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To examine the role of brain natriuretic peptide (BNP) in acute myocardial infarction (AMI), we measured the plasma concentration of immunoreactive (ir) BNP together with that of atrial natriuretic peptide (ANP) over the 4-week course of AMI in 16 patients treated with early coronary angioplasty. Both the plasma ir-ANP and ir-BNP levels were increased on the first day of the infarction compared with the values in normal subjects. During the clinical course of the infarction, the plasma ir-ANP concentration soon decreased, while the plasma ir-BNP level remained elevated at 2 weeks after the infarction, also exhibiting a high level at 4 weeks. Plasma ir-BNP levels on day 1 or days 14 and 28 were inversely correlated with left ventricular ejection fraction obtained by left ventriculography at the acute or chronic phase, respectively. Plasma ir-BNP concentrations on days 14 and 28 were positively correlated with the maximal myosin light chain I level, an indicator of infarct size. These observations suggest that the plasma ir-BNP level increased to compensate for the ventricular dysfunction associated with the size of the infarct in AMI. BNP may act as a cardiac hormone in AMI, differing somewhat from ANP in its synthetic, secretory, or clearance behavior.

To examine the effects of lipoproteins on the secretion of endothelin-1 from endothelial cells, we measured immunoreactive (ir) endothelin-1 release from cultured human umbilical vein endothelial cells in the presence or absence of various concentrations of native low density lipoprotein (LDL), oxidized LDL, and very low density lipoprotein (VLDL). Cultured endothelial cells secreted ir-endothelin-1 into serum-free medium in a time-dependent manner, and the secretion was clearly stimulated following a 15-24-h incubation with 10 micrograms/ml oxidized LDL. The secretion of ir-endothelin-1 increased in a dose-dependent manner after a 24-h incubation with oxidized LDL, while only a high dose of native LDL and VLDL significantly increased ir-endothelin-1 secretion. The release of ir-endothelin-1 stimulated by 20 micrograms/ml oxidized LDL was reproduced by the same concentration of acetylated LDL but not native LDL. These observations indicate that the release of ir-endothelin-1 from endothelial cells is stimulated by lipoproteins, in particular by oxidized LDL, probably through the endothelial scavenger receptor. This increase in ir-endothelin-1 release induced by oxidized LDL may contribute to the development of atherosclerotic vascular lesions.

Recently, we have reported two cases with endothelin (ET)-secreting tumor presenting with hypertension and elevated plasma endothelin-1 (ET-1) levels. The present study examines the histopathology of the ET-secreting tumor in one of these cases. The neoplasm was located in the skin and microscopically characterized as a malignant hemangioendothelioma by remarkable intravascular proliferations of atypical endothelium with the expression of Factor VIII-related antigen in the tumor cells. The tumor enlarged rapidly with rising ET-1 and blood pressure levels. The ET-1 content and its messenger RNA expression in the tumor extract were higher than those from normal parts of skin. ET-1 may play a pathophysiological role in patients with ET-secreting malignant hemangioendothelioma.

The effect of glucocorticoids on the atrial natriuretic factor (ANF)-mediated formation of cyclic guanosine monophosphate (cGMP) by intact vascular smooth muscle cells (VSMC) was studied in rats. Cultured VSMC were obtained from the renal arteries of 14-week-old Wistar rats by the explant method. Micromolar concentrations of dexamethasone, given as pretreatment for 48 hours, suppressed the ANF-mediated response. The dexamethasone-induced suppression was detectable at 6 hours and reached a maximum 24 hours after administration in a dose-dependent manner. Inhibitors of protein synthesis blocked this effect of the glucocorticoid. The basal activity of guanylate cyclase in the dexamethasone-treated cells was lower than in the control cells. Other steroids having glucocorticoid action mimicked this suppression of the ANF-mediated response. This suppression was blocked by a glucocorticoid receptor antagonist. The results suggest that glucocorticoids suppress ANF-mediated cGMP formation by VSMC through glucocorticoid type II receptors and the induction of protein synthesis. Suppression of the ANF-mediated response may play a role in glucocorticoid-induced hypertension.

