Heterogeneity and underlying mechanism for inotropic action of endothelin-1 in rat ventricular myocytes

1. To clarify the mechanisms underlying the positive inotropic action of endothelin-1 (ET-1), we investigated the effect of ET-1 on twitch cell shortening and the Ca2+ transient in rat isolated ventricular myocytes loaded with a fluorescent Ca2+ indicator indo-1. 2. There was a cell-to-cell heterogeneity in response to ET-1. ET-1 (100 nM) increased twitch cell shortening in only 6 of 14 cells (44%) and the increase in twitch cell shortening was always accompanied by an increase in the amplitude of the Ca2+ transient. 3. The ET(A)- and ET(B)-receptors antagonist TAK-044 (100 nM) almost reversed both the ET-1-induced increases in twitch cell shortening and in the Ca2+ transient. In the ET-1 non-responding cells, the amplitude of the Ca2+ transient never increased. 4. Intracellular pH slightly increased (approximately 0.08 unit) after 30 min perfusion of ET-1 in rat ventricular myocytes. However, ET-1 did not change the myofilament responsiveness to Ca2+, which was assessed by (1) the relationship between the Ca2+ transient amplitude and twitch cell shortening, and by (2) the Ca2+ transient-cell shortening phase plane diagram during negative staircase. 5. We concluded that there was a cell-to-cell heterogeneity in the positive inotropic effect of ET-1, and that the ET-receptor-mediated positive inotropic effect was mainly due to an increase in the Ca2+ transient amplitude rather than to an increase in myofilament responsiveness to Ca2+.     

Changes in the responsiveness to endothelin-1 in isolated atria from diabetic rats

This study investigates the influence of diabetes on the cardiac responsiveness to endothelin-1. The effects of endothelin-1 on rate and force of contraction were examined in isolated right and left atria, respectively, obtained from either streptozotocin (65 mg/kg)-treated rats (diabetic) or vehicle (0.02 M citric acid)-treated rats (control). The positive chronotropic and inotropic effects of endothelin-1 did not change in atria from diabetic rats at 2 and 4 weeks, but were reduced at 8 and 12 weeks. The positive chronotropic response to noradrenaline, but not to sympathetic nerve stimulation, was also reduced in 12-week diabetic rats. Endothelin-1 caused a decrease in the positive chronotropic and inotropic responses to sympathetic nerve stimulation and to noradrenaline; these inhibitory effects of endothelin-1 were not altered in 2-, 4-, 8- or 12-week diabetic rats. The study demonstrates that atrial responses to endothelin-1 and to noradrenaline are reduced by streptozotocin-induced diabetes, but the alteration depends on the duration of diabetes.     

Role of endothelium in the endothelin-1-mediated potentiation of the norepinephrine response in the aorta of hypertensive rats

