AJP - Heart Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 275: H176-H182, 1998;
0363-6135/98 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Burrell, L. M.
Right arrow Articles by Johnston, C. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Burrell, L. M.
Right arrow Articles by Johnston, C. I.
Vol. 275, Issue 1, H176-H182, July 1998

Long-term effects of nonpeptide vasopressin V2 antagonist OPC-31260 in heart failure in the rat

Louise M. Burrell, Paddy A. Phillips, John Risvanis, Robert K. Chan, Kathryn L. Aldred, and Colin I. Johnston

Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg 3084, Victoria, Australia

    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

The hormone arginine vasopressin (AVP) contributes to water retention and vasoconstriction in congestive heart failure (CHF) through effects at the V2 and V1a receptors, respectively. The effect of long-term V2 receptor (V2R) blockade using OPC-31260 was assessed in a rat model of postinfarction-induced CHF. Rats underwent coronary artery ligation or sham operation and were treated for 6 mo with oral OPC-31260 (10 mg · kg-1 · day-1) or vehicle. CHF was characterized by left ventricular remodeling and impaired systolic function, increased cardiac and lung weight, and elevated plasma atrial natriuretic peptide; plasma AVP and plasma renin activity were not increased. Chronic V2R blockade increased urine volume (P < 0.01) and decreased urine osmolality (P < 0.01) but had no natriuretic effects. V2R blockade did not activate the renin-angiotensin system but increased plasma AVP in CHF (P < 0.01). V2R blockade did not influence cardiac remodeling, cardiac function, or survival. These results suggest that AVP plays a major role in water retention through the renal V2R in a rat model of CHF. V2R blockade using OPC-31260 may represent an alternative to standard diuretic therapy in the management of water retention that characterizes heart failure.

myocardial infarction; receptors; echocardiography; survival

    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

CONGESTIVE HEART FAILURE (CHF) is a clinical syndrome characterized by impaired cardiac function, decreased exercise tolerance and quality of life, and high morbidity and mortality. Although angiotensin-converting enzyme inhibitors have improved the morbidity and mortality of CHF (30), current therapy for heart failure is still not optimal. Diuretics remain the mainstay of treatment to relieve congestive symptoms and reduce edema in heart failure, but data on long-term efficacy, adverse effects, and influence on survival remain unknown (7). An alternative approach to symptom relief in heart failure may be the use of aquaretic or selective water diuretics.

The hormone arginine vasopressin (AVP) plays a critical role in water balance and contributes to water retention and hyponatremia through effects at the renal V2 receptor (V2R) and also contributes to increased peripheral resistance through potent constrictor actions at the V1a receptor (V1R) (15, 17, 21, 25).

The recent development of nonpeptide orally active AVP-receptor antagonists has allowed reevaluation of the precise role of AVP in experimental models of disease including hypertension (5, 6) and heart failure (24). Marked species heterogeneity exists for V2R antagonists in vivo, which has complicated their development as selective water diuretics (19). The description of OPC-31260 (39) was particularly interesting because this was the first nonpeptide V2R blocker that was effective in humans to increase free water clearance (28). OPC-31260 has beneficial aquaretic effects in rat models of disease such as experimental liver cirrhosis (35), the syndrome of inappropriate secretion of vasopressin (11), and high-output heart failure (26).

Coronary artery ligation in the rat results in a transmural anterior infarct followed by hemodynamic alterations and neurohumoral changes (16, 29) similar to those seen in patients with anterior infarction, and results from such studies have clinical implications (30). To date, the effects of V2R antagonism in a rat model of postinfarction CHF are unknown. The present study was designed 1) to assess whether the renal effects of V2R blockade are maintained with long-term therapy, 2) to determine the effect of V2R blockade on cardiac function and structure and on survival, and 3) to assess the effect of V2R blockade on neurohormones in a rat model of CHF.

    METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Experimental procedures were approved by the Austin Hospital Animal Research Ethics Committee and performed according to the National Health and Medical Research Council of Australia Guidelines for animal experimentation. OPC-31260 {5-dimethylamino-1-[4-(2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine} was a gift from Otsuka Pharmaceutical.

