Effects of cardiac resynchronisation therapy in patients with heart failure having a narrow QRS Complex enrolled in PROSPECT.

INTRODUCTION: Current guidelines recommend cardiac resynchronisation therapy (CRT) in patients with severe symptomatic heart failure, depressed left ventricular (LV) systolic function and a wide QRS complex (>or=120 ms). However, patients with heart failure having a narrow QRS complex might also benefit from CRT. DESIGN SETTING PATIENTS INTERVENTIONS: During the Predictors of Response to Cardiac Resynchronisation Therapy (PROSPECT) trial, 41 patients were enrolled in a 'narrow' QRS sub-study. These patients had a QRS complex <130 ms, but documented evidence of mechanical dyssynchrony by any of seven pre-defined echocardiographic measures. RESULTS: After 6 months of CRT, 26 (63.4%) patients showed improvement according to the Clinical Composite Score, 4 (9.8%) remained unchanged and 11 (26.8%) worsened. In patients with paired data, the 6-min walking distance increased from 334+/-118 m to 382+/-128 m, (p=0.003) and quality-of-life score improved from 44.2+/-19.7 to 26.8+/-20.2 (p<0.0001). Furthermore, there was a significant decrease in LV end-systolic diameter (from 59+/-9 to 55+/-12 mm, p=0.002) and in LV end-diastolic diameter (from 67+/-9 to 63+/-11 mm, p=0.007). CONCLUSION: The results suggest that CRT may have a beneficial effect in heart failure patients with a narrow QRS complex and mechanical dyssynchrony as assessed by echocardiography. The majority of patients improved on clinical symptoms, and there was an evident reduction in LV diameters. Larger studies are needed to clearly define selection criteria for CRT in patients with a narrow QRS complex.

Interactions between CB(1) receptors and TRPV1 channels mediated by 12-HPETE are cytotoxic to mesencephalic dopaminergic neurons.

BACKGROUND AND PURPOSES: We recently proposed the existence of neurotoxic interactions between the cannabinoid type 1 (CB(1)) receptor and transient receptor potential vanilloid 1 (TRPV1) channels in rat mesencephalic cultures. This study seeks evidence for the mediator(s) and mechanisms underlying the neurotoxic interactions between CB(1) receptors and TRPV1 in vitro and in vivo. EXPERIMENTAL APPROACH: The mediator(s) and mechanism(s) for the interactions between CB(1) receptors and TRPV1 were evaluated by cell viability assays, immunocytochemistry, Fura-2 calcium imaging, mitochondrial morphology assay, ELISA and Western blot assay in vitro in neuron-enriched mesencephalic cultures. Injections into the substantia nigra and subsequent cell counts were also used to confirm these interactions in vivo. KEY RESULTS: The neurotoxic interactions were mediated by 12(S)-hydroperoxyeicosatetraenoic acid (12(S)-HPETE), an endogenous TRPV1 agonist. CB(1) receptor agonists (HU210 and WIN55,212-2) increased the level of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), a downstream metabolite of 12(S)-HPETE, which stimulates TRPV1-mediated death of mesencephalic neurons, both in vitro and in vivo. The neurotoxicity was mediated by increased intracellular Ca(2+) concentration ([Ca(2+)](i)) through TRPV1, consequently leading to mitochondrial damage and was attenuated by baicalein, a 12-lipoxygenase inhibitor. CONCLUSION AND IMPLICATIONS: Activation of CB(1) receptors in rat mesencephalic neurons was associated with biosynthesis of 12(S)-HPETE, which in turn stimulated TRPV1 activity, leading to increased [Ca(2+)](i), mitochondrial damage and neuronal death.

Adult living donor liver transplantation using the right lobe.

