Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies.

AIMS: To assess if treatment with the alpha-glucosidase inhibitor acarbose can reduce cardiovascular events in type 2 diabetic patients. METHODS AND RESULTS: This meta-analysis included seven randomized, double-blind, placebo-controlled acarbose studies with a minimum treatment duration of 52 weeks. Type 2 diabetic patients valid for safety were randomized to either acarbose (n=1248) or placebo (n=932). The primary outcome measure was the time to develop a cardiovascular event. Primary analysis was conducted using Cox regression analysis. The effect of acarbose on metabolic parameters was also investigated. Acarbose therapy showed favourable trends towards risk reduction for all selected cardiovascular event categories. The treatment significantly reduced the risk for "myocardial infarction" (hazards ratio=0.36 [95% Cl 0.16-0.80], P=0.0120) and "any cardiovascular event" (0.65 [95% Cl 0.48-0.88], P=0.0061). Glycaemic control, triglyceride levels, body weight and systolic blood pressure also improved significantly during acarbose treatment. CONCLUSION: Intervention with acarbose can prevent myocardial infarction and cardiovascular disease in type 2 diabetic patients while most of them are already on intensive concomitant cardiovascular medication.

Regional blood volume distribution during positive and negative airway pressure breathing in supine humans.

To assess the effects of continuous positive (CPAP) or negative airway pressure (CNAP) breathing (+/- 10-12 cmH2O, duration 25 min) on blood content in the body's capacitance vasculature, regional distribution of labeled red blood cells was evaluated in seven spontaneously breathing supine volunteers. Counts were acquired by whole body scans and detectors overlying the liver, intestine, left ventricle, and lower arm, and arterial pressure, heart rate, calf blood flow and vascular resistance, hematocrit, vasopressin, and atrial natriuretic peptide plasma concentrations were also obtained. With CPAP, thoracic, cardiac, and left ventricular counts diminished significantly by 7-10%, were accompanied by significant increases in counts over both the gut and liver, and remained decreased during CPAP but reversed to baseline with zero airway pressure. Calf blood flow and vascular resistance significantly decreased and increased, respectively, whereas limb counts, arterial pressure, heart rate, and hormone concentrations remained unchanged. With CNAP, in contrast, regional counts and other variables did not change. Thus, moderate levels of CPAP deplete the intrathoracic vascular bed and heart, shifting blood toward the gut and liver but not toward the limbs. No short-term compensation increasing cardiac filling during CPAP was seen. In contrast, CNAP did not alter intrathoracic or organ blood content and, therefore, does not simply mirror the effects evoked by CPAP.

Effect of monoclonal anti-ANP antibodies on the acute functional adaptation to unilateral nephrectomy.

The role of endogenous atrial natriuretic peptide (ANP) in the immediate response of sodium excretion to unilateral nephrectomy (UNX) was investigated in anesthetized euvolemic rats through measurement of UNX-induced change in plasma ANP concentration and the response of the remaining kidney to UNX following administration of monoclonal anti-ANP antibodies. The circulating ANP levels almost tripled (from 23 +/- 4 to 66 +/- 13 fmol/ml, P < 0.01) within two minutes after UNX, whereas no change resulted from sham intervention. In the control group receiving vehicle injection, UNX resulted in a twofold increase in urinary sodium excretion (from 1.39 +/- 0.25 to 2.88 +/- 0.28 mumol/min, P < 0.01) related to a decrease in the fractional reabsorption of sodium at both proximal and distal sites (estimated from fractional excretion of lithium). Urinary excretion of cyclic guanosine 3'-5'-monophosphate (cGMP) increased as well, but glomerular filtration rate did not change. In addition, UNX was associated with a short-lived (< 20 min) rise in systemic arterial pressure and a transient fall in right atrial pressure. Administration of monoclonal anti-ANP antibodies totally prevented the UNX-associated natriuresis by blunting both proximal and distal tubular reabsorption of sodium, and suppressed the rise in urinary cGMP excretion following UNX. The duration of the post-UNX increase in arterial pressure was longer when compared to values observed in controls. These observations indicate that ANP release is stimulated after uninephrectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition by atrial natriuretic peptide of endothelin-1-stimulated proliferation of vascular smooth-muscle cells.

