Reduction of ACE activity is insufficient to decrease microalbuminuria in normotensive patients with type 1 diabetes.

OBJECTIVE: To study whether administration of 1.25 and 5.0 mg ramipril daily, compared with placebo treatment, reduces the urinary albumin excretion rate (UAER) in normotensive patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Ramipril was administered double blind at two different doses (1.25 [n = 19] and 5.0 mg [n = 18]), and compared with placebo (n = 18) after a single-blind placebo period of 1-4 weeks. The patients (total, n = 55; women, n = 14) were followed for 2 years. To document an effect on the renin-angiotensin system, ACE activity and plasma-renin activity (PRA) were measured. In addition, 24-h ambulatory blood pressure (BP) was recorded at baseline and repeated after 1 and 2 years using a Spacelab 90207 ambulatory BP recording device (Spacelab, Redmont, CA). RESULTS: Both doses of ramipril were sufficient to reduce ACE activity and to increase PRA significantly as compared with placebo (P < 0.05 for both). On the other hand, neither ambulatory nor clinic BP was affected by either dose of ramipril compared with the placebo group. There was no progression of UAER in the placebo group during the 2 years of the study. Analysis of covariance showed no differences in UAER between the three treatment groups at year 1 (P = 0.94) or year 2 (P = 0.97), after adjusting for baseline. Furthermore, there were no statistically significant changes from baseline UAER within any of the three treatment groups. CONCLUSIONS: Treatment with ramipril did not affect microalbuminuria or clinic or ambulatory BP in this study. On the basis of the present study, we question the clinical use of ACE inhibitors in stably normotensive patients with type 1 diabetes and microalbuminuria in whom a concomitant reduction in BP is not demonstrated.

Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study.

BACKGROUND: Calcium antagonists are a first-line treatment for hypertension. The effectiveness of diltiazem, a non-dihydropyridine calcium antagonist, in reducing cardiovascular morbidity or mortality is unclear. We compared the effects of diltiazem with that of diuretics, beta-blockers, or both on cardiovascular morbidity and mortality in hypertensive patients. METHODS: In a prospective, randomised, open, blinded endpoint study, we enrolled 10,881 patients, aged 50-74 years, at health centres in Norway and Sweden, who had diastolic blood pressure of 100 mm Hg or more. We randomly assigned patients diltiazem, or diuretics, beta-blockers, or both. The combined primary endpoint was fatal and non-fatal stroke, myocardial infarction, and other cardiovascular death. Analysis was done by intention to treat. FINDINGS: Systolic and diastolic blood pressure were lowered effectively in the diltiazem and diuretic and beta-blocker groups (reduction 20.3/18.7 vs 23.3/18.7 mm Hg; difference in systolic reduction p<0.001). A primary endpoint occurred in 403 patients in the diltiazem group and in 400 in the diuretic and beta-blocker group (16.6 vs 16.2 events per 1000 patient-years; relative risk 1.00 [95% CI 0.87-1.15], p=0.97). Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 in the diuretic and beta-blocker group (6.4 vs 7.9 events per 1000 patient-years; 0.80 [0.65-0.99], p=0.04) and fatal and non-fatal myocardial infarction in 183 and 157 patients (7.4 vs 6.3 events per 1000 patient-years; 1.16 [0.94-1.44], p=0.17). INTERPRETATION: Diltiazem was as effective as treatment based on diuretics, beta-blockers, or both in preventing the combined primary endpoint of all stroke, myocardial infarction, and other cardiovascular death.

Efficacy and safety of a new long-acting drug combination, trandolapril/verapamil as compared to monotherapy in primary hypertension. Swedish TARKA trialists.