BACKGROUND: This article reviewed our experience with right lobe donor hepatectomy in living donor liver transplantations (LDLT), particularly in the context of preserving donor safety. MATERIALS AND METHODS: From January 2000 to August 2005, we performed 206 adult LDLT operations using the right lobe. The donor characteristics, operative findings, postoperative results including the peak values of liver enzymes (aspartate transferase [AST], alanine transferase [ALT], and bilirubin) and regeneration volumes, as evaluated by computed tomography volumetry, were reviewed at 1 week, as well as 3 and 6 months after surgery. The effects of three risk factors on donor safety were analyzed: age (<55 years, > or =55 years): fatty change in the donor liver (<10%, > or =10%); and remnant volume (<35%, > or =35%). RESULTS: The liver enzymes and regeneration volumes showed no significant difference according to age, only ALT was significant increased associated with the severity of fatty change (P < .05). There were significant differences in postoperative AST, ALT, and regeneration volume between the group with <35% and the group with > or =35% remnant liver volume (P < .05). Upon further analysis with combinations of two out of three risk factors, the group according to remnant volume and fatty change was meaningful. Follow-up data on donor ALT showed a return normal levels and after postoperative 3 months there was regeneration of the remnant liver to more than 70% of the whole liver preoperatively. There was no donor mortality, but postoperative complications were observed in 39 patients (39/206, 18.9%). Biliary complications were encountered in 24 patients: one bile duct injury, 22 bile leakages, and one bile duct stricture. Other complications consisted of pleural effusion (n = 8), delayed gastric emptying (n = 6), atelectasis (n = 1), and hepatic encephalopathy (n = 1). CONCLUSION: In cases of careful donor selection, a right lobectomy can be performed safely with minimal risks when the remnant liver volume exceeds 35% of the total liver volume and shows less than 10% fatty changes.

Current state of treatment for primary cutaneous melanoma.

The incidence of malignant melanoma has been rising steadily for the last 30 years. Through physician and patient education, surveillance of high-risk individuals, and biopsy of any suspicious lesions, more lesions are being diagnosed earlier, where there is a high cure rate. Unfortunately many patients will still present with thicker lesions or nodal involvement, which carries a significantly worse prognosis. Over the past decade, there have been several changes in the management of primary cutaneous melanoma. These have stemmed from novel surgical approaches, a new understanding of melanoma biology, and randomized clinical trials designed to improve outcome and decrease the morbidity of therapy. This article will review the clinical evidence behind the current treatment recommendations for primary cutaneous melanoma as well as some of the emerging data on innovative immunologic-approaches to melanoma treatment.

The relationship of histologic activity to serum ALT, HCV genotype and HCV RNA titers in chronic hepatitis C.

It is unclear whether serum ALT levels or virological characteristics of hepatitis C virus(HCV) including HCV genotypes and HCV RNA titers, can reflect the degree of histological injury in chronic hepatitis C. The aim of this study was to investigate the relationships between the levels of histological damage and serum ALT levels, HCV genotypes or circulating HCV RNA titers in chronic hepatitis C. A total of 56 patients underwent liver biopsy and the histological activity index (HAI) was evaluated by Knodell's scoring system. HCV genotype by RT-nested PCR and HCV RNA quantitation by competitive RT-PCR were performed. Thirty-four patients were infected with HCV genotype 1b, 20 patients with genotype 2a, and 2 patients with undetermined type. Serum ALT levels were not positively correlated with total HAI score or HCV RNA titers, but showed a linear correlation with scores of piecemeal necrosis (r=0.32, p<0.05) and portal inflammation (r=0.27, p<0.05). HCV genotype had no significant correlation with RNA titers, HAI score or with serum ALT levels. Also, no statistical relationship was seen between HCV RNA titer and HAI score. These results suggest that liver histology is essential to evaluate the severity of chronic hepatitis C precisely.

Chronic ethanol enhances adenosine antiadrenergic actions in the isolated rat heart.

BACKGROUND: Chronic alcohol consumption elicits an increase in catecholamine release, which may be detrimental to heart function. Adenosine attenuates adrenergic stimulation via an adenosine receptor-mediated antiadrenergic action. This study investigated the effect of ethanol on adenosine antiadrenergic actions and adenosine release in the rat heart. METHODS: Rats were pair-fed a liquid diet with or without ethanol for 4 weeks or 8 months. Hearts were isolated for determination of contractile function, and coronary effluents were collected for adenosine content. Dose-response relationships for phenylisopropyladenosine (PIA) were determined for hearts adrenergically stimulated by isoproterenol. Experiments were also conducted with normal hearts with or without ethanol (25 mM) administered acutely. The effect of PIA on adenylyl cyclase activities of adrenergic-stimulated crude membrane preparations obtained from alcoholic and nonalcoholic hearts was determined. RESULTS: Acute ethanol reduced basal adenosine release by 39%, but it did not significantly decrease adenosine release during adrenergic stimulation. In hearts chronically treated with ethanol for 4 weeks, adenosine release values before and during adrenergic stimulation were significantly reduced from control values. After 8 months of ethanol, adenosine release was similar with or without adrenergic stimulation. PIA 50% inhibiting concentration (IC50) values for contractile function were reduced from pair-fed control values. Acute ethanol did not significantly change the PIA IC50 value. Chronic ethanol reduced the PIA IC50 for adenylyl cyclase by 96%. CONCLUSIONS: Chronic ethanol treatment increases the antiadrenergic action of adenosine by mechanisms that seem independent of changes in adenosine concentration. Therefore, adenosine-induced cardioprotection against increased catecholamine stimulation is enhanced by ethanol.

GT1b ganglioside induces death of dopaminergic neurons in rat mesencephalic cultures.

We examined neurotoxicity of GT1b against dopaminergic neurons in vitro. Cultures of mesencephalic cells deprived of serum underwent the loss of 19% of tyrosine hydroxylase immunopositive (TH-ip) neurons. In cultures deprived of serum, treatment with 10-30 microg/ml GT1b attenuated the number of TH-ip neurons by 26-69%, respectively, compared to non-treated cultures. Intriguingly, cultures deprived of serum were more vulnerable to GT1b-induced neurotoxicity. Application of 60 microg/ml GT1b to cultures grown in serum containing media resulted in the loss of 26% of TH-ip neurons, similar to that (28%) observed in serum-deprived cultures treated with 10 microg/ml GT1b. Moreover, in our cultures, absence of nitric oxide (NO) production after GT1b treatment was obvious. The present results strongly suggest direct neurotoxic actions of GT1b against dopaminergic neurons regardless of NO.

Antiadrenergic effects of adenosine in pressure overload hypertrophy.

In the present study, we sought to evaluate whether the antiadrenergic action of adenosine in the heart is altered in pressure overload hypertrophy produced in rats by suprarenal aortic banding. Epicardial and coronary effluent adenosine and inosine concentrations and release were significantly elevated in compensated pressure overload hypertrophy but not in hearts with left ventricular failure. In pressure overload hearts, the contractile response to beta-adrenergic stimulation was less inhibited by incremental concentrations of either adenosine or the selective A(1) receptor agonist chloro-N:(6)-cyclopentyl adenosine than in controls. Furthermore, the extent of desensitization to the antiadrenergic actions of adenosine in pressure overload hypertrophy appeared to be proportional to the extent of chamber dilation and dysfunction. A 60-minute infusion of adenosine produced a sustained antiadrenergic effect that lasted up to 45 minutes after the infusion was terminated in both controls and hearts with compensated hypertrophy. This effect was not observed in the decompensated left ventricular failure group. Subsequent infusion with adenosine of the A(2A) receptor antagonist 8-(3-chlorostyryl)-caffeine to counteract the proadrenergic effect of A(2A) receptor stimulation did not alter the decreased sensitivity to the antiadrenergic actions of adenosine in hypertrophied hearts. Finally, isolated myocytes from hypertrophied hearts demonstrated a decreased ability to suppress isoproterenol-elicited increases in [Ca(2+)](i) transients in the presence of adenosine and the A(2A) receptor antagonist compared with myocytes from control hearts. Myocardial adenosine concentrations increase during the compensated phase of pressure overload hypertrophy but then decrease when there is evidence of decompensation. The antiadrenergic actions of adenosine transduced via the myocardial A(1) receptor are diminished in pressure overload hypertrophied hearts. These factors may render these hearts more vulnerable to the detrimental effects of chronically increased sympathetic activity.

Reduction in myocardial collagen cross-linking parallels left ventricular dilatation in rat models of systolic chamber dysfunction.