Surgical production of myocardial infarction. Left ventricular (LV) free wall myocardial infarction was induced in female Sprague-Dawley rats (200-250 g) by ligation of the proximal left anterior descending artery as described previously (3, 9, 10) using Ethrane anesthesia. Sham-operated (control) rats underwent an identical operation, but the suture was not tied. Rats were housed at 23-25°C in a 12:12-h light-dark cycle, with ad libitum food containing 0.4-0.6% NaCl (Norco) and water.

Experimental design. All rats that survived for 24 h postoperatively were randomized to vehicle (once-daily gavage of 5% arabic gum) or OPC-31260 (5 mg/kg, once-daily gavage) for 24 wk. OPC-31260-treated rats also received OPC-31260 in their drinking water at a concentration adjusted according to weight and daily fluid intake to give a dose of 10 mg/kg daily (based on data from metabolic studies). Treated rats therefore received a total daily OPC-31260 dose of 10 mg/kg. The dose was based on data showing that 10 mg/kg OPC-31260 had similar effects to 30 mg/kg in terms of reducing urine osmolality and increasing urine volume in normal rats (39).

Body weight and systolic blood pressure (SBP) were measured weekly. SBP was measured by the indirect tail cuff technique (38L flatbed recorder, model 229 Amplifier, IITC Life Science, Woodland Hills, CA) in conscious, lightly restrained rats. Metabolic studies to assess V2R blockade were performed at 4 and 20 wk. A randomly selected subset of rats (n = 13-16/group for control; n = 10-16/group for CHF rats) were placed into individual metabolic cages for 3 days, and fluid and food intake as well as urine volume osmolality and sodium were assessed. Cardiac geometry and function were assessed at 4 and 20 wk by transthoracic echocardiography (3) after anesthesia with intraperitoneal methohexital sodium in randomly selected animals from each group (n = 10-13/group for control; n = 18-25/group for CHF rats).

At 24 wk, surviving rats were weighed and killed, and trunk blood was collected into lithium heparin tubes for the measurement of plasma osmolality, sodium, and plasma AVP and into EDTA tubes for the measurement of atrial natriuretic peptide (ANP). The LV and interventricular septum were dissected from the heart, weighed, and fixed in 10% buffered Formalin. The right ventricle (RV), right atrium (RA), left atrium (LA), lungs, and liver were weighed.

Infarct size. The LV was sectioned at four levels from the base to the apex and paraffin fixed, and sections were cut and stained with Masson's trichrome and hematoxylin and eosin. The mean epicardial and endocardial scar circumference was compared with total LV circumference to calculate total infarct size (29). Rats with a subendocardial infarct or infarct size of <20% were excluded from analysis.

Cardiac geometry and function. Anesthetized rats were studied in a randomized fashion by a sonographer unaware of the rats' status using a commercially available echocardiographic system (XP128/10c, Acuson, Mountain View, CA) equipped with a 7.0-MHz linear array carotid artery ultrasound (3). This methodology has resolution to 0.1 mm. A two-dimensional, short-axis view of the LV was obtained at the level of the papillary muscles, M-mode echocardiograms of the anteroseptal and posterior LV walls were then recorded at paper speed of 100 mm/s, and images were stored on video tapes. Echocardiographic images were analyzed off-line by a single observer unaware of the status of the rats. Dimensions were measured from five cardiac cycles, and the values were averaged for each rat. Measurements of the anteroseptal end-diastolic wall thickness, posterior end-diastolic wall thickness, and LV internal dimensions at end diastole (LVDD) and end systole (LVSD) were made according to the American Society for Echocardiography leading edge method independent of the heart rate (32). Fractional shortening (FS) of the LV was calculated using the following formula: FS = (LVDD - LVSD)/LVDD × 100 (%).

Analytic methods. Plasma AVP was extracted using acetone and ether and measured by radioimmunoassay (inter- and intra-assay coefficients of variation both <8%) using a specific rabbit AVP antiserum (31). Urine and plasma osmolalities were measured using a Wescor Vapor Pressure Osmometer 5100C (Logan, UT). Plasma renin activity (PRA) was measured as described previously (18). Plasma ANP was measured after Florisil extraction by radioimmunoassay (4, 36). Plasma and urine sodium was measured using a flame photometer (Instrumentation Laboratories, Milan, Italy).

Statistics. All results except survival data are presented as means ± SE. Comparison of survival in untreated and treated CHF and control rats was performed using Kaplan-Meier analysis. Differences between values were assessed using two-factor ANOVA, one factor being the disease (control or CHF) and the other being treatment (vehicle or OPC-31260), followed by post hoc analysis using ANOVA and the Fisher test when appropriate. Significant differences were obtained when P < 0.05.