OBJECTIVE: To evaluate the clinical efficacy and safety of a new antihypertensive drug combination of trandolapril/verapamil compared to monotherapy with verapamil or trandolapril, in patients with mild to moderate primary hypertension. DESIGN: A multicentre, prospective, randomized, double-blind, controlled cross-over study with specific statistical considerations. SETTINGS: Eighteen primary health care centres and out-patient hospital clinics in Sweden. PATIENTS: Two hundred and twenty-six outpatients with uncomplicated primary hypertension with a baseline sitting diastolic blood pressure (BP) between 95 and 115 mmHg. INTERVENTIONS: After a 4-week placebo period, patients were randomized to treatment for 8 weeks with trandolapril/verapamil (2 mg/180 mg) or each drug alone (verapamil 240 mg, trandolapril 2 mg) for 8 weeks. MAIN OUTCOME MEASURES: Treatment responses (blood pressure (BP) fall and rate pressure product) to the three regimens with statistical comparison and also in relation to plasma concentrations of active renin (AR). Adverse events and safety were also evaluated. RESULTS: The mean BP fall was significantly greater with the combination (20/15 mmHg), p < 0.00054, as compared to both trandolapril (14/11 mmHg) or verapamil (13/11) mmHg. The difference between verapamil and trandolapril was not significant. Rate pressure product decreased significantly more on the combination, p < 0.001, than on trandolapril or verapamil alone. Treatment response to trandolapril was positively correlated to initial AR (r = 0.30-0.43). All treatments were well tolerated and safe. CONCLUSIONS: The new fixed drug combination trandolapril/verapamil was superior to monotherapy with either of these drugs alone regarding reduction of both BP and rate pressure product. This combination can be safely and effectively used for the treatment of mild to moderate primary hypertension.

The renin-angiotensin-aldosterone system is suppressed in adults with Type 1 diabetes.

Poor glycaemic control and high blood pressure are two important risk factors for the development of retinopathy and nephropathy in Type 1 diabetes. The renin-angiotensin-aldosterone system (RAAS) may be involved in this process, since treatment with angiotensin-converting enzyme (ACE) inhibitors postpones the development of these complications. We investigated whether plasma renin activity (PRA), plasma angiotensin II (Ang II) and atrial natriuretic peptide (ANP) differed in Type 1 diabetic patients compared with healthy controls. We recruited 80 patients with Type 1 diabetes of more than 10 years' duration and 75 age-matched controls. We found that PRA and Ang II concentrations were significantly lower in patients than in the controls. The levels of ANP, on the other hand, were higher in patients than in controls. PRA correlated negatively to the mean value of HbA(1c) during the previous five years. PRA and Ang II were significantly lower in patients with mean HbA(1c) >8.4% compared with those with mean HbA(1c) <7.2%. In summary, we found patients with Type 1 diabetes to have RAAS suppression and increased ANP levels, suggesting a state of fluid retention.

The circulating renin-angiotensin system during treatment with metoprolol or captopril in patients with heart failure due to non-ischaemic dilated cardiomyopathy.

OBJECTIVE: To investigate the effects of beta-blocker (metoprolol) or angiotensin-converting enzyme inhibitor (captopril) treatment on neurohormonal function in a randomized prospective study on patients with heart failure due to dilated cardiomyopathy. PATIENTS: Fifty-four patients (42 men and 12 women, mean age 50 years) were studied. There were three patients in NYHA (New York Heart Association) functional class I, 32 patients in class II and 19 patients in class III. METHODS: Measurements of plasma renin activity (PRA). plasma angiotensin II (A II) concentration and plasma atrial natriuretic peptide (ANP) concentration were made at rest and also in a subgroup (n = 32) during exercise. The urinary excretion of aldosterone was also determined. Investigations were performed at baseline, and after 3 and 6 months. Therapy was then stopped and the patients were re-investigated 1 month thereafter. RESULTS: The mean level of PRA was normal at baseline, reduced during therapy with metoprolol, and increased during therapy with captopril. The mean plasma concentration of A II was reduced during exercise and there was a trend towards a reduction even at rest in the metoprolol group, but not in the captopril group. The urinary excretion of aldosterone decreased in both groups. The mean plasma concentration of ANP was elevated at baseline and declined during exercise in the metoprolol group. CONCLUSION: In patients with dilated cardiomyopathy and only a partly activated renin-angiotensin system, both metoprolol and captopril reduced urinary excretion of aldosterone. Furthermore, metoprolol suppressed the exercise-induced increase in ANP, suggesting a favourable effect on ventricular performance.

Efficacy and safety of telmisartan, a selective AT1 receptor antagonist, compared with enalapril in elderly patients with primary hypertension. TEES Study Group.

