[ARENA-Project atrial fibrillation in the Rhein-Neckar region]. / ARENA ­ Projekt Vorhofflimmern in der Rhein-Neckar-Region.

Atrial fibrillation (AF) is the most common form of cardiac tachyarrhythmia. It is estimated that in the Rhein-Neckar region approximately 40,000-50,000 out of 2 million people are affected. Due to demographic changes in the near future there will be a significant increase in the prevalence of AF within the next decades. The ARENA project was initiated by the Foundation Institute for Cardiac Infarction Research (IHF) Ludwigshafen in cooperation with cardiological and neurological departments of neighboring hospitals, resident doctors and pharmacies to improve the awareness and care of patients with AF. The particular aim is the prevention of stroke as one of the most dreaded complications. The project focusses on the following three subtopics: interventions, medication, migration. The aim of the intervention project is to raise awareness of AF as a risk factor for stroke and to improve the diagnostic work-up and care for patients with diagnosed or unknown AF. The subproject medication focusses on the adherence of patients with AF to the prescribed antithrombotic medication. To evaluate differences concerning patients with and without a migration background the subproject migration was initiated.

Circulating atrial natriuretic peptides in conscious rats: regulation of release by multiple factors.

Cardiocytes in the atria contain a prohormone that gives rise to atrial natriuretic peptides (ANP's), which have intrinsic hemodynamic regulatory activity. The distribution of ANP's in the brain suggests the involvement of these peptides in central cardiovascular regulation. In conscious rats with chronic indwelling catheters, volume loading with isotonic saline or glucose increased the amount of circulating immunoreactive ANP's by a factor of 4 to 5, as determined by radioimmunoassay. Hyperosmotic challenge with a hypertonic NaCl solution or anesthesia with halothane caused similar increases in plasma ANP's. Results obtained with the denervated-heart preparation indicate that neuronal influences are important in the release of ANP's induced by volume loading. As judged from reversed-phase high-performance liquid chromatography of extracted plasma and radioimmunoassay of collected fractions, the circulating physiologically important ANP's in the conscious rodent appear to be alpha-rANP(5-28) (atriopeptin III) and either alpha-rANP(3-28) [ANF(8-33)] or alpha-rANP(1-28) (ANF).

Potential of mid-infrared spectroscopy to aid the triage of patients with acute chest pain.

A total of 1,429 serum samples from 389 consecutive patients with acute chest pain were analyzed with the goal to aid the rapid diagnosis of acute myocardial infarction. To the best of our knowledge this is the largest and most comprehensive study on mid-infrared spectroscopy in cardiology. We were able to identify those signatures in the mid-infrared spectra of the samples, which were specific to either acute myocardial infarction or chest pain of other origin (angina pectoris, oesophagitis, etc). These characteristic spectral differences were used to distinguish between the cause of the donor's acute chest pain using robust linear discriminant analysis. A sensitivity of 88.5% and a specificity of 85.1% were achieved in a blind validation. The area under the receiver operating characteristics curve amounts to 0.921, which is comparable to the performance of routine cardiac laboratory markers within the same study population. The biochemical interpretation of the spectral signatures points towards an important role of carbohydrates and potentially glycation. Our studies indicate that the "Diagnostic Pattern Recognition (DPR)" method presented here has the potential to aid the diagnostic procedure as early as within the first 6 hours after the onset of chest pain.

Impact of apoptosis in acute rejection episodes after heart transplantation: immunohistochemical examination of right ventricular myocardial biopsies.

OBJECTIVE: Acute rejection may lead to cell death following heart transplantation. Programmed cell death (apoptosis) has been described as a cofactor for cell loss in cardiac tissue. The aim of our study was to quantify the amount and extent of apoptotic cells during acute rejection episodes after orthotopic heart transplantation. PATIENTS AND METHODS: Right ventricular biopsies from 27 heart transplant recipients were classified histologically according to rejection grade. Formalin-fixed sections were processed for immunohistochemistry. TUNEL-positive cells were counted and the expression of apoptosis-modulating factors Bax, Bcl-x(L), Bcl-2, and Ki-67 (proliferation marker) was scored. P

Interstitial leukocytes in right ventricular endomyocardial biopsies after heart transplantation in patients with complicated versus uneventful postoperative course.

