Use of vasopressin after Caesarean section in idiopathic pulmonary arterial hypertension.

We report the successful use of vasopressin in the management of hypotension in association with severe right ventricular (RV) failure in two patients with advanced idiopathic pulmonary arterial hypertension. Both patients were pregnant and developed systemic hypotension after delivery by Caesarean section. Placental autotransfusion and possibly oxytocin use were thought to be the major contributing factors in worsening RV function. After the use of vasopressin in both patients, cardiovascular variables improved without untoward effect on RV function, and provided rescue therapy for systemic hypotension in this setting. Vasopressin, a direct vasopressor acting via V1 receptors on the vascular endothelium, has been shown to cause pulmonary vasodilatation experimentally and in animal models of pulmonary hypertension. Its synthetic analogue, terlipressin, has been shown to reduce pulmonary vascular resistance in humans with cirrhosis. Vasopressin may therefore have differential effects on the pulmonary and systemic circulations, allowing systemic pressure to be supported without detrimental effects on the pulmonary circulation.

Esterified estrogens combined with methyltestosterone improve emotional well-being in postmenopausal women with chest pain and normal coronary angiograms.

OBJECTIVE: The cardiac syndrome X is described as the triad of angina pectoris, a positive exercise test for myocardial ischemia, and angiographically smooth coronary arteries. Although syndrome X does not result in an increased risk of cardiovascular mortality, the symptoms are often troublesome and unresponsive to conventional antianginal therapy. The majority of patients are postmenopausal, and estrogen therapy can alleviate anginal symptoms. We investigated the effect of esterified estrogens combined with methyltestosterone (Estratest) on quality of life in postmenopausal women with syndrome X. DESIGN: Patients were withdrawn from antianginal therapy. Sublingual nitrates were allowed for treatment of anginal episodes. Patients underwent treadmill testing, and quality of life was assessed by using the Short Form-36 and Cardiac Health Profile questionnaires after the women had received 8 weeks of Estratest or identical placebo in a randomized, double-blind, cross-over study. RESULTS: Nineteen patients were randomized, and 16 patients completed the protocol. Plasma 17beta-estradiol concentrations were significantly increased by Estratest; however, total testosterone levels were not. The "emotional" score of the Cardiac Health Profile questionnaire was significantly improved after Estratest use compared with placebo (p = 0.03); however, there was no significant change in the Short Form-36 questionnaire for any variable. Estratest significantly increased systolic blood pressure and rate pressure product at rest but had no effect on exercise parameters. Time to onset of chest pain during exercise was also unaffected. CONCLUSIONS: We have demonstrated a beneficial effect of Estratest on emotional well-being in postmenopausal women with cardiological syndrome X. There was no significant treatment effect on exercise parameters, including time to onset of chest pain.

SERCA2A overexpression decreases the incidence of aftercontractions in adult rabbit ventricular myocytes.

K. Davia, E. Bernobich, H. K. Ranu, F. del Monte, C. M. N. Terracciano, K. T. MacLeod, D. L. Adamson, B. Chaudhri, R. J. Hajjar and S. E. Harding. SERCA2a Overexpression Decreases the Incidence of Aftercontractions in Adult Rabbit Ventricular Myocytes. Journal of Molecular and Cellular Cardiology (2001) 33, 1005-1015. Slow relaxation and poor contractile response to increasing stimulation frequency in failing human heart have been strongly linked to a decrease in the activity of the sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a). Restoration of SERCA2a levels using gene transfer has beneficial effects on contractile function but, like beta -adrenoceptor stimulation, could potentially produce excess SR Ca(2+), arrhythmias and cell death. We have examined the effects of SERCA2a overexpression in adult rabbit cardiac myocytes, and compared changes in relaxation with those following beta -adrenoceptor stimulation. Myocytes were infected with an adenovirus carrying both SERCA2a and green fluorescent protein (GFP) for positive identification of infected cells. Myocyte survival was significantly enhanced in the infected cultures. There was a reduction in both time-to-peak contraction and time-to-50% relaxation (R50) 48 h after infection. Time-to-90% relaxation (R90) was particularly improved (non-infected 516+/-41 ms, AD.SERCA2a-GFP 230+/-23 ms, n=7 preparations, P<0.001). There was also a decreased incidence of aftercontractions in Ad.SERCA2a-GFP infected myocytes (21+/-5%v 41+/-4% in controls, P<0.01). This contrasts with beta -adrenoceptor stimulation, which reduced R50 but prolonged R90 by 158+/-76 ms (P<0.02, n=16). At higher stimulation frequencies (2-3 Hz) contraction amplitude and SR calcium content were increased and diastolic contracture was reduced following SERCA2a overexpression. Overall, increasing levels of SERCA2a resulted in an improvement in systolic and diastolic function and a reduction in cell death and arrhythmic aftercontractions. SERCA2a overexpression therefore lacks the detrimental effects associated with some other inotropic interventions.

