Food does not affect the pharmacokinetics of tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist.

Tesaglitazar is a dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist in development to treat lipid and glucose abnormalities associated with type 2 diabetes. This study evaluated the effects of food on tesaglitazar pharmacokinetics. In an open, randomized, 2-way crossover study, 20 healthy men received tesaglitazar 1 mg during fasting and after a high-fat, high-calorie breakfast. Blood samples were taken to assess pharmacokinetic variables. Systemic exposure to tesaglitazar was unaffected by food intake. Estimated ratios were 0.99 (90% confidence interval [CI], 0.94-1.04) for fed/fasted area under plasma concentration-time curve and 0.82 (90% CI, 0.78-0.86) for fed/fasted maximum plasma concentration (C(max)). Mean C(max) was approximately 18% lower (0.41 [95% CI, 0.38-0.43] versus 0.50 [95% CI, 0.47-0.53] mumol/L), and median time to C(max) was increased (2.00 vs 0.75 h) in fed versus fasted state. The median difference of t(max) was 1.25 h (P = .0001, signed-rank test). Tesaglitazar was well tolerated. Tesaglitazar pharmacokinetics is unaffected by food intake, allowing once-daily administration of tesaglitazar with or without food in clinical practice.

Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients.

OBJECTIVES: To determine whether polymorphisms in the renin-angiotensin system can predict blood pressure-lowering response to antihypertensive treatment; more specifically, in response to treatment with irbesartan or atenolol. DESIGN AND METHODS: Eighty-six patients with hypertension were randomized to double-blind treatment with either the angiotensin II type 1 receptor antagonist irbesartan or the beta1 adrenergic receptor blocker atenolol and followed for 3 months. We analysed angiotensinogen T174M and M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C polymorphisms and related them to blood pressure reduction. RESULTS: The mean reductions in blood pressure were similar for both treatments. In the irbesartan group, individuals homozygous for the ACE gene I allele showed a greater reduction in diastolic blood pressure, exceeding those with the D allele (-18 +/- 11 SD versus -7 +/- 10 mmHg, P = 0.0096). This was not the case during treatment with atenolol, and the interaction term between type of treatment and ACE II genotype was significant (P = 0.0176). The angiotensinogen and angiotensin II type 1 receptor polymorhisms were not related to the response to treatment. CONCLUSIONS: ACE genotyping predicted the blood pressure-lowering response to antihypertensive treatment with irbesartan but not atenolol. Thus, specific genotypes might predict the response to specific antihypertensive treatment.

Regression of left ventricular hypertrophy in human hypertension with irbesartan.

BACKGROUND: The Swedish irbesartan left ventricular hypertrophy investigation versus atenolol (SILVHIA). OBJECTIVE: Angiotensin II induces myocardial hypertrophy. We hypothesized that blockade of angiotensin II subtype 1 (AT1) receptors by the AT1-receptor antagonist irbesartan would reduce left ventricular mass (as measured by echocardiography) more than conventional treatment with a beta blocker. DESIGN AND METHODS: This double-blind study randomized 115 hypertensive men and women with left ventricular hypertrophy to receive either irbesartan 150 mg q.d. or atenolol 50 mg q.d. for 48 weeks. If diastolic blood pressure remained above 90 mmHg, doses were doubled, and additional medications (hydrochlorothiazide and felodipine) were prescribed as needed. Echocardiography was performed at weeks 0, 12, 24 and 48. RESULTS: Baseline mean blood pressure was 162/ 104 mmHg, and mean left ventricular mass index was 157 g/m2 for men and 133 g/m2 for women. Systolic and diastolic blood pressure reductions were similar in both treatment groups. Both irbesartan (P < 0.001) and atenolol (P< 0.001) progressively reduced left ventricular mass index, e.g. by 26 and 14 g/m2 (16 and 9%), respectively, at week 48, with a greater reduction in the irbesartan group (P = 0.024). The proportion of patients who attained a normalized left ventricular mass (i.e. < or = 131 g/m2 for men and < or = 100 g/m2 for women) tended to be greater with irbesartan (47 versus 32%, P = 0.108). CONCLUSIONS: Left ventricular mass was reduced more in the irbesartan group than in the atenolol group. These results suggest that blocking the action of angiotensin II at AT1-receptors may be an important mechanism, beyond that of lowering blood pressure, in the regulation of left ventricular mass and geometry in patients with hypertension.