OBJECTIVE: To investigate the role of the endothelium in the functional interaction between endothelin-1 and norepinephrine in the contractile response of aortas from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). METHODS: Thoracic aorta rings with and without endothelium from SHR and from WKY rats were suspended in an organ bath to record the isometric tension. After an equilibration period of 120 min, the preparations with and without endothelin-1 were subjected to single and cumulative additions of norepinephrine in different experiments. To characterize the mechanisms involved in the interaction between endothelin-1 and norepinephrine, the aortic rings were pretreated with a cyclooxygenase pathway inhibitor (piroxicam, SO29548), an inhibitor of NO synthase [NG-nitro-L-arginine (NLA)], or selective endothelin receptor blockers (BQ-123 or BQ-788). In some experiments we examined the contractile responses to norepinephrine in aortas pretreated either with angiotensin II (AII) or with U46619, an agonist of prostaglandin H2-thromboxane A2 receptors. Finally, we examined the effect of the combination of calcium-entry blockade by administration of nifedipine and treatment with either endothelin-1 or U46619 on the norepinephrine reactivity. RESULTS: Administration of 3 x 10(-10) mol/l endothelin-1 potentiated the contractile response to norepinephrine in SHR aortas with endothelium, irrespective of whether they had been treated with NLA. No endothelin-1-mediated enhancement of the response to norepinephrine was observed in SHR denuded rings and in untreated and NLA-treated WKY rat aortas. All did not affect the response to norepinephrine in SHR rings with endothelium. The amplification by endothelin-1 of the response to (1-100) x 10(-9) mol/l norepinephrine was abolished by blockade of the cyclooxygenase pathway with piroxicam or SO29548. In WKY rat and SHR denuded aortas, 10(-8) mol/l U46619 potentiated the contractile responses to norepinephrine. Administration of 3 x 10(-6) mol/l BQ-123 abolished the increase in reactivity to norepinephrine evoked by endothelin-1 in intact SHR aorta, whereas 3 x 10(-6) mol/l BQ-788 failed to modify this potentiating effect. Administration of 10(-8) mol/l nifedipine inhibited the potentiation of the norepinephrine-induced contractions evoked both by endothelin-1 in SHR aortic rings with endothelium and by U46619 in SHR denuded rings. CONCLUSION: Our results show that a low concentration of endothelin-1 induced potentiation of the contractile response to norepinephrine in SHR aortas but not in WKY rat aortas. This response was endothelium-dependent. Furthermore, our study affords functional arguments that both endothelial and smooth muscle pathways are involved in the potentiating interaction. We propose that endothelin-1 stimulates the production of endothelium- and cyclooxygenase-generated vasoconstrictor factors, which in turn may serve directly as priming stimuli at the vascular smooth muscle level, to activate the Ca(2+)-signal pathway and consequently to increase locally the vascular sensitivity to norepinephrine.     

Elevated plasma endothelin-1 level in streptozotocin-induced diabetic rats and responsiveness of the mesenteric arterial bed to endothelin-1

Acute swimming stress destroyed the circadian rhythm of motility in rats. Bilateral electrolytic lesion of the dorsal hippocampus increased the night activity and resistance of animals to stress. Pinealectomy did not affect the circadian locomotion but increased rats' sensitivity to dysrhythmic stress effect.     

Effect of endothelin-1 on some hemostatic parameters in normotensive rats

Some parameters of hemostasis and fibrinolysis were investigated in rats administered with endothelin-1 (ET-1). ET-1 (0.5, 1.0, 5.0 nmol/kg) dose-dependently shortened the bleeding time (BT). Concomitantly significant shortening of the clotting time (CT) was observed. ET-1 produced prolongation of the activated partial thromboplastin time (APTT), whereas prothrombin time (PT) remained unchanged. ET-1 did not influence in vitro platelet aggregation induced by ADP and collagen. The euglobulin clot lysis time (ECLT) was significantly shortened after ET-1 administration. Our results suggest that ET-1 modulates the process of hemostasis and fibrinolysis in the rat.     

Plasma and blood vessel endothelin-1 concentrations in hypertensive uremic rats treated with erythropoietin