    RESULTS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Cages were examined twice daily to assess the health of the animals. If dead animals were found, the heart was removed and placed in Formalin for later assessment of infarct size. All sham-operated rats (n = 31) survived to 24 h and were randomized to vehicle (n = 16) or OPC-31260 (n = 15). Of 100 rats operated on to produce a myocardial infarction, ~80% (n = 79) were alive at 24 h and were randomized to vehicle (n = 39) or OPC-31260 (n = 40). Of the "infarct" rats, histological examination showed no infarct in eight rats (vehicle, n = 4; OPC-31260, n = 4) and small infarcts (<20%) or subendocardial infarcts in nine rats (vehicle, n = 5; OPC-31260, n = 4). These rats were therefore excluded, and results are reported on 62 infarct rats (vehicle, n = 32; OPC-31260, n = 30).

Infarct size and survival. The average infarct size was 36-37% and was similar in vehicle- and V2R antagonist-treated CHF rats (Table 1). No control animal had evidence of cardiac damage. Survival curves are shown in Fig. 1. No control rat died during the study. Chronic V2R blockade did not affect median survival time compared with vehicle (P < 0.77). The infarct size of rats that died spontaneously during the study was 36 ± 1% (range 23-53%) for those treated with OPC-31260 and 37 ± 2% (range 20-56%) in the vehicle-treated group (not significant).

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Infarct size, body weight, and blood pressure in control and CHF rats after 24-wk treatment with vehicle or OPC-31260


View larger version (13K):
[in this window]
[in a new window]
  		Fig. 1.   Plot shows Kaplan-Meier survival curves for congestive heart failure (CHF) rats treated with OPC-31260 (n = 30) or vehicle (n = 32) and control rats treated with vehicle (n = 16). Administration of OPC-31260 was not associated with improved or decreased survival compared with vehicle-treated CHF rats. Survival was 100% in control rats.

Body weight and SBP. There was no significant difference in body weight of control and CHF rats throughout the duration of the study. SBP was also similar in CHF and control rats, with no group or treatment effect on blood pressure throughout the treatment period. Data at 24 wk of treatment are shown in Table 1.

Metabolic parameters. Metabolic caging studies showed no significant differences in terms of fluid intake, urine volume, osmolality, or sodium excretion between control and CHF rats. V2R blockade increased urine volume (P < 0.01) and decreased urine osmolality (P < 0.01) in control and CHF rats, and these effects were seen at 4 and 20 wk (Fig. 2). V2R blockade had no effect on sodium excretion in either control or CHF rats. V2R blockade generally increased fluid intake, and this reached significance in V2R-treated control rats at 4 wk and in CHF rats at 20 wk.


View larger version (48K):
[in this window]
[in a new window]
  		Fig. 2.   Results of metabolic studies to assess vasopressin V2 receptor blockade at 4 and 20 wk of treatment. A randomly selected subset of rats (n = 13-16/group for control; n = 10-16/group for CHF rats) were placed into individual metabolic cages for 3 days, and fluid intake, urine volume, osmolality, and sodium were assessed. Data are presented as means ± SE. Hatched bars, OPC-31260-treated rats; open bars, vehicle-treated rats. BW, body weight. * P < 0.05, ** P < 0.01 OPC-31260 vs. vehicle.

Echocardiography. Echocardiographic studies in CHF rats showed evidence of LV remodeling with increased LVSD and LVDD and reduced FS, indicating impaired systolic function (P < 0.01) compared with control rats. These changes were present at the first study (4 wk) and also at 20 wk when, in addition, significant increases in noninfarcted posterior wall thickness occurred in CHF rats (P < 0.01) (Table 2). No treatment effects were apparent at either time point. In particular, V2R blockade had no significant adverse or beneficial effect on cardiac geometry and function in control or CHF rats.

                              
View this table:
[in this window]
[in a new window]
  		Table 2.   LV size assessed by histology and function assessed with M-mode echocardiography in control and CHF rats after 4- and 20-wk treatment with vehicle or OPC-31260

Cardiovascular structure. CHF was characterized by increased relative LV, RV, LA, RA (P < 0.01), and lung mass (P < 0.01) compared with control rats (Table 3). Chronic V2R blockade had no effect on these parameters in either CHF or control rats.

                              
View this table:
[in this window]
[in a new window]
  		Table 3.   Organ weights in control and CHF rats treated for 24 wk with vehicle or OPC-31260

Biochemical and hormonal data. Table 4 shows the effects of chronic V2R blockade on biochemical and hormonal data in CHF and control rats. Plasma ANP concentrations were significantly elevated in CHF compared with control rats (P < 0.01) and were unchanged by V2R blockade. There was no group or treatment effect on plasma sodium, osmolality, or PRA. Plasma AVP concentrations were similar in vehicle-treated control and CHF rats. V2R blockade led to significant increases in plasma AVP in CHF but not control rats (P < 0.01).

                              
View this table:
[in this window]
[in a new window]
  		Table 4.   Biochemical and hormonal data in control and CHF rats measured after 24-wk treatment with vehicle or OPC-31260

    DISCUSSION
Top
Abstract
Introduction
Methods
Results
Discussion
References

The results of the present study indicate that V2R blockade using the nonpeptide antagonist OPC-31260 resulted in significant aquaretic effects that were maintained with long-term therapy in a postinfarction rat model of heart failure. V2R blockade had no natriuretic effects and did not activate the renin-angiotensin system (RAS). Significant increases in circulating AVP concentrations were noted in CHF rats. V2R blockade did not aggravate LV dilatation and did not influence cardiac structure or long-term survival in CHF.

Postinfarction heart failure model. Coronary artery ligation in the rat produces a uniform model of CHF characterized by impaired systolic function and increased cardiac and lung weight (3, 9, 10, 16). It is a model of compensated heart failure with no elevation of plasma AVP or PRA but with significant increases in plasma ANP. As the present data indicate, the postinfarction CHF model provides a homogeneous study group with similar degrees of LV dysfunction.

Metabolic and neurohormonal effects. The majority of studies using V2R antagonists have been acute in nature, and the acute effects of an intervention do not necessarily predict its long-term efficacy. For example, there was tachyphylaxis to the V2R-blocking effects of a combined peptide V2/V1R antagonist when used over an 11-day period in postinfarction heart failure in the rat (37). In the present study, OPC-31260 was equally effective in control and CHF rats, and its water diuretic effects were maintained long term. The renal effects of OPC-31260 were not accompanied by increases in plasma sodium or osmolality, as has been noted in acute dosing studies (2, 24). This may reflect that animals had free access to water.

Chronic V2R blockade was not associated with any natriuretic effect, which may explain the lack of activation of the RAS observed in this study. By contrast, the use of chlorothiazide in the same model of CHF led to stimulation of the RAS with increased PRA (20). Plasma ANP levels were significantly elevated in CHF rats and were not changed with V2R blockade, which is perhaps not surprising given that treatment did not improve LV dysfunction.

As shown previously (16), compensated heart failure was not associated with elevation in circulating plasma AVP, perhaps because the stimulus of low arterial pressure (3) was offset by elevated LA pressure. In this study, V2R blockade was associated with significant increases in plasma AVP in CHF but not control rats. Osmotic stimulation of AVP does not account for the increase, because plasma osmolality did not rise. One explanation may be baroreceptor-mediated nonosmotic release of AVP. If OPC-31260 treatment reduced atrial pressure in CHF rats, then lowered arterial pressure would now stimulate AVP release. This would explain why AVP increased only in CHF and not control rats. Although one could argue that a fall in arterial pressure sufficient to stimulate AVP should be counteracted by activation of the RAS, any rise in PRA would actually be prevented by both the high AVP and high ANP levels that act to suppress renal renin release. Because neither arterial nor atrial pressure was measured in this study, these explanations remain speculative.

Others (34) have suggested that binding of OPC-31260 to renal receptors reduces the clearance of AVP, resulting in increased plasma levels. This is unlikely, because increased AVP should have been seen in both control and CHF rats if this were the case.