Efficacy, tolerance and hormonal effects of a new oral angiotensin converting enzyme inhibitor, ramipril (HOE 498), in mild to moderate primary hypertension.

The immediate (0 to 24 hours) and long-term (4 weeks) hypotensive effects of a new long-acting angiotensin converting enzyme inhibitor, ramipril (HOE 498), as well as adverse effects and tolerance, were evaluated in 34 patients with primary hypertension. Further, effects on serum and urinary aldosterone and circulating angiotensin II concentrations were measured. After short- and long-term administration of 5 or 10 mg of ramipril, the mean blood pressure was significantly lowered compared with placebo. The mean maximum decrease in blood pressure was noted 4 to 8 hours after administration of ramipril once daily. Sustained blood pressure reduction was achieved after 4 weeks of treatment. Serum concentrations of aldosterone and plasma levels of circulating angiotensin II were reduced for up to 12 hours after drug intake, and tended to return to pretreatment levels at 24 hours. Serum angiotensin converting enzyme activity was markedly suppressed for more than 24 hours after a single dose of 5 or 10 mg ramipril. No subjective or objective adverse effects were noted, and the tolerance to the drug was very good.

Effect of amlodipine versus felodipine extended release on 24-hour ambulatory blood pressure in hypertension.

Amlodipine and felodipine are calcium antagonists of the dihydropyridine type. The elimination half-life of amlodipine is longer than that of felodipine. To study whether the different elimination rates of the drugs were reflected in different duration of blood pressure (BP) control, we compared amlodipine and felodipine extended release (ER) by both conventional clinic BP 24 h after drug intake and 24 h ambulatory BP monitoring (ABPM), with special reference to nighttime and morning blood pressure. Two hundred and sixteen patients with primary hypertension (supine diastolic BP, 95 to 115 mm Hg) were randomized to receive amlodipine or felodipine ER in a multicenter study. The starting dose of both drugs was 5 mg. If the target clinic diastolic BP (90 mm Hg) had not been achieved after 4 weeks the dose was increased to 10 mg. Twenty-four-hour ABPM was performed with the subjects taking placebo medication before randomization and after 4 and 8 weeks undergoing active treatment. Significantly more patients responded after 4 weeks of treatment with amlodipine (50%) as compared with felodipine (33%) (P = .013). ABPM during daytime (07:00 to 23:00) was similar during both treatments, but nighttime systolic (P = .026) and diastolic (P = .019) BP was more effectively reduced by amlodipine than by felodipine. After 8 weeks 82% achieved the target pressure with amlodipine and 69% with felodipine (P = .036 for the difference). Amlodipine seems to be more effective than felodipine when the drugs are compared in the same dose, with regard to the effect on clinic BP 24 h after dosing and to ambulatory BP during the night. The longer elimination half-life of amlodipine as compared to felodipine is the probable reason for this finding.

The initial vasodilation and the later vasoconstriction of endothelin-1 are selective to specific vascular beds.

The regional hemodynamic effects of endothelin-1 (ET-1) were studied in Wistar-Kyoto rats. Endothelin-1 caused a transient increase in blood flow in the carotid and femoral arteries but a decrease in flow in the renal and mesenteric arteries. The resistance in the carotid and femoral beds decreased while it increased in the renal and mesenteric beds. Subsequently there was a variable increase in resistance in all vascular beds with a maximal increase in the renal bed. Thus, ET-1 initially causes a selective vasorelaxation in musculocutaneous beds but not in visceral beds; the cause of this selectivity is unknown.

Pitfalls in Doppler evaluation of diastolic function: insights from 3-dimensional magnetic resonance imaging.

Ultrasound-Doppler assessment of diastolic function is subject to velocity errors caused by angle sensitivity and a fixed location of the sample volume. We used 3-dimensional phase contrast magnetic resonance imaging (MRI) to evaluate these errors in 10 patients with hypertension and in 10 healthy volunteers. The single (Doppler) and triple (MRI) component velocity was measured at early (E) and late (A) inflow along Doppler-like sample lines or 3-dimensional particle traces generated from the MRI data. Doppler measurements underestimated MRI velocities by 9.4% +/- 8.6%; the effect on the E/A ratio was larger and more variable. Measuring early and late diastolic inflows from a single line demonstrated the error caused by their 3-dimensional spatial offset. Both errors were minimized by calculating the E/A ratio from maximal E and A values without constraint to a single line. Alignment and spatial offset are important sources of error in Doppler diastolic parameters. Improved accuracy may be achieved with the use of maximal E and A velocities from wherever they occur in the left ventricle.