Endothelin plays a role in the regulation of vascular tonus. Therefore, it has been hypothesized that increased production or release of endothelin or both may contribute to the pathogenesis of hypertension. To assess any changes in the plasma endothelin concentration in essential hypertension, plasma immunoreactive endothelin concentrations were measured in patients with essential hypertension.We measured plasma immunoreactive endothelin concentrations in 42 subjects with essential hypertension, 12 subjects with borderline hypertension, and 25 normotensive control subjects.The concentrations were higher in hypertensive patients than in borderline hypertensive patients and normotensive subjects (both p less than 0.05), although values in normotensives and hypertensives overlapped. Reverse-phase high-performance liquid chromatography (HPLC) and radioimmuno-assay showed two components of plasma endothelin, one corresponding to synthetic endothelin-1 (1-21) and the other corresponding to synthetic big endothelin (human, 1-38). The HPLC profile of plasma endothelin of hypertensive patients was the same as that of normotensive subjects. Hypertensives with reduced glomerular filtration rates or increased serum creatinine levels had higher plasma endothelin concentrations than hypertensive patients as a whole (p less than 0.05). Mean blood pressure and serum creatinine levels were correlated to plasma endothelin in the hypertensives. Correlation was negative between glomerular filtration rate and the endothelin level in the hypertensives.Plasma endothelin was elevated in many hypertensive patients with severe hypertension or renal involvement. Its major components were endothelin-1 and big endothelin.

The present study was designed to examine the effect of antihypertensive therapy on plasma and atrial concentration of atrial natriuretic peptides (ANP) in spontaneously hypertensive rats (SHR) by using alpha-methyldopa and hydralazine. Methyldopa and hydralazine treatment reduced blood pressure (P less than .05, P less than .05, respectively); however, ventricular weight was reduced by methyldopa (P less than .05) but not by hydralazine. Plasma ANP concentration in untreated SHR was higher than that observed in Wistar-Kyoto rats (WKY). Methyldopa treatment decreased plasma ANP concentration, but hydralazine treatment did not. Moreover, plasma ANP concentration and ventricular weight were positively correlated in untreated and treated SHR. The left atrial ANP concentration in untreated SHR was lower than that observed in WKY. Methyldopa treatment increased left atrial ANP concentration, but hydralazine treatment did not. These results suggest that the ANP release from the left atrium is chronically stimulated in adult SHR, and that a decrease in plasma ANP concentration by methyldopa treatment is, in part, associated with the decline of ANP release from the heart due to the reductions of blood pressure and cardiac hypertrophy.

Heparin shows a blood pressure-lowering effect in various hypertensive rat models. This study was designed to examine the effect of heparin on vasoconstrictor endothelin-1 (ET-1) production by cultured human umbilical vein endothelial cells (HUVECs). ET-1 and cyclic GMP levels in the medium were determined by radioimmunoassay. ET-1 mRNA was quantified by densitometric Northern blot analysis. ET-1 was released into the medium in a time-dependent manner, and its release was augmented by thrombin (10 U/ml). Heparin suppressed both basal and thrombin-stimulated ET-1 secretion and its mRNA expression in a dose-dependent manner. Heparin suppressed ET-1 mRNA expression in a time-dependent fashion. Heparin did not suppress both basal and thrombin-stimulated ET-1 production in the presence of NG-monomethyl-L-arginine (L-NMMA) (10(-5) M). The production of cGMP stimulated by thrombin was significantly enhanced by heparin, but not in the presence of L-NMMA (10(-5) M). Heparin may suppress vasoconstrictor ET-1 production mediated by the enhancement of endothelium-derived nitric oxide in HUVECs.

The present study was designed to examine the possible influence of hypoxia on plasma immunoreactive (ir) endothelin-1 concentrations in anesthetized rats. Plasma ir-endothelin-1 concentration, blood pressure, heart rate, and arterial gas levels were measured 1 and 2 hours after exposure to normoxic (20% O2), mildly hypoxic (16% O2), and severely hypoxic (12% O2) gas. Mean blood pressure and heart rate were significantly decreased and the plasma ir-endothelin-1 concentration was significantly increased in severely hypoxic rats after both 1 and 2 hours. In mildly hypoxic rats, the plasma ir-endothelin-1 concentration was also increased, but this value was not statistically significant. The plasma ir-endothelin-1 concentration was inversely correlated with arterial blood PO2 in the three study groups (normoxic, mildly hypoxic, and severely hypoxic rats) after 1 hour (n = 18, r = -.74, P less than .01), and after 2 hours (n = 18, r = .71, P less than .01). Our results indicate that severe hypoxia increased the plasma ir-endothelin-1 level in anesthetized rats. The observed increase in plasma ir-endothelin-1 level may represent a compensatory mechanism against the blood pressure reduction associated with severe hypoxia.

