[Hyperuricemia - more than gout : Impact on cardiovascular risk and renal insufficiency]. / Hyperurikämie - mehr als Gicht : Auswirkung auf das kardiovaskuläre Risiko und die Niereninsuffizienz.

BACKGROUND: Hyperuricemia is not only associated with gout but also with hypertension, atherosclerosis and chronic kidney disease (CKD); however, in cases of disproportionally high serum uric acid levels without symptoms of gout and slowly progressive chronic kidney failure especially in young people, a genetic cause of hyperuricemia needs to be considered. PATHOGENETIC ASSOCIATIONS: The results of experimental studies suggest that hyperuricemia can be a pathophysiologically relevant cardiovascular risk factor. In animal studies hyperuricemia leads to oxidative stress and vascular dysfunction and chronically elevated uric acid levels can result in structural changes of the vessel wall. Epidemiological data show a connection between hyperuricemia and hypertension and uric acid lowering therapy has been shown to lower arterial blood pressure. In CKD, uric acid increases in parallel with the decline in GFR and an increase in proteinuria. Several ongoing prospective clinical trials will clarify if pharmacological lowering of uric acid will translate into reduction of relevant cardiovascular and renal endpoints. THERAPY: The treatment of gout and the medicinal prophylaxis of further gout attacks depend on the comorbidities and especially CKD.

[Medicinal or instrumental (corrected) therapy of renal artery stenosis?]. / Medikamentöse oder instrumentelle Therapie der Nierenarterienstenose?

Arteriosclerotic renal artery stenosis (RAS) has an increased incidence in patients with cardiovascular risk factors. Clinically RAS presents in some patients as secondary, sometimes resistant arterial hypertension and in others as chronic renal insufficiency, sometimes with acute renal failure and in a third group both symptoms are observed. Doppler ultrasound plays a central role in the diagnosis of RAS. Therapeutically, it is important to identify hemodynamically relevant RAS before interventional therapy is initiated. The therapy of RAS has been under intensive debate since the publication of randomized controlled trials (RCT) which showed that only a subset of RAS can be successfully treated by interventional therapy. Since then the medicinal therapy of RAS has gained more and more impact. The following questions are raised: which forms of RAS can be treated by which therapy? What is the best medicinal therapy to treat RAS? What substances are recommended?

Chronic treatment with angiotensin-(1-7) improves renal endothelial dysfunction in apolipoproteinE-deficient mice.

BACKGROUND AND PURPOSE: ApolipoproteinE-deficient [apoE (-/-)] mice, a model of human atherosclerosis, develop endothelial dysfunction caused by decreased levels of nitric oxide (NO). The endogenous peptide, angiotensin-(1-7) [Ang-(1-7)], acting through its specific GPCR, the Mas receptor, has endothelium-dependent vasodilator properties. Here we have investigated if chronic treatment with Ang-(1-7) improved endothelial dysfunction in apoE (-/-) mice. EXPERIMENTAL APPROACH: ApoE (-/-) mice fed on a lipid-rich Western diet were divided into three groups and treated via osmotic minipumps with either saline, Ang-(1-7) (82 µg·kg(-1) ·h(-1) ) or the same dose of Ang-(1-7) together with D-Ala-Ang-(1-7) (125 µg·kg(-1) ·h(-1) ) for 6 weeks. Renal vascular function was assessed in isolated perfused kidneys. KEY RESULTS: Ang-(1-7)-treated apoE (-/-) mice showed improved renal endothelium-dependent vasorelaxation induced by carbachol and increased renal basal cGMP production, compared with untreated apoE (-/-) mice. Tempol, a reactive oxygen species (ROS) scavenger, improved endothelium-dependent vasorelaxation in kidneys of saline-treated apoE (-/-) mice whereas no effect was observed in Ang-(1-7)-treated mice. Chronic treatment with D-Ala-Ang-(1-7), a specific Mas receptor antagonist, abolished the beneficial effects of Ang-(1-7) on endothelium-dependent vasorelaxation. Renal endothelium-independent vasorelaxation showed no differences between treated and untreated mice. ROS production and expression levels of the NAD(P)H oxidase subunits gp91phox and p47phox were reduced in isolated preglomerular arterioles of Ang-(1-7)-treated mice, compared with untreated mice, whereas eNOS expression was increased. CONCLUSION AND IMPLICATIONS: Chronic infusion of Ang-(1-7) improved renal endothelial function via Mas receptors, in an experimental model of human cardiovascular disease, by increasing levels of endogenous NO.

Effects of high dose olmesartan medoxomil plus hydrochlorothiazide on blood pressure control in patients with grade 2 and grade 3 hypertension.

High dose (40 mg) olmesartan medoxomil (OM) blocks the angiotensin II receptor, significantly reducing blood pressure (BP). Adding hydrochlorothiazide (HCTZ) to OM increases efficacy, but has not been evaluated in patients inadequately controlled by OM 40 mg. Patients with grade 2 and grade 3 hypertension with inadequately controlled BP (seated diastolic blood pressure [SeDBP] 90-115 mm Hg and seated systolic blood pressure [SeSBP] 140-180 mm Hg, plus ambulatory BP criteria) after 8 weeks of OM 40 mg open-label treatment were randomized to 8 weeks of double-blind treatment with OM/HCTZ 40/25 (n=140), 40/12.5 (n=278), 20/12.5 mg (n=280) or OM 40 mg (n=274). Treatment with OM/HCTZ 40/25 mg and 40/12.5 mg significantly reduced SeDBP (-5.3 and -3.4 mm Hg, respectively), and SeSBP (-7.4 and -5.2 mm Hg, respectively), vs OM 40 mg monotherapy (P<0.0001 for each) in patients inadequately controlled on OM 40 mg alone. OM/HCTZ 40/12.5 mg reduced SeSBP significantly more than OM/HCTZ 20/12.5 mg (-2.6 mm Hg, P=0.0255), and also produced a further reduction in SeDBP vs the lower dose. All treatments were well tolerated, with similar low proportions of patients reporting treatment-emergent adverse events in all treatment groups. In conclusion, adding HCTZ to OM 40 mg significantly improves BP reductions and target BP rates in harder-to-treat patients and a clear dose-response was observed for efficacy.

Nephrolithiasis and hematuria--sometimes a stony road to diagnosis.

We report a case of a young man with a history of kidney stones. Occurrence of gross hematuria several months after the extracorporeal shock wave, lithotripsy (ESWL) treatment lead to hospitalization. By ultrasound and abdominal CT scan, the urologist could exclude post-renal causes of the gross hematuria and acute renal failure. After transfer to a department of nephrology hemodialysis was started, an immediate kidney biopsy was performed and prednisolone was administered on the same day. The kidney biopsy revealed an anti-glomerular basement membrane (GBM) disease. The renal function did not recover and the patient remained on hemodialysis. In the literature it has been hypothesized that ESWL-treated patients are prone to develop anti-GBM disease by liberation of glomerular basement antigen through the ESWL high energy shock waves. An additional hypothesis considering the higher susceptibility for anti-GBM disease among certain HLA-tissue types is discussed with regard to our case. Unfortunately, the prolonged track to diagnosis and delayed immunosuppressive treatment could not prevent poor clinical outcome. Although anti-GBM disease is a rather rare disease, it should be included as a differential diagnosis for hematuria--especially months after ESWL treatment. Otherwise early diagnosis may be missed and as in our patient immunosuppressive treatment will remain unsuccessful to recover renal function.

Dihydrotachysterol therapy for hypoparathyroidism: consequences of inadequate monitoring. Five cases and a review.

BACKGROUND: The half synthetic Vitamin D analogue dihydrotachysterol (DHT) is widely used for hypocalcaemic hypoparathyroidism following surgical removal of parathyroids. Such treatment generally initiated by surgeons right after surgery has to be continued in clinical practice. Unfortunately, the required careful monitoring of calcium metabolism is often lacking and as demonstrated may lead to life-threatening conditions. PATIENTS AND METHODS: Here we report on five patients referred to our nephrology unit because of unknown impairment of renal function during therapy with DHT. All patients had clinical signs of hypercalcaemia. Since most symptoms are nonspecific they were not perceived by primary care physicians. In fact DHT treatment was continued for 4 - 50 years. In all cases calcium levels were determined after inadequate long intervals ranging from 3.08 to 4.97 mmol/l. Creatinine levels ranged from 277 to 365 micromol/l. All patients suffered from symptoms of severe hypercalcaemia, three of them needing intensive care unit treatment. RESULTS: All patients were treated effectively with a regimen consisting of intravenous saline, a loop diuretic, and application of bisphosphonates. As confirmed by renal biopsy persisting alleviation of renal function was due to calcifications. After discontinuation of DHT therapy patients were safely switched to shorter acting vitamin D derivates maintaining a normal calcium level. CONCLUSIONS: In comparison to short acting vitamin-D derivates hypercalcaemic episodes with DHT appear to last longer and may therefore occur with higher incidence. A future option could be the use of synthetic parathyroid hormone (s-PTH) recently shown to be safe and effective. Nevertheless a customized therapy and careful monitoring is indispensable in any case to prevent irreversible organ damage.

