Yukihisa Umeda

The role of atrial pressure in secreting atrial natriuretic polypeptides

The role of atrial pressure and catecholamines in secreting human atrial natriuretic polypeptides (hANP) were investigated in patients with acute or old myocardial infarction (AMI or OMI). No differences were observed in hANP levels obtained from brachial vein, right atrium, pulmonary artery and femoral artery, suggesting that hANP degradation in the pulmonary circulation has little clinical significance in hANP measurement. Plasma hANP levels in 10 patients with AMI were higher than those in controls and significantly correlated to both mean right atrial pressure (mRA) and pulmonary wedge pressure (PCW) (r = 0.76, p less than 0.05; r = 0.95; p less than 0.01, respectively). In 12 patients with OMI, plasma hANP levels were normal at rest and were significantly increased (p less than 0.01) with bicycle ergometer exercise associated with significant elevations of plasma catecholamine levels, mRA, and PCW. However, the increments of hANP correlated only to those of PCW. These results suggest that the elevation of atrial (principally left atrial) pressure rather than catecholamine stimulates hANP secretion.

Effects of steroid and thyroid hormones on synthesis of atrial natriuretic peptide by cultured atrial myocytes of rat

The in vitro effects of various steroid and thyroid hormones on synthesis of rat atrial natriuretic peptide (rANP) were studied using new-born rat atrial myocytes in culture. Dexamethasone, testosterone and triiodothyronine markedly stimulated both synthesis and secretion of immunoreactive (IR)-rANP with the same peak after 4-day-culture. Dexamethasone and testosterone dose-dependently (10(-7)-10(-6) M) stimulated synthesis of IR-rANP and were the most potent among various steroids tested. Triiodothyronine (T3) also stimulated synthesis of IR-rANP in a dose-dependent manner (10(-8)-10(-7) M), of which effect was more potent than that of tetraiodothyronine, whereas reverse T3 was ineffective. The present study clearly shows that glucocorticoids, androgens and thyroid hormones directly stimulate synthesis of ANP by atrial myocytes and suggests that ANP may play a potential role in mediating and/or modulating the biological effects by these hormones in the cardiovascular system.

Predominant tubulointerstitial nephritis in a patient with systemic lupus nephritis.

In most cases of systemic lupus erythematosus (SLE), glomerular lesions are the main renal complication. Although tubulointerstitial lesions are often associated with severe glomerular lesions, predominant or isolated tubulointerstitial injury in the presence of minimal glomerular abnormalities with SLE, so-called predominant tubulointerstitial lupus nephritis, is rare. Only ten cases are reported in the English literature. Herein, we describe the case of a 64-year-old man with SLE who presented with acute renal deterioration attributable to acute tubulointerstitial nephritis. Renal biopsy showed diffuse infiltration of inflammatory mononuclear cells in the interstitium and tubulitis without significant glomerular lesions. Immunofluorescence study revealed positive staining for IgG, C3, and C1q along the renal tubular basement membrane (TBM). Electron microscopy also showed electron-dense deposits in the TBM. Other causes of tubulointerstitial injury, such as drug use and infection, were ruled out. Taking these findings together with the presence of antitubular basement membrane antibody, predominant tubulointerstitial lupus nephritis was diagnosed. Treatment with oral corticosteroids for 6 weeks improved renal function. Even after tapering of the corticosteroid, renal function and serological markers of SLE activity have remained stable in this patient for more than 12 months.

Vasopressin-induced pressor response elicited by electrical stimulation of solitary nucleus and dorsal motor nucleus of vagus of rat

Electrical stimulation of the solitary nucleus and dorsal motor nucleus of the vagus elicited a pressor response in vagotomized rat with the spinal cord cut at C1. The response was entirely accounted for by an increased release of vasopressin upon stimulation as evidenced by absence of response in rats pretreated with a vasopressin antagonist and in Brattleboro rats.

Ventricular myocytes from neonatal rats are more responsive to dexamethasone than atrial myocytes in synthesis of atrial natriuretic peptide

Using the primary culture of neonatal rat ventricular myocytes, synthesis and secretion of rat atrial natriuretic peptide (rANP) were studied. Ventricular myocytes in culture, although contained less amounts of cellular immunoreactive (IR)-rANP, secreted substantial amounts of IR-rANP at a rate comparable to that of atrial myocytes. Dexamethasone markedly stimulated synthesis and secretion of IR-rANP by cultured ventricular myocytes in a dose-dependent manner (10(-10)-10(-6) M), of which effect was far more potent than that in atrial myocytes. Testosterone and triiodothyronine also stimulated synthesis and secretion of ventricular IR-rANP to the extent comparable to that of atrial IR-rANP. The present study suggests that tissue-dependent difference in glucocorticoids sensitivity plays an important role in the regulation of developmental ANP gene expression in mammalian heart.

CHARACTERIZATION OF HUMAN PLATELET VASOPRESSIN RECEPTOR AND THE RELATION BETWEEN VASOPRESSIN‐INDUCED PLATELET AGGREGATION AND VASOPRESSIN BINDING TO PLATELETS

Immunoreactive AVP was found to be much higher in platelets than in platelet‐free plasma (PFP) in normal subjects (12–8 ± 6–3 versus 1 –7 ± 0–8 fmol/ml). AVP levels in PFP were appreciably elevated in parallel with the elevation of plasma osmolality induced by the acute osmotic stimulation, while the AVP levels in platelets did not change before and after the stimulation.