OBJECTIVE: To assess the antihypertensive efficacy and safety of the novel AT1 receptor antagonist, telmisartan, compared with that of enalapril in elderly patients with mild to moderate hypertension. DESIGN: A 26-week, multicenter, double-blind, parallel-group, dosage titration study. METHODS: A total of 278 patients aged > or = 65 years were randomized to eithertelmisartan or enalapril once a day. The telmisartan dosage was increased from 20 to 40-80 mg and that of enalapril from 5 to 10-20 mg at 4-week intervals until trough supine diastolic blood pressure was < 90 mmHg. After 12 weeks, hydrochlorothiazide at 12.5-25 mg once a day was added to the treatment regimen of those patients not controlled on monotherapy. RESULTS: Both treatments lowered blood pressure in a comparable and clinically meaningful manner. The adjusted mean changes from baseline in supine diastolic blood pressure at trough were -12.8 mmHg for telmisartan and -11.4 mmHg for enalapril (P = 0.074). Mean changes in supine systolic blood pressure were -22.1 mmHg for telmisartan and -20.1 mmHg for enalapril (P = 0.350). Overall, 63 and 62% of patients responded to telmisartan and enalapril, respectively, with a supine diastolic blood pressure of < 90 mmHg. Both regimens provided effective blood pressure lowering over the 24 h dosing interval, as determined by ambulatory blood pressure monitoring. Both regimens were well tolerated; however, patients on the enalapril regimen had more than double the incidence of treatment-related cough compared with those on the telmisartan regimen (16 versus 6.5%). CONCLUSIONS: These results demonstrate that telmisartan is well tolerated and is at least as effective as enalapril in treating elderly patients with mild to moderate hypertension.

Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial.

BACKGROUND: Angiotensin-converting-enzyme (ACE) inhibitors have been used for more than a decade to treat high blood pressure, despite the lack of data from randomised intervention trials to show that such treatment affects cardiovascular morbidity and mortality. The Captopril Prevention Project (CAPPP) is a randomised intervention trial to compare the effects of ACE inhibition and conventional therapy on cardiovascular morbidity and mortality in patients with hypertension. METHODS: CAPPP was a prospective, randomised, open trial with blinded endpoint evaluation. 10,985 patients were enrolled at 536 health centres in Sweden and Finland. Patients aged 25-66 years with a measured diastolic blood pressure of 100 mm Hg or more on two occasions were randomly assigned captopril or conventional antihypertensive treatment (diuretics, beta-blockers). Analysis was by intention-to-treat. The primary endpoint was a composite of fatal and non-fatal myocardial infarction, stroke, and other cardiovascular deaths. FINDINGS: Of 5492 patients assigned captopril and 5493 assigned conventional therapy, 14 and 13, respectively, were lost to follow-up. Primary endpoint events occurred in 363 patients in the captopril group (11.1 per 1000 patient-years) and 335 in the conventional-treatment group (10.2 per 1000 patient-years; relative risk 1.05 [95% CI 0.90-1.22], p=0-52). Cardiovascular mortality was lower with captopril than with conventional treatment (76 vs 95 events; relative risk 0.77 [0.57-1-04], p=0.092), the rate of fatal and non-fatal myocardial infarction was similar (162 vs 161), but fatal and non-fatal stroke was more common with captopril (189 vs 148; 1.25 [1-01-1-55]. p=0.044). INTERPRETATION: Captopril and conventional treatment did not differ in efficacy in preventing cardiovascular morbidity and mortality. The difference in stroke risk is probably due to the lower levels of blood pressure obtained initially in previously treated patients randomised to conventional therapy.

Whole-body cooling increases plasma endothelin-1 levels in women with primary Raynaud's phenomenon.

To understand better the role of endothelin-1 (ET-1) in the pathogenesis of primary Raynaud's phenomenon (PRP), we investigated the basal ET-1 plasma levels and changes after whole-body cooling in healthy women and those with PRP. The study was performed as an open parallel-group comparison during the month of February. The Raynaud group included 21 female patients (mean age 45.3 years, range 21-57 years) who had had disabling Raynaud's phenomenon for a mean period of 17 years (range 2-26 years). The control group consisted of 25 healthy women (mean age 43.6 years, range 27-56 years). Plasma levels of ET-1 were measured on two separate occasions: once after 30 min of rest at room temperature and after 40 min of whole-body cooling. There were no significant differences in baseline plasma ET-1 levels between the two groups of women. The plasma ET-1 levels increased significantly in the PRP group after cold exposure (mean difference 0.11 pmol l-1, 95% CI 0.005-0.214, P = 0.012). In contrast, the levels of plasma ET-1 in the control group did not change significantly after cold provocation. In conclusion, no differences in plasma basal levels of ET-1 were observed between the two groups. However, women suffering from Raynaud's phenomenon responded with a slight but significant elevation in plasma levels of ET-1 after whole-body cooling, whereas the healthy control subjects did not. The results from the present study confirm previous observations that endothelial dysfunction may be of aetiological importance in PRP.

Unchanged incidence of severe retinopathy in a population of Type 1 diabetic patients with marked reduction of nephropathy.