The present study was designed to evaluate whether changes in plasma and blood vessel endothelin-1 (ET-1) concentrations may play a role in the enhanced blood pressure response to recombinant human erythropoietin (r-HuEPO) replacement therapy in uremia. Renal failure was induced by 5/6 nephrectomy (Nx). Uremic rats received either r-HuEPO (100 u s.c. three times a week) or the vehicle for 5 weeks. They were compared to control rats receiving the vehicle. Systolic blood pressure (tail cuff method), hematocrit, serum creatinine, plasma and tissue ET-1 were measured at the end of the protocol. Immunoreactive ET-1 (ir-ET-1) was determined by radioimmunoassay of acid-extracts from the plasma, thoracic aorta and mesenteric arterial bed. Creatinine increased about three fold in Nx animals. Blood pressure in control rats was 120+/-3 mmHg compared to 161 +/-6 mmHg in the Nx + vehicle group (p <0.01) and 199+/-9 mmHg in the Nx + r-HuEPO group (p <0.01 vs Nx + vehicle). Hematocrit in control rats was 41.3+/-0.4% vs 32.6+/-1.8% in the Nx + vehicle group (p <0.01) and 47.6+/-1.5% in the Nx + r-HuEPO group (p <0.01). Plasma ir-ET-1 levels were similar in the Nx + vehicle and Nx + r-HuEPO groups (7.9+/-1.0 and 7.8+/-0.8 pg/ml). In contrast, thoracic aorta ir-ET-1 content was significantly higher in the Nx + r-HuEPO group than in the Nx + vehicle group (20.3+/-2.9 vs 13.4+/-1.9 pg, p <0.05). Similar results were obtained in the mesenteric arterial bed. There were significant correlations between blood pressure and ir-ET-1 content in the thoracic aorta (r= 0.45, p<0.05) and in the mesenteric arterial bed (r= 0.41, p<0.05). Vascular ET-1 content but not plasma levels are increased in uremic rats treated with r-HuEPO suggesting an increase in blood vessel ET-1 production which may play a role in the pathogenesis of r-HuEPO-induced hypertension.     

Altered myocardial phenotype after mechanical support in human beings with advanced cardiomyopathy

BACKGROUND: Left ventricular assist devices (LVAD) provide lifesaving circulatory support to patients awaiting heart transplantation. To date, the extent to which sustained mechanical unloading alters the phenotype of pathologic myocardial hypertrophy in dilated cardiomyopathy is unknown. METHODS: We examined left ventricular size, myocyte and myocardial immunoreactivity for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in eight patients with advanced dilated cardiomyopathy before and after LVAD support. The mean duration of congestive heart failure was 18 +/- 5 months, and LVAD support averaged 42 +/- 4 days before heart transplantation. RESULTS: Echocardiographically determined left ventricular mass decreased from 505 +/- 83 to 297 +/- 52 gm (p < 0.05) during LVAD support, whereas minimum myocyte diameter decreased from 28.1 +/- 0.9 to 21.7 +/- 0.6 microns (p < 0.01) in transmural myocardial tissue specimens. Overall left ventricular ANP immunopositivity decreased from 48% at LVAD placement to 12% at transplantation (p < 0.05), whereas BNP immunopositivity decreased from 28% to 4% after LVAD support. Moreover, a gradient of ANP and BNP immunostaining from subendocardium to epicardium observed before mechanical unloading diminished after LVAD support. Analysis of the relationship between left ventricular mass and ANP immunopositivity revealed a close and highly significant correlation between these variables. CONCLUSIONS: These studies demonstrate remarkable left ventricular plasticity even in the presence of advanced cardiomyopathy. Parallel reductions in myocardial mass and myocyte size with reductions in ventricular ANP and BNP immunostaining indicate a novel regression of the phenotype of pathologic hypertrophy within the human myocardium after LVAD support.     

Increased plasma endothelin-1 concentrations in E. coli septic peritonitis rats with diabetes mellitus

To study the diabetic mellitus (DM) patient's reaction to sepsis, we investigated the survival rate, the bacteremia, plasma endotoxin and plasma endothelin-1 levels in E. coli septic peritonitis rats with or without streptozotocin-induced DM. No significant difference could be detected between the DM and nondiabetic rats in the survival rate, the bacteremia level or the plasma endotoxin level. The DM rat manifested a significant increase compared to the nondiabetic rat in the plasma endothelin-1 level four hours after the outbreak of peritonitis. Endothelin-1 may thus play some role in the E. coli septic peritonitis rat with DM.     