The effect of Gi-protein inactivation on basal, and beta(1)- and beta(2)AR-stimulated contraction of myocytes from transgenic mice overexpressing the beta(2)-adrenoceptor.

The atria and ventricles of transgenic mice (TGbeta(2)) with cardiac overexpression of the human beta(2)-adrenoceptor (beta(2)AR) were initially reported to show maximum contractility in the absence of beta-AR stimulation. However, we have previously observed a different phenotype in these mice, with myocytes showing normal contractility but reduced betaAR responses. We have investigated the roles of cyclic AMP and Gi in basal and betaAR function in these myocytes. ICI 118,551 at inverse agonist concentrations decreased contraction by 32%. However, the cyclic AMP antagonist Rp-cAMPS had no effect on contraction in TGbeta(2) myocytes, indicating that there was no tonic influence of raised cyclic AMP. These findings cannot be explained by the proposed model for inverse agonism, where the activated receptor (R*) raises cyclic AMP levels and so increases contraction in the absence of agonist. After pertussis toxin (PTX) pretreatment to produce inactivation of Gi, the basal contraction in 1 mM Ca(2+) was increased in TGbeta(2) mice (7.82+/-0.47%, n=23) compared to LM mice (3.60+/-0.59%, n=11) (P<0.001). The contraction amplitude of myocytes to the maximal concentration of isoprenaline was also increased significantly by PTX in TGbeta(2) mice (9.40+/-1.22%, n=8) and was no longer reduced compared to LM mice (8.93+/-1.50%, n=11). Both beta(1)- and beta(2)AR subtypes were affected both by the original desensitization and by the resensitization with PTX. PTX treatment has therefore restored the original phenotype, with high basal contractility and little further effect of isoprenaline. We suggest that both beta-AR desensitization and lack of increased basal contraction in ventricular myocytes from our colony of TGbeta(2) mice were due to increased activity of PTX-sensitive G-proteins.

Functional evidence for a cyclic-AMP related mechanism of action of the beta(2)-adrenoceptor in human ventricular myocytes.

The human ventricle contains both beta(1)- and beta(1)-adrenoceptors (AR) and both have been shown to be present on a single myocyte. In animal ventricular myocardium there is evidence that beta(1)ARs increase cardiac contraction by non-cAMP-dependent mechanisms. We have used the anti-adrenergic effects of carbachol and the cAMP antagonist Rp -cAMPS to investigate the functional contribution of cAMP to beta(2)AR responses in human ventricular myocytes isolated from cardiac biopsies or explants. Concentration-response curves to isoproterenol (Iso) were constructed in the absence and presence of a beta(1)AR antagonist, CGP 207 12A (300 nmol/l) to determine the contribution of the beta(2)AR to contraction. The cells were rechallenged with sub-maximal dose of Iso under beta(2)AR-specific conditions and Rp -cAMPS (100-200 micromol/l) or carbachol (1-3 microm/l) added. Rp -cAMPS significantly decreased contraction amplitude (% shortening; Iso 7.1+/-0.7, Iso+Rp -cAMPS 3.5+/-0.5, n=7, P<0.001) though not completely to the baseline (2.2+/-0.6, n=7). Rechallenge with Iso alone reversed the effects of Rp -cAMPS, and subsequent addition of the beta(1)AR antagonist ICI 118,551 reduced the response to baseline (1.6+/-0.3, n=4) confirming beta(2)AR involvement. Similarly, carbachol decreased Iso-stimulated contraction from 7.5+/-1.2% to 3.2+/-0.9% (P<0.05, n=4), but not completely to basal levels (1.6+/-0.3%). These results provide functional evidence for a predominantly cAMP-mediated mechanism of contractile stimulation by beta(1)ARs in human ventricular myocardium, although a small contribution from a non-cAMP dependent pathway may occur.

Rp-cAMPS has no effect on adenosine A1 receptors in guinea-pig cardiomyocytes.

Rp-cAMPS, a protein kinase A inhibitor, is used in the investigation of the cAMP-dependent systems. A report by Musgrave et al. has suggested that Rp-cAMPS may also act on adenosine receptors. To determine whether this occurs in guinea-pig ventricular myocytes, Rp-cAMPS was applied in the presence and absence of DCPCX, an adenosine A receptor antagonist. The isoprenaline-induced response was significantly decreased by Rp-cAMPS and the effect was not altered by the presence of DCPCX. Therefore Rp-cAMPS has no effect on cell contraction via adenosine A1 receptors and can reliably be used to investigate cyclic AMP-dependent systems in isolated cardiac myocytes.

Effect of acute testosterone on myocardial ischemia in men with coronary artery disease.

The effect of acute testosterone administration on exercise-induced myocardial ischemia was assessed in 14 men with coronary artery disease and low plasma testosterone concentrations in a study of randomized, double-blind, crossover design. Testosterone increased time to 1-mm ST-segment depression compared with placebo by 66 (15 to 117) seconds (p = 0.016), suggesting a beneficial effect of testosterone on myocardial ischemia in these patients.

Fetal proinsulin and birth weight.

In both diabetic and non-diabetic pregnancies fetal insulin is an important anabolic hormone. Fetal hyperinsulinaemia is associated with accelerated fetal growth and increased birth weight. Insulin and C-peptide concentrations in both umbilical cord and amniotic fluid reflect fetal beta-cell secretion and are correlated with birth weight. In the present study umbilical venous proinsulin and insulin concentrations were measured in 54 term infants born to women with and without mild disturbances of glucose tolerance. Umbilical venous cord proinsulin, assayed using a highly specific immunoradiometric assay, was independently correlated with infant birth weight (Rho = 0.53, p < 0.0001) and birth percentile (Rho = 0.65, p < 0.0001). The correlation between birth weight and birth percentile weight with umbilical venous insulin, measured using a non-specific insulin assay, was lost following correction for the influence of proinsulin. Umbilical venous cord proinsulin appears to be a good indicator of fetal beta-cell activity, and in this study, a superior marker to insulin assayed using a non-specific insulin radioimmunoassay. The longer half-life of proinsulin compared with insulin may contribute to proinsulin being a more robust marker of overall fetal beta-cell activity than insulin.

The effect of altering airway tone on the sensitivity of the cough reflex in normal volunteers.

Cough is frequently the presenting symptom of bronchial asthma, although cough can result from a wide variety of other respiratory disease. Treatment of chronic cough has proved extremely difficult. It has been suggested that treatment with bronchodilators may reduce the symptom of cough. In this study the effect of altering airway tone on the sensitivity of the cough reflex was determined. Twelve normal, healthy volunteers took part. The number of coughs following inhalations of single breaths of doubling concentrations of capsaicin (1.95-500 microM) was recorded before and after doses of salbutamol, methacholine and saline which altered forced expiratory volume in one second (FEV1) by 6.2 +/- 2.6%, -8.8 +/- 3.2% and -0.18 +/- 1.38%, respectively. In a further study the cough response was recorded before and after doses of salbutamol and ipratropium bromide, both of which reduced baseline respiratory resistance and resistance measured after capsaicin. Ipratropium bromide, salbutamol and methacholine, despite having significant effects on airway tone, did not change the sensitivity of capsaicin-induced cough. Thus, if bronchodilator drugs are antitussive in non-asthmatic patients, then this is unlikely to be due to an effect on the sensitivity of the cough reflex.