The cytoplasmic C-terminal fragment of polycystin-1 regulates a Ca2+-permeable cation channel.

The cytoplasmic C-terminal portion of the polycystin-1 polypeptide (PKD1(1-226)) regulates several important cell signaling pathways, and its deletion suffices to cause autosomal dominant polycystic kidney disease. However, a functional link between PKD1 and the ion transport processes required to drive renal cyst enlargement has remained elusive. We report here that expression at the Xenopus oocyte surface of a transmembrane fusion protein encoding the C-terminal portion of the PKD1 cytoplasmic tail, PKD1(115-226), but not the N-terminal portion, induced a large, Ca(2+)-permeable cation current, which shifted oocyte reversal potential (E(rev)) by +33 mV. Whole cell currents were sensitive to inhibition by La(3+), Gd(3+), and Zn(2+), and partially inhibited by SKF96365 and amiloride. Currents were not activated by bath hypertonicity, but were inhibited by acid pH. Outside-out patches pulled from PKD1(115-226)-expressing oocytes exhibited a 5.1-fold increased NP(o) of endogenous 20-picosiemens cation channels of linear conductance. PKD1(115-226)-injected oocytes also exhibited elevated NP(o) of unitary calcium currents in outside-out and cell-attached patches, and elevated calcium permeability documented by fluorescence ratio and (45)Ca(2+) flux experiments. Both Ca(2+) conductance and influx were inhibited by La(3+). Mutation of candidate phosphorylation sites within PKD1(115-226) abolished the cation current. We conclude that the C-terminal cytoplasmic tail of PKD1 up-regulates inward current that includes a major contribution from Ca(2+)-permeable nonspecific cation channels. Dysregulation of these or similar channels in autosomal dominant polycystic kidney disease may contribute to cyst formation or expansion.

Origin and appearance of HITS induced by prosthetic heart valves: an in vitro study.

Patients with mechanical heart valve prostheses show significantly enhanced numbers of HITS detected by transcranial Doppler ultrasound. In order to assess the origin of HITS formation, an in vitro study was set out to quantify valve induced microemboli for mechanical and bioprosthetic valves under various circulatory conditions by means of Ultrasound-Doppler-Sonography. At the same time the influence of CO2 partial pressure on HITS rate vas investigated. It can be summarised that for mechanical heart valve prostheses a strong correlation exists between left ventricular dp/dtmax and the detected HITS rates. It was also demonstrated that a bioprosthesis generates significantly less HITS than a mechanical valve. The origin of HITS is gaseous since the tests were carried out using a cell-free filtered water-glycerol test fluid. The HITS rate could be increased by increasing the amount of dissolved gas within the test fluid. The results support the hypothesis that cavitation is the key factor in the appearance of gaseous microemboli at heart valve prostheses.

14-3-3 interacts with regulator of G protein signaling proteins and modulates their activity.

Regulator of G protein signaling (RGS) proteins function as GTPase-activating proteins (GAPs) that stimulate the inactivation of heterotrimeric G proteins. We have recently shown that RGS proteins may be regulated on a post-translational level (Benzing, T., Brandes, R., Sellin, L., Schermer, B., Lecker, S., Walz, G., and Kim, E. (1999) Nat. Med. 5, 913-918). However, mechanisms controlling the GAP activity of RGS proteins are poorly understood. Here we show that 14-3-3 proteins associate with RGS7 and RGS3. Binding of 14-3-3 is mediated by a conserved phosphoserine located in the Galpha-interacting portion of the RGS domain; interaction with 14-3-3 inhibits the GAP activity of RGS7, depends upon phosphorylation of a conserved residue within the RGS domain, and results in inhibition of GAP function. Collectively, these data indicate that phosphorylation-dependent binding of 14-3-3 may act as molecular switch that controls the GAP activity keeping a substantial fraction of RGS proteins in a dormant state.

Upregulation of RGS7 may contribute to tumor necrosis factor-induced changes in central nervous function.