Renoprotective effect of contemporary blocking of angiotensin II and endothelin-1 in rats with membranous nephropathy

Glutathione has a central role in the defence against oxidative damage; however, the data on glutathione concentrations in the semen of infertile men are limited. To expand this knowledge the glutathione content of the ejaculates and blood plasmas of 77 infertile men and 11 controls were analysed. The concentrations of total glutathione were assessed in spermatozoa, seminal plasma and blood plasma using a coupled spectrophotometric assay. In the spermatozoa of patients with oligozoospermia the glutathione concentrations (2.57+/-0.96 nmol/10[8] spermatozoa; mean +/- SD) were significantly lower than in the controls (3.49+/-0.87 nmol/10[8] spermatozoa; P +/- 0.03). The glutathione content of spermatozoa from patients with normozoospermia showed large variations (3.04+/-1.37 nmol/10[8] spermatozoa). An association between the intracellular glutathione content and the ability to penetrate bovine cervical mucus was observed (r = 0.2, P = 0.04). The intracellular glutathione concentrations correlated with the glutathione levels in seminal plasma (r = 0.46, P < 0.0001). There was no correlation between glutathione concentrations in blood plasma and those in seminal plasma or in spermatozoa. The glutathione concentrations in seminal plasmas did not differ between the different groups, however, correlated with the serum follicle stimulating hormone concentrations (r = 0.53, P = 0.005). This study demonstrated that intracellular glutathione levels of spermatozoa are decreased in certain populations of infertile men.     

Sarcoplasmic reticulum Ca2+ ATPase promoter activity during endothelin-1 induced hypertrophy of cultured rat cardiomyocytes

Proliferation in mammalian cells is controlled primarily in the G1-phase of the cell cycle through the action of the G1 cyclin-dependent kinases, CDK4 and CDK2. To explore the mechanism of cellular response to extrinsic factors, specific loss of function mutations were generated in two negative regulators of G1 progression, p21 and pRB. Individually, these mutations were shown to have significant effects in G1 regulation, and when combined, Rb and p21 mutations caused more profound defects in G1. Moreover, cells deficient for pRB and p21 were uniquely capable of anchorage-independent growth. In contrast, combined absence of pRB and p21 function was not sufficient to overcome contact inhibition of growth nor for tumor formation in nude mice. Finally, animals with the genotype Rb+/-;p21(-/-) succumbed to tumors more rapidly than Rb+/- mice, suggesting that in certain contexts mutations in these two cell cycle regulators can cooperate in tumor development.     

Cyclooxygenase inhibition potentiates the renal vascular response to endothelin-1 in humans

Vascular endothelin-receptor stimulation results in vasoconstriction and concomitant production of the vasodilators prostaglandin I2 and nitric oxide. The vascular effects of cyclooxygenase (COx) blockade (diclofenac intravenously) and the subsequent vasoconstrictor response to endothelin-1 (ET-1) infusion 30 min after diclofenac were studied in healthy men. With COx blockade, cardiac output (7%) and splanchnic (14%) and renal (12%) blood flows fell (all P < 0.001). Splanchnic blood flow returned to basal value within 30 min. Mean arterial blood pressure increased (4%, P < 0.001). Splanchnic glucose output fell (22%, P < 0.01). Subsequent ET-1 infusion caused, compared with previous ET-1 infusion without COx blockade (G. Ahlborg, E. Weitzberg, and J. M. Lundberg. J. Appl. Physiol. 77: 121-126, 1994; E. Weitzberg, G. Ahlborg, and J. M. Lundberg. Biochem. Biophys. Res. Commun. 180: 1298-1303, 1991; E. Weitzberg, G. Ahlborg, and J. M. Lundberg. Clin. Physiol. (Colch.) 13: 653-662, 1993), the same increase in mean arterial blood pressure (4%), decreases in cardiac output (13%) and splanchnic blood flow (38%), but no significant change in splanchnic glucose output. Renal blood flow reduction was potentiated (33 +/- 3 vs. 23 +/- 2%, P < 0.02), with a total reduction corresponding to 43 +/- 3% (P < 0.01 vs. 23 +/- 3%). We conclude that COx inhibition induces renal and splanchnic vasoconstriction. The selectively increased renal vascular responsiveness to ET-1 emphasizes the importance of endogenous arachidonic acid metabolites (i.e., prostaglandin I2) to counteract ET-1-mediated renal vasoconstriction.     