BACKGROUND: Infections and rejections play key roles in morbidity and mortality in the early postoperative period after orthotopic heart transplantation (HTX). The aim of this study was to evaluate whether qualitative and quantitative analyses of various interstitial leukocytes in endomyocardial biopsies during the first 2 weeks after HTX provided early information on these complications. PATIENTS AND METHODS: During and after HTX, endomyocardial biopsies were obtained in 51 patients. By immunohistochemistry we determined the CD3-, CD4-, CD8-, CD15-, CD20-, CD57-, and CD68-positive cell numbers projected to planimetrically measured areas. To compare morbidity in the postoperative course, the patients were subdivided into complicated versus uncomplicated after 3 months. RESULTS: In the uncomplicated group, the cell counts of CD3-, CD8-, CD57-, and CD68-positive cells were significantly lower than in the complicated group. CD3-, CD4-, and CD8-positive cell numbers showed a significant decrease in the first week among the uncomplicated group. In the complicated group, the cell counts increased significantly in the second week. The numbers of CD57-positive cells were significantly lower during the first and second weeks among the uncomplicated group. CONCLUSIONS: Increased T lymphocytes, natural killer cells, and macrophages observed in the second week after HTX indicated increased morbidity. A reduction in CD3-positive cells in the first week indicated a low morbidity risk; an increase indicated a higher risk.

Right ventricular expression of extracellular matrix proteins, matrix-metalloproteinases, and their inhibitors over a period of 3 years after heart transplantation.

Fibrillar collagens I and III, nonfibrillar collagen IV, and the glycoproteins fibronectin and laminin, are elements of the myocardial extracellular matrix (ECM). Alterations in the normal concentrations and ratios of these elements may reflect remodeling in response to physiologic stress. In the case of patients' post-heart transplantation (HTx), specific patterns of alteration may herald myocardial dysfunction. Right ventricular biopsies were taken from the same 28 HTx patients before implantation and 1 week, 2 weeks, and 1, 2, and 3 years after HTx. The above-noted five ECM proteins, six matrix metalloproteinases (MMPs) and two of their tissue inhibitors (TIMPs) were detected by immunohistochemistry and scored as cells per square millimeter or semiquantitatively. The total connective tissue fibers were detected by connective tissue stain and morphometry. Variations in these ECM components were followed in the same patient cohort over 3 years. In summary, during the first 2 weeks after HTx, a predominant increase in connective tissue occurred. Increases in MMP-8 and MMP-9 were found. By 3 years after transplantation, there was a decrease of connective tissue fibers and a significant reduction of all ECM components and an increase in MMPs and TIMPs. These findings may reflect a pattern of remodeling specific to the transplanted heart.

Respiratory muscle dysfunction in congestive heart failure: clinical correlation and prognostic significance.