BACKGROUND: The transition from compensated left ventricular hypertrophy (LVH) to heart failure is associated with alterations in the myocardial interstitium. We hypothesized that LV dilatation is associated with modifications in collagen cross-linking. METHODS AND RESULTS: We studied 2 rat models of LV dilatation: (1) pressure-overload hypertrophy with heart failure (POH-F) induced by suprarenal abdominal aortic banding and (2) LVH induced by 7 months of isoproterenol (ISO, 0.04 mg x kg(-1) x d(-1)) administration. In POH-F rats and in rats receiving ISO, LV dilatation and a reduced systolic chamber performance were noted. Myocardial hydroxyproline concentrations ([HPRO]) were increased in the POH-F rats, whereas in rats receiving ISO, [HPRO] was decreased. In POH-F rats, the ratio of myocardial collagen type I to type III was increased, but in rats receiving ISO, myocardial collagen I/III was unchanged. In contrast to the diverse changes in myocardial collagen concentrations and phenotypes observed in the 2 models of LV dilatation, the ratio of myocardial insoluble to soluble (relationship between cross-linked and non-cross-linked) collagen was decreased in both the POH-F and ISO groups. Moreover, administration of captopril (0.22 mmol x kg(-1) x d(-1)), which inhibited the ISO-induced reduction in myocardial insoluble/soluble collagen but not the reduction in [HPRO], prevented the ISO-induced alterations in LV dimensions and performance. CONCLUSIONS: Because decreases in the ratio of myocardial insoluble to soluble collagen parallel LV dilatation in rats, reductions in myocardial collagen cross-linking may be an important mechanism contributing to LV dilatation in heart disease.

Development of a newly designed double-fixed Seoul-type keratoprosthesis.

OBJECTIVE: To develop a newly designed double-fixed keratoprosthesis (Seoul-type keratoprosthesis [S-KPro]) and to assess its mechanical stability and biocompatibility. METHODS: Twenty-five rabbits were divided into 4 groups by fixation technique, amniotic membrane (AM) implantation, and skirt material. The eyes were studied with the use of slitlamp, light, and electron microscopy. Stress testing was performed. In addition, 2 human subjects underwent S-KPro implantation. Best-corrected visual acuity was checked, and ophthalmic examination was performed. RESULTS: The average retention period of the group receiving double-fixated polyurethane-S-KPro with AM was longer (>24 weeks) than that of the others. Fibroblast invasions were found in polyurethane pores but not in polytetrafluoroethylene (Gore-Tex) pores on light microscopy. The minimal pressure that induced aqueous leakage was greater than 250 mm Hg in all of the tested eyes. Two human subjects have maintained a good postoperative condition for 18 and 8 months. CONCLUSIONS: The double-fixation technique of applied S-KPro and AM appears to be helpful in improving the stability of the keratoprosthesis. Polyurethane with relatively large pore size (40 microm) may be used successfully as a material for the keratoprosthesis skirt. CLINICAL RELEVANCE: Our results may be important for improving the clinical outcome of keratoprosthesis.

Norepinephrine concentrations in the epicardial transudate reflect early changes in adrenergic activity in the isolated perfused heart.

The aim of this study was to establish whether epicardial transudates could be used to uncover small, but physiologically important changes in interstitial NE concentrations under normal and pathological conditions. Norepinephrine (NE) concentrations measured in epicardial transudate fluid were compared to NE levels in the coronary effluent in normal and pressure overload hypertrophied (POH) rat hearts. Hearts were isolated together with the stellate ganglion and perfused in the inverted position. Epicardial surface transudates, representative fluid of the interstitial myocardial compartment, and coronary effluents were collected for determination of NE levels in the presence and absence of stellate ganglion stimulation. The same protocol was repeated in the presence and absence of nisoxetine, a NE uptake blocker. NE concentrations in epicardial transudates were 16- and 19-fold higher than in the coronary effluent in both sham and POH groups, respectively. NE concentrations in the transudates but not in the coronary effluents were significantly higher (1.6-fold) in hearts with POH when compared to normal hearts. Likewise, nisoxetine (10(-5)m) increased (1.3-fold) NE concentrations in the transudates but not in the effluents of sham animals. As expected, stellate ganglion stimulation increased NE concentrations in both transudates and effluents in sham and POH hearts. In conclusion, determination of NE concentrations in epicardial transudates represents a simple, rapid and sensitive method to detect increases in adrenergic activity in normal and abnormal hearts.