Altered neuropeptide Y Y1 responses in mesenteric arteries in rats with congestive heart failure

The aim of the present study was to elucidate if the potentiating effect of neuropeptide Y on various vasoactive agents in vitro is (1) altered in mesenteric arteries from rats with congestive heart failure and (2) mediated by the neuropeptide Y Y1 receptor. The direct vascular effects of neuropeptide Y and its modulating effects on the contractions induced by endothelin-1-, noradrenaline-, 5-hydroxytryptamine (5-HT)-, U46619-(9,11-dideoxy-11alpha, 9alpha-epoxymethano-prostaglandin F2alpha) and ATP, and acetylcholine-induced dilatations were studied in the presence and absence of the neuropeptide Y Y1 antagonist, BIBP3226 (BIBP3226?(R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl ]-D-arginine-amide?). Neuropeptide Y, per se, had no vasoactive effect in the arteries. The potency of endothelin-1 was significantly decreased in congestive heart failure rats. Neuropeptide Y and neuropeptide Y-(13-36) potentiated the endothelin-1-induced contraction in congestive heart failure mesenteric arteries. In 20% of the congestive heart failure rats, sarafotoxin 6c induced a contraction of 31+/-4%. Neuropeptide Y also potentiated U46619- and noradrenaline-induced contractions but not 5-HT-induced contractions in congestive heart failure arteries. In sham-operated animals neuropeptide Y potentiated noradrenaline- and 5-HT-induced contractions. These potentiations were inhibited by BIBP3226. Acetylcholine induced an equipotent relaxation in both groups which was unaffected by neuropeptide Y. In conclusion, neuropeptide Y responses are altered in congestive heart failure rats. The potentiating effect differs between vasoactive substances. Neuropeptide Y Y1 and non-neuropeptide Y1 receptors are involved.     

Comparable potent coronary constrictor effects of endothelin-1 and big endothelin-1 in humans

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor produced from the precursor big ET-1 in endothelial cells. The coronary effects of these peptides in humans in vivo are unknown. Therefore, the effects of ET-1 and big ET-1 on coronary blood flow in relation to plasma ET-1 and big ET-1 levels were compared in healthy subjects. METHODS AND RESULTS: The peptides were infused intravenously at the rates of 0.2, 1, and 8 pmol/kg per minute. Each dose administered for 20 minutes except the highest dose of ET-1, which was administered for 10 minutes. ET-1 and big ET-1 evoked dose-related increases in mean arterial blood pressure from 93 +/- 4 to 107 +/- 4 mm Hg and from 89 +/- 2 to 122 +/- 5 mm Hg, respectively, at the highest dose. ET-1 and big ET-1 reduced coronary sinus blood flow, measured with thermodilution by a maximum of 25 +/- 4% and 28 +/- 8% and increased coronary vascular resistance by 50 +/- 9% and 107 +/- 26%, respectively. Coronary sinus, but not arterial, oxygen saturation was reduced in parallel with the coronary sinus blood flow. The effects of ET-1 and big ET-1 were similar at corresponding time points. During infusion of ET-1, a 19 +/- 5% extraction of ET-1 was observed over the coronary vascular bed (P < .05). Administration of big ET-1 elevated arterial plasma ET-1 levels by 2.4-fold, and after correction for the local extraction of ET-1, a myocardial production of ET-1 was observed. CONCLUSIONS: ET-1 and big ET-1 induce comparable increases in blood pressure and coronary constriction in humans in vivo. The results also suggest a net local removal of circulating ET-1 and big ET-1 and a local conversion of big ET-1 into ET-1 within the coronary vascular bed.     