BACKGROUND: In congestive heart failure (CHF), the prognostic significance of impaired respiratory muscle strength has not been established. METHODS AND RESULTS: Maximal inspiratory pressure (Pi(max)) was prospectively determined in 244 consecutive patients (207 men) with CHF (ischemic, n=75; idiopathic dilated cardiomyopathy, n=169; age, 54+/-11 years; left ventricular ejection fraction [LVEF], 22+/-10%). Pi(max) was lower in the 244 patients with CHF than in 25 control subjects (7.6+/-3.3 versus 10.5+/-3.7 kPa; P=0.001). The 57 patients (23%) who died during follow-up (23+/-16 months; range, 1 to 48 months) had an even more reduced Pi(max) (6.3+/-3.2 versus 8.1+/-3.2 kPa in survivors; P=0.001). Kaplan-Meier survival curves differentiated between patients subdivided according to quartiles for Pi(max) (P=0.014). Pi(max) was a strong risk predictor in both univariate (P=0.001) and multivariate Cox proportional hazard analyses (P=0.03); multivariate analyses also included NYHA functional class, LVEF, peak oxygen consumption (peak VO(2)), and norepinephrine plasma concentration. The areas under the receiver-operating characteristic curves for prediction of 1-year survival were comparable for Pi(max) and peak VO(2) (area under the curve [AUC], 0.68 versus 0.73; P=0.28), and they improved with the triple combination of Pi(max), peak VO(2), and LVEF (AUC, 0.82; P=0.004 compared with AUC of Pi(max)). CONCLUSIONS: In patients with CHF, inspiratory muscle strength is reduced and emerges as a novel, independent predictor of prognosis. Because testing for Pi(max) is simple in clinical practice, it might serve as an additional factor to improve risk stratification and patient selection for cardiac transplantation.

Prognostic value of Doppler echocardiographic mitral inflow patterns: implications for risk stratification in patients with chronic congestive heart failure.

OBJECTIVES: This prospective study tested whether transmitral flow patterns add incremental value to peak oxygen consumption (VO2) in determining the prognosis of patients with chronic congestive heart failure (CHF) and systolic dysfunction. BACKGROUND: Peak VO2 is an objective marker of functional capacity and is routinely used as a criterion to identify heart transplant candidates. Diastolic dysfunction limits functional capacity, but its prognostic importance relative to that of peak VO2 is unknown. METHODS: Peak VO2 and mitral inflow velocities were prospectively measured in 311 consecutive patients (mean age 54 years, 84% male) with impaired left ventricular function (ejection fraction <40%; 88 patients with ischemic and 223 with dilated cardiomyopathy) who were evaluated for heart transplant candidacy. RESULTS: During a mean follow-up period of 512 +/- 314 days, 65 patients died and 43 patients underwent heart transplantation. Diastolic filling patterns, peak VO2 and left ventricular end-diastolic diameters were independent predictors of cardiac mortality. In patients with peak VO2 < or = 14 ml/min per kg body weight, the outcome was markedly poorer in the presence of restrictive filling patterns as compared with their absence (two-year survival rate 52% vs. 80%). Similarly, despite peak VO2 levels >14 ml/min per kg, the outcome was less favorable in the presence of restrictive filling patterns (two-year survival rate 80% vs. 94%). A risk-stratification model based on the identified independent noninvasive predictors separated groups into those with high (93%), intermediate (65%) and low (39%) two-year survival rates. CONCLUSIONS: Transmitral flow patterns add incremental value to peak VO2 in determining the prognosis of patients with CHF and impaired systolic function.

Desensitization of the pulmonary adenylyl cyclase system: a cause of airway hyperresponsiveness in congestive heart failure?

OBJECTIVES: This study was designed to investigate whether the adrenergic signal transduction in the lung and the responsiveness of airway smooth muscle to adrenergic stimulation are modulated in congestive heart failure. BACKGROUND: Wheezing and airway hyperresponsiveness are often present in heart failure. In the failing heart, chronic adrenergic stimulation down-regulates beta-adrenergic receptors and adenylyl cyclase. We hypothesized that airway dysfunction in heart failure could be due to a similar modulation of pulmonary adrenergic signal transduction. METHODS: Heart failure was induced in rats by aortic banding, resulting in increases in plasma norepinephrine, lung wet weight indicating congestion and left ventricular end diastolic pressure after four weeks. Beta-receptor densities in pulmonary plasma membranes were measured by radioligand binding using [125I]iodocyanopindolol. The G protein levels were determined by Western blot. Adenylyl cyclase activities in lung membranes were quantified as [32P]cAMP (cyclic adenosine-5'-monophosphate) synthesis rate. To functionally assess airway smooth muscle relaxation, carbachol-precontracted isolated tracheal strips were used. RESULTS: Beta-receptor density was significantly decreased in heart failure from 771 +/- 89 to 539 +/- 44 fmol/mg protein without changes in receptor affinities. The beta1-/beta2-subtype ratio, however, remained constant. The G(i and alpha) and G(s alpha) protein expression was unchanged. Adenylyl cyclase activity stimulated directly with forskolin was decreased by 28%. Relaxation of tracheal strips in response to isoproterenol and forskolin, but not to papaverin, was diminished by 30%. CONCLUSIONS: In heart failure, the down-regulation of pulmonary beta-receptors and concomitant decrease in adenylyl cyclase activity result in a significant attenuation of cAMP-mediated airway relaxation. These mechanisms may play a pivotal role in the pathogenesis of"cardiac asthma."

