Jean R. Cusson

First-time use of newer oral contraceptives and the risk of venous thromboembolism

Recent epidemiologic studies reported that the risk of venous thromboembolism (VTE) was higher with the use of the newer third generation oral contraceptives than with second generation agents. Although the overall findings of these studies are similar, the results, as they relate to patterns and duration of oral contraceptive use particularly among first-time users, are inconsistent. We reanalyzed data from the Transnational case-control study to assess the risk of VTE associated with first-time use of oral contraceptives as a function of its duration of use. Over the period 1993 to 1995, 471 cases of venous thromboembolism were identified in Germany and the United Kingdom. For each case, up to four controls were obtained, for a total of 1772 controls. Data on oral contraceptive use and confounding variables, including data on sociodemographic, lifestyle, medical history, and family history of disease, were obtained by interview. Data analysis was based on the 105 cases and 422 controls who were first-time users of second or third generation agents, or never users of oral contraception. Rate ratios, adjusted for confounders and approximated by odds ratios, were estimated as a continuous function of duration of oral contraceptive use by logistic regression and quadratic spline models. We found, for first-time users, that the adjusted rate ratio of VTE as a function of the duration of oral contraceptive use is essentially identical for second and third generation pills relative to never users. This rate ratio increases to around 10 in the first year of use and decreases to around two after 2 years of use, remaining at this risk level thereafter for both second and third generation agents. We conclude that second and third generation agents are associated with identical risks of venous thromboembolism when they are prescribed to women who are using oral contraceptives for the first time ever.

Effects of atrial natriuretic factor on natriuresis and cGMP in patients with essential hypertension

Human atrial natriuretic factor (h-ANF) or its vehicle only, were infused at rates of 0.8, 1.6 and 3.2 μg/min over three successive 30-min periods, into five patients with mild essential hypertension and seven normotensive controls. Baseline (mean ± s.e.m.) plasma ANF levels were 13 ± 2 in patients and 8 ± 1 pg/ml in controls. During the first period, plasma ANF and cyclic guanosine monophosphate (cGMP) levels increased in both groups without significant alteration of blood pressure, heart rate, diuresis, natriuresis or cGMP excretion rate. During the second period of infusion, plasma ANF levels increased up to 179 ± 39 and 177 ± 30 pg/ml in patients and controls and plasma cGMP concentrations increased x 5.0 and x 4.9, respectively; natriuresis increased x 2.4 in patients and x 3.1 in controls while urinary cGMP increased x 10.9 in patients and x 10.5 in controls. During the last period, three controls became hypotensive while blood pressure remained stable in the other controls and in the patients with essential hypertension. During this period, the increases in plasma ANF concentration, diuresis, natriuresis and urinary cGMP excretion were similar in both groups. However, the mean plasma cGMP concentration after 90 min infusion was significantly higher in hypertensive patients than in control subjects (30.7 ± 3.3 versus 15.6 ± 3.4 pmol/ml, P < 0.05). The haif-life and clearance of plasma ANF, upon discontinuation of the infusion, were similar in both groups. Our data suggest that patients with mild essential hypertension have enhanced increases in plasma cGMP but normal increases in diuresis, natriuresis and cGMP excretion following infusion of h-ANF at pharmacological rates.

Posture- and emotion-induced severe hypertensive paroxysms with baroreceptor dysfunction

In a patient followed up for 30 years, severe but brief posture- or emotion-induced hypertensive paroxysms with flushing were associated with an increased cardiac output [inconsistently accompanied by increased plasma catecholamines (CA)] and a decreased blood pressure reactivity to norepinephrine with decreased reflex bradycardia. Sodium depletion further accentuated the latter abnormality and reproducibly reversed orthostatic hypertension to orthostatic hypotension. Abnormal responses in the Valsalva manoeuvre in an upright position suggested a defect in baroreceptor sensitivity, but may also have been due to an impaired venous return. The indices of the efferent portion of the reflex and central nervous system responses to stimuli were normal or exaggerated. The abnormality was probably due to a hypothalamic dysfunction and/or an abnormal central baroreceptor integration in the nucleus tractus solitarii. The absence of left ventricular hypertrophy and other target lesions, despite spectacular rises in blood pressure, suggests an excellent cardiovascular tolerance of hypertensive episodes if they are short-lived.