Circulating endothelin-1 in non-insulin-dependent diabetic patients with retinopathy

Chronic foot dermatitis can be disabling and footwear allergy is not always excluded as a cause, partly because patch testing to shoes and their components can be daunting. Once the diagnosis of shoe allergy is made, the difficult problem of finding suitable footwear remains. There is a lack of literature regarding the follow-up of these patients. We analysed the data on 55 patients with allergic contact dermatitis from their shoes and followed them up to see whether knowledge of the allergen had enabled them to find suitable footwear and to improve their dermatitis. The files of 55 patients with shoe allergy were analysed and 48 were followed up. Rubber was the commonest allergen, followed by chromate, p-tertiary-butylphenol-formaldehyde resin and colophony. All parts of the feet were affected, except the interdigital areas. The majority of patients suffered from hyperhidrosis. 43% were atopics, who had a super-added shoe allergy. The mean duration of the foot dermatitis before patch testing was 4 years 8 months. Follow-up of 48 cases showed that 87.5% had either improved or resolved completely. Most of our patients were successful in finding suitable footwear and many differing strategies were used. All patients with foot dermatitis which does not respond to treatment should be patch tested to exclude shoe allergy.     

Cardiac muscarinic receptor function in rats with cirrhotic cardiomyopathy

The pathogenesis of cirrhotic cardiomyopathy remains unclear. Because ventricular contractility is dependent on the interplay of stimulatory beta-adrenergic and inhibitory muscarinic receptors, we aimed to examine a possible role of muscarinic M2 receptor overactivity in a rat model of cirrhotic cardiomyopathy. Cirrhosis was induced by bile duct ligation (BDL), while controls underwent sham operations. Contractile responses to the muscarinic agonist carbachol were measured in situ in the autonomic-denervated pithed rat and in vitro in isolated ventricular papillary muscles. Ventricular sarcolemmal plasma membranes were isolated by sucrose density gradients, and muscarinic receptor characteristics were studied using 1-[N-methyl-3H]scopolamine (NMS). Membrane adenylyl cyclase activity was tested by a protein binding assay. Maximum first time derivative of peak ventricular systolic pressure (+dP/dt) for sham-operated and cirrhotic rats at baseline was 3,599 +/- 296 versus 1,226 +/- 63 mm Hg/sec (P < .01). Maximum first time derivative of ventricular diastolic relaxation (-dP/dt) for sham and cirrhotic rats at basal levels was -3,040 +/- 235 versus -864 +/- 59 (P < .01). The +dP/dt(max), and -dP/dt(max) responses to carbachol were blunted in the cirrhotic rats. The cirrhotic papillary muscles showed significantly less inhibition to incremental doses of carbachol than control rat muscles. Likewise, isoproterenol-stimulated membrane adenylyl cyclase activity was significantly less inhibited by carbachol doses in the cirrhotic rats. Membrane M2 receptor density and binding affinity in cirrhotic rat hearts were similar to controls. We conclude that muscarinic responsiveness was blunted in cirrhotic hearts, but this was not caused by receptor down-regulation, suggesting changes in postreceptor factors. These changes in muscarinic function are likely compensatory, and M2 receptor overactivity is not involved in the genesis of cirrhotic cardiomyopathy.     

Modulation by endothelin-1 of tissue plasminogen activator and plasminogen activator inhibitor-1 release from cultured human vascular endothelial cells: interaction of endothelin-1 with cytokines

The interaction of endothelin-1 (ET-1) with either interleukin-1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF alpha) on the release of tissue plasminogen activator antigen (t-PA:Ag) and plasminogen activator inhibitor-1 antigen (PAI-1:Ag) was investigated in a culture system of vascular endothelial cells derived from human umbilical vein. The t-PA:Ag release was significantly decreased by either IL-1 beta or TNF alpha; ET-1 intensified the suppressive effect of the cytokines. In contrast, PAI-1:Ag release was significantly increased by either IL-1 beta or TNF alpha; ET-1 significantly reduced the stimulatory effect of the cytokines. The data suggest that endothelial cell-mediated fibrinolysis may be modulated by ET-1.     