Extracellular matrix proteins and matrix metalloproteinases differ between various right and left ventricular sites in end-stage cardiomyopathies.

This study was undertaken to investigate whether there might be differences in the distribution of extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs), depending on their specific sites within the heart. We investigated 33 explanted human hearts, 15 with dilated cardiomyopathy (DCM) and 18 with ischemic cardiomyopathy (ICM). Transmural samples from the right ventricle, the interventricular septum and the left ventricle, either from near the apex or from near the base were taken from every heart. Frozen sections were processed for connective tissue staining and immunohistochemistry for collagens type I, III, IV, laminin and fibronectin, as well as MMP-1, -2 and -9. Volume densities of laminin in ICM as well as of fibronectin and collagen types I and IV in DCM showed significant differences between right and left ventricular sites. The volume densities of matrix proteins usually did not reveal significant differences among the three left ventricular sites tested in both DCM and ICM. MMPs partly showed differences between the right and the left ventricular myocardium. These results suggest that the distributions of ECM proteins and MMPs differ between the two ventricles in both end-stage DCM and ICM. This gives rise to the hypothesis that a specific pattern of ECM degradation exists in the right and left ventricular myocardium.

The bradycardic agent zatebradine enhances baroreflex sensitivity and heart rate variability in rats early after myocardial infarction.

OBJECTIVE: The bradycardic agent zatebradine (UL-FS 49) reduces heart rate without negative inotropic or proarrhythmic effects. The aim was to experimentally characterize the influence of zatebradine on arterial baroreflex sensitivity (BRS) and heart rate variability (HRV) which are generally considered as estimates of vagal activity and have prognostic value in patients after myocardial infarction (MI). METHODS: Conscious rats were studied 3 days after left coronary artery ligation or sham-operation (SH). BRS was determined by linear regression analysis of RR-interval and mean arterial pressure changes evoked by intravenous (i.v.) injections of methoxamine and nitroprusside. HRV at rest was calculated from high-resolution electrocardiogram-recordings. RESULTS: In MI-rats heart rate was similar to SH-rats, mean arterial pressure was lower and both BRS and HRV were markedly reduced. Zatebradine (0.5 mg/kg i.v.) reduced heart rate in MI-rats from 400 +/- 15 to 350 +/- 19 and in SH-rats from 390 +/- 19 to 324 +/- 6 beats/min without changing mean arterial pressure. Both BRS and HRV were restored in MI- and further increased in SH-rats by the drug. Effects of 0.05, 0.5 and 5 mg/kg zatebradine revealed a dose-dependency of heart rate reduction. The lowest dose enhanced reflex bradycardia despite little effect on heart rate and lack of effect on both reflex tachycardia and HRV. CONCLUSIONS: Both BRS and HRV are reduced in rats early after MI, indicating a depressed reflex and tonic vagal activity. Treatment with zatebradine enhances both BRS and HRV. These data suggest that the drug has both peripheral and central effects, leading to an increase of vagal control of heart rate.

Angiotensin inhibition and atrial natriuretic peptide release after acute volume expansion in rats with aortocaval shunt.