Prolonged Low Dose Infusion of Atrial Natriuretic Factor in Essential Hypertension

The C-terminal fragment of atrial natriuretic factor (ANF) was infused intravenously at 0.5 pmol/kg/min during 12 hours in 6 patients with mild to moderate essential hypertension, and in 6 normotensive volunteers, all recumbent and well hydrated, under a daily intake of 200 and 120 mmoles of sodium and potassium, respectively. Plasma C-terminal ANF tended to increase during ANF and to decrease during vehicle infusions. Plasma concentrations of the N-terminal fragment of ANF decreased by 20 to 40% (p less than 0.05) during ANF and remained unchanged following vehicle infusion, suggesting that exogenous ANF reduces endogenous ANF secretion. ANF increased significantly plasma cyclic guanosine monophosphate (p less than 0.01) from 3.1 +/- 0.4 to 4.3 +/- 0.8 and from 2.8 +/- 0.4 to 5.1 +/- 0.5 nmol/L in controls and patients respectively. ANF reduced systolic diastolic blood pressure during the last 8 hours of the infusion, by about 5% (p = 0.055) in patients, but did not alter blood pressure in controls. Sodium excretion during ANF increased 42% vs vehicle (p less than 0.05), in the patients group and remained unchanged in controls. Hematocrit levels increased significantly in both groups with ANF infusion. We conclude that a prolonged infusion of ANF at a physiological rate causes a modest increase in plasma cyclic guanosine monophosphate, hemoconcentration, and reduces endogenous ANF secretion. It also stimulates diuresis and natriuresis and slightly reduces systolic blood pressure in patients with essential hypertension.

The Atrial Natriuretic Factor in Hypertension

Plasma immunoreactive atrial natriuretic factor (IR-ANF) concentration measured by radioimmunoassay after extraction on Sep-Pak cartridges was studied in 64 control normotensive subjects, 25 patients with labile essential hypertension, 67 patients with mild essential hypertension (diastolic pressure between 90 and 105 mm Hg and no left ventricular hypertrophy) and 9 patients with moderate to severe essential hypertension (diastolic pressures between 105 and 120 mm Hg). An additional group of 16 patients under medication but without effective control of their blood pressure and with diastolic pressure above 110 mm Hg also was studied. Results show that plasma IR-ANF concentrations are within normal range in patients with labile, mild, and moderate hypertension. In view of the reported increased right and left atrial pressures and distension in patients with mild and moderate hypertension, these findings strongly suggest a state of hyporesponsiveness of the atria to release ANF.

Prostaglandins and renal function in hypertensive patients with unilateral renal artery stenosis and patients with essential hypertension

Objective This study was designed to compare the effects of prostaglandin synthesis inhibition on calculated preglomerular and postglomerular resistance in hypertensive patients with unilateral renal artery stenosis (RAS) and in patients with essential hypertension. Designand methods Sixteen patients with suspected renovascular hypertension underwent renal angiography: eight had unilateral renal artery stenosis ≥ 70% and eight had normal angiograms or stenosis ≤ 40%. Radionuclide renography and 6 h urinary collection were performed twice for each subject, at baseline and after indomethacin administration. Levels of urinary vasodilatory prostaglandins were measured by specific radioimmunoassays. Visual image analysis was performed to determine the parenchymal transit time (PTT). The glomerular filtration rate (GFR) was calculated from the plasma clearance of [99mTc]-diethylenetriamine pentaacetic acid (DTPA). The preglomerular and postglomerular resistances were estimated according to Gomezs equations. Results The prostaglandin excretion decreased significantly after indomethacin administration both in RAS and in essential hypertension patients. The PTT increased from 230 ± 10 to 340 ± 40s in the stenotic kidney compared with the contralateral kidney and the kidneys of essential hypertension patients. The GFR was decreased both in stenotic and in contralateral kidneys (48 ± 4 to 37 ± 5 and 60 ± 4 to 52 ± 5 ml/min, respectively) but did not decline in the kidneys of essential hypertension patients. The preglomerular resistance increased both in stenotic and in contralateral kidneys, whereas it did not rise significantly in the kidneys of essential hypertension patients. The postglomerular resistance in stenotic and contralateral kidneys of RAS patients was not altered. Conclusions Prostaglandins limit GFR decreases in RAS by preventing preglomerular constriction without interfering with postglomerular constriction. Thus, the action of vasoactive prostaglandins on preglomerular resistance might maintain renal function in the short term by limiting the fall in GFR in the stenotic kidney and by increasing the GFR in the contralateral kidney.

Negative chronotropic effect of the atrial natriuretic peptide in an anaesthetized dog model

The effects of atrial natriuretic peptide (ANP) on heart rate and on the chronotropic response induced by angiotensin II were evaluated. The action of angiotensin II, injected into the sinus node artery, on heart rate was determined in anaesthetized and vagotomized dogs pretreated with beta-adrenoceptor antagonist (n = 9), before and after the infusion of physiological and pharmacological doses (10 and 50 ng/kg per min) of ANP. ANP plasma concentrations were determined by radioimmunoassay. Compared to the baseline concentration values (117 +/- 3 pg/ml), a slight increase was produced by the lower dose (293 +/- 45 pg/ml), whereas a significant augmentation was noted with the higher dose of ANP (1024 +/- 255 pg/ml). The basal heart rate and mean systemic arterial pressure were decreased (26.3 and 13.5%) during the intravenous infusion of the physiological dose of the peptide and were significantly reduced (32.5 and 29.2%, P < 0.05) by the administration of the pharmacological dose of ANP. Angiotensin II had a positive chronotropic effect (29 +/- 3 beats/min) that was significantly inhibited by the pharmacological dose of ANP. Our results suggest that ANP might have a role in the control of heart rate.