The effect of endothelin-1 (ET-1) on proliferation of aortic vascular smooth-muscle cells (VSMCs) from spontaneously hypertensive (SHRs) and normotensive Wistar-Kyoto (WKY) rats was assessed by the measurement of [3H]-thymidine incorporation into DNA. ET-1 stimulated DNA synthesis in a concentration-dependent manner. Half-maximal stimulation occurred at a concentration of 7 x 10(-11) M. Three separate administrations of ET-1 to the cell cultures resulted in a half-maximal stimulation at 3 x 10(-12) M in of VSCMs from SHRs. VSMCs from SHRs responded to a far greater extent compared with WKY rats. The stimulatory effect of ET-1 was significantly attenuated by atrial natriuretic peptide (ANP). Repeated administration of ANP led to exacerbation of the inhibitory effect. Serum-stimulated DNA synthesis was not influenced by ANP. The proliferative action of ET-1 and the inhibition by ANP are discussed with respect to the development of vascular disease in atherosclerosis and hypertension.

Atrial natriuretic peptide decreases hepatic and cardiac blood content, but increases intestinal blood content in supine humans.

The authors evaluated in humans whether atrial natriuretic peptide (ANP) alters the regional distribution of blood in capacitance vessels. Eight healthy male volunteers (mean age: 30 years, range: 24-39) were studied twice. On different days and in a randomized, double blind fashion they received either alpha h-ANP (99-126), 25 micrograms intravenously followed by infusion of 0.1 microgram kg-1 min-1, or vehicle. Changes of regional blood content in heart, liver, and intestine were evaluated at 3-min intervals using autologous radioactively (99mTc) labeled red cells. Calf circumference (strain gauge), central venous pressure, and heart rate were recorded continuously while arterial pressure (oscillometry), hematocrit, ANP and cGMP plasma concentrations were determined intermittently. Exogenous ANP increased plasma concentrations of ANP (49 pg ml-1 +/- 8 SE to 614 +/- 190) and cGMP (1.7 pmol ml-1 +/- 0.2 to 30.8 +/- 4.4). This elicited significant and profound decreases in liver (-11%) and cardiac (-10%) radioactivity, contrasted by a smaller but significant increase (+4%) of intestinal radioactivity. These changes became gradually apparent about 15 min during ANP administration and reached their nadir at the end of the infusion period. Central venous pressure significantly decreased by 3.4 cm H2O and calf volume by 0.3 ml/100 ml while hematocrit increased by 2.6%. All changes were at least partly reversed when ANP administration ceased. Of note, two subjects developed a near syncope with abrupt bradycardia and arterial hypotension following an initial gradual decrease in cardiac counts and central venous pressure. We conclude that in humans ANP markedly alters the regional blood distribution in the capacitance vasculature as blood content decreased profoundly in both heart and liver, but increased in the intestine, albeit to a lesser extent. Accordingly, a redistribution of blood away from the heart represents another unique mechanism by which ANP can exert its cardiovascular actions.

Endogenous atrial natriuretic factor is involved in the natriuresis following sodium loading in rats with chronic heart failure.

STUDY OBJECTIVE: Plasma levels of atrial natriuretic factor are increased in chronic heart failure; however, it is still controversial whether these raised levels contribute to the diuresis and natriuresis in this setting. To address this issue the potential contribution of endogenous atrial natriuretic factor in the renal excretion of a moderate oral sodium load in a rat model of chronic heart failure was studied. DESIGN: A monoclonal antibody against atrial natriuretic factor was used for specific antagonisation of its in vivo effects. Animals were subjected to oral sodium loading (30 ml.kg-1 0.9% NaCl, 2.5% dextrose) at baseline, immediately after, and 5 d after injection of monoclonal antibody or control solvent. EXPERIMENTAL MATERIAL: Sham operated rats and rats with chronic heart failure due to myocardial infarction (infarct size 35(SEM 4)% of left ventricle) were studied 4-5 weeks after surgery. MEASUREMENTS AND MAIN RESULTS: The renal excretion of cyclic guanosine monophosphate (cGMP), which represents a specific marker for the activation of the atrial natriuretic factor system, was markedly increased in infarcted rats, at 17.9(SEM 3.4) vs 5.8(1.2) nmol.kg-1, p less than 0.01. Atrial natriuretic factor antibody given immediately before sodium loading reduced the natriuretic response (0-4 h period) in infarcted rats from 1270(171) to 805(76) mumol.kg-1 (p less than 0.01) but not in sham operated animals. Similarly, the excretion of cGMP was only decreased by atrial natriuretic factor antibody in infarcted rats, from 29.8(6.3) to 20.7(3.7) nmol.kg-1. The reduction in sodium and cGMP excretion in infarcted rats was confirmed with a purified antibody preparation. CONCLUSIONS: Endogenous atrial natriuretic factor appears to be involved in the natriuresis following a moderate oral volume load in chronic heart failure. Thus the raised concentrations found in chronic heart failure may contribute to the regulation of urinary sodium excretion under these conditions despite the fact that the diuretic effects of exogenous atrial natriuretic factor are attenuated in chronic heart failure.