A number of studies have now shown increased AVP levels with V2R blockade (26, 28), and it remains unclear what the consequences of such an increase might be in terms of renal or hemodynamic effects. Certainly in this study, increased AVP did not overcome the receptor blockade, because the aquaretic effects of OPC-31260 in CHF rats were similar to those in control rats. However, AVP has direct vasoconstrictor actions in several vascular beds through the V1R and certainly contributes to systemic vasoconstriction in some patients with heart failure (8, 14). Although SBP was unchanged in OPC-31260-treated CHF rats, this is a crude measure of hemodynamics, and studies assessing cardiac output, peripheral resistance, and arterial pressures are needed. In addition, there is increasing evidence that the heart may be a target organ of AVP. In vitro studies show that AVP mediates negatively inotropic effects in dog hearts (12) and modulates nitric oxide synthase activity in cardiac myocytes (38) via the V1R. In this study, OPC-31260 did not appear to adversely effect cardiac function and there was no increase in sudden death in V2R antagonist-treated CHF rats, which might be expected if increased circulating AVP contributed to arrhythmias.

Cardiovascular structure. LV dilatation plays a role in development of CHF after infarction, and the degree of LV enlargement is adversely related to survival in postinfarction patients (30). This is the first study to assess the effect of long-term V2R blockade on cardiac function and survival. Echocardiography demonstrated LV remodeling with increased LV systolic and diastolic dimensions and impaired systolic function. Although chronic V2R blockade had no significant beneficial effects on cardiac geometry or function in CHF, it is important that it had no adverse effects on these parameters, nor did it adversely effect survival. By contrast, a recent study using the same model of CHF showed that 8 wk of calcium channel blockade using anipamil increased LV dilatation and reduced survival by 35% (13). In keeping with the echocardiographic findings, no significant effects of OPC-31260 on cardiovascular structure were seen.

One must be careful in extrapolating results of studies between different animal models of CHF, between different degrees of heart failure, and using different doses and types of vasopressin-receptor antagonists. In contrast to the lack of cardiac structural effects seen in the postinfarction model of CHF, in a high-output aortocaval fistula model of CHF (26), 4 wk of OPC-31260 increased plasma AVP significantly but also improved hemodynamic parameters and reduced RV weight. In an earlier study using the postinfarction model, the benefits of a peptide V2/V1R antagonist depended on the degree of cardiac dysfunction, and increased cardiac output and decreased vascular resistance were only seen in rats with extensive infarcts (>50%) (22). We have preliminary data in which 7 days of OPC-31260 in a severe decompensated model of pacing-induced heart failure in the sheep (23) had significant aquaretic effects and beneficial hemodynamic effects.

The V2R antagonist OPC-31260 is effective in man and is equipotent to frusemide in causing a diuresis in healthy volunteers (27). However, at higher doses OPC-31260 (1 mg/kg) caused a doubling of plasma vasopressin and increased plasma osmolality despite subjects having access to fluids. In fluid-restricted volunteers OPC-31260 was an effective aquaretic but again increased plasma AVP at higher doses (1 mg/kg) (33). Data on V2R antagonism in human heart failure is lacking and limited to one abstract (1). In this study, fluid-restricted heart failure patients were given a single dose of the V2R antagonist WAY-VPA-985. (Full details as to the selectivity and specificity of WAY-VPA-985 have not yet been published.) The results are promising, with WAY-VPA-985 causing similar reductions in urine osmolality in doses from 75 to 250 mg per person (1). No data as to hormonal or hemodynamic parameters are yet available.

In heart failure the adverse effects of diuretics to induce electrolyte disturbances such as hypokalemia or hyponatremia and to cause neurohumoral activation are well known. Equally well known are the dangers of a rapidly rising plasma sodium concentration, particularly in the setting of hyponatremia. More research is necessary before the V2R antagonists are shown to be a truly safe alternative to diuretic therapy.

The results of the present study indicate that in a postinfarction rat model of heart failure AVP V2R blockade using OPC-31260 resulted in significant aquaretic effects that were not associated with activation of the RAS. V2R blockade did not aggravate LV dilatation and had no adverse effects on cardiac structure or long-term survival but did significantly increase plasma AVP. AVP V2R antagonism may be a useful alternative to diuretic therapy in the management of water retention that characterizes heart failure.

    ACKNOWLEDGEMENTS

We thank Melinda Rockell for excellent technical assistance. The support of the National Health and Medical Research Council and the Austin Hospital Medical Research Foundation is gratefully acknowledged.

    FOOTNOTES

Address for reprint requests: L. M. Burrell, Dept. of Medicine, Univ. of Melbourne, Austin and Repatriation Medical Centre, Heidelberg 3084, Victoria, Australia.

Received 12 December 1997; accepted in final form 24 March 1998.