The present study was designed to examine the effect of synthetic rat endothelin, a novel potent vasoconstrictor isolated from endothelial cells, on the release of immunoreactive atrial natriuretic factor (ir-ANF) in anesthetized rats. Systemic blood pressure and plasma ir-ANF concentration were measured at 1, 3, 5, 15, 30, and 60 minutes after rat endothelin administration (0.01, 0.10, 1.00 nmol/kg body weight [BW]). Administration of rat endothelin caused a long-lasting increase in mean blood pressure and produced a dose-dependent increase in plasma ir-ANF that peaked 5 minutes after the injection and remained higher than the basal value 60 minutes after the injection. These data suggest that administration of pharmacological doses of rat endothelin produces a profound release of ir-ANF into the circulation, which may cause vasodilation and diuresis to antagonize the effect of endothelin.

Erythrocyte deformation is an important regulatory factor of the microcirculation. The present study was designed to examine whether erythrocyte deformability is altered in hypercholesterolemic patients and, if so, whether cholesterol-lowering therapy affects this parameter in these patients. The erythrocyte deformability of 37 hypercholesterolemic patients was evaluated before and after 1 year of therapy with pravastatin, an inhibitor of hepatic hydroxymethyl glutaryl coenzyme A reductase, under various shear stresses (4.7, 9.5, 23.6, 47.3, 118.1, and 236.2 dyne/cm2) using laser diffractometry. At study entry, erythrocyte deformability under 4.7 and 9.5 dyne/cm2 shear stress, which is actually observed in human vessels, was reduced compared with that in 20 age-matched normocholesterolemic subjects and was inversely correlated with serum cholesterol and low-density lipoprotein (LDL) cholesterol. Pravastatin therapy for 1 year, which reduced serum cholesterol from 288 ± 28 to 223 ± 20 mg/dL, significantly improved erythrocyte deformability by approximately 20%. There was a significant relation between the improvement of erythrocyte deformability and the reduction of serum cholesterol or LDL cholesterol. The results suggest that erythrocyte deformability is reduced in hypercholesterolemic patients, and that long-term cholesterol-lowering therapy can improve reduced erythrocyte deformability, which may contribute to the improvement of organ perfusion.

Endothelin (ET)-1 causes mesangial cell contraction and proliferation. The present study was designed to evaluate the functional ET receptor subtype in cultured rat mesangial cells by measuring intracellular Ca2+ signaling with the use of a newly synthesized ET receptor type A selective antagonist-BQ123. The ET-1, ET-2 and ET-3 increased intracellular Ca2+ level in a dose-dependent manner. BQ-123 suppressed intracellular Ca2+ elevation in response to ET-1 in a dose-dependent manner with its half maximal inhibition value of 28 nM. BQ-123 (10(-6) M) did not affect ET-3 (10(-7) M)-induced Ca2+ response. The peak Ca2+ levels after addition of ET-3 without BQ-123 were similar to those in response to ET-1, ET-2 and ET-3 in the presence of BQ-123. Northern blot analysis showed that cultured mesangial cells expressed both ETA and ETB receptor mRNA. These results suggest that cultured mesangial cells have, at least, two types of functional receptors, one of which is an ETA receptor.

Cultured porcine endothelial cells (EC) released immunoreactive endothelin-1 (ir-endothelin-1) and big endothelin-1 (ir-big endothelin-1) into the medium in a time-dependent way. Reverse-phase high-pressure liquid chromatography coupled with radioimmunoassay showed that the major component of ir-endothelin-1 corresponded to standard endothelin-1 (1-21) and that the major component of ir-big endothelin-1 corresponded to standard big endothelin-1 (porcine 1-39). This release was strongly inhibited by cycloheximide and was, therefore, related to de novo protein synthesis. The release of greater amounts was stimulated by thrombin. The protein kinase C (PKC) inhibitors from two chemical classes, H7 and staurosporine, inhibited release following such stimulation in a relatively dose-dependent way. Neither H7 nor staurosporine affected the basal release of both endothelin-1 and big endothelin-1. Phorbol myristate acetate, which activates PKC and the Ca2+ ionophore A23187, stimulated the release of ir-endothelin-1 and ir-big endothelin-1 in a dose-dependent way, respectively. In addition, the combination of both compounds had a synergistic effect. An inactive enantiomer of phorbol ester, 4 alpha-phorbol-12,13-didecanoate had no effect on the release of ir-endothelin-1 and ir-big endothelin-1. These results suggest that cultured EC release endothelin-1 and big endothelin-1 simultaneously, and that thrombin stimulates this release by a mechanism that probably involves intracellular Ca2+ mobilization and the activation of PKC.