OBJECTIVE: In heart failure atrial natriuretic peptide (ANP) release in response to volume expansion is impaired while the renin-angiotensin system is activated. This study was designed to test the hypothesis that ANP release in heart failure is dependent on an activated angiotensin system. METHODS: We studied the ANP and renin-angiotensin systems in a rat model of shunt-induced high-output heart failure, in which we rapidly increased circulating fluid volume with a 5 ml, hyperoncotic infusion, and evaluated the effects of acute inhibition of the angiotensin converting enzyme as well as of the blockade of the angiotensin II type 1 receptors on the ANP release and on renal excretory function. RESULTS: ANP and angiotensin II plasma concentrations prior to volume expansion were elevated (p < 0.05) in rats with aortocaval shunt compared to controls. The diuretic response to acute volume expansion (18.5 +/- 1.5 vs. 48.2 +/- 2.4 microliters/min, p < 0.001) was markedly blunted. ANP release was attenuated in rats with aortocaval shunt, as was the increase of its second messenger cGMP in plasma and urine. The blunted increase in ANP plasma levels was not due to depleted cardiac stores as cardiac ANP content, as well as ANP synthesis, were increased (p < 0.05). Acute inhibition of the angiotensin converting enzyme as well as blockade of the angiotensin II type 1 receptors restored ANP release in response to volume expansion (p < 0.01). Moreover, acute inhibition of the renin-angiotensin system completely normalized the diuretic response. CONCLUSIONS: Our data suggest that the ANP system is impaired in rats with aortocaval shunt. The activation of the angiotensin system contributes to the impairment of the ANP system. Acute inhibition of the angiotensin II system significantly improved the ability of the ANP system to respond to acute volume expansion. Our findings indicate a hitherto fore unappreciated interaction between both systems and suggest additional mechanisms for the beneficial effects of angiotensin converting enzyme inhibition or angiotensin II type 1 receptor antagonists in heart failure.

Two different cDNAs encoding TFIID proteins of maize.

Two different complementary DNAs (cDNAs) encoding maize TFIID proteins were isolated from a maize leaf cDNA. Both cDNA sequences reveal two types of TFIID, each encoding an open reading frame of 200 amino acids. The two cDNAs are 76% identical at the DNA level and their putative amino acid sequences differ at only three amino acids. Like TATA box binding proteins from other organisms they show a bipartite structure containing a specific N-terminal region and a highly conserved C-terminal domain expected to be necessary and sufficient for the essential TFIID functions in transcriptional initiation.

Role of right and left atrial dimensions for release of atrial natriuretic peptide in left-sided valvular heart disease and idiopathic dilated cardiomyopathy.

To evaluate the role of atrial dimensions for release of atrial natriuretic peptide (ANP), right and left atrial dimensions (cross-sections) were determined by 2-dimensional echocardiography in 50 patients with left-sided valvular heart disease or idiopathic dilated cardiomyopathy. All patients underwent right- and left-sided heart catheterization with measurement of central hemodynamics. Plasma samples for ANP were withdrawn from femoral vein (ANPv) and ascending aorta. An estimate of right and left meridional atrial wall stress was derived by multiplying cross-sectional areas with pressures of the respective atria. As expected ANPv was closely related to mean right (r = 0.63; p less than 0.001; n = 50) and left atrial pressures (r = 0.61; p less than 0.001; n = 47). Furthermore, a positive correlation between ANPv and right (r = 0.56; p less than 0.001; n = 48) and left (r = 0.30; p less than 0.05; n = 48) atrial cross-sections was obtained. Finally, an excellent relation was found between ANPv and right (r = 0.73; p less than 0.001; n = 48) as well as left (r = 0.58; p less than 0.001; n = 44) meridional atrial wall stress, indicating that atrial wall stress rather than atrial pressures or dimensions alone determines plasma ANP concentrations. However, for identical right and left meridional atrial wall stress 3- to 4-times higher plasma ANPv levels were obtained in patients with idiopathic dilated cardiomyopathy than in patients with left-sided valvular heart disease. This indicates that release of ANP to the same stimulus may be modulated by the nature of the underlying heart disease.