The central nervous dysfunctions of lethargy, fever and anorexia are manifestations of sepsis that seem to be mediated by increased cytokine production. Here we demonstrate that tumor necrosis factor (TNF)-alpha, an essential mediator of endotoxin-induced sepsis, prevents the proteasome-dependent degradation of RGS7, a regulator of G-protein signaling. The stabilization of RGS7 by TNF-alpha requires activation of the stress-activated protein kinase p38 and the presence of candidate mitogen-activated protein kinase phosphorylation sites. In vivo, RGS7 is rapidly upregulated in mouse brain after exposure to either endotoxin or TNF-alpha, a response that is nearly abrogated in mice lacking TNF receptor 1. Our findings indicate that TNF-mediated upregulation of RGS7 may contribute to sepsis-induced changes in central nervous function.

Interaction between RGS7 and polycystin.

Regulators of G protein signaling (RGS) proteins accelerate the intrinsic GTPase activity of certain Galpha subunits and thereby modulate a number of G protein-dependent signaling cascades. Currently, little is known about the regulation of RGS proteins themselves. We identified a short-lived RGS protein, RGS7, that is rapidly degraded through the proteasome pathway. The degradation of RGS7 is inhibited by interaction with a C-terminal domain of polycystin, the protein encoded by PKD1, a gene involved in autosomal-dominant polycystic kidney disease. Furthermore, membranous expression of C-terminal polycystin relocalized RGS7. Our results indicate that rapid degradation and interaction with integral membrane proteins are potential means of regulating RGS proteins.

Effects of combination antihypertensive therapy on baroreflex sensitivity and heart rate variability in systemic hypertension.

Earlier studies have shown that cardiovascular autonomic regulation is impaired in untreated or poorly controlled systemic hypertension. The purpose of this double-blind, randomized parallel trial was to evaluate whether improved blood pressure (BP) control can reverse this impairment. The study group consisted of 33 patients (age 45 to 63 years) with poor BP control who received randomized metoprolol or enalapril monotherapy. Baroreflex sensitivity (BRS) was assessed by phenylephrine test and time- and frequency-domain measurements of heart rate variability (HRV) were analyzed from 24-hour ambulatory electrocardiographic recordings during monotherapy and after 10 weeks of combination therapy with metoprolol + felodipine or enalaril + hydrochlorothiazide to lower casual BP to < 140/90 mm Hg. Intensified treatment decreased 24-hour systolic and diastolic BP from 139 +/- 12/86 +/- 8 mm Hg to 126 +/- 8/80 +/- 7 mm Hg (p <0.0001). BRS improved from 6.2 +/- 3.2 ms/mm Hg to 8.9 +/- 4.1 ms/mm Hg (p <0.0001) and measurements of HRV (e.g., SD of all RR intervals from 128 +/- 45 ms to 145 +/- 46 ms, p <0.001) improved significantly during the combination therapy. Changes in BRS and HRV were similar in magnitude in both treatment arms. Mean RR intervals were comparable before and after intensive antihypertensive therapy (850 +/- 124 ms vs 937 +/- 279 ms, p = NS). These data indicate that adequate BP control with modem antihypertensive combination therapy can improve cardiovascular autonomic function, which may partially explain the reduced cardiac mortality observed in patients with intensified antihypertensive therapy.

Using simulated noise to define optimal QT intervals for computer analysis of ambulatory ECG.

The ambulatory electrocardiogram (ECG) is an important medical tool, not only for diagnosis of adverse cardiac events, but also to predict the risk of such events occurring. The 24-hour ambulatory ECG has certain problems and drawbacks because the signal is corrupted by noise from various sources and also several other conditions which may alter the ECG morphology. We have developed a Windows based program for the computer analysis of ambulatory ECG which attempts to address these problems. The software includes options for importing ECG data, different methods of waveform analysis, data-viewing, and exporting the extracted time series. In addition, the modular structure allows for flexible maintenance and expansion of the software. The ECG was recorded using a Holter device and oversampled to enhance the fidelity of the low sampling rate of the ambulatory ECG. The influence of different sampling rates on the interval variability were studied. The noise sensitivity of the implemented algorithm was tested with several types of simulated noise and the precision of the interval measurement was reported with SD values. Our simulations showed that, in most of the cases, defining the end of QT interval at the maximum of the T wave gave the most precise measurement. The definition of the onset of the ventricular repolarization duration is most precisely made on the maximum or descending maximal slope of the R wave. We also analyzed some examples of time series from patients using power spectrum estimates in order to validate the low level QT interval variability.