    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

1.   Abraham, W., R. Oren, A. Robertson, and R. Schrier. Effects of an oral, nonpeptide, selective V2 receptor AVP antagonist in human heart failure (Abstract). Nephrology 3: S15, 1997.

2.   Brooks, D. P., M. Valente, G. Petrone, P. D. Depalma, M. Sbacchi, and G. D. Clarke. Comparison of the water diuretic activity of kappa receptor agonists and a vasopressin receptor antagonist in dogs. J. Pharmacol. Exp. Ther. 280: 1176-1183, 1997[Abstract/Free Full Text].

3.   Burrell, L., R. Chan, P. Phillips, P. Calafiore, A. Tonkin, and C. Johnston. Validation of an echocardiographic assessment of cardiac function following moderate size myocardial infarction in the rat. Clin. Exp. Pharmacol. Physiol. 23: 570-572, 1996[Medline].

4.   Burrell, L. M., J. Palmer, J. A. Charlton, T. Thomas, and P. H. Baylis. A new radioimmunoassay for human atrial natriuretic peptide and its physiological validation. J. Immunoassay 11: 159-175, 1990[Medline].

5.   Burrell, L. M., P. A. Phillips, J. Risvanis, K. L. Aldred, A. M. Hutchins, and C. I. Johnston. Attenuation of genetic hypertension after short-term vasopressin V1A receptor antagonism. Hypertension 26: 828-834, 1995[Abstract/Free Full Text].

6.   Burrell, L. M., P. A. Phillips, J. M. Stephenson, J. Risvanis, K. A. Rolls, and C. I. Johnston. Blood pressure-lowering effect of an orally active vasopressin V1 receptor antagonist in mineralocorticoid hypertension in the rat. Hypertension 23: 737-743, 1994[Abstract/Free Full Text].

7.  Cody, R. J. Clinical trials of diuretic therapy in heart failure: research directions and clinical considerations. J. Am. Coll. Cardiol. 22, 4 Suppl. A: 165A-171A, 1993.

8.   Creager, M. A., D. P. Faxon, S. S. Cutler, O. Kohlmann, T. J. Ryan, and H. Gavras. Contribution of vasopressin to vasoconstriction in patients with congestive heart failure: comparison with the renin-angiotensin system and the sympathetic nervous system. J. Am. Coll. Cardiol. 7: 758-765, 1986[Abstract].

9.   Duncan, A.-M., L. M. Burrell, A. Kladis, and D. J. Campbell. Effect of angiotensin converting enzyme inhibition on angiotensin and bradykinin peptides in myocardial infarction. J. Cardiovasc. Pharmacol. 28: 746-754, 1996[Medline].

10.   Duncan, A.-M., L. M. Burrell, A. Kladis, and D. J. Campbell. Angiotensin and bradykinin peptides in rats with myocardial infarction. J. Card. Fail. 3: 41-52, 1997.[Medline]

11.   Fujisawa, G., S. Ishikawa, Y. Tsuboi, K. Okada, and T. Saito. Therapeutic efficacy of non-peptide ADH antagonist OPC-31260 in SIADH rats. Kidney Int. 44: 19-23, 1993[Medline].

12.   Furukawa, Y., S. Takayama, L. M. Ren, S. Sawaki, Y. Inoue, and S. Chiba. Blocking effects of V1 (OPC-21268) and V2 (OPC-31260) antagonists on the negative inotropic response to vasopressin in isolated dog heart preparations. J. Pharmacol. Exp. Ther. 263: 627-631, 1992[Abstract/Free Full Text].

13.   Gaudron, P., M. Blumrich, and G. Ertl. Aggravation of left ventricular dilatation and reduction of survival by a calcium channel blocker in rats with chronic myocardial infarction. Am. Heart J. 125: 1226-1233, 1993[Medline].

14.   Goldsmith, S. R., G. S. Francis, A. W. Cowley, Jr., I. F. Goldenberg, and J. N. Cohn. Hemodynamic effects of infused arginine vasopressin in congestive heart failure. J. Am. Coll. Cardiol. 8: 779-783, 1986[Abstract].

15.   Goldsmith, S. R., G. S. Francis, A. W. Cowley, Jr., T. B. Levine, and J. N. Cohn. Increased plasma arginine vasopressin levels in patients with congestive heart failure. J. Am. Coll. Cardiol. 1: 1385-1390, 1983[Medline].