Clinical analysis of central islands after laser in situ keratomileusis.

PURPOSE: To analyze the incidence and clinical characteristics of central islands after laser in situ keratomileusis (LASIK) and to elucidate factors associated with their formation. SETTING: Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. METHODS: Laser in situ keratomileusis was performed in 103 eyes of 61 patients with myopia ranging from -4.0 to -13.5 diopters (D) using the Hansatome (Chiron) and SVS Apex Plus (version 3.2.1) excimer laser (Summit Technology) in which the anti-central-island program was implemented. After 1 week, corneal topography (Orbscan, Orbtek) was done and manifest refraction and visual acuity were measured. RESULTS: Postoperatively, the mean uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) were 0.12 and 0.06 (logMAR scale), respectively, and the mean refractive error (spherical equivalent) was 0.07 D +/- 0.76 (SD). On topographic examination, a central island was defined as an area of higher refractive power of more than 1.5 D and 2.5 mm or more in diameter. Budding or isolated central islands were observed in 12 eyes of 12 patients (11.7%). The peak, height, and area of the islands were 41.5 +/- 3.1 D, 5.6 +/- 1. 9 D, and 3.5 +/- 1.1 mm(2), respectively. In the eyes with central islands, there were statistically significant differences in the postoperative change in UCVA and BCVA (P <.05). There was no significant correlation between the occurrence of a central island and preoperative refractive error, corneal thickness, age, or in sex and correction of astigmatism (P >.05). CONCLUSION: Despite use of the anti-central-island pretreatment program, the occurrence of central islands after LASIK was significant, as in photorefractive keratectomy. Further studies of the effect of central islands on surgical results and clinical progress and measures to prevent the occurrence are needed.

Worsening of mitral regurgitation secondary to ventricular pacing.

A 68-year-old woman was admitted to hospital for possible mitral valve surgery for severe mitral regurgitation (MR). Six months before admission, a DDD pacemaker was implanted for symptomatic bradycardia. She developed atrial fibrillation and the pacer was changed to a VVI mode. At cardiac catheterization, the pulmonary artery and wedge pressures were elevated; coronary angiography showed non-obstructive coronary artery disease. 2-D echocardiography confirmed preserved left ventricular function, severe MR and moderate tricuspid regurgitation. The change in pacing had a dramatic effect on MR severity; ventricular pacing was associated with a MR jet that occupied a larger area of the left atrium than with the unpaced rhythm, the continuous-wave mitral regurgitant Doppler profile was 'dagger'-shaped, and the signal intensity stronger compared with the unpaced rhythm. These findings are consistent with severe MR. The pacer was reprogrammed to reduce the pacing rate from 70 to 45 beats/min, allowing an unpaced rhythm for the most part. The patient improved and was discharged two days later. Six months later she was asymptomatic; repeat echocardiography confirmed mild to moderate MR.

Clinical characteristics of Peutz-Jeghers syndrome in Korean polyposis patients.

Peutz-Jeghers syndrome is an autosomal dominant inherited disorder characterized by hamartomatous polyps in the small bowel and mucocutaneous pigmentation. Patients with Peutz-Jeghers syndrome often present as surgical emergencies with complications of the polyps, such as intussusception, bowel obstruction, and bleeding. Recently an increased risk of malignancies has also been reported. This study was initiated to determine the clinical features of Peutz-Jeghers syndrome in Korean patients, with special attention to the development of malignancies. Thirty patients with Peutz-Jeghers syndrome were investigated; their median age was 23.5 years, and symptoms appeared at a median age of 12.5 years. Family history was positive in one-half of cases, and mucocutaneous pigmentation was observed in almost all patients (93%). The jejunoileum was the most frequent site of the polyps, and there were generally 10-100 polyps. Multiple laparotomies were performed in a substantial portion of the patients, due mainly to polyp-induced bowel obstruction, and the surgical interventions were begun at a relatively young age (average 21.4 years). Four cases of small-bowel cancer and one case of breast cancer were detected in probands, at a relatively young age (mean 36 years). Cancers of the small bowel, stomach, colon, breast and cervix were diagnosed in the first relatives of the probands. Close follow-up from an early age should thus be performed in patients with Peutz-Jeghers syndrome as they are at high risk of surgical emergency and development of malignancy.