Modulation of renal tubular cell function by RGS3.

The recently discovered family of regulators of G protein signaling (RGS) accelerates the intrinsic GTPase activity of certain Galpha subunits, thereby terminating G protein signaling. Particularly high mRNA levels of one family member, RGS3, are found in the adult kidney. To establish the temporal and spatial renal expression pattern of RGS3, a polyclonal antiserum was raised against the COOH terminus of RGS3. Staining of mouse renal tissue at different gestational stages revealed high levels of RGS3 within the developing and mature tubular epithelial cells. We tested whether RGS3 can modulate tubular migration, an important aspect of tubular development, in response to G protein-mediated signaling. Several mouse intermedullary collecting duct (mIMCD-3) cell lines were generated that expressed RGS3 under the control of an inducible promoter. Lysophosphatidic acid (LPA) is a potent chemoattractant that mediates its effects through heterotrimeric G proteins. We found that induction of RGS3 significantly reduced LPA-mediated cell migration in RGS3-expressing mIMCD-3 clones, whereas chemotaxis induced by hepatocyte growth factor remained unaffected by RGS3. Our findings suggest that RGS3 modulates tubular functions during renal development and in the adult kidney.

Cellular activation triggered by the autosomal dominant polycystic kidney disease gene product PKD2.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by germ line mutations in at least three ADPKD genes. Two recently isolated ADPKD genes, PKD1 and PKD2, encode integral membrane proteins of unknown function. We found that PKD2 upregulated AP-1-dependent transcription in human embryonic kidney 293T cells. The PKD2-mediated AP-1 activity was dependent upon activation of the mitogen-activated protein kinases p38 and JNK1 and protein kinase C (PKC) epsilon, a calcium-independent PKC isozyme. Staurosporine, but not the calcium chelator BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N', N'-tetraacetate], inhibited PKD2-mediated signaling, consistent with the involvement of a calcium-independent PKC isozyme. Coexpression of PKD2 with the interacting C terminus of PKD1 dramatically augmented PKD2-mediated AP-1 activation. The synergistic signaling between PKD1 and PKD2 involved the activation of two distinct PKC isozymes, PKC alpha and PKC epsilon, respectively. Our findings are consistent with others that support a functional connection between PKD1 and PKD2 involving multiple signaling pathways that converge to induce AP-1 activity, a transcription factor that regulates different cellular programs such as proliferation, differentiation, and apoptosis. Activation of these signaling cascades may promote the full maturation of developing tubular epithelial cells, while inactivation of these signaling cascades may impair terminal differentiation and facilitate the development of renal tubular cysts.

The polycystic kidney disease 1 gene product modulates Wnt signaling.

Two distinct signaling pathways, involving Wnt signaling and polycystin, have been found to be critical for normal kidney development. Renal tubulogenesis requires the presence of certain Wnt proteins, whereas mutations in polycystin impede the terminal differentiation of renal tubular epithelial cells, causing the development of large cystic kidneys that characterize autosomal dominant polycystic kidney disease. Polycystin is an integral membrane protein, consisting of several extracellular motifs indicative of cell-cell and cell-matrix interactions, coupled through multiple transmembrane domains to a functionally active cytoplasmic domain. We report here that expression of the C-terminal cytoplasmic domain of polycystin stabilizes soluble endogenous beta-catenin and stimulates TCF-dependent gene transcription in human embryonic kidney cells. Microinjection of the polycystin C-terminal cytoplasmic domain induces dorsalization in zebrafish. Our findings suggest that polycystin has the capacity to modulate Wnt signaling during renal development.

Effect of 3,4-diaminopyridine on rat extensor digitorum longus muscle paralyzed by local injection of botulinum neurotoxin.

