxer is associated with the striatin deletion. ANIMALS: Thirty-three adult Boxer dogs with DCM, 29 adult Boxer dogs with the striatin deletion and ARVC, and 16 Boxers without cardiac disease. METHODS: DNA samples were evaluated for the striatin deletion. Association of the deletion with the DCM phenotype was tested by a Fisher's exact test. T-tests were used to evaluate potential differences between the positive heterozygous and positive homozygous groups with DCM with regard to age, LVIDD, LVIDS, and FS%. RESULTS: Thirty of 33 dogs with DCM were positive for the striatin deletion. The striatin mutation and the homozygous genotype were strongly associated with the DCM phenotype (P < .001 and P = .005). There was no statistical difference between the heterozygous and homozygous groups with regard to age and echocardiographic measurements. CONCLUSIONS AND CLINICAL IMPORTANCE: This study demonstrates an association between DCM in the Boxer dog and the striatin mutation, particularly with the homozygous genotype. The observation that 3/33 dogs developed DCM and lacked the striatin mutation suggests that there is at least 1 other cause of DCM in the Boxer dog.

Short-term effects of atorvastatin in normal dogs and dogs with congestive heart failure due to myxomatous mitral valve disease.

BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may improve heart failure class and survival in people with congestive heart failure (CHF) of various etiologies. HYPOTHESIS/OBJECTIVES: To evaluate the tolerability of atorvastatin in healthy dogs, and the short-term effects of atorvastatin on clinical markers of disease severity, lipid profiles, and markers of systemic inflammation and oxidative stress in dogs with CHF. ANIMALS: Eleven normal dogs and 12 client-owned animals with CHF attributable to myxomatous mitral valve disease. METHODS: Prospective nonblinded observational study. Normal dogs (n = 11) were first treated with atorvastatin and re-evaluated after 14 and 30 days for clinical tolerability and alterations in certain laboratory results. Subsequently, dogs with CHF (n = 12) were treated with atorvastatin at a dosage of 2 mg/kg q24 h for 8 weeks. Echocardiography, blood pressure (BP), quality of life questionnaire, and blood sampling were performed pre and post atorvastatin administration. RESULTS: Atorvastatin was well tolerated and did not result in apparent adverse effects or biochemical abnormalities in healthy dogs and in dogs with CHF. Healthy dogs experienced a decrease in total cholesterol (TC) concentration (P = .03) after atorvastatin administration. Decreases in TC concentration (P = .02), non-HDL cholesterol concentration (P = .02), total white blood cell count (P = .03), neutrophils (P = .01), and systolic BP (P = .01) were noted in the CHF group after 8 weeks of atorvastatin. CONCLUSIONS AND CLINICAL IMPORTANCE: Atorvastatin was well tolerated at clinically relevant doses in healthy dogs and dogs with CHF. Further investigation into the effects of statin treatment in dogs with CHF is warranted.

Systemic inflammation and endothelial dysfunction in dogs with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) is associated with endothelial dysfunction in people and in dogs with experimentally induced CHF, but this is not well characterized in dogs with naturally occurring CHF. HYPOTHESIS/OBJECTIVES: To evaluate endothelial function via assessment of reactive hyperemia (RH) in healthy dogs and dogs with CHF, and to assess for relationships with plasma biomarkers of vascular function and clinical markers of disease severity. ANIMALS: Twenty client-owned animals with CHF due to myxomatous mitral valve disease (n = 15) or dilated cardiomyopathy (n = 5) and 17 healthy control dogs. METHODS: Prospective case-controlled observational study. Dogs underwent blood sampling, echocardiography, and Doppler assessment of brachial artery velocity (VTI) at baseline and during reactive hyperemia (RH-VTI). RH-VTIs between control dogs and dogs with CHF were compared, and the relationships between RH-VTI, clinical parameters, and plasma biomarkers were assessed. RESULTS: Dogs with CHF (96.5 ± 51.7%) had an attenuated % increase in VTI during RH compared to healthy controls (134.8 ± 58.7%; P = .04). Increasing ISACHC class (R(2) = 0.24; P = .004), plasma NT-proBNP (R(2) = 0.15; P = .03) and CRP (R(2) = 0.2; P = .02) were associated with reduced RH-VTI. Increased plasma CRP, NO(x) , and NT-proBNP concentrations were found in dogs with CHF (P < .02 for all). No differences were detected in other plasma markers. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with CHF have an attenuated RH response, and increased plasma CRP and NO(x) concentrations. Doppler assessment of RH velocity could represent a novel noninvasive method of evaluating endothelial function in the dog.

Perceptions of quality of life and priorities of owners of cats with heart disease.