The incidence of nephropathy in Type 1 diabetes mellitus has declined during the past decade, probably as a result of improved glycaemic control. We wanted to investigate whether the incidence of severe retinopathy has changed during the same time period and to evaluate the importance of glycaemic control in relation to the development of severe retinopathy and nephropathy. All 213 patients in whom Type 1 diabetes mellitus was diagnosed before the age of 15 years between 1961 and 1980 in a district in southeastern Sweden were studied. Ninety-two per cent of the patients were followed from the onset of diabetes to 1991 or to death. The cumulative incidence of severe retinopathy was not significantly different between the patients with diabetes onset 1961-65, 1966-70, 1971-75, and 1976-80. The risk of developing severe retinopathy or nephropathy was higher in patients with very poor glycaemic control (HbA1c > or = 8.4%) vs patients with poor control (HbA1c > or = 7.2 < 8.4%; p < 0.001). Patients with poor control had an increased risk of developing severe retinopathy vs patients with good control (HbA1c < 7.2%; p < 0.008) but there was no difference in the risk of nephropathy. No patients with good control developed nephropathy and only one patient developed severe retinopathy during 25 years of diabetes.

Salivary cortisol--an alternative to serum cortisol determinations in dynamic function tests.

Salivary cortisol was measured as an alternative to serum cortisol as a marker for adrenocortical function following insulin tolerance test, corticotropin-releasing-hormone stimulation and adreno-corticotrophic hormone stimulation. During insulin tolerance test and corticotropin-releasing-hormone stimulation adreno-corticotrophic hormone was also measured. The tests were performed on healthy control subjects as well as on patients under investigation for various disturbances in the hypothalamic-pituitary-adrenocortical axis (insulin tolerance test: 3 controls on two occasions and 14 patients; corticotropin-releasing-hormone stimulation: 4 controls and 18 patients; adreno-corticotrophic hormone stimulation: 6 controls and 10 patients). Five patients underwent both insulin tolerance test and corticotropin-releasing-hormone stimulation. Using criteria for adequate cortisol response in serum, the patients were classified as good or poor responders. In 42 of the 45 tests performed the same conclusion as to cortisol status was drawn when based on serum and salivary cortisol responses. In healthy subjects and good responders the mean cortisol relative increase was greater in saliva than in serum in all three tests (p < 0.05). Characteristic of the results for the insulin tolerance test was a significant initial mean decrease (p < 0.05), not found in serum, and the highest observed salivary cortisol value was delayed for at least 30 minutes compared to that in serum. Plasma adreno-corticotrophic hormone correlated significantly with the cortisol concentrations determined 15 minutes later in serum (r = 0.54-0.64) and in saliva (r = 0.76-0.85). The more pronounced cortisol response in saliva than in serum and its closer correlation with adreno-corticotrophic hormone offer advantages over serum cortisol, suggesting salivary cortisol measurement may be used as an alternative parameter in dynamic endocrine test.

Circulating plasma prekallikrein and tissue kallikrein in normotensive and hypertensive humans: effects of angiotensin II infusion.

Kinins lower blood pressure but the stimuli leading to kinin generation and their origin are less well known. We administered angiotensin II in graded infusion doses to patients with primary hypertension and normotensive controls to study the effects of on circulating kallikreins. Angiotensin II infusion did not significantly alter plasma prekallikrein or tissue kallikrein levels and the plasma levels and their changes did not correlate with blood pressure levels or changes. In the normotensive group prekallikrein levels and renin activity correlated negatively with urinary sodium and chloride excretion during basal conditions and partially during the infusion. U-tissue kallikrein concentration increased in the normotensive group. Thus, acute elevation of blood pressure induced by angiotensin II does not activate the circulating kallikrein-kinin systems. Data rather indicate that the circulating kallikrein-kinin systems may be related to alterations in volume and sodium balance and that these mechanisms may be altered in primary hypertension.

A population-based study of plasma cyclic guanosine monophosphate: relations to age, atrial natriuretic factor and angiotensin-converting enzyme activity.