purpose: A natriuretic peptide, brain natriuretic peptide (BNP), has been isolated from porcine hearts. We performed this study to determine if BNP is secreted from the heart and to identify changes, if any, in the plasma BNP concentration in essential hypertension. patients and methods: We measured the immunoreactive (ir) BNP concentration at intracardiac sites including the coronary sinus of five patients with heart disease during cardiac catheterization. We examined plasma ir-BNP in 48 hypertensive patients, 15 borderline hypertensive patients, and 25 normotensive subjects. results: Plasma ir-BNP in the coronary sinus was greater than at other cardiac sites. The concentration was significantly higher in hypertensive subjects than in borderline hypertensive or normotensive subjects. Hypertensive patients with left ventricular hypertrophy (LVH) established by echocardiography had higher plasma ir-BNP levels than those without LVH. In the hypertensive group, plasma ir-BNP was closely correlated with the LV mass index. In these patients, BNP levels were correlated with mean arterial pressure and inversely correlated with the LV ejection fraction, although these correlations were weak. Reverse-phase high-pressure liquid chromatography showed that the major component of circulating ir-BNP in the hypertensive and normotensive subjects corresponded to authentic human BNP-32. conclusions: Human BNP-32 was secreted through the coronary sinus from the heart and may act as a cardiac hormone. Plasma BNP was increased in many of the hypertensive subjects with LVH The increase in BNP seemed to be related to LVH or the cardiac overload associated with LVH.

Effects of endothelin-3 on the secretion of endothelin-1 and other endothelium-derived substances were investigated in cultured human umbilical vein endothelial cells. The present binding study showed two distinct subpopulations of binding sites for endothelin-3 with higher and lower affinities in cultured human endothelial cells. Endothelin-3 caused an increase in intracellular Ca2+ and inositol 1,4,5-trisphosphate levels and activated protein kinase C in a dose-dependent manner. Endothelin-3 also caused an increase in [3H]thymidine incorporation into cellular DNA and stimulated the production of cyclic guanosine 3',5'-monophosphate, 6-ketoprostaglandin F1 alpha, and immunoreactive endothelin-1 in cultured human endothelial cells. NG-Monomethyl L-arginine (3 x 10(-4) mol/l) and indomethacin (10(-5) mol/l) enhanced endothelin-3-induced endothelin-1 production. These results suggest that endothelin-3 bound to its specific receptors and then caused phosphoinositide breakdown, subsequently mobilizing intracellular Ca2+ and leading to protein kinase C activation and the initiation of DNA synthesis, resulting in the stimulation of endothelin-1 production by human endothelial cells. Furthermore, this endothelin-1 production may be suppressed by endothelium-derived relaxing factor and prostacyclin produced in response to endothelin-3 in cultured human endothelial cells.

We measured plasma concentrations of immunoreactive endothelin-1 (irET-1) in the prehypertensive and hypertensive phases in spontaneously hypertensive rats (SHR) and in malignant hypertension caused by deoxycorticosterone acetate (DOCA)-salt administration in SHR. We also measured concentrations of this peptide in another model of malignant hypertension, the two-kidney, one clip (2K1C) renovascular hypertensive rats chronically given caffeine. Plasma irET-1 concentrations in young (6-week-old) and mature (18-week-old) SHR did not differ from those of age-matched Wistar-Kyoto (WKY) rats. Four weeks of treatment with DOCA-salt increased blood pressure, blood urea nitrogen, serum creatinine, and plasma irET-1 in SHR but not in WKY rats. Eight weeks of DOCA-salt treatment further increased these values in SHR. Plasma irET-1 concentrations were not increased in the 2K1C rats. Six weeks of caffeine administration increased blood pressure, blood urea nitrogen, serum creatinine, plasma renin activity, and plasma irET-1 in the 2K1C rats but not in the sham-operated rats. High-performance liquid chromatographic profiles of plasma extracts pooled from these rats with malignant hypertension showed that a major component of irET-1 eluted in the position of synthetic ET-1 (1-21). Furthermore, acute hypertension induced by angiotensin II or phenylephrine did not affect the plasma irET-1 concentration in rats. The results suggested that the plasma ET-1 concentration is increased in rat models of malignant hypertension and that the high blood pressure itself is not the main factor involved in the increase of plasma ET-1.