Risk stratification in middle-aged patients with congestive heart failure: prospective comparison of the Heart Failure Survival Score (HFSS) and a simplified two-variable model.

AIMS: The performance of a US-American scoring system (Heart Failure Survival Score, HFSS) was prospectively evaluated in a sample of ambulatory patients with congestive heart failure (CHF). Additionally, it was investigated whether the HFSS might be simplified by assessment of the distance ambulated during a 6-min walk test (6'WT) instead of determination of peak oxygen uptake (peak VO(2)). METHODS AND RESULTS: In 208 middle-aged CHF patients (age 54+/-10 years, 82% male, NYHA class 2.3+/-0.7; follow-up 28+/-14 months) the seven variables of the HFSS: CHF aetiology; heart rate; mean arterial pressure; serum sodium concentration; intraventricular conduction time; left ventricular ejection fraction (LVEF); and peak VO(2), were determined. Additionally, a 6'WT was performed. The HFSS allowed discrimination between patients at low, medium and high risk, with mortality rates of 16, 39 and 50%, respectively. However, the prognostic power of the HFSS was not superior to a two-variable model consisting only of LVEF and peak VO(2). The areas under the receiver operating curves (AUC) for prediction of 1-year survival were even higher for the two-variable model (0.84 vs. 0.74, P<0.05). Replacing peak VO(2) with 6'WT resulted in a similar AUC (0.83). CONCLUSION: The HFSS continued to predict survival when applied to this patient sample. However, the HFSS was inferior to a two-variable model containing only LVEF and either peak VO(2) or 6'WT. As the 6'WT requires no sophisticated equipment, a simplified two-variable model containing only LVEF and 6'WT may be more widely applicable, and is therefore recommended.

Atrial natriuretic factor. Its possible role in hypertension and congestive heart failure.

The atrial natriuretic factor (ANF) is a circulating peptide, consisting of 24 to 28 amino acids. Atrial natriuretic factor is synthetized in atrial cardiomyocytes and stored in specific cytoplasmatic granules. It possesses potent diuretic, natriuretic, and vasorelexant properties. The possible role of ANF in the pathogenesis of hypertension and heart failure was investigated in animal models and in men. We were able to show that the release of ANF from cardiac atria is positively correlated with atrial pressures in both men and rats. In experimental studies, plasma levels of ANF measured by radioimmunoassay, were increased by up to four-fold after acute blood volume expansion. Atrial natriuretic factor release in response to volume loading was markedly attenuated in four-week-old spontaneously hypertensive rats as compared to age-matched normotensive Wistar-Kyoto rats, but a similar responsiveness was found in 16-week-old rats of both strains. This finding can be reconciled with the hypothesis that ANF plays a pathophysiological role in initiating but not maintaining high blood pressure. Clinical studies demonstrate elevated plasma concentrations of ANF in patients with organic heart disease. Further increments in plasma levels of ANF were obtained during physical exercise and after acute volume loading. In patients with congestive cardiomyopathy, the elevated plasma concentrations of ANF reached almost normal levels following improvement of their hemodynamic disturbances after treatment with converting-enzyme inhibitors. These findings suggest that in patients with organic heart disease, plasma concentrations of ANF reflect the hemodynamic burden of the heart and may, therefore, be used as a noninvasive marker of the efficacy of the current cardiac therapy.

Atrial natriuretic peptide mRNA in patients with heart disease.