Coronary arterial dimension-to-left ventricular mass ratio in idiopathic dilated cardiomyopathy.

This study demonstrated that, compared with normal controls, coronary artery dimensions are not increased appropriately for the increase in left ventricular mass in patients with nonischemic cardiomyopathy. The extent of coronary artery dimension to left ventricular mass mismatch did not correlate with the severity of heart failure.

Adenosine A1 receptor-mediated antiadrenergic effects are modulated by A2a receptor activation in rat heart.

Presently, the physiological significance of myocardial adenosine A2a receptor stimulation is unclear. In this study, the influence of adenosine A2a receptor activation on A1 receptor-mediated antiadrenergic actions was studied using constant-flow perfused rat hearts and isolated rat ventricular myocytes. In isolated perfused hearts, the selective A2a receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2, 4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-241385) potentiated adenosine-mediated decreases in isoproterenol (Iso; 10(-8) M)-elicited contractile responses (+dP/dtmax) in a dose-dependent manner. The effect of ZM-241385 on adenosine-induced antiadrenergic actions was abolished by the selective A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10(-7) M), but not the selective A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1, 4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191, 10(-7) M). The A2a receptor agonist carboxyethylphenethyl-aminoethyl-carboxyamido-adenosine (CGS-21680) at 10(-5) M attenuated the antiadrenergic effect of the selective A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), whereas CSC did not influence the antiadrenergic action of this agonist. In isolated ventricular myocytes, CSC potentiated the inhibitory action of adenosine on Iso (2 x 10(-7) M)-elicited increases in intracellular Ca2+ concentration ([Ca2+]i) transients but did not influence Iso-induced changes in [Ca2+]i transients in the absence of exogenous adenosine. These results indicate that adenosine A2a receptor antagonists enhance A1-receptor-induced antiadrenergic responses and that A2a receptor agonists attenuate (albeit to a modest degree) the antiadrenergic actions of A1 receptor activation. In conclusion, the data in this study support the notion that an important physiological role of A2a receptors in the normal mammalian myocardium is to reduce A1 receptor-mediated antiadrenergic actions.

Paclitaxel reduces anti-dsDNA antibody titer and BUN, prolonging survival in murine lupus.

We evaluated the effect of paclitaxel on the severity of autoimmunity in the murine model of systemic lupus erythematosus (SLE), NZB x NZW F1 mice. Fifteen 20 week old (NZB x NZW) F1 female mice were given a dose of 10 mg/kg paclitaxel by the intraperitoneal route on three alternate days followed by 7.5 mg/kg on three additional alternate days. This pattern of treatment was repeated every 4 weeks for a period of 28 weeks. 20 control mice were injected intraperitoneally with an equal volume of the vehicle used. Serum anti-double stranded DNA (dsDNA) antibody titers and the blood urea nitrogen (BUN) were significantly diminished in the paclitaxel treated group compared to the vehicle treated group. While the onset of proteinuria appeared to be delayed in the experimental group, the difference was not significant. Survival rate improved significantly in paclitaxel treated group (p = 0.04 by log-rank test). These results suggest that paclitaxel is beneficial in the suppression of autoimmunity in this strain of mice by reducing the anti-dsDNA antibody titer and the BUN, prolonging survival.

Effects of chronic adenosine uptake blockade on adrenergic responsiveness and left ventricular chamber function in pressure overload hypertrophy in the rat.