The actions of the K+ channel blocker, 3,4-diaminopyridine (3,4-DAP), were studied in the rat extensor digitorum longus (EDL) muscle following local inhibition of neuromuscular transmission by botulinum neurotoxin (BoNT). Local paralysis of the EDL muscle was induced by s.c. injections of BoNT serotypes A, B, E or F over the anterior tibialis muscle. One to 14 days later, the rats were anesthetized with urethane, and isometric twitch tensions following stimulation of the peroneal nerve were measured in situ. Muscles were paralyzed within 24 hr of administration of 5 mouse LD50 units (U) of BoNT/A and remained inhibited for the entire 14-day period of observation. Similar levels of inhibition, but of shorter duration, were observed after local injection of 20 U of BoNT/E, 10(4) U of BoNT/B or 20 U of BoNT/F. 3,4-DAP (4 mg/kg, i.v.) potentiated twitch tensions markedly in BoNT/A intoxicated muscle. The increase in tension developed rapidly (halftime = 5.81 +/- 0.6 min), persisted for approximately 1 hr, then decayed slowly with a halftime of 25.2 +/- 4.6 min. Subsequent administration of 3,4-DAP restored tensions to the original maxima, and this procedure could be repeated up to eight times with no decrement. The action of 3,4-DAP was comparable when given 1, 2, 3 or 7 days after BoNT/A and enhanced when administered 14 days after toxin injection. 3,4-DAP was less effective in reversing BoNT/E-induced muscle paralysis and nearly ineffective in antagonizing the paralytic actions of BoNT/B or BoNT/F. The results indicate that 3,4-DAP is of benefit in BoNT/A and BoNT/E intoxication, but is of marginal value after exposure to serotypes B and F.

Conformational analysis of a toxic peptide from Trimeresurus wagleri which blocks the nicotinic acetylcholine receptor.

The 22-residue toxic peptide (WTX1) from the venom of the Southeast Asian snake Trimeresurus wagleri has multiple sites of action, but its lethal effect has been attributed to blocking the postsynaptic acetylcholine receptor at the neuromuscular junction. The 3-dimensional structure of WTX1 was studied using 2-dimensional nuclear magnetic resonance spectroscopy, circular dichroism, and computer simulations. In aqueous solution, WTX1 was shown to have extended and flexible "tails" defined by a short, rigid disulfide-bonded loop. The flexible regions can undergo structural rearrangement when moved from an aqueous to a less polar environment and may contribute to its effectiveness at different receptor sites. By substituting Gly or Phe for His at position 10, significant effects on the disulfide bond formation and, thereby, the activity of the peptide were observed. These results suggest that even subtle differences in single residues can have profound effects on the dynamics of folding, disulfide bond formation, and activity of this toxic peptide.

On the possible origin of giant or slow-rising miniature end-plate potentials at the neuromuscular junction.

Giant or slow-rising miniature end-plate potentials (GMEPPs) caused by vesicular release of acetylcholine (ACh) occur at any time in about 50% of mouse diaphragm neuro muscular junctions, but generally at frequencies less than 0.03 s-1. Their frequency is, unlike that of miniature end-plate potentials (MEPPs), not affected by nerve terminal depolarization. Unlike MEPPs and stimulus-evoked end-plate potentials, GMEPPs have a prolonged time-to-peak and show an increase in time-to-peak with amplitude. By using these differences in amplitude and time course, GMEPPs can be separated from MEPPs. In contrast to MEPPs, GMEPPs are not blocked by botulinum neurotoxin type A. GMEPPs have a greater temperature sensitivity than MEPPs, disappearing at temperatures below 15 degrees C. Long-term paralysis by botulinum toxin and certain drugs which inhibit protein kinase C or affect actin filament polymerization (cytochalasins) enhance the frequency of GMEPPs. End-plate current recordings show that similar postsynaptic ACh receptors are activated by MEPPs and GMEPPs. It is suggested that GMEPPs are not caused by mechanisms involved in regulated neurotransmitter release but are generated by constitutive secretion.

Multiple effects of salicylaldoxime on rat cardiac action potentials.

The effect of salicylaldoxime, 2-(OH)C6H4CH = NOH, on the resting membrane potential and action potential characteristics was studied using isolated right ventricular strips from rat heart. Salicylaldoxime (1-3 mM) reversibly hyperpolarized the cells, increased action potential amplitude, decreased the maximal rate of rise (Vmax) and prolonged duration. The prolongation of the action potential produced by 1 mM salicyaldoxime could not be reversed with isoprenaline (10 microM). Salicyalaldoxime (0.3-1 mM) had no effect on the Ca(2+)-dependent slow action potential for periods up to 60 min. Initial exposure to 3 mM salicylaldoxime produced no changes in the slow action potential, but after 30 min. there was a gradual reduction in amplitude. This effect was completely reversible within 10-15 min. of washout. These data suggest that salicyaladoxime can block Na+, K+ and Ca2+ currents in rat cardiac muscle. Furthermore, it appears that the slow inward Ca2+ current, as measured by the slow action potential, may be sensitive to a dephoshorylating action of this oxime.