In order to study the relations between plasma cyclic guanosine monophosphate (cGMP) and anthropometric variables, plasma atrial natriuretic factor (ANP) and serum angiotensin-converting enzyme activity (ACE), a population study with random selection of 217 subjects (49% men) 18-69 years old was performed. Venous blood was drawn at 08.00 h and ambulatory blood pressure (ABP) recording was then performed. There was no gender-difference in cGMP levels (men 2.2 +/- 1.1 nmol L-1, women 2.2 +/- 1.1 nmol L-1). A weak negative correlation was seen between cGMP and systolic ABP in both genders 20-44 years of age (r = -0.3, p = 0.05 for both), but this correlation did not persist in multivariate analysis with correction for ANP, age and ACE. In women, cGMP correlated positively with ANP (r = 0.27, p = 0.005) independently of ANP, ACE, ABP and age. ACE correlated negatively with cGMP in men (all; r = -0.22, p = 0.03, 45-69 years of age r = -0.49, p = 0.0002) and this correlation was independent of ANP, ACE, ABP and age. ACE catalyses the breakdown of bradykinin, which stimulates the release of NO. As the second messenger of NO is cGMP, the negative correlation between ACE and cGMP in men might be a reflection of reduced production of NO. Our results also suggest that there are gender differences in the stimuli for basal cGMP production.

An experimental study of cardiac natriuretic peptides as markers of development of congestive heart failure.

The use of cardiac peptide measurements as possible diagnostic tools in congestive heart failure has been extensively discussed in the recent literature. Therefore, the aim of this study was to establish a model of experimental chronic heart failure, and thereby perform a comparative study of secretion and circulating levels of the cardiac peptides atrial natriuretic peptide (ANP), N-terminal proatrial natriuretic peptide (N-terminal proANP) and brain natriuretic peptide (BNP) during evolving heart failure. Chronic heart failure was induced in seven pigs by rapid left atrial pacing for three weeks. The effects of failure induction were documented 24 h after pacemaker deactivation. Hemodynamic indices of cardiac preload, like pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP), were all considerably increased compared to sham operated controls. Likewise, plasma endothelin-L, noradrenaline, renin activity, aldosterone and angiotensin II were all markedly increased. Heart failure was accompanied by significant increases in both estimated cardiac secretory rate and plasma concentrations of all three cardiac peptides, significantly correlated to the PCWP. The directional changes during evolving heart failure were similar, although the percentage increase in plasma BNP was much larger than for ANP and N-terminal proANP. In absolute molar terms, however, the BNP concentration changes were minor compared to those of the other two peptides. The larger percentage increase of BNP might indicate its superiority as a marker of heart failure development, provided a functional assay suitable for clinical use can be designed for a peptide circulating in this low concentration range.

Serum angiotensin-converting enzyme activity correlates positively with plasma angiotensin II: a population-based study of ambulatory blood pressure and the renin-angiotensin system.

A population-based study was performed in order to study the interrelationships of the circulating components of the renin-angiotensin system during basal conditions and their relations to blood pressure (BP), age and gender. One hundred and four women and 95 men, 16-70 years old, evenly age distributed and randomly selected from the population of Linköping, Sweden, participated. Venous blood was drawn at 08.00 hours and ambulatory BP recording was then performed. Serum angiotensin-converting enzyme (ACE) activity correlated with plasma angiotensin II (r = 0.20, P = 0.004), but when calculated separately according to gender, the correlation remained significant only in men (r = 0.33, P = 0.001). Plasma renin activity (PRA) correlated negatively with age (r = -0.30, P < 0.0001), but immunoreactive active renin (IRR) and angiotensin II did not. PRA and IRR correlated negatively with BP in women but correlations disappeared after age adjustment. The 23 women on oestrogen medication did not differ from the remaining 81 with respect to age (P = 0.5), IRR (P = 0.96) or angiotensin II (P = 0.4) levels, but PRA was higher (2.2 +/- 1.4 ng Ang l/ml/h and 1.5 +/- 0.9 ng Ang l/ml/h, respectively, P = 0.004). PRA (r = 0.38, P < 0.0001) and IRR (r = 0.49, P < 0.0001) correlated positively with the levels of angiotensin II. In conclusion the fact that PRA, but not IRR, declined with age and was higher among oestrogen-treated women, although angiotensin II was unaffected suggests IRR to be a more robust marker of angiotensin II levels than is PRA in a population-based setting. ACE correlates positively with angiotensin II in men.

Circulating kallikreins during sodium chloride infusion in normal and hypertensive humans.