BACKGROUND: Increased sympathetic activity contributes to the progression of heart failure. Adenosine counteracts sympathetic activity by inhibition of presynaptic norepinephrine release and attenuation of the metabolic and contractile responses to beta-adrenergic stimulation. In this study, we tested the hypothesis that the adenosinergic effects (uptake blockade) of dipyridamole may retard the progression of pressure overload hypertrophy in the rat. METHODS AND RESULTS: To verify that the administration of dipyridamole increases myocardial adenosine levels in the rat, epicardial adenosine concentrations were measured from 12 isolated, perfused rat hearts exposed to 10(-7) and 10(-6) mol/l dipyridamole. Adenosine concentrations were increased with both doses of dipyridamole. Also, 9 weeks of dipyridamole treatment resulted in decreased sensitivity to the adenosine A1-receptor agonist, 2-chloro-N6-cyclopentyl adenosine, suggesting that dipyridamole increases adenosine levels in the intact rat. In the second part of the study, rats were divided into either abdominal aortic-banded or sham-operated groups and were treated with either dipyridamole or saline. After 9 weeks of treatment, two-dimensional Doppler echocardiographic studies were performed and the adrenergic responsiveness to 10(-8) mol/l isoproterenol was assessed in vitro. The saline-treated banded group demonstrated concentric left ventricular hypertrophy, abnormal diastolic filling, increased wet lung weights and attenuation of adrenergic responsiveness. In contrast, the dipyridamole-treated banded rats exhibited more concentric geometry (higher relative wall thickness with similar left ventricular mass), normal left ventricular filling characteristics and preserved adrenergic responsiveness. Systolic left ventricular chamber and myocardial function, as assessed by stress-endocardial and midwall shortening relationships, were not significantly altered by banding or dipyridamole treatment. CONCLUSIONS: Dipyridamole treatment prevented the development of abnormal left ventricular chamber filling, preserved adrenergic responsiveness and appeared to attenuate detrimental chamber remodeling in rats with pressure overload hypertrophy.

Adenosine mediates sustained adrenergic desensitization in the rat heart via activation of protein kinase C.

Adenosine attenuates the myocardial metabolic and contractile responses induced by ss-adrenergic stimulation. Our study was conducted to investigate the longevity of this antiadrenergic action after adenosine exposure. Adenosine (33 micromol/L) was infused into isolated perfused rat hearts for 1, 5, 30, or 60 minutes, and the adrenergic responsiveness (AR) to isoproterenol (10(-8) mol/L) was determined at the end of each infusion period and during a 45-minute adenosine washout period. Interstitial levels of adenosine, as determined from epicardial surface transudates, returned to preinfusion levels within 10 minutes of washout. The duration of adenosine infusion had no effect on the extent of attenuation of AR at the end of the infusion. Whereas AR returned to preadenosine levels with washout of shorter adenosine infusions (1 and 5 minutes), there was a slow and incomplete recovery of AR after the longer exposures (30 and 60 minutes) to adenosine. The magnitude of this persistent antiadrenergic effect (PAE) of adenosine at 15 minutes of washout was proportional to the epicardial concentration of adenosine during infusion of the nucleoside. Infusion of adenosine either with the nonselective adenosine receptor antagonist 8-p-sulfophenyl theophylline or with the selective A1-receptor antagonist 1,3-dipropyl, 8-cyclopentylxanthine, abolished the PAE during the washout period. In addition, the PAE could be demonstrated only with the selective A1-receptor agonist 2-chloro-N6-cyclopentyladenosine and not with the selective A3-receptor agonist 4-aminobenzyl-5'-N methylcarboxamido-adenosine. When the protein kinase C (PKC) inhibitor chelerythrine was coadministered with adenosine, the PAE of adenosine was not apparent during adenosine washout. A 30-minute infusion of phenylephrine, an alpha-adrenergic agonist that enhances PKC activity, produced a PAE that lasted for up to 30 minutes of washout. This effect was prevented by the coinfusion of chelerythrine. Thus, it is concluded that the PAE of adenosine is determined by the myocardial concentration of this nucleoside and is manifested when myocardial concentrations of adenosine returned to baseline levels. Moreover, a 5-minute duration of adenosine exposure is required for the expression of the PAE. This latter effect seems to be dependent on adenosine-induced PKC activation via A1-receptors.