BACKGROUND: Owners' perceptions and priorities regarding quality of life (QoL) are important considerations given the unknown efficacy of many commonly administered medications, stress of hospital visits, difficulties providing home care, and personal choices including euthanasia. OBJECTIVE: To describe the relative importance of quality versus quantity of life to owners of cats with heart disease. ANIMALS: Two hundred and thirty-nine cats with heart disease. METHODS: Prospective questionnaire-based clinical study. Cat owners completed a questionnaire to identify important parameters when assessing their cat's QoL, the relative importance of quality versus quantity of life, and willingness to trade survival time for QoL. Variables associated with these parameters were evaluated with multivariate analyses. RESULTS: Appetite, owner interaction, sleep patterns, and litterbox habits were deemed important to QoL. Concern over pet suffering was significantly greater than concern over life expectancy. Ninety-three percent of owners were willing to trade survival time for good QoL; 57% of these were willing to trade up to 6 months. On multivariate analysis, the only factor significantly (P=.002) associated with willingness to trade 6 months was study site. Owner concern regarding stress of administering medications at home increased with number and frequency of medications. CONCLUSIONS AND CLINICAL RELEVANCE: These results indicated that QoL is more important to owners of cats with heart disease than longevity. The various priorities and concerns of cat owners should be taken into account in order to provide optimal care.

Echocardiographic ratio indices in overtly healthy Boxer dogs screened for heart disease.

BACKGROUND: Boxer dogs are routinely screened by echocardiography to exclude congenital and acquired heart disease. Individuals of a given breed may span a large range of body sizes, potentially invalidating linear regression of M-mode measurements against body weight. Echocardiographic ratio indices (ERIs) provide a novel method of characterizing echocardiographic differences between Boxers and other dog breeds. HYPOTHESIS: ERIs obtained from overtly healthy Boxer dogs presented for cardiac screening will be different from ERIs established for normal non-Boxer dogs, and those differences will be unrelated to aortic velocity or systolic blood pressure. ANIMALS: Eighty-one Boxers with no outward clinical signs of heart disease were studied. METHODS: All dogs were examined by 2-dimensional, M-mode, and Doppler echocardiography. M-mode measurements were used to perform ERI calculations, and the indices in Boxers were compared between Boxers with varying severity of arrhythmia and those of normal non-Boxer dogs. RESULTS: Differences in weight-based ERIs, which reflect increased thickness of the left ventricular free wall (LVW) and interventricular septum (IVS) and smaller aortic size, were found in overtly healthy Boxer dogs compared with normal non-Boxer dogs. ERIs of left atrial and LV cavity size in overtly healthy Boxers were not significantly different from those of non-Boxer dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Boxer dogs may have an increased relative thickness of the LVW and IVS that is independent of aortic size, aortic velocity, or arterial blood pressure, and this morphology should be taken into consideration when screening Boxers by echocardiography.

Regional differences in the sympathetic innervation of the guinea pig large intestine by neuropeptide Y- and tyrosine hydroxylase-immunoreactive nerves of divergent extrinsic origin.

Region-specific patterns of nerves with immunoreactivity to neuropeptide Y (NPY) have been described previously in the submucous plexus of guinea pig large intestine. Because these may have functional significance, the possibility of similar, characteristic variations of NPY-like immunoreactivity (NPY-ir) in the myenteric plexus was explored. Regional differences were found in the occurrence and pattern of distribution of NPY-ir in the myenteric plexus of the guinea pig large intestine. NPY-ir was present rarely within neuron somata in any region of the large intestine, and NPY-ir nerve fibers were present only within the distal large intestine, increasing progressively in density from the distal spiral to the rectum. Lesion of the colonic nerves, but not the hypogastric, intermesenteric, or lumbar splanchnic nerves, resulted in a loss of NPY-ir in the distal spiral and transverse colon but not in the descending colon or rectum. Ring myotomies in the descending colon resulted in a loss of NPY-ir proximal to the lesion. Dual-labeling immunohistochemical studies revealed that the NPY-ir nerve fibers rarely contained immunoreactivity for tyrosine hydroxylase (TH). Extrinsic nerve lesions resulted in an unequivocal reduction in NPY-ir in intraganglionic fibers of the submucosal plexuses of the transverse colon and a partial loss in the distal spiral and descending colon: the rectum was unaffected; in only a minority of guinea pigs, however, was any decrease in the NPY-ir innervation of submucosal blood vessels detected. The principal projections of NPY-ir nerves were from and through the inferior mesenteric ganglion; however, NPY-ir was not colocalized with TH-ir. It is proposed that nonnoradrenergic, NPY-containing neurons located in the inferior mesenteric ganglion project through the colonic nerves and that these proximally directed fibers innervate the transverse colon and the distal spiral. Nonnoradrenergic, NPY-ir neurons lying in the pelvic ganglia or sacral sympathetic chain may make an important contribution to the innervation of the myenteric plexus of the rectum and the descending colon.

Migraine: helping clients choose treatment and identify triggers.