Atrial natriuretic peptide gene expression and its secretion by pneumocytes derived from neonatal rat lungs

Using a primary culture of pneumocytes derived from neonatal rat lungs, we investigated the synthesis and secretion at transcriptional and peptide levels of pulmonary rat(r) atrial natriuretic peptide (ANP). Total RNA extracted from pneumocytes contained a hybridizing RNA band of the same size as atrial rANP mRNA. Immunoreactive (IR)-rANP content in pneumocytes was 0.5% of that in atrial myocytes, and 8.6% of that in ventricular myocytes, while the secretory rate from pneumocytes was about 7% of atrial and ventricular myocytes. Triiodothyronine (T3, 5 x 10(-10) to 5 x 10(-8) M), dexamethasone and testosterone (5 x 10(-9) to 5 x 10(-8) M) significantly stimulated the synthesis of IR-rANP by pneumocytes in a dose-dependent manner. However, the stimulatory effect exerted by T3 on rANP synthesis, unlike in the case of cardiocytes, was much more potent than that of dexamethasone, as evidenced by the significant difference in potency at both transcriptional and peptide levels. The present study suggests that ANP secreted from lungs may at least in part contribute to circulating ANP pool, and that the tissue-dependent difference of sensitivity to thyroid hormone may play an important role in the regulation of developmental ANP gene expression in mammalian lungs.

Role of atrial natriuretic polypeptides for exaggerated natriuresis in essential hypertension

Eighteen patients with essential hypertension were separated into 2 groups, renin-unresponsive and renin-responsive, on the basis of their plasma renin response when challenged by furosemide and upright posture. The response to acute infusion of hypertonic saline solution (1.4% saline solution at a rate of 0.3 ml/min/kg over 60 minutes) was then studied. In the renin-unresponsive group, peak rate of fractional excretion of sodium and peak urine flow after saline loading were 7.6 +/- 0.7% and 476 +/- 34 ml/hour, respectively, and peak value of atrial natriuretic polypeptides (ANP) was 784 +/- 140 pg/ml. In the renin-responsive group, the values were 3.1 +/- 0.4%, 194 +/- 29 ml/hour and 115 +/- 33 pg/ml. Both fractional excretion of sodium, urine flow and ANP response were significantly higher (p less than 0.01) in the renin-unresponsive group. Moreover, a highly significant relation (r = 0.82, p less than 0.01) was observed between fractional excretion of sodium and ANP levels in all hypertensive patients. The degree of saline-induced natriuresis was not related to blood pressure, heart rate, endogenous creatinine clearance, antidiuretic hormone or preexisting level of aldosterone. Plasma renin activity changed little in either group during saline infusion, but tended to be higher at all times in the renin-responsive patients. The present findings suggest that the enhanced secretion of ANP is an important determinant for exaggerated natriuresis observed in patients with renin-unresponsive hypertension.

Intrapulmonary bronchial circulation during hemorrhage

SummaryExperiments were conducted on 119 anesthetized and artificially ventilated rats to evaluate effects of a physiological stimulus (hemorrhage) to the sympothoadrenal system on the bronchial circulation. In the presence of a sufficient dose of a vasopressin V1-receptor antagonist, moderate (81 mmHg on average, 33 rats) or severe hypotension (69 mmHg, 28 rats) was produced by controlled hemorrhage (11 or 9 rats, respectively), or by treatment with phenoxybenzamine (0.1 mg/kg, i.v., 12 rats, or 1.0 mg/kg, 10 rats), or the highly selective alpha1-adrenoceptor antagonist, bunazosin (0.01 mg/kg i.v., 10 rats, or 0.1 mg/kg, 9 rats). During hypotension, the intrapulmonary bronchial blood flow (microsphere method) was decreased in a dose-dependent manner in the two antagonist-treated groups. However, these decreases were only of a moderate degree compared to the severe decrease in the hemorrhage group. Although the bronchovascular resistance was not significantly changed after treatment with either antagonist, this variable was greatly elevated during severe hemorrhagic hypotension, reaching 240±51% (P<0.001 with either antagonist study) of its baseline level. Changes in the pulmonary arterial and left atrial pressures, plasma vasopressin concentration, and renin activity were found to be less influential on these responses in 58 rats. Overall, we concluded that the sympathoadrenal mechanism powerfully increased the resistance and decreased the blood flow of the intrapulmonary bronchial circulation.

Platelet vasopressin receptor in essential hypertension.

The specific vasopressin receptor of V1 vascular subtype, which mediates platelet aggregation, has been found on human platelets. We investigated the binding characteristics using tritiated arginine vasopressin [3H]-AVP and platelet aggregation with AVP turbidometrically in normal subjects, patients with WHO class II essential hypertension and patients with malignant-phase hypertension. In essential hypertensives Bmax was significantly higher than that in normal subjects, but there were no differences in affinity and the maximal percentage aggregation between them. In malignant-phase hypertensives Bmax and maximal percentage aggregation were significantly lower than those in normals and essential hypertensives, although there was no difference in the affinity between them. With radio-immunoassay, the mean platelet-free plasma AVP level was significantly higher in malignant-phase hypertensives than those in normals and essential hypertensives, whereas there was no difference in mean platelet AVP levels between them. In essential hypertensives Bmax and maximal percentage aggregation did not change, but in malignant-phase hypertensives Bmax increased significantly and maximal percentage aggregation tended to normalize after treatment.