Autoradiographic localization of 125I-big endothelin-1 in rat tissues.

Endothelin-1 (ET-1), a potent vasoconstrictor with a characteristically long-acting activity in vitro and in vivo, is thought to be generated in endothelial cells from a less active intermediate, big endothelin-1 (big ET-1). In addition to ET-1, big ET-1 is also present in the circulation. The autoradiographic localization of 125I-big ET-1 has been studied after intravenous administration in rat tissues. Highest enrichment of radioactivity was found in the kidney cortex. Compared to blood levels, enrichment of radioactivity is also detected, especially in the vascular wall of the aorta. Comparing the radioactivity pattern of ET-1 and big ET-1, a nearly identical tissue distribution is observed, with the exception of the relative enrichment in the lung, the endocardium and the zona glomerulosa.

Long-term protective effects of nitrendipine in experimental hypertension.

The antihypertensive and tissue-protective effects of nitrendipine were studied after long-term treatment of rats with experimental hypertension. Nitrendipine had opposite effects in comparison with vasodilators like hydralazine or minoxidil. Nitrendipine lowered heart weights, plasma atrial natriuretic peptide levels, and plasma renin activity, and was diuretic. Also, in spontaneously hypertensive rats that had been hypertensive for more than half of their life span prior to treatment, nitrendipine still had these effects. Nitrendipine prevented hypertension-induced mortality, even at subantihypertensive doses. Nitrendipine inhibited endothelin-1-induced DNA synthesis in isolated vascular smooth muscle cells as well as atherosclerotic plaque formation in cholesterol-fed rats.

Influence of transplantation of parathyroid glands on blood pressure development in stroke prone spontaneously hypertensive rats and in normotensive Wistar Kyoto rats.

The influence of the parathyroid glands (PTG) on the development of high blood pressure (BP) in stroke prone spontaneously hypertensive (SHR/SP) and Wistar Kyoto (WKY) rats has been studied. After ablation of their own PTG's SHR/SP received PTG's from WKY rats and vice versa. After transplantation (TRPL) a normal calcium and parathyroid hormone (PTH) status was preserved during the whole observation period. One group of animals received a high salt diet (8% NaCl) for 4 weeks after transplantation, the other group received a normal rat chow for 3 months. In SHR/SP, which had PTG-transplants from WKY rats, the development of BP was clearly attenuated compared to sham operated rats in both experimental groups. WKY rats with PTG's from SHR/SP became hypertensive after two weeks during salt loading and after six weeks under normal diet. Sham operated WKY rats remained normotensive. The results demonstrate that the parathyroid gland is involved in the pathogenesis of hypertension, but the only known secretory product of PTG's parathyroid hormone, seems not to be responsible for these effects.

125I-endothelin-1 and 125I-big endothelin-1 in rat tissues: autoradiographic localization and receptor binding.

The potent vasoconstrictor peptide, endothelin-1 (ET-1), which exhibits a characteristically long-acting activity in vitro and in vivo, is thought to be generated in endothelial cells from a less active intermediate, big endothelin-1 (big ET-1). In addition to ET-1, big ET-1 is also present in the circulation. The autoradiographic localization of 125I-big ET-1 and 125I-ET-1 has been studied after intravenous administration in rat tissues. Highest enrichment of radioactivity was found in the kidney cortex for both peptides. Compared to blood levels, enrichment of radioactivity is also detected, in the vascular wall of the aorta. Comparing the radioactivity pattern of ET-1 and big ET-1, a nearly identical tissue distribution is observed, with the exception of the relative enrichment in the lung and the zona glomerulosa after administration of ET-1. Both radioligands show a specific and saturable binding to lung and kidney membranes. In the case of lung tissue, Ki values are 10(-10) M for endothelin-1 and 10(-8) M for big endothelin-1. This difference in affinities may account for the lack of binding of big endothelin-1 to lung tissue.

Development of hypertension in WKY rats after transplantation of parathyroid glands from SHR/SP.

We have investigated the role of the parathyroid gland (PTG) in the long-term development of blood pressure (BP) in stroke prone spontaneously hypertensive rats (SHR/SP) and Wistar Kyoto (WKY) rats. After ablation of their own PTGs, SHR/SP animals received PTGs from WKY rats and vice versa. Transplantation resulted in a normal calcium and parathyroid hormone status without signs of hypoparathyroidism. All animals received a high salt diet (8% NaCl) for 4 weeks after transplantation of PTGs. In SHR/SP, which received PTGs from WKY, development of high BP was clearly attenuated when compared to sham-operated SHR/SP rats. WKY rats with PTGs from SHR/SP rats became hypertensive, while WKY sham-operated animals remained normotensive. PTGs from SHR/SP rats are able to induce hypertension in normotensive WKY rats.