The stimuli generating kinins participating in blood pressure, volume and sodium homeostasis and their origin are not fully known. We studied the effects of a combined sodium and volume load on circulating plasma and tissue kallikreins. Normal saline (2000 ml) was infused over 4 h in 14 subjects with primary hypertension and 15 age- and sex-matched normotensive control subjects. The infusion increased blood pressure slightly in both groups. Plasma prekallikrein levels fell in both groups (normotensives: 98 +/- 4 to 87 +/- 5%, p = 0.002; hypertensives: 106 +/- 5 to 94 +/- 6%, p = 0.003), but more rapidly in normotensives. Circulating tissue kallikrein did not change significantly in the normotensive group but was reduced in the hypertensive group. Sodium excretion during the infusion correlated negatively with changes in plasma prekallikrein and positively with plasma levels of tissue kallikrein in the normotensive group only. Urinary tissue kallikrein excretion during the infusion increased significantly only in the normotensive group. The levels or changes of circulating prekallikrein and tissue kallikrein were not related to the levels or changes in blood pressure in any of the groups. In the hypertensive group there was a negative correlation between blood pressure changes and urinary sodium and tissue kallikrein excretion. Thus, in normotensive subjects an acute sodium and volume load appears to activate the plasma kallikrein system and the activation correlates with sodium excretion. There are subtle differences in subjects with primary hypertension. The relevance of these differences with respect to the pathogenesis of primary hypertension remains to be evaluated.

Population-based reference values for IGF-I and IGF-binding protein-1: relations with metabolic and anthropometric variables.

Population-based reference values for IGF-I and IGF-binding protein-1 (IGFBP-1) have been established. One hundred and one women and the same number of men, 20-70 years old, were randomly selected from the population registry in the community of Linköping. Participation rate was 67%. Venous blood was drawn in the fasting state. Serum IGF-I was measured by RIA after acid-ethanol extraction and IGFBP-1 was determined by ELISA. IGF-I levels did not differ between genders and the decline with age was similar in men and women (men: Y = 366-3.28 x age (years), r = -0.61, P < 0.0001; women: Y = 386-3.49 x age, r = -0.57, P < 0.0001, P = 0.4 for difference in slope). There were negative correlations between IGF-I and plasma lipids and blood pressure in both genders, but none was independent of age. Serum angiotensin-converting enzyme activity correlated positively with IGF-I in men independently from age (r = 0.21, P = 0.01). The distribution of IGFBP-1 was positively skewed and it was higher in women than in men (5.9 +/- 4.8 micrograms/l and 4.0 +/- 3.3 micrograms/l respectively; Mann-Whitney, P = 0.002). In men and in the women not taking oestrogen, IGFBP-1 correlated positively with age (Spearman rank correlation (Spearman: men: r = 0.32, P = 0.002; women: r = 0.24, P = 0.03). C-peptide correlated negatively (Spearman: men: r = -0.38, P = 0.002; women: r = -0.49, P < 0.000) and sex hormone binding globulin positively with IGFBP-1 (Spearman: men: r = 0.50, P < 0.0001; women: r = 0.55, P < 0.0001). IGF-I declined with age while IGFBP-1, which is considered to modulate the free bioactive fraction of IGF-I, increased. This suggests that IGF-I activity might be even lower in elderly subjects than is accounted for by the low total IGF-I.

Effects of naturally acquired decompensated mitral valve regurgitation on the renin-angiotensin-aldosterone system and atrial natriuretic peptide concentration in dogs.

OBJECTIVE: To investigate activity of the renin-angiotensin-aldosterone system and N-terminal pro-atrial natriuretic peptide (NT-proANP) during development of clinical signs of decompensated mitral valve regurgitation (MR). ANIMALS: 11 Cavalier King Charles Spaniels with advanced MR attributable to chronic valvular disease. PROCEDURE: Dogs were subjected to repeated examinations at 6-month intervals until signs of decompensation had developed (end point). Data acquired at end point were compared with data obtained from examinations 1 year and 1 to 6 months before decompensation. Each examination included physical examination, collection of venous blood, thoracic radiography, and echocardiography. RESULTS: Echocardiographic measurements of left atrial-to-aortic root ratio and left ventricular end diastolic diameter increased considerably during the study, whereas left ventricular end systolic diameter remained unchanged. The increase in cardiac size was associated with increased plasma concentration of NT-proANP. In contrast, plasma concentrations of aldosterone and angiotensin II were reduced at decompensation (aldosterone compared with the 2 earlier examinations and angiotensin II compared with values obtained 1 to 6 months before), despite decreased plasma protein concentration and hematocrit, suggesting fluid retention. The urine-to-plasma creatinine ratio was reduced at end point. CONCLUSION AND CLINICAL IMPLICATIONS: Early decompensated MR in dogs was not associated with increased circulating renin-angiotensin-aldosterone system activity, which may be caused by increased activity of ANP, and may be important for future therapeutic strategies of MR.