16.   Hodsman, G. P., M. Kohzuki, L. G. Howes, E. Sumithran, K. Tsunoda, and C. I. Johnston. Neurohumoral responses to chronic myocardial infarction in rats. Circulation 78: 376-381, 1988[Abstract/Free Full Text].

17.   Johnston, C. I. Vasopressin in circulatory control and hypertension. J. Hypertens. 3: 557-569, 1985[Medline].

18.   Johnston, C. I., F. A. O. Mendelsohn, and D. J. Casely. Evaluation of renin and angiotensin assays and their clinical applications. Med. J. Aust. 1: 126-128, 1971[Medline].

19.   Kinter, L., S. Caltabiano, and W. Hoffman. Anomalous antidiuretic activity of antidiuretic hormone antagonists. Biochem. Pharmacol. 45: 1731-1737, 1993[Medline].

20.   Kohzuki, M., M. Kanazawa, K. Yoshida, E. Tsutsumi, M. Yasujima, K. Abe, C. I. Johnston, and T. Sato. Cardiomegaly and vasoactive hormones in rats with chronic myocardial infarction: long-term effects of chlorothiazide. Clin. Sci. (Colch.) 90: 31-36, 1996[Medline].

21.   Martin, P. Y., and R. W. Schrier. Sodium and water retention in heart failure: pathogenesis and treatment. Kidney Int. Suppl. 59: S57-S61, 1997[Medline].

22.   Mulinari, R. A., I. Gavras, Y. X. Wang, R. Franco, and H. Gavras. Effects of a vasopressin antagonist with combined antipressor and antiantidiuretic activities in rats with left ventricular dysfunction. Circulation 81: 308-311, 1990[Abstract/Free Full Text].

23.   Naitoh, M., L. M. Burrell, J. Risvanis, C. L. Johnston, and J. Power. Comparison of chronic V2R blockade and ACE inhibition in CHF in sheep (Abstract). Nephrology 3: S52, 1997.

24.   Naitoh, M., H. Suzuki, M. Murakami, A. Matsumoto, K. Arakawa, A. Ichihara, H. Nakamoto, K. Oka, Y. Yamamura, and T. Saruta. Effects of oral AVP receptor antagonists OPC-21268 and OPC-31260 on congestive heart failure in conscious dogs. Am. J. Physiol. 267 (Heart Circ. Physiol. 36): H2245-H2254, 1994[Abstract/Free Full Text].

25.   Nicod, P., B. Waeber, J. P. Bussien, J. J. Goy, G. Turini, J. Nussberger, K. G. Hofbauer, and H. R. Brunner. Acute hemodynamic effect of a vascular antagonist of vasopressin in patients with congestive heart failure. Am. J. Cardiol. 55: 1043-1047, 1985[Medline].

26.   Nishikimi, T., Y. Kawano, Y. Saito, and H. Matsuoka. Effect of long-term treatment with selective vasopressin V1 and V2 receptor antagonist on the development of heart failure in rats. J. Cardiovasc. Pharmacol. 27: 275-282, 1996[Medline].

27.   Ohnishi, A., Y. Orita, R. Okahara, H. Fujihara, T. Inoue, Y. Yamamura, Y. Yabuuchi, and T. Tanaka. Potent aquaretic agent. A novel nonpeptide selective vasopressin V2 antagonist (OPC-31260) in men. J. Clin. Invest. 92: 2653-2659, 1993.

28.   Ohnishi, A., Y. Orita, N. Takagi, T. Fujita, T. Toyoki, Y. Ihara, Y. Yamamura, T. Inoue, and T. Tanaka. Aquaretic effect of a potent, orally active, nonpeptide V2 antagonist in men. J. Pharmacol. Exp. Ther. 272: 546-551, 1995[Abstract/Free Full Text].

29.   Pfeffer, J. M., M. A. Pfeffer, and E. Braunwald. Hemodynamic benefits and prolonged survival with long-term captopril therapy in rats with myocardial infarction and heart failure. Circulation 75,1Pt2: I149-I155, 1987.

30.   Pfeffer, M., E. Braunwald, L. Moye, L. Basta, E. J. Brown, T. Cuddy, B. Davis, E. Geltman, S. Goldman, and G. Flaker. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N. Engl. J. Med. 327: 669-677, 1992[Abstract].