We examined the inhibition by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) of endothelin-1 secretion stimulated by angiotensin II (ANGII) and thrombin using cultured human umbilical-vein endothelial cells. ANGII and thrombin dose-dependently stimulated immunoreactive (ir) endothelin-1 secretion. Human ANP(1-28) and human BNP-32 both inhibited such secretion in a dose-dependent way. Inhibition of this secretion by ANP and BNP was paralleled by an increase in the level of cyclic guanosine 5'-monophosphate (GMP). The addition of a cyclic GMP analogue, 8-bromo cyclic GMP, reduced this stimulated secretion. Rat ANP(5-25) was weaker than human ANP(1-28) at inhibiting ir-endothelin-1 secretion and increasing cyclic GMP in the cells. ir-Endothelin-1 in the medium consisted of two components separated by high pressure liquid chromatography; the major one corresponded to endothelin-1(1-21) and the minor one corresponded to big endothelin-1(1-38). Treatment with ANP and BNP did not affect this profile. These findings suggest that human ANP and BNP inhibit endothelin-1 secretion stimulated by ANGII and thrombin in these cells through a cyclic GMP-dependent process. Taken together with endothelin stimulation of ANP and BNP secretion from the heart, our results suggest the existence of a cardiac-endothelium feedback.

In a randomized study in 26 elderly patients with mild essential hypertension, acute effects of alpha- and beta-adrenoceptor blockade on plasma ANP levels were examined at rest and during ergometric exercise. Plasma ANP level and LVEF were measured before and after administration of prazosin (an alpha 1-adrenergic blocker), atenolol (a cardioselective beta-adrenergic blocker), or carteolol (a nonselective beta-adrenergic blocker). Plasma ANP level was increased by exercise. Carteolol and atenolol increased plasma ANP levels at rest and during exercise, but the effect of atenolol was not statistically significant. Prazosin significantly suppressed the ANP values at rest and during exercise. The LVEF was increased by prazosin and decreased by beta-blockers, especially by carteolol. Multivariate regression analysis showed that LVEF was the most significant predictor of the plasma ANP level at maximal exercise; the resting blood pressure and heart rate were not predictors of this value. The results showed that single administrations of an alpha-blocker and a nonselective beta-blocker had opposite effects on the plasma ANP level both at rest and during exercise in elderly patients with mild essential hypertension. The observed difference in the ANP response seems to be related to changes in left ventricular function rather than changes in blood pressure or heart rate.

Endothelin-1, a potent vasoconstrictor peptide that has recently been isolated from the supernatant of cultured porcine aortic endothelial cells (1), is involved in some vascular disorders (2). Mal...

This study was designed to investigate the effect of propranolol on endothelin (ET)-1-induced increase in cytosolic Ca2+ [( CA2+]i) in cultured vascular smooth muscle cells (VSMCs) obtained from rat aorta. Propranolol (0.01 to 1 mmol/L) reduced the changes in the initial transient and the later sustained phase of [Ca2+]i induced by 100 nmol/L ET-1 as well as 10 mmol/L procaine. The inhibitory action of propranolol on the change in [Ca2+]i induced by ET-1 may be involved in one of the mechanisms of propranolol-induced reduction of vasospasms.

The present study was designed to examine the effect of thrombin on endothelin production by cultured human umbilical vein endothelial cells (HUVEC) by radioimmunoassay. Cultured HUVEC released immunoreactive endothelin-1 (ir-endothelin-1) into the medium in a time-dependent manner. This release was inhibited completely by 10 micrograms/mL cycloheximide and is, therefore, directly related to de novo protein synthesis. Further endothelin release was stimulated by the addition of thrombin to the culture medium. Thrombin-induced ir-endothelin-1 release also was inhibited completely by 10 micrograms/mL cycloheximide. These results suggest that HUVEC in culture produce ir-endothelin-1 slowly, but continuously, and that this production is stimulated by thrombin.

The effects of endothelin-1 on cytosolic Ca2+ and inositol 1,4,5-triphosphate (IP3) levels were investigated in cultured, untreated human endothelial cells and in endothelial cells pretreated with anti-endothelin-1 serum for 24 h to exclude the effect of endogenous endothelin-1. Endothelin-1 was found to increase the intracellular Ca2+ level, either in the presence or absence of extracellular Ca2+, in endothelial cells pretreated with antiserum by the fura-2 fluorescence technique. IP3 levels immediately started to rise following endothelin-1 stimulation. Resting intracellular Ca2+ levels were significantly lower when the cells were pretreated with antiserum than without antiserum pretreatment. Following stimulation by endothelin-1, intracellular Ca2+ and IP3 levels in endothelial cells pretreated with antiserum increased significantly compared to those in untreated endothelial cells. Endothelin-1 also increased 45Ca influx from the extracellular space. These results suggest that endothelin-1 increases intracellular Ca2+ in endothelial cells through extracellular Ca2(+)-dependent mechanisms and by the release of Ca2+ from intracellular stores, this presumably being induced by IP3 formation.

We recently demonstrated that porcine endothelin increases intracellular calcium ion concentration ([Ca2+]i) in monolayers of cultured vascular smooth muscle cells isolated from rat renal arteries. The present study was designed to examine the effect of porcine endothelin on [Ca2+]i in the platelets of rats. [Ca2+]i was serially measured with the fluorescent dye, fura 2, and the photoprotein, aequorin. Endothelin (10(-9) mol/L, 10(-8) mol/L, and 10(-7) mol/L) did not induce any change in [Ca2+]i in the platelets of rats while thrombin (2 U/mL) dramatically increased [Ca2+]i as measured by these methods. Our results indicate that [Ca2+]i in rat platelets is not influenced by porcine endothelin.

The effect of glucocorticoid on the prostaglandin E1 (PGE1)-mediated cyclic AMP (cAMP) formation by vascular smooth muscle cells (VSMC) from renal arteries (RA) was studied in rats. Dexamethasone (DEX) at concentrations ranging from 10(-10) to approximately 10(-8) mol/l dose-dependently potentiates the PGE1-mediated response. This facilitation began at 6 h and reached its maximum after 24 h of DEX administration. Aldosterone (10(-6) mol/l) did not affect the dose-response curve of PGE1. Inhibitors of protein and RNA synthesis blocked this glucocorticoid effect. The basal activity of adenylate cyclase in DEX-treated cells was twice as high as in control cells. Treatment of VSMC with DEX increased cholera toxin- and pertussis toxin-stimulated adenylate cyclase activity. DEX treatment also augments forskolin-stimulated adenylate cyclase activity. These results suggest that DEX increases PGE1-mediated cAMP formation of VSMC from RA through a mechanism that involves the induction of protein synthesis, and that the activation of the catalytic unit may play some role in this facilitating process.

The present study was designed to determine the possible involvement of atrial natriuretic factor (ANF) in the hypotensive action of a high-calcium diet. The effects of increased dietary calcium (2.9% calcium, HCa) on blood pressure, urinary sodium excretion, and ANF were examined in 30 spontaneously hypertensive rats (SHR) and 30 Wistar-Kyoto rats (WKY). Control groups of 30 SHR and 30 WKY were fed normal calcium lab chow (0.4% calcium, NCa). The HCa diet reduced blood pressure and serum phosphorus concentration and increased urinary excretion of sodium and calcium in SHR and WKY. The HCa diet also caused a sustained increase in plasma ANF concentration and, finally, a decrease in atrial ANF concentration in both groups. A significant inverse correlation was observed between ANF concentrations in plasma and atria of the four experimental groups. Plasma ANF concentration was positively correlated with daily calcium consumption, and blood pressure was inversely correlated with daily calcium consumption in HCa- and NCa-SHR groups and in HCa- and NCa-WKY groups, respectively. Furthermore, a significant inverse correlation between blood pressure and plasma ANF concentration was observed in SHR groups and in WKY groups, respectively. The observed sustained increment in endogenous plasma ANF concentration, which is probably caused by increased secretion from the atrium, may contribute, in part, to the blood-pressure-lowering effects of the HCa diet.

The present study was designed to examine the possible effect of long-term treatment with diltiazem on plasma and atrial concentrations of atrial natriuretic peptides (ANP) in spontaneously hypertensive rats (SHR). Diltiazem treatment reduced blood pressure and ventricular weight in SHR. Plasma ANP concentration in untreated SHR was higher than Wistar-Kyoto rats (WKY). Diltiazem treatment decreased plasma ANP concentration in SHR near to the level of WKY; moreover, plasma ANP concentration was correlated with blood pressure and ventricular weight in treated and untreated SHR. Left atrial ANP concentration in untreated SHR was lower than WKY. Diltiazem treatment increased left atrial ANP concentration in SHR, but this effect was not noted in WKY. These results suggest that the ANP release from the left atrium is chronically stimulated in adult SHR, and that the prevention of an increase in plasma ANP by diltiazem treatment may be, in part, attributed to the improvement of cardiac overload induced by reductions in blood pressure and cardiac hypertrophy.

A novel and potent vasoconstrictive peptide, endothelin, has recently been purified from the culture supernatant of porcine aortic endothelium. In this study we examined the acute effects of synthetic endothelin on renal hemodynamics and blood pressure in anesthetized rats. Blood pressure and renal blood flow were measured before and 1, 2, 5, and 10 minutes after endothelin administration (1.0, 0.5, or 0.1 nM/kg body weight). After a transient fall, the blood pressure gradually increased. At five and ten minutes after administration of each of the three doses, the blood pressure was significantly elevated compared with baseline values. Renal blood flow decreased immediately after infusion of 1 nM/kg endothelin, and this decrease lasted throughout the observation periods, while 0.1 nM/kg endothelin did not affect renal blood flow. At 2, 5, and 10 minutes after infusion of 1.0 or 0.5 nM/kg endothelin, renal vascular resistance was significantly elevated. These hemodynamic alterations were dose-dependent. The results show that endothelin has potent hypertensive and renal vasoconstrictive effects in rats.

1. The cytoplasmic free calcium concentration ([Ca2+]i) in the platelets of spontaneously hypertensive rats (SHR), Wistar–Kyoto rats (WKY), deoxycorticosterone–salt hypertensive rats (DOC) and normotensive Sprague–Dawley rats (SD) was measured with the fluorescent dye, quin-2-tetra-acetoxymethyl ester. 2. No significant difference in platelet [Ca2+]i was found between SHR and WKY or between DOC and SD rats. 3. No correlations were found between systolic blood pressure and [Ca2+]i. 4. These results suggest that the elevation of platelet [Ca2+]i does not necessarily accompany hypertension in rats.

To investigate the significance of atrial natriuretic peptides (ANP) in essential hypertension, plasma ANP concentrations in 43 essential hypertensives, 16 borderline hypertensives and 17 normotensive controls were measured. Furthermore, effects of high-sodium and low-sodium intakes on plasma ANP concentration were examined in "salt-sensitive" [SS] and "nonsalt-sensitive" [NSS] patients with essential hypertension. Plasma ANP concentration was significantly higher in hypertensives than in borderline hypertensives and in normotensive controls. No significant difference in plasma ANP concentration was observed between borderline hypertensives and normotensive controls. Plasma ANP concentration increased with the high-sodium diet in both the SS and NSS patients, but the mean increment was significantly greater in the SS than the NSS patients. Urinary excretion of sodium was lower in the SS patients taking the high-sodium diet than the corresponding value in the NSS patients. These findings suggest that an increased level of circulating ANP in hypertensive patients represents a compensatory mechanism to offset further elevation of blood pressure and sodium retention.

We have recently shown that circulating atrial natriuretic polypeptide (ANP) in adult spontaneously hypertensive rats (SHR) is higher than that in age-matched Wistar-Kyoto rats (WKY). The present experiment was designed to examine the possible effects of chronic treatment with angiotensin I converting enzyme inhibitors (ACEI) on plasma ANP levels in SHR. Captopril and enalapril lowered blood pressure and reduced relative ventricular weight in SHR but not to the level of WKY. Plasma ANP levels were decreased by captopril and enalapril compared with untreated SHR. These results suggest that the ANP release may be suppressed in ACEI-treated SHR compared with untreated SHR. We speculate that a reduction of cardiac overload by ACEI may in part explain the decline of circulating ANP.

Calcium-activated phospholipid-dependent protein kinase (protein kinase C) and cyclic AMP-dependent protein kinase (protein kinase A) were measured in tissue extracts of aortas from 7-, 14- and 20-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Protein kinase C and protein kinase A activity was significantly higher in 14- and 20-week-old SHR. Furthermore, protein kinase C and protein kinase A activity in the aorta was positively correlated with systolic blood pressure. Since protein kinase A is known to relax vascular smooth muscle, the observed increase in its activity may represent a compensatory mechanism to offset further elevation of blood pressure in SHR. These results suggest that protein kinase C in the aorta may play a role in the maintenance of hypertension in SHR.