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.

Endothelin induces an initial increase in cardiac output associated with selective vasodilation in rats.

The systemic and regional hemodynamic effects of endothelin (ET), a novel endothelial derived vasoconstrictor peptide were studied in Wistar Kyoto rats. A bolus of 1 nmol/Kg ET intravenously induced a transient 43% decrease in blood pressure associated with a 57% decrease in systemic resistance and a 30% increase in cardiac output (p less than 0.01 for all parameters). This was followed by an increase of 20% in arterial pressure and of 71% in systemic resistance and a decrease of 30% in cardiac output at 10 minutes. The initial fall in blood pressure was not abolished by pretreatment with verapamil, captopril, indomethacin, ketanserin, atropine, methylene blue or ethanol. Verapamil abolished the hypertensive phase by markedly decreasing cardiac output. ET had selective effects on the arterial tree; during the hypotensive phase it caused a transient increase in blood flow in the carotid and femoral arteries (+41% and +83% respectively, p less than 0.01) but a decrease in flow in the renal and mesenteric arteries (-53% and -44% respectively, p less than 0.05). Accordingly, there was a decrease in resistance in the carotid and femoral beds (-55% and -67% respectively, p less than 0.01) and an increase in resistance in the renal and mesenteric beds (+102%; p less than 0.01 and +23%; p = N.S. respectively). Subsequently there was an increase in resistance in all vascular beds to variable degrees. The maximal increase in resistance was in the renal bed (+156%). Thus, ET causes initially a potent systemic vasorelaxation and an increase in cardiac output later progressing to systemic vasoconstriction and a decrease in cardiac output. The initial vasodilation is selective, appearing in musculocutaneous beds but not in visceral beds.

Beta1-adrenergic receptor gene polymorphisms and response to beta1-adrenergic receptor blockade in patients with essential hypertension.

BACKGROUND: Studies suggest that the Ser49Gly and Arg389Gly polymorphisms in the beta1-adrenergic receptor might be of functional importance for the cardiovascular system. Both have been associated with altered receptor activity in vitro, and with hypertension and cardiac failure in vivo. HYPOTHESIS: The aim of this study was to test whether these polymorphisms were associated with the change in heart rate or blood pressure in patients with essential hypertension and left ventricular (LV) hypertrophy treated with the beta1-adrenergic receptor blocker atenolol. METHODS: Blood pressure and heart rate were measured in 101 hypertensive patients with echocardiographically verified LV hypertrophy, randomized in a double-blind study to treatment with either the beta1-adrenergic receptor blocker atenolol or the angiotensin II type I receptor antagonist irbesartan. Changes in blood pressure and heart rate were evaluated after 12 weeks. Beta1-adrenergic receptor genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism. RESULTS: We found no significant associations between the changes in the measured variables and either of the two polymorphisms. However, carriers of the 49Gly allele showed a tendency toward a greater reduction in heart rate compared with patients with the Ser/Ser49 genotype (p = 0.06). CONCLUSIONS: The Ser49Gly and Arg389Gly beta1-adrenergic receptor polymorphisms do not seem to exert a major effect on the changes in heart rate and blood pressure during 12 weeks of treatment with atenolol in patients with essential hypertension and LV hypertrophy.

Gender-specific association between preproendothelin-1 genotype and reduction of systolic blood pressure during antihypertensive treatment--results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA).

BACKGROUND: Studies suggest that endothelin-1 contributes to the pathogenesis of hypertension. A G5665T gene polymorphism of preproendothelin-1 has been shown to be associated with higher blood pressure in overweight patients. No study has yet determined the effect of this polymorphism on the change in blood pressure during antihypertensive treatment. HYPOTHESIS: This study aimed to determine this effect in hypertensive patients with left ventricular (LV) hypertrophy during antihypertensive treatment with either irbesartan or atenolol. METHODS: We determined the preproendothelin-1 genotype using minisequencing in 102 patients with essential hypertension and LV hypertrophy verified by echocardiography, randomized in a double-blind fashion to treatment with either the AT1-receptor antagonist irbesartan or the beta1-adrenoceptor antagonist atenolol. RESULTS: The change in systolic blood pressure (SBP) after 12 weeks of treatment was related to the preproendothelin-1 genotype in men; after adjustment for potential covariates (age, blood pressure, and LV mass index at study entry, dose of irbesartan/atenolol, and type of treatment), those carrying the T-allele responded on average with a more than two-fold greater reduction than those with the G/G genotype (-21.9 mmHg 13.9] vs. -8.9 [2.3], p = 0.007). No significant differences in blood pressure change between G/G and carriers of the T-allele were seen among women. CONCLUSIONS: Our finding suggests a gender-specific relationship between the G5665T preproendothelin-1 polymorphism and change in SBP in response to antihypertensive treatment with irbesartan or atenolol, suggesting the endothelin pathway to be a common mechanism included in the hypertensive action of the drugs.

Enalapril and atenolol in primary hypertension--a comparative study of blood pressure lowering and hormonal effects.

The efficacy and tolerability of the new ACE-inhibitor enalapril (MK 421) and the beta 1-selective adrenoceptor blocker atenolol for the treatment of primary hypertension were compared in a double blind parallel study. 12 patients were randomized to each drug. The doses of enalapril were 20 and 40 mg o.d. and of atenolol 50 and 100 mg o.d. for 4 weeks each, whereafter hydrochlorothiazide (HCTZ) 25 or 50 mg o.d. was added if necessary to achieve a supine diastolic blood pressure (BP) less than 90 mm Hg 24 hours after drug intake. Supine BP was reduced from 160 +/- 7/111 +/- 4 mm Hg to 153 +/- 13/101 +/- 9 mm Hg (p less than 0.05/p less than 0.005) with enalapril and from 163 +/- 17/109 +/- 6 mm Hg to 145 +/- 11/95 +/- 7 mm Hg (p less than 0.005/p less than 0.001) with atenolol. The addition of HCTZ caused a profound additive BP reduction to 132 +/- 7/88 +/- 6 mm Hg with enalapril and to 130 +/- 10/88 +/- 7 mm Hg with atenolol. There was no significant difference between the efficacy of enalapril and atenolol alone or combined with HTCZ. The reduction in mean arterial pressure with enalapril tended to correlate with pre-treatment stimulated plasma renin activity and 24 hours urinary kallikrein excretion. Both drugs tended to reduce serum and urinary aldosterone and kallikrein excretion to the same extent. There was one drop-out in each group, one due to impotence on the combination of enalapril and HCTZ and one due to peripheral coldness during atenolol treatment. Other side effects were mild. No toxic adverse effects were registered.

Enalapril and lisinopril in renovascular hypertension--antihypertensive and hormonal effects of two new angiotensin-converting-enzyme (ACE) inhibitors. A preliminary report.

We assessed the antihypertensive and hormonal effects of two new angiotensin converting enzyme (ACE) inhibitors, enalapril (MK-421) and lisinopril (MK-521) in 22 patients with renovascular hypertension. All patients had angiographically verified renal artery lesions, 3 had bilateral renal artery stenosis and one a stenosis in a single kidney, and the rest had unilateral renal artery stenosis. After placebo treatment for 3 days in hospital, increasing doses from 5 to 40 mg daily, of both ACE-inhibitors were given. Both drugs induced a significant fall in blood pressure (BP). Significant BP reductions were seen after 2 h with a maximum fall for the enalapril group at a dose of 40 mg 4 h after drug intake (mean supine BP decrease - 31/24 mm Hg, standing - 29/16 mmHg). The corresponding maximal BP reductions were for the lisinopril group at a dose of 40 mg o.d. at 6 h: mean supine BP fall - 25/28 mmHg and standing - 33/31 mm Hg. Both drugs significantly inhibited serum ACE to about 5 to 10% of initial values and with a duration for more than 24 h. Both drugs also caused a decrease in plasma-AII levels and also in plasma aldosterone concentrations. There were not toxic effects and no serious side effects. Careful monitoring of biochemical variables showed no significant changes. We conclude that both enalapril and lisinopril are effective and very safe agents for the treatment of renovascular hypertension and with a long duration of action and with very good tolerance.

Different effects of two angiotensin converting enzyme inhibitors in primary hypertension--a comparison of captopril and enalapril.

A comparison of the antihypertensive effect and tolerability of captopril and enalapril was performed. Forty patients with primary hypertension were treated in randomized order, investigated immediately and in a crossover trial with treatment for 6 weeks, with an intermediate placebo wash-out of 3 weeks. A plasma renin profile was obtained from each patient before treatment. The immediate maximal mean change in supine blood pressure (BP) was similar with both drugs, but occurred earlier with captopril. After 6 weeks of treatment enalapril was more potent than captopril in the mean reduction of supine BP produced. This was even more evident in patients with low-renin hypertension (LRH), where captopril had practically no effect. The different chronic BP response in relation to initial renin activity may indicate different mechanisms or modalities of action. Following the recommended doses and administration intervals of captopril and enalapril, the latter seems more effective, but there seems to be no difference in tolerability.

Circulating kallikreins in normotensive and hypertensive humans: effects of mineralocorticoid administration.

The aim of the study was to evaluate if short-term mineralocorticoid administration activates the circulating kallikrein-kinin systems in normotensive humans and patients with hypertension. Fludrocortisone was given daily for 1 week and circulating components of the plasma and tissue kallikrein-kinin systems and renin-angiotensin-aldosterone system were measured repeatedly. Fludrocortisone increased blood pressure in the normotensive group. A significant reduction in circulating pre-kallikrein and increase in tissue kallikrein occurred only in the normotensive group. Changes in blood pressure in the normotensive group correlated negatively with changes in plasma pre-kallikrein and positively with changes in circulating tissue kallikrein. In the hypertensive group the correlation with pre-kallikrein was non-significant and with tissue kallikrein negative. We conclude that short-term administration of fludrocortisone in moderate doses to normotensive humans induces changes compatible with increased activity in the circulating plasma and tissue kallikrein-kinin systems and that this activation may be abnormal in subjects with primary hypertension.

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.

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.

Plasma and tissue kallikrein-kinin systems during acute administration of frusemide in normotensive and hypertensive humans.

1. This study aims to further elucidate the role of the tissue and plasma kallikrein-kinin systems in blood pressure, electrolyte and volume homoeostasis. Components thereof and of the renin-angiotensin-aldosterone system were measured in conjunction with frusemide administration, in normotensive subjects and in patients with primary hypertension. 2. Frusemide increased plasma pre-kallikrein, angiotensin II and aldosterone concentrations and plasma renin activity, whereas the plasma level of tissue kallikrein remained unchanged. Basal values and the induced changes were similar in both groups. 3. Frusemide increased the urine volume and the excretion of Na+, K+, Mg2+, Cl-, aldosterone, prostaglandin E2 and tissue kallikrein. These changes were similar in both groups, but the total tissue kallikrein excretion was significantly lower in the hypertensive patients. Excretion of electrolytes and hormones was also measured during three 24 h urine collection periods and did not differ between the two groups. 4. Thus, acute administration of frusemide to hypertensive patients and normal subjects increased the plasma level of pre-kallikrein, possibly indicating less activation to kallikrein and subsequently less kinin generation in the blood stream. This also suggests a role for the plasma kallikrein-kinin system in the regulation of vascular tone and blood volume. Circulating tissue kallikrein does not seem to be acutely involved. 5. Urinary excretion of kallikrein is reduced in patients with primary hypertension after the administration of frusemide, apparently without affecting the renal excretory response.

Thyroid hormone restores atrial stretch-induced secretion of atrial natriuretic peptide in hypophysectomized rats.

Acute blood volume expansion caused a rapid and profound release of atrial natriuretic peptides (ANP) from cardiac atria. The stimulated release of ANP was markedly blunted (more than 50%) in hypophysectomized rats (8 days after surgery). Daily subcutaneous injections of thyroxine (30 micrograms/kg) to hypophysectomized rats for 7 days, completely restored acute volume expansion induced release of ANP. Our data suggest that thyroid hormone is required for ANP secretion in response to acute volume expansion.