Effects and pharmacokinetics of bolus injections of atrial natriuretic factor in normal volunteers

The aim of this study was to examine the hemodynamic, renal, and endocrine effects of exogenous human atrial natriuretic factor (ANF), together with its pharmacokinetics, in healthy volunteers. Ten subjects participated in this study, in which the effects of a single bolus dose of ANF and of a matched vehicle injection were compared under a 135 mmol/day sodium intake. Doses of 3, 12.5, and 25 micrograms of ANF were given to 1 subject each, and doses of 50 and 100 micrograms were given to 4 and 3 subjects, respectively. Significantly, hemodynamic changes occurred at the 100 micrograms dose, when mean blood pressure decreased by 15% and heart rate increased reciprocally. Diuresis and natriuresis tended to increase following 50 micrograms but increased significantly and in a prolonged fashion following 100 micrograms of ANF. Atrial natriuretic factor did not cause significant changes in plasma catecholamine, renin activity, and aldosterone levels at any dose, although aldosterone tended to decrease. Plasma arginine-vasopressin concentrations decreased significantly following 100 micrograms. Plasma cyclic GMP levels increased in all subjects and in a dose-dependent fashion. Plasma ANF concentrations peaked 3-5 min following the bolus injection and returned toward baseline values within 10-60 min. Although with doses of less than or equal to 50 micrograms plasma ANF levels increased up to 8 to 50-fold, compared to baseline values, the only significant change was the increase in plasma cyclic GMP levels, perhaps because the effects of ANF were successfully masked by counter-regulatory mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Ketoprofen on Blood Pressure, Endocrine and Renal Responses to Chronic Dosing with Captopril in Patients with Essential Hypertension

The effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the blood pressure and renal function of essential hypertensive patients depend on the specific type of NSAID and antihypertensive drug administered. Twelve patients with essential hypertension, aged 35 to 59 years, stabilized (blood pressure less than 140/90 mmHg) with captopril, received ketoprofen (100 mg bid for 7 days) or matching placebo in a randomized double-blind cross-over fashion. A 3-week wash-out period was included between treatment periods. Blood pressure on the first and last days of the placebo treatment period (137 +/- 7 (SD)/80 +/- 8 and 139 +/- 11/81 +/- 9 mmHg) was similar to respective values during ketoprofen therapy (136 +/- 10/79 +/- 7 and 143 +/- 10/81 +/- 9 mmHg). The mean differences in systolic and diastolic blood pressures, at the end of the treatment periods, between ketoprofen and placebo were 4 (95% confidence intervals -5, +13) and 0 (-8, +8) mmHg, respectively. Ketoprofen had no effect on 24-h urinary sodium excretion (160 +/- 33 and 147 +/- 39 mmol/24 h for ketoprofen and placebo, respectively). Ketoprofen was without effect on glomerular filtration rate, renal plasma flow and filtration fraction. In conclusion, our data suggest that ketoprofen is a safe choice when short-term treatment with a NSAID is indicated in an essential hypertensive patient treated with a converting enzyme inhibitor such as captopril.

Altered regulation of natriuretic peptides in the rat heart by prenatal exposure to morphine

1 Both endogenous and exogenous opioids modulate blood pressure and cardiac function by stimulating cardiac synthesis of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). Since morphine crosses the placental barrier, it could alter the ANF‐BNP system in the fetal heart. The aim of this study was to characterize cardiac natriuretic peptides in normal rat development and in rats prenatally exposed to morphine. 2 Female rats received either saline or morphine (10 or 20 mg kg−1 day−1) via osmotic minipumps during gestation. The effects of this treatment were investigated in offspring at 1, 4 and 22 days of age. 3 During maturation, atrial ANF and ANF mRNA increased by 3‐fold from birth to 3 weeks of age, but BNP and BNP mRNA tended to decrease. In the ventricles, both ANF and BNP content decreased at 3 weeks after birth, from 25.11 ± 3.6 to 0.81 ± 0.1 ng (P < 0.001), and from 3.36 ± 0.33 to 0.19 ± 0.01 ng (P < 0.001), respectively. However, whereas ventricular ANF mRNA decreased, BNP mRNA levels did not change during maturation. Prenatal exposure to morphine significantly increased ANF content in the left atria of 22‐day‐old rats, and in the right atria of 1‐, 4‐ and 22‐day‐old rats compared with age‐matched saline controls. In contrast, prenatal exposure to 20 mg kg−1 day−1 morphine significantly inhibited BNP and BNP mRNA in the ventricles at all ages studied. 4 These observations suggest that alterations in mRNA synthesis or stability and/or post‐translational processing of ANF and BNP occur in the heart during maturation, and that prenatal exposure to morphine alters cardiac production, and possibly release, of both peptides.