[Suppression of the immediate pressive response to unilateral nephrectomy by atrial natriuretic peptide in the rat]. / Suppression de la réponse pressive immédiate à la néphrectomie unilatérale par le peptide natriurétique auriculaire chez le rat.

Unilateral nephrectomy (UNX) is associated with an immediate and transient increase in arterial pressure and in prompt natriuresis from the remaining kidney. The hypothesis that atrial natriuretic peptide (ANP) is involved in the acute adaptation to unilateral nephrectomy was tested in euvolemic anesthetized Sprague-Dawley rats. In a first series of experiments, an increase in circulating ir-ANP levels (from 23.5 +/- 3.6 to 66.3 +/- 12.8 fmol/ml; p less than 0.01) was found within 2 minutes following renal exclusion. In a second set of experiments, the ANP response was inhibited by performing a right atrial appendectomy, in order to eliminate the major source of ANP, or by intravenous administration of monoclonal antibodies directed against ANP. When UNX was performed in the control groups (sham atrial appendectomy and administration of non specific monoclonal antibodies), mean arterial pressure rose immediately (maximal about 12% within 4 minutes) and transiently (return to pre-UNX values within 20 minutes) after UNX. At the same time, central venous pressure, monitored in the right atrium, tended to decrease slightly. In rats pretreated by right atrial appendectomy or by monoclonal antibodies directed against ANP, arterial pressure increased to the same extent as observed in control groups; this increase however was significantly more prolonged. In control groups, urinary cGMP excretion, the biological marker of ANP, increased twofold in parallel with the natriuretic response. These two responses were blunted in right atrial appendectomized rats and in rats receiving antibodies against-ANP. These results suggest that atrial natriuretic peptide plays a major role in the immediate functional adaptation to unilateral nephrectomy by blunting the increase in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term hypotensive effect of parathyroid hormone in stroke prone spontaneously hypertensive rats.

The influence of long-term treatment with parathyroid hormone (PTH) on blood pressure (BP) development in stroke prone spontaneously hypertensive rats (SHR/SP) was investigated. Acute i.v. administration of PTH decreased BP dose dependently. Long-term treatment of SHR/SP with 300 IU PTH s.c. per day clearly attenuated the BP increase. Treatment with PTH was associated with marked hypercalcemia, increased urinary excretion of calcium and cAMP.

Role of endogenous ANP on endocrine function investigated with a monoclonal antibody.

Substantial volume expansion in conscious rats induces a strong natriuresis, cyclic GMP excretion, increase in cyclic GMP in plasma and kidney tissue, decrease in plasma renin activity and plasma aldosterone concentration. These effects are directly related to an increase in plasma levels of atrial natriuretic peptides. The renal response and the changes in plasma and kidney cyclic GMP, plasma renin activity and aldosterone could be totally blocked by simultaneous administration of monoclonal antibodies directed against ANP. From this study it seems to be clear that the rise in cyclic GMP and the inhibition of the renin-aldosterone system is not a direct effect of volume expansion but is specifically mediated by the released ANP. The great importance of ANP in acute volume expansion made us wonder about the role of ANP in chronic volume expansion and under basal conditions without volume loading. Chronic volume loading was induced pharmacologically by the sodium retaining vasodilatator minoxidil. Under both chronic volume expansion and basal conditions the neutralization of the circulation ANP by antibody administration leads to reduced plasma cyclic GMP levels. No alterations in urinary sodium excretion, plasma renin activity and plasma aldosterone concentration could be observed: In conclusion, the monoclonal antibody directed against ANP is a useful tool for the investigation of the physiological role of endogenous ANP.

Vasodilatory action of endogenous atrial natriuretic factor in a rat model of chronic heart failure as determined by monoclonal ANF antibody.

Elucidation of the role of (elevated) endogenous atrial natriuretic factor (ANF) in chronic heart failure has been hampered by a lack of specific inhibitors. We used a newly developed monoclonal antibody that has been shown to specifically block both exogenously and endogenously released ANF in vivo. For assessment of the vasodilatory action of ANF in chronic heart failure, either this antibody against ANF or ascites (control serum) was injected in rats with myocardial infarction and failure and in sham animals. Ascites did not alter central hemodynamics in either the sham or infarcted group. Antibody significantly increased right atrial pressure, left ventricular end-diastolic pressure, and systemic vascular resistance (SVR) in the infarction group but did not affect these variables in the sham group. Because renal blood flow, as measured by radioactive microspheres, decreased significantly in all four groups, probably due to nonspecific renal vasoconstrictor effects of the ascites, a separate group of infarcted animals was treated with purified ANF antibody (devoid of nonspecific effects) or mouse IgG as a control injection. In these animals, right atrial pressure increased from 1.1 +/- 0.7 to 2.6 +/- 0.7 mm Hg (p less than 0.001). Although SVR, renal blood flow velocity (measured by Doppler probe), and renal vascular resistance did not change in the infarcted animals after administration of purified ANF antibody, a significant correlation was found between baseline plasma ANF values and the change in SVR exerted by purified ANF antibody (r = 0.758, p less than 0.02, n = 9); that is, SVR increased in rats with high baseline plasma ANF (greater than 350 pg/ml), but decreased in animals with plasma ANF less than 200 pg/ml. These results suggest that moderately elevated endogenous plasma ANF levels in chronic heart failure do affect central hemodynamics, primarily by reducing venous pressure (e.g., by decreasing intravascular volume or by venous dilation). Arterial vasodilation, however, appears to emerge when plasma ANF is greatly increased.

Endothelin receptors in cultured renal epithelial cells.

We demonstrated the presence of specific binding sites for endothelin in the renal epithelial cell lines. MDCK and LLC-PK1. Endothelin binding induced mobilisation of intracellular calcium, as shown by an increase in 45Ca2+ efflux. This suggests a direct effect of endothelin on renal reabsorption in addition to the effects on the renal vasculature.

Mitogenic activity of endothelin-1 and -3 on vascular smooth muscle cells is inhibited by atrial natriuretic peptides.

The effect of endothelin-1 (ET-1) and endothelin-3 (ET-3) on the proliferation of aortic vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) was assessed by the measurement of (3H)-thymidine incorporation into DNA. ET-1 and ET-3 stimulated the DNA synthesis in a dose-dependent manner. ET-3 was less potent than ET-1 in its stimulatory activity. The increase in (3H)-thymidine incorporation is clearly attenuated by Atriopeptin III (ANP 5-28). Atriopeptin I (ANP 5-25), a ANP fragment with the reduced biological activity compared to ANP 5-28, has no effect on the endothelin mediated stimulation of DNA-synthesis.

Effects of nisoldipine on atrial natriuretic peptides, blood pressure and cardiac hypertrophy in Dahl rats.

The role of the calcium antagonist nisoldipine and the arteriolar vasodilator minoxidil on plasma levels of atrial natriuretic peptides (ANP), systolic blood pressure and heart weight was estimated in inbred Dahl salt sensitive (S) rats and inbred Dahl resistant (R) rats in long-term experiments. S rats develop quickly malignant hypertension, cardiac hypertrophy and have increased ANP plasma levels when fed a high salt diet (8% NaCl), while R rats on a high salt stay normotensive. In S rats 5 weeks on a high salt diet, therapeutic treatment with nisoldipine for 5 weeks not only decreased blood pressure but also produced a regression in cardiac hypertrophy and a reduction in elevated ANP plasma levels in comparison to the untreated salt-loaded S controls. Similar results were achieved in a preventive trial. In contrast with nisoldipine, therapeutic treatment with minoxidil in salt-loaded S rats lead to no reduction in cardiac hypertrophy and produced an additional increase in plasma ANP despite a reduction in blood pressure. The increase in plasma ANP level in this model of hypertension and its modulation by antihypertensive treatment with a calcium antagonist or an arteriolar vasodilator show that the changes in ANP plasma levels are probably secondary to hypertensive disease and the associated cardiac volume overload.

Influence of calcium antagonists on renal function and secondary hyperparathyroidism in acute renal failure in rats.

Glycerol-induced acute renal failure (ARF) is characterized by an increase in serum creatinine, urea, and phosphate concentration, and severe impairment of creatinine clearance. Secondary hyperparathyroidism develops rapidly during ARF. The calcium antagonist nisoldipine clearly improves renal function, which becomes evident by an improvement of creatinine clearance and attenuation of the increase of serum creatinine, urea, and phosphate concentrations. Further secondary hyperparathyroidism is ameliorated by nisoldipine treatment. In spite of normalization of the hypocalcemia in ARF by nisoldipine, weak hyperparathyroidism persists, suggesting that hypocalcemia is not exclusively responsible for elevated parathyroid hormone serum levels in ARF.