Immunoreactive endothelin-1, endothelin-2 and big endothelin-1 in follicular fluids of women undergoing ovulation induction for in-vitro fertilization

Atlantic cod (Gadus morhua) transferrin cDNAs were isolated from a liver cDNA library using a cod transferrin-derived polymerase chain reaction product as a hybridization probe. The composite nucleotide sequence of two overlapping clones was 2223 bp in length excluding the poly(A) sequence and was equivalent to 87% of the 3' end of the Atlantic salmon transferrin cDNA sequence. Comparison of the deduced amino acid sequence of cod, salmon, Xenopus and several mammalian transferrins revealed that the two fish sequences are more similar with respect to their amino acid sequence and the position of additions/deletions than to other vertebrate transferrins. Conservation of the iron-binding domains and cysteine residues involved in disulphide bridges indicates that all transferrins share similar tertiary structure and support the hypothesis that extant vertebrate transferrin genes were derived from a gene duplication before the divergence of fish, frogs and mammals. Cod transferrin mRNA was detected in both brain and liver RNA and to a much lesser extent in RNA isolated from kidney and heart in contrast to salmon and several other vertebrates in which the transferrin gene is not expressed in brain.     

Are mu-opioid receptors involved in the control of endothelin-1 release from the pituitary gland in normal and dehydrated rats?

A stereognostic ability test was performed in 60 patients. Forty patients were rehabilitated by means of osseointegrated implants. One group consisted of 20 patients with fixed prostheses on implants in both the upper and lower jaws. The other 20 patients had a maxillary denture while in the mandible an overdenture was retained by means of two implants connected by a bar. They were compared to a group of 20 subjects (controls) with a non-restored natural dentition. For the stereognostic ability test, subjects had to recognise ten different test pieces by manipulating them with two antagonistic incisor teeth, avoiding any contact with other oral structures. Both response time and percentage accuracy of recognition were evaluated. The present findings indicated that subjects with an overdenture on implants did not score significantly different from those with an implant-supported fixed prosthesis. In contrast, subjects with teeth had a significantly better stereognostic ability. The percentage of correct responses was 52% for overdentures, 56% for fixed prostheses on implants and 75% for natural dentitions. From these results, it could be concluded that the stereognostic ability is impaired in subjects rehabilitated with osseointegrated implants by about one-third to one-quarter compared to subjects with natural teeth.     

Endothelin ET(B) receptors counteract venoconstrictor effects of endothelin-1 in anesthetized rats

The inhibitory effects of BQ 788 (3 mg/kg, i.v., ET(B)-receptor antagonist) on endothelin-1 (ET-1)- or IRL 1620 (ET(B)-receptor agonist)-induced changes in mean arterial pressure (MAP), mean circulatory filling pressure (MCFP, driving force of venous return), arterial resistance (RA), venous resistance (RV) and cardiac output (CO) were characterized in 6 groups of pentobarbital-anesthetized rats. ET-1 or IRL 1620 (0.5, 1 and 2 nmol/kg, i.v.) dose-dependently increased MAP, RA, RV and MCFP and decreased CO. Maximum changes in RA, RV and CO elicited by ET-1 were greater than those by IRL 1620. Equimolar doses of ET-1 and IRL 1620 also caused similar initial transient decreases in MAP. BQ 788 alone slightly elevated MCFP, but did not alter other variables. The ET(B)-blocker abolished all changes elicited by IRL 1620, but only partially inhibited its responses on MCFP, showing the presence of BQ 788-insensitive receptors. BQ 788 also abolished ET-1's depressor response, partially inhibited its effect on MCFP, and markedly augmented its effects on RA, RV and CO. Thus, ET(B)-receptors counteract the sustained constrictor effects of ET-1 on arterial and venous resistance vessels Our results indicate a substantial arterial and venous dilator role for ET(B) receptors.