Migraine is a common complaint causing untold difficulties or aggravation for the sufferer. Clients with migraine can have very real fears of possible pathologies and the nurse is in a strong position to dispel these fears with information and reassurance. This article discusses information and knowledge which nurses can use to enable clients to take control over their migraine: from the range of choices about treatment to the identification of triggers that precipitate migraine or identification of factors to inhibit attacks. Treatments may be broad ranging from non-pharmacological to pharmacological approaches, which may be either symptomatic or prophylactic. Pharmacological treatments are presented in detail indicating the range of types from analgesia to antidepressants.

Expression of beta-amylase from alfalfa taproots.

Alfalfa (Medicago sativa L.) roots contain large quantities of beta-amylase, but little is known about its role in vivo. We studied this by isolating a beta-amylase cDNA and by examining signals that affect its expression. The beta-amylase cDNA encoded a 55.95-kD polypeptide with a deduced amino acid sequence showing high similarity to other plant beta-amylases. Starch concentrations, beta-amylase activities, and beta-amylase mRNA levels were measured in roots of alfalfa after defoliation, in suspension-cultured cells incubated in sucrose-rich or -deprived media, and in roots of cold-acclimated germ plasms. Starch levels, beta-amylase activities, and beta-amylase transcripts were reduced significantly in roots of defoliated plants and in sucrose-deprived cell cultures. beta-Amylase transcript was high in roots of intact plants but could not be detected 2 to 8 d after defoliation. beta-Amylase transcript levels increased in roots between September and October and then declined 10-fold in November and December after shoots were killed by frost. Alfalfa roots contain greater beta-amylase transcript levels compared with roots of sweetclover (Melilotus officinalis L.), red clover (Trifolium pratense L.), and birdsfoot trefoil (Lotus corniculatus L.). Southern analysis indicated that beta-amylase is present as a multigene family in alfalfa. Our results show no clear association between beta-amylase activity or transcript abundance and starch hydrolysis in alfalfa roots. The great abundance of beta-amylase and its unexpected patterns of gene expression and protein accumulation support our current belief that this protein serves a storage function in roots of this perennial species.

Presynaptic calcium channels mediating synaptic transmission in submucosal neurones of the guinea-pig caecum.

1. Intracellular recording techniques were used to examine the voltage-activated calcium channels mediating neurotransmitter release from nerve terminals of extrinsic, sympathetic origin and intrinsic (enteric) origin innervating submucosal neurones of the guinea-pig caecum. 2. The noradrenergic slow inhibitory postsynaptic potential (IPSP) was abolished by superfusion of omega-conotoxin (omega-CTX) GVIA (3-300 nM), with an apparent IC50 of 8.6 nM. Superfusion of omega-CTX MVIIC (500 nM) also suppressed the amplitude of slow IPSPs, but both omega-agatoxin IVA (100 nM) and nicardipine (1-10 microM) were ineffective. The hyperpolarization induced by exogenous noradrenaline was not affected by omega-CTX GVIA (100 nM). 3. In contrast to the slow IPSP, the amplitude of the cholinergic fast excitatory postsynaptic potential (EPSP) was partially inhibited, but not abolished, by omega-CTX GVIA (0.1-1 microM). Furthermore, omega-agatoxin IVA (0.1-1 microM) or omega-CTX MVIIC (0.1-1 microM) also affected the fast EPSP, but nicardipine (1-10 microM) was ineffective. In combination, omega-CTX GVIA (100 nM) and omega-agatoxin IVA (100 nM) inhibited the fast EPSP by 74 +/- 6 %; the residual fast EPSP was not affected by omega-CTX MVIIC (100 nM). The fast EPSP was completely abolished by low Ca2+, high Mg2+ Krebs solution or Krebs solution containing Co2+ (2 mM) and Cd2+ (400 microM). The depolarization induced by exogenous acetylcholine was not affected by either omega-CTX GVIA (100 nM), omega-agatoxin IVA (100 nM) or omega-CTX MVIIC (100 nM). 4. Taken together, these results suggest that, in the submucosal plexus of the guinea-pig caecum, release of noradrenaline from extrinsic nerve terminals is regulated by N-type calcium channels, whereas release of acetylcholine from intrinsic nerve terminals involves several types of calcium channel.

Electrophysiology of neurochemically identified submucosal neurones of the guinea-pig intestine.

A number of electrophysiological studies have shown that neurones in the submucous plexus are endowed with three major types of synaptic potentials in response to nerve stimulation: a fast EPSP, a slow IPSP, and a slow EPSP. Combined electrophysiological and immunohistochemical studies enabled analysis of the types of neurochemically identified neurones which receive each type of synaptic input. This short review briefly summarizes the results obtained from these studies.

Electrophysiological characteristics of submucosal neurones in the proximal colon of guinea-pigs: comparisons with caecum and descending colon.