31.   Pullan, P. T. C., C. I. Johnston, W. P. Anderson, and P. I. Korner. The role of vasopressin in blood pressure control and in experimental hypertension. Clin. Sci. Mol. Med. 5: 251S-254S, 1978.

32.   Sahn, D., A. DeMaria, J. Kisslo, and A. Weyman. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 58: 1072-1083, 1978[Abstract/Free Full Text].

33.   Shimizu, K. Aquaretic effects of the nonpeptide V2 antagonist OPC-31260 in hydropenic humans. Kidney Int. 48: 220-226, 1995[Medline].

34.   Tsuboi, Y., S. Ishikawa, G. Fujisawa, K. Okada, and T. Saito. In vivo diuretic effect of a new non-peptide arginine vasopressin antagonist, OPC-31260, in conscious rats. J. Endocrinol. 143: 227-234, 1994[Abstract/Free Full Text].

35.   Tsuboi, Y., S. Ishikawa, G. Fujisawa, K. Okada, and T. Saito. Therapeutic efficacy of the non-peptide AVP antagonist OPC-31260 in cirrhotic rats. Kidney Int. 46: 237-244, 1994[Medline].

36.   Tsunoda, K., G. P. Hodsman, E. Sumithran, and C. I. Johnston. Atrial natriuretic peptide in chronic heart failure in the rat: a correlation with ventricular dysfunction. Circ. Res. 59: 256-261, 1986[Abstract/Free Full Text].

37.   Wang, Y. X., R. Franco, I. Gavras, and H. Gavras. Effects of chronic administration of a vasopressin antagonist with combined antivasopressor and antiantidiuretic activities in rats with left ventricular dysfunction. J. Lab. Clin. Med. 117: 313-318, 1991[Medline].

38.   Yamamoto, K., U. Ikeda, K. Okada, T. Saito, Y. Kawahara, M. Okuda, M. Yokoyama, and K. Shimada. Arginine vasopressin increases nitric oxide synthesis in cytokine-stimulated rat cardiac myocytes. Hypertension 30: 1112-1120, 1997[Abstract/Free Full Text].

39.   Yamamura, Y., H. Ogawa, H. Yamashita, T. Chihara, H. Miyamoto, S. Nakamura, T. Onogawa, T. Yamashita, T. Hosokawa, and T. Mori. Characterization of a novel aquaretic agent, OPC-31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist. Br. J. Pharmacol. 105: 787-791, 1992[Medline].

Am J Physiol Heart Circ Physiol 275(1):H176-H182
0002-9513/98 $5.00 Copyright © 1998 the American Physiological Society


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
B. Bishara, H. Shiekh, T. Karram, I. Rubinstein, Z. S. Azzam, N. Abu-Saleh, S. Nitecki, J. Winaver, A. Hoffman, and Z. A. Abassi
Effects of Novel Vasopressin Receptor Antagonists on Renal Function and Cardiac Hypertrophy in Rats with Experimental Congestive Heart Failure
J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 414 - 422.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
H. R. De Smet, M. F. Menadue, J. R. Oliver, and P. A. Phillips
Increased thirst and vasopressin secretion after myocardial infarction in rats
Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R1203 - R1211.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
R. B. Felder, J. Francis, Z.-H. Zhang, S.-G. Wei, R. M. Weiss, and A. K. Johnson
Heart failure and the brain: new perspectives
Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R259 - R276.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. J. Clair, M. K. King, A. T. Goldberg, J. W. Hendrick, R. Nisato, D. M. Gay, A. E. Morrison, J. H. McElmurray III, R. S. Krombach, B. R. Bond, et al.
Selective Vasopressin, Angiotensin II, or Dual Receptor Blockade with Developing Congestive Heart Failure
J. Pharmacol. Exp. Ther., June 1, 2000; 293(3): 852 - 860.
[Abstract] [Full Text]

Home page
 J. Histochem. Cytochem.Home page
R. Dean, S. R. Edmondson, L. M. Burrell, and L. A. Bach
Localization of the Insulin-like Growth Factor System in a Rat Model of Heart Failure Induced by Myocardial Infarction
J. Histochem. Cytochem., May 1, 1999; 47(5): 649 - 660.
[Abstract] [Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Burrell, L. M.
Right arrow Articles by Johnston, C. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Burrell, L. M.
Right arrow Articles by Johnston, C. I.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online