Effect of radiation monitoring method and formula differences on estimated physician dose during percutaneous coronary intervention.

BACKGROUND: Currently, one or two dosimeters are used to monitor radiation exposure in most cardiac laboratories. In addition, several different formulas are used to convert exposure data into an effective dose (ED). PURPOSE: To clarify the effect of monitoring methods and formula selection on the estimated ED for physicians during percutaneous coronary interventions (PCIs). MATERIAL AND METHODS: The ED of physicians during cardiac catheterization was determined using an optically stimulated luminescence dosimeter (Luxel badge). Two Luxel badges were worn: one beneath a personal lead apron (0.35-mm lead equivalent) at the chest and one outside of the apron at the neck. RESULTS: The difference in the average ED of seven physicians was approximately fivefold (range 1.13-5.43 mSv/year) using the six different formulas in the clinical evaluation. The estimated physician ED differed markedly according to both the monitoring method and formula selected. CONCLUSION: ED estimation is dependent on both the monitoring method and the formula used. Therefore, it is important that comparisons among laboratories are based on the same monitoring method and same formula for calculating the ED.

Influence of the target vessel on the location and area of maximum skin dose during percutaneous coronary intervention.

BACKGROUND: A number of cases involving radiation-associated patient skin injury attributable to percutaneous coronary intervention (PCI) have been reported. Knowledge of the location and area of the patient's maximum skin dose (MSD) in PCI is necessary to reduce the risk of skin injury. PURPOSE: To determine the location and area of the MSD in PCI, and separately analyze the effects of different target vessels. MATERIAL AND METHODS: 197 consecutive PCI procedures were studied, and the location and area of the MSD were calculated by a skin-dose mapping software program: Caregraph. The target vessels of the PCI procedures were divided into four groups based on the American Heart Association (AHA) classification. RESULTS: The sites of the MSD for AHA #1-3, AHA #4, and AHA #11-15 were located mainly on the right back skin, the lower right or center back skin, and the upper back skin areas, respectively, whereas the MSD sites for the AHA #5-10 PCI were widely spread. The MSD area for the AHA #4 PCI was larger than that for the AHA #11-15 PCI (P<0.0001). CONCLUSION: Although the radiation associated with PCI can be widely spread and variable, we observed a tendency regarding the location and area of the MSD when we separately analyzed the data for different target vessels. We recommend the use of a smaller radiation field size and the elimination of overlapping fields during PCI.

Endothelin-1 augments pressor response to angiotensin II infusion in rats.

To assess possible roles of endothelin in the regulation of blood pressure, we studied effects of a subpressor dose of endothelin-1 (3 micrograms/kg/day) on chronic blood pressure responses to infusion of angiotensin II and norepinephrine in rats. Rats were infused with angiotensin II at a subpressor dose (400 micrograms/kg/day i.p.) or with norepinephrine at a subpressor dose (360 micrograms/kg/day i.p.) for 6 days. Systolic blood pressure was significantly elevated during combined infusion of endothelin-1 and angiotensin II, whereas endothelin-1 alone or angiotensin II alone failed to induce any significant changes in systolic blood pressure compared with vehicle alone. This effect was sustained for the whole experimental period and was not associated with any significant changes in body weight, fluid intake, urine volume, or urinary electrolyte excretion. In contrast, combined infusion of endothelin-1 and norepinephrine failed to elevate systolic blood pressure, and no significant difference in systolic blood pressure was observed for the whole experimental period among the four groups of rats with endothelin-1 in combination with norepinephrine, endothelin-1 alone, norepinephrine alone, and vehicle alone. The present results indicate that angiotensin II and endothelin-1, but not norepinephrine and endothelin-1, work synergistically to raise the blood pressure and also suggest the possibility that endothelin-1 may modulate blood pressure control.

Role of thromboxane A2 in the hypotensive effect of captopril in essential hypertension.

We have previously reported that captopril stimulates thromboxane A2 synthesis in patients with essential hypertension. In the present study, the hypotensive effects of captopril and OKY-046, a selective inhibitor of thromboxane A2 synthetase, were studied in nine patients with essential hypertension to determine whether thromboxane A2 is involved in the regulation of blood pressure. A single oral dose of OKY-046 (400 mg) decreased urinary thromboxane B2 (a stable metabolite of thromboxane A2) excretion significantly (from 113 +/- 19.0 to 51.0 +/- 6.1 pg/min; p less than 0.01) and increased urinary sodium excretion significantly (from 73.0 +/- 15.3 to 113.0 +/- 14.4 microEq/min; p less than 0.01), but no change was observed in mean arterial pressure. The administration of OKY-046 (600 mg/day) for 3 days induced a significant and sustained decrease in urinary thromboxane B2 excretion, but it did not affect the mean arterial pressure. Although captopril (50 mg) alone induced a significant increase in urinary thromboxane B2 excretion (from 91.4 +/- 11.0 to 297.3 +/- 30.8 pg/min; p less than 0.001) and a significant decrease in mean arterial pressure (from 97.0 +/- 4.7 to 88.1 +/- 5.1 mm Hg; p less than 0.01), captopril in combination with OKY-046 induced a decrease both in urinary thromboxane B2 excretion (from 70.8 +/- 12.3 to 54.2 +/- 14.7 pg/min; p less than 0.01) and in mean arterial pressure (from 105.1 +/- 3.8 to 84.2 +/- 3.6 mm Hg; p less than 0.01). Thus, the hypotensive effect of captopril was potentiated by OKY-046. OKY-046 did not affect the changes in plasma renin activity and plasma aldosterone concentration and blunted urinary prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion in response to captopril. These results indicate that thromboxane A2 counteracts the hypotensive effect of captopril in patients with essential hypertension.

Effect of atrial natriuretic factor on angiotensin II-induced hypertension in rats.

To assess the physiological role of atrial natriuretic factors in blood pressure regulation, we studied the effect of chronic infusion of a synthetic atrial natriuretic factor of 25 amino acid residues (Arg 102-Tyr 126) in rats with angiotensin II-induced hypertension. Rats were studied while on a normal sodium diet or during sodium loading with 1% NaCl solution used as drinking water. Systolic blood pressure decreased slightly during combined infusion of synthetic atrial natriuretic factor, 150 micrograms/kg/day, and angiotensin II, 900 micrograms/kg/day. This effect was sustained for 3 days in rats receiving a regular sodium intake (p less than 0.01) and during sodium loading (p less than 0.01). Administration of synthetic atrial natriuretic factor to rats made hypertensive by a 3-day infusion of angiotensin II reduced blood pressure slightly, but not to control levels, and this effect was sustained for the remaining 3 days of the experiment in both dietary groups. These results indicate that a nonhypotensive dose of synthetic atrial natriuretic factor can modulate the vasopressor effect of angiotensin II. Thus, the attenuating effect may be involved in blood pressure regulation independently of sodium metabolