Molecular variants of the sodium/hydrogen exchanger type 3 gene and essential hypertension

OBJECTIVES: The objectives of this study were to identify polymorphic variants within the gene coding for the sodium/hydrogen exchanger type 3 (NHE3) and to examine their relationship with hypertension and biochemical indices of sodium balance. DESIGN AND METHODS: Case-control comparisons on a total of 691 subjects of which 399 (68% with essential hypertension) were of African or Afro-Caribbean origin (blacks) and 292 (50% with essential hypertension) were of Caucasian origin (whites). RESULTS: Eight exons of the C terminus of the NHE3 gene were screened systematically. A total of six variants were identified: (G1579A, G1709A, G1867A, C1945T, A2041G and C2405T). Further analyses in relation to essential hypertension and phenotypic characteristics were confined to the more frequent A2041G and the C2405T polymorphisms. The genotype frequencies of the A2041G polymorphism were significantly different between the whites and blacks, with the A allele being more frequent in the white population (0.43 for the whites and 0.14 for the blacks, respectively; P < 0.001). In contrast, there was no significant difference in the C2405T polymorphism between whites and blacks (C allele frequency: 0.86 for the whites and 0.88 for the blacks, respectively). In both the white and the black groups, there were no significant associations between these variants and essential hypertension (P > 0.05) or with serum electrolytes, creatinine or plasma renin activity (PRA) (ANOVA P > 0.05). CONCLUSIONS: These results suggest a high degree of structural conservation of the NHE3 gene; however, the lack of association between these polymorphisms and blood pressure status does not necessarily eliminate the participation of this important sodium/hydrogen exchanger in the pathophysiology of essential hypertension, as we cannot exclude the existence of functionally important genetic variants in other sequences within the NEH3 gene.     

Physiology of breathing and respiratory control during sleep

Studies of respiratory control during sleep have revealed that multiple sites of central CO (2) chemosensitivity exist within the brainstem, and different chemosensory sites may function only during certain sleep states. In general, chemical control of respiratory function, related to both hypercapnia and hypoxia, appears to be blunted during sleep. The decline in respiratory activity during sleep is particularly marked in the muscles of the upper airway. A variety of neuromechanical factors originating in the lungs, chest wall, and upper airway also modify respiratory function during sleep. Cardiorespiratory function seems to be less stable during sleep, and arousal responses represent a final element in the control system that preserves cardiorespiratory function by terminating the sleep state and restoring more effective control mechanisms.     

Abnormal breathing during sleep and chemical control of breathing during wakefulness in patients with sleep apnea syndrome

The possible role of ventilatory control in relation to sleep apnea has not yet been clarified. We investigated the relationship between awake ventilatory drives to hypoxia and hypercapnia and sleep-disordered breathing in 21 subjects with sleep apnea syndrome. The awake hypoxic ventilatory drive, which was evaluated by occlusion pressure responses, was inversely correlated with the magnitude of maximal oxygen desaturation during sleep as well as the ratio of duration with more than 4 and 10% oxygen desaturation to total sleep time. On the other hand, the awake hypercapnic ventilatory drive was not correlated with these parameters of sleep desaturation. Apnea index and duration were not correlated with the degree of hypoxic or hypercapnic ventilatory drive, respectively. Our study concluded that sleep desaturation is better correlated with hypoxic ventilatory drive than with hypercapnic ventilatory drive in patients with sleep apnea syndrome. These results are different from the results obtained in the patients with COPD in our previous study.     

The control of breathing during weaning from mechanical ventilation

Using the recruitment threshold technique, we measured the CO2 responsiveness of the unloaded respiratory pump in 14 mechanically ventilated patients prior to weaning. The CO2 recruitment threshold (CO2RT) was compared with the arterial CO2 tension during unassisted breathing (CO2SB) and with the PaCO2 during mechanical ventilation (CO2MV) at machine settings determined by the primary physician. Based on these comparisons, we tested the hypotheses that (1) patients without weaning-induced respiratory distress (group 1) maintain CO2SB near CO2RT, (2) patients with weaning-induced respiratory distress (group 2) retain CO2SB above CO2RT, thereby manifesting incomplete load compensation, and (3) CO2MV is ventilator setting dependent and provides insufficient information about the ventilatory requirement during weaning. Respiratory distress was prospectively defined as sustained tachypnea (rate greater than or equal to 30) or intense dyspnea (Borg scale rating) and limited weaning in nine of 14 patients. The average CO2RT was 40 mm Hg in both groups. All patients in group 1 maintained CO2SB near CO2RT (p greater than 0.1). Seven of nine patients in group 2 retained CO2 by greater than or equal to 3 mm Hg above CO2RT (p less than 0.01). There was no significant difference between CO2MV and CO2SB in either group. We conclude that CO2RT provides a better reference of the adequacy of ventilatory load compensation during weather than CO2MV.     

Leukapheresis for control of chronic myelogenous leukemia during pregnancy

Leukapheresis was used as the sole modality of treatment of a patient with chronic myelogenous leukemia (CML) during her pregnancy. The specific requirements for safe leukapheresis during pregnancy are discussed, and the literature describing the management of CML during pregnancy is reviewed. Leukapheresis may be the treatment of choice in selected pregnancy patients with CML since it avoids the potential teratogenic effects of chemotherapy or radiation therapy.     

Mechanisms of periodic breathing during exercise in patients with chronic heart failure

BACKGROUND: Periodic breathing (PB) in heart failure (HF) is attributed to many factors, including low cardiac output delaying the time it takes pulmonary venous blood to reach the central and peripheral chemoreceptors, low lung volume, lung congestion, augmented chemoreceptor sensitivity, and the narrow difference between eupneic carbon dioxide tension and apneic/hypoventilatory threshold. METHODS AND RESULTS: We measured expired gases, ventilation, amplitude, and duration of PB in 23 patients with PB during progressive exercise tests done with 0 mL, 250 mL, or 500 mL of added dead space. Periodicity of PB remained constant despite heart rate, oxygen consumption, and minute ventilation increasing. Within each PB cycle, starting from the beginning of exercise, the largest (peak) tidal volume approached maximum observed tidal volume, while the smallest (nadir) tidal volume increased as exercise power output increased. PB ceased when nadir tidal volume reached peak tidal volume. End-tidal carbon dioxide increased with added dead space, and PB ceased progressively earlier during the exercise done with increased dead space. CONCLUSION: Circulatory delay does not contribute to the PB observed in exercising HF patients. The pattern of gradually increasing nadir tidal volume during exercise and the effect of dead space on both PB ceasing and end-tidal carbon dioxide suggest that low tidal volume and carbon dioxide apnea threshold are important contributors to PB that occurs during exercise in HF.     

Role of the cardiac Na+/H+ exchanger during ischemia and reperfusion

The coupled exchanger theory describes one of the central mechanisms of damage in the ischemic heart. The theory proposes that anaerobic glycolysis produces lactate and protons and that the protons can leave the cardiac cell on the cardiac Na+/H+ exchanger (NHE1). The subsequent rise in [Na+]i stimulates the cardiac Na+/Ca2+ exchanger (NCX) and results in an increase in [Ca2+]i which promotes myocardial cell damage. Although the general features of this theory are widely accepted, there is dispute about some aspects, specifically whether the NHE1 remains active during ischemia or not. We review the evidence on this issue and conclude that NHE1 is substantially inhibited during ischemia. This issue is central to the design of a clinical trial of NHE1 inhibitors in the treatment of human cardiac ischemia and the existing clinical trials are considered in this light.     

Potential uses of intravenous proton pump inhibitors to control gastric acid secretion

Proton pump inhibitors are the most effective agents for suppressing gastric acidity and are the preferred therapy for many acid-related conditions. While proton pump inhibitors have been accessible in intravenous formulations in several European countries, they have been available only as oral drugs in the United States. In the near future, the proton pump inhibitor pantoprazole is likely to become available in an intravenous formulation for American patients. Potential uses for intravenous proton pump inhibitors include treatment of Zollinger-Ellison syndrome and peptic ulcers complicated by bleeding or gastric outlet obstruction, as well as prevention of stress ulcers and acid-induced lung injury. These intravenous proton pump inhibitors are also likely to be beneficial to patients undergoing long-term maintenance with oral proton pump inhibitors who cannot take oral therapy for a period of time. Intravenous pantoprazole is especially distinguished in its lack of clinically relevant drug interactions, and it requires no dosage adjustment for patients with renal insufficiency or with mild to moderate hepatic dysfunction. Both omeprazole and pantoprazole are well tolerated in both oral and intravenous forms. Although further studies are needed to define their roles clearly, the availability of intravenous formulations of proton pump inhibitors will certainly assist with the treatment of gastric acid-related disorders.     

Role of the renal nerves in the control of renin synthesis during different sodium intakes in the rat.