The regulation of atrial natriuretic peptide (ANP) synthesis within cardiac atrial myocytes was investigated in 8 patients undergoing cardiac surgery (valve replacement or coronary bypass graft). Hemodynamic data were obtained during cardiac catheterization and venous plasma samples for ANP were withdrawn prior to surgery. Probes for determination of tissue ANP levels and ANPmRNA concentrations were taken from the right atrium. Both plasma ANP (r = 0.75; P less than .05) and ANPmRNA (r = 0.86; P less than .01) were closely related to mean pulmonary artery pressure. ANPmRNA was also related to plasma ANP (r = 0.60; P less than .07). However, no significant relationships were obtained between either plasma ANP or ANPmRNA and right atrial ANP concentrations. These data suggest that right atrial ANP synthesis is regulated by cardiac filling pressures and possibly by plasma ANP levels, independent from corresponding ANP tissue concentrations.

Neuropeptide Y and peptide YY mediate nonadrenergic vasoconstriction and modulate sympathetic responses in rats.

The modulation of cardiovascular sympathetic responses by neuropeptide Y (NPY) and peptide YY (PYY) was assessed in vivo, in pithed rats. Both peptides (0.02-2 nmol/kg) caused similar dose-dependent pressor responses, resistant to adrenergic blockade but antagonized by the calcium channel blocker, nifedipine. Only NPY, at the lowest dose, slightly accelerated heart rate (by 10 +/- 4 beats/min). At the pressor dose (0.6 nmol/kg) but not subpressor dose (0.2 nmol/kg), the increase in blood pressure induced by stimulation of the sympathetic outflow (ST: 0.3 Hz, 50 V, 1 min) was attenuated by PYY (by 40%), whereas ST-evoked tachycardia was reduced by NPY (by 35%). Neither NPY- nor PYY-pretreatment affected ST-induced increments in plasma norepinephrine (NE) and epinephrine concentrations. In addition, regional hemodynamic effects of NPY were studied in conscious rats instrumented with Doppler flow probes. The hypertension caused by NPY was attended by reflex bradycardia and marked rise in peripheral vascular resistance in renal (+ 233 +/- 59%), superior mesenteric (+ 183 +/- 65%) and hindquarter (+ 65 +/- 10%) circulation. The pattern of hemodynamic responses of NPY was similar to that of NE but, unlike the latter, persisted after adrenergic blockade.

Effect of moxonidine on blood pressure and sympathetic tone in conscious spontaneously hypertensive rats.

The effects of moxonidine on blood pressure, heart rate and sympathetic tone were studied in conscious spontaneously hypertensive rats. Intravenous moxonidine (80 nmol) transiently increased blood pressure without affecting heart rate or splanchnic nerve activity. Moxonidine (20-80 nmol) given into the fourth cerebral ventricle dose-dependently lowered mean arterial pressure, heart rate and sympathetic outflow (maximally by 60 +/- 3 mm Hg, 148 +/- 10 beats min(-1) and 15 +/- 3 microV). Moxonidine was more effective by this route than after the injection into the lateral ventricle. Clonidine (20-80 nmol) produced an initial pressor response after both intracerebroventricular routes of administration. A decrease in blood pressure was observed only when clonidine was given into the fourth ventricle. Clonidine decreased heart rate and splanchnic nerve activity similarly like moxonidine when the substances were given into the fourth ventricle. The data imply that the hypotensive effect of moxonidine is related to central sympathoinhibition. The main site of this action appears to be in the brainstem region.

Neuropeptide Y mRNA regulation in rat sympathetic ganglia: effect of reserpine.

To study the mechanism underlying trans-synaptic neuropeptide regulation, mRNA levels of neuropeptide Y were examined in the rat stellate and superior cervical ganglia using a specific neuropeptide Y cRNA probe. Basal levels of neuropeptide Y mRNA were detectable in total RNA extracts from single ganglia. Reserpine induced a large rise in ganglion neuropeptide Y mRNA. Decentralization prevented the increase of neuropeptide Y mRNA content in the ganglia. This suggests that the reserpine induced increase in neuropeptide Y mRNA was dependent on transsynaptic stimulation. Consequently, neuropeptide mRNA levels in sympathetic ganglia may be under the control of preganglionic impulse flow.