Plasma concentrations of atrial natriuretic peptides were measured in 32 normal control subjects, 25 patients with hyperthyroidism, and 18 patients with hypothyroidism. Atrial natriuretic peptide values were measured before and after successful therapy with methimazole or 1-thyroxine. Plasma atrial natriuretic peptide concentration was increased in patients with hyperthyroidism (48.0 +/- 19.5 pg/ml) but was decreased in patients with severe hypothyroidism (16.3 +/- 5.7 pg/ml) compared with values in normal control subjects (31.2 +/- 9.5 pg/ml). There was no significant difference between values in normal control subjects and mildly hypothyroid patients (35.0 +/- 12.2 pg/ml). The plasma atrial natriuretic peptide concentration was correlated with the serum thyroxine level and heart rate. The elevated atrial natriuretic peptide concentration in hyperthyroidism decreased, whereas the reduced atrial natriuretic peptide concentration in severe hypothyroidism increased, compared with the initial value after successful therapy. These results suggest that plasma atrial natriuretic peptide concentration is frequently increased in hyperthyroidism and is frequently decreased in severe hypothyroidism, and that thyroid hormone is one of the regulatory factors for circulating atrial natriuretic peptides.

Effects of salt-loading on erythrocyte and erythrocyte ghost deformabilities were measured by laser diffractometry using a flat cell and a helium-neon laser in spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY). Salt-loading did not affect the deformability of erythrocytes in SHR and WKY, although a significantly reduced deformability was observed in salt-loaded SHR compared with values in control WKY and salt-loaded WKY (p less than 0.05, p less than 0.05, respectively). In contrast, salt-loading significantly reduced the deformability of erythrocyte ghosts in WKY and SHR (p less than 0.05, p less than 0.05, respectively). Our results suggest that salt-loading reduces erythrocyte membrane viscoelasticity in both WKY and SHR, and that the observed reduction of ghost deformability induced by salt-loading may influence the peripheral circulation.

The hemodynamic effect of a novel potent vasoconstrictive peptide (endothelin) on systemic blood pressure was studied in bilaterally nephrectomized and sham-operated rats under conscious and almost unrestrained condition. Following bolus IV administration of porcine endothelin, plasma endothelin concentration was measured by radioimmunoassay. After a transient decline, blood pressure was gradually elevated by endothelin administration. At 20, 30, and 40 minutes after injection, blood pressure was significantly elevated in bilaterally nephrectomized rats compared with sham-operated rats. Arterial plasma endothelin concentrations increased and rapidly decreased after injection in both rat groups. Bilateral nephrectomy significantly delayed the disappearance of endothelin from the plasma. These results suggest that the kidney plays a role in the plasma clearance of IV bolus endothelin administration and that the prolonged plasma half-life of endothelin is in part associated with the prolonged blood pressure elevation after endothelin administration in bilaterally nephrectomized rats.

In seven patients with mild to moderate essential hypertension, the effect of a new angiotensin converting enzyme (ACE) inhibitor, cilazapril, on atrial natriuretic factor (ANF) was examined at rest and during exercise. The exercise protocol consisted of three fixed workloads (25, 50 and 75W) every 4 min with the use of a sitting bicycle ergometer. Cilazapril reduced blood pressure without increasing the heart rate, both at rest and during exercise. The resting pre-exercise left ventricular ejection fraction was not altered. The plasma ANF level was increased by exercise, but at the 75-W workload it was decreased by cilazapril; the resting plasma ANF value was not altered. At the 75-W workload the plasma ANF level was inversely correlated to the left ventricular ejection fraction (n = 14, r = -0.64, P less than 0.01). These results suggest that the observed decrease in the plasma ANF level during exercise induced by cilazapril is, in part, related to an improvement in the cardiac overload, and that cilazapril may be effective in physically active hypertensive patients.

Cultured porcine endothelial cells derived from aortas spontaneously released immunoreactive endothelin into the medium in a time-dependent manner. This release was completely inhibited by cycloheximide and is, therefore, directly related to de novo protein synthesis. The endothlin-induced release was further stimulated by adrenaline. Adrenaline-induced stimulation was completely inhibited by the alpha-adrenergic blocker phentolamine and was not inhibited by the beta-adrenergic blocker propranolol. Cycloheximide completely prevented the adrenaline-stimulated as well as the basal release. These results suggest that cultured endothelial cells release endothelin slowly but continuously and that this release can be stimulated by adrenaline via alpha-adrenergic receptors. We speculate that the endothelium generates vasoconstrictor signals through endothelin production, thus contributing to the regulation of vascular tone.