A systematic examination has been made of the active and passive electrophysiological properties and synaptic inputs of forty-four randomly impaled submucosal neurones in the proximal colon of the guinea-pig to compare these characteristics directly with those of submucosal neurones in the caecum (n = 70) and descending colon (n = 45). Within each of the three electrophysiological classes of submucosal neurones identified (S, S/AH and AH), no statistically significant regional differences were found with respect to the resting membrane potential, membrane time constant or input resistance between neurones of the proximal colon, descending colon and caecum. Of submucosal neurones from the proximal colon, forty-three of forty-four (98%) received fast excitatory synaptic potentials (fast EPSPs); thirty-nine (91%) were S neurones and the others were S/AH neurones; only one of the forty-four cells (2%) was an AH neurone. An idazoxan-sensitive slow inhibitory postsynaptic potential (slow IPSP) was induced in thirty of forty-three S and S/AH neurones (70%) of the proximal colon, compared with sixty-one of sixty-six caecal neurones (92%) and twelve of forty-one neurones (29%) in the descending colon. The mean (+/- S.E.M.) amplitude of the slow IPSP in proximal colonic neurones was 17 +/- 1 mV (range, 6-30 mV; n = 30), compared with the significantly larger synaptic response (25 +/- 1 mV; range, 7-38 mV; n = 66; P < 0.05) recorded in the caecum; the mean slow IPSP amplitude in the descending colon was significantly smaller (12 +/- 2 mV; range, 5-27 mV; n = 12; P < 0.05) than that in the caecum. In the proximal colon and caecum, only those neurones with a slow IPSP had a hyperpolarizing response to noradrenaline, whereas about 50% of those neurons of the descending colon that lacked a slow IPSP were hyperpolarized by noradrenaline, acting via alpha 2-adrenoceptors. Thus, the electrophysiological characteristics of the submucosal neurones of the proximal colon more closely resemble those of the caecum than those of the descending colon, of which many do not have a functional noradrenergic synaptic input. Furthermore, the results confirm that there are fundamental regional differences in the guinea-pig large intestine with respect to the synaptic organization of submucosal neurones of particular electrophysiological classes.

Neuropeptide Y in submucosal ganglia: regional differences in the innervation of guinea-pig large intestine.

Since information about possible regional differences in the innervation of the guinea-pig large intestine is incomplete, a comparative study was made of the occurrence of neurones and nerve fibres of the submucosa showing immunoreactivity (IR) to neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP). In addition, a quantitative analysis was made of submucosal neurones in regions of guinea-pig large intestine selected for probable differences in their function. There were two principal findings: First, the density of NPY-IR neurone somata was high in the ascending colon (mean +/- SEM 3148 +/- 464 neurones/cm2; n = 5 animals) and progressively declined in an anal direction, the descending colon having 348 +/- 125 neurones/cm2 (in the same 5 animals); immunoreactive cell bodies were rare in the rectum. The reduced density was also reflected in a fall in the number of NPY-IR neurones/ganglion from 3.0 +/- 0.3 in the ascending colon to 0.5 +/- 0.2 in the descending colon. Second, varicose NPY-IR intraganglionic fibres were a conspicuous feature of the duodenum, caecum, transverse colon, descending colon and rectum, but not of the ileum, ascending colon or distal spiral. Moreover, in the descending colon and rectum the fibres were arranged in a loose 'cobweb' structure around non-NPY-IR neurone somata; in the caecum, there was an apparent paucity of NPY-IR somata but the exceptionally dense intraganglionic varicose fibre network may have obscured NPY-IR somata. In all regions, fibre baskets were rare. In the ascending colon, only 25 +/- 5% of ganglia (compared to 92 +/- 2% of ganglia in the descending colon) showed any intraganglionic nerve fibres; furthermore, when they occurred, these were not of the 'cobweb' type but, rather, they gave the ganglia a speckled appearance. In very immature fetuses at a stage of development when no neuropeptide somata could be found in either the myenteric or submucosal plexuses, many NPY-IR nerve fibres were present in the submucosa with a distribution similar to that of adult guinea pigs. With respect to the density of VIP-IR neurones in the large intestine, there was only a 40% reduction in the number of neurones/cm2 from proximal to distal colon, in contrast to the corresponding 90% reduction in the density of NPY-IR neurones. The number of VIP-IR neurones/ganglion (6.4) and the proportion of ganglia with VIP-IR fibres (> 90%) were constant. It is concluded that the striking regional dissimilarities in (i) the occurrence of NPY-IR neurone somata and (ii) in the disposition of intraganglionic NPY-IR nerve fibres indicate potentially important regional differences in the functions of neuropeptide Y as an antisecretory peptide in the local regulation of chloride transport in the mucosa and as a modulator of ganglionic transmission, respectively.