OBJECTIVE: The aim of this study was to evaluate the role of the renal nerves in the regulation of renin synthesis in normotensive rats at different sodium balance. METHODS: Forty-eight male Sprague-Dawley rats were divided in six experimental groups, combining three diets at different NaCl content (normal 0.4%, low 0.04% or high 4.0%), and the surgical, bilateral renal denervation or the sham procedure. After 7 days of dietary treatment, all rats were sacrificed and plasma renin activity (PRA) was measured. Renin messenger RNA (mRNA) levels in the renal cortex were determined by semiquantitative polymerase chain reaction. RESULTS: PRA was higher in animals fed the low sodium diet compared with those at standard diet, while it was lower in animals fed the high sodium diet. Renal denervation decreased PRA in normal and low sodium groups, while it did not alter the PRA values in the high sodium group. Renin gene expression significantly increased in rats fed with the low sodium diet compared with the standard diet group, and significantly decreased in rats fed the high sodium diet Renal denervation significantly reduced renin mRNA levels in rats receiving the low sodium diet, but did not produce any significant change in normal or high-sodium groups. CONCLUSION: The activation of renin gene expression during sodium depletion in rats is dependent on the presence of the renal nerves, while the suppression of renin gene expression during a sodium load seems to be due to the macula densa mechanism alone.     

Sleep arterial oxygen desaturation and chemical control of breathing during wakefulness in COPD

Recent studies have demonstrated that oxygen desaturation occurs during sleep in some patients with chronic obstructive pulmonary disease (COPD). The degree of sleep hypoventilation in COPD may be related to an inadequate chemical control of ventilation. To investigate this relationship, we compared maximal sleep changes in arterial oxygen saturation (SaO2) with the hypercapnic and hypoxic ventilatory control during wakefulness in 24 patients with COPD. Both hypercapnic and hypoxic ventilatory responses were inversely correlated with the degree of maximal sleep desaturation in rapid-eye-movement (REM) sleep. Furthermore, the level of baseline SaO2 during wakefulness was also negatively related to the magnitude of sleep desaturation. Patients with insufficient chemical control of breathing appear to have larger falls in SaO2, particularly if they have lower baseline SaO2.     

Periodic breathing during incremental exercise predicts mortality in patients with chronic heart failure evaluated for cardiac transplantation

OBJECTIVES: We hypothesized that exercise-related periodic breathing (EPB) would be associated with poor prognosis in advanced chronic heart failure (CHF). BACKGROUND: Patients with CHF might present instability of the ventilatory control system characterized by cyclic waxing and waning of tidal volume (periodic breathing [PB]). This condition is associated with several deleterious circulatory and neuro-endocrine responses; in fact, PB in awake and asleep patients has been identified as an independent risk factor for cardiac death. During exercise, however, the prognostic value of PB is still unknown in CHF patients awaiting heart transplantation. METHODS: Eighty-four patients with established CHF (65 male, 19 female) were submitted to clinical evaluation, echocardiogram, ventricular scintigraphy, determination of resting serum norepinephrine levels, and an incremental cardiopulmonary exercise test on cycle ergometer. Patients were followed for up to 49.7 months (median = 15.3), and 26 patients (30.9%) died during this period. RESULTS: Twenty-five of 84 patients presented EPB (29.7%). The following variables were related to mortality according to Kaplan-Meier and univariate Cox regression analysis: EPB (p = 0.004), New York Heart Association class (p = 0.04), serum norepinephrine (p = 0.06), peak oxygen uptake (ml.min(-1).kg(-1) and % predicted; p = 0.085 and p = 0.10, respectively), slope of the ratio of change in minute ventilation to change in carbon dioxide output during exercise (p = 0.10), and scintigraphic left ventricular ejection fraction (p = 0.10). Cox multivariate analysis identified EPB as the only independent variable for cardiac death prediction (p = 0.007). Therefore, EPB alone was associated with a 2.97-fold increase in risk of death in this population (95% confidence interval = 1.34 to 6.54). CONCLUSIONS: Exercise-related periodic breathing independently predicts cardiac mortality in CHF patients considered for heart transplantation.     

Role of bacteria in chronic prostatitis/ chronic pelvic pain syndrome

Throughout the past century, we have refined our understanding of prostatitis, moving from using a primarily clinical definition to considering it as a complex inflammatory condition. The inconsistency in identifying uropathogens in patients with symptoms of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has led to controversy in therapeutic management. There is compelling evidence that the normal prostate has minimal inflammation and no bacteria. Clinicians using the Meares/Stamey criteria identified uropathogens localized to the prostate in only 6% to 8% of CP/CPPS patients. This suggests that bacteria may have a role in less than 10% of men with CP/CPPS. That some patients respond to antimicrobials could suggest that eradication of bacteria reduces symptoms. However, the beneficial effect of antimicrobial drugs may not be due to their antibacterial action, but to their anti-inflammatory action. The normal prostate shows minimal inflammation, but only 50% of CP/CPPS patients exhibit prostatic leukocytosis. Prudence demands that we examine the function of the white blood cells—the cytokines produced. Several basic science advances allowed new avenues of research regarding the detection of molecular evidence of causative uropathogens. New research brings new controversy and unexpected findings, but further refines our understanding of the immune system and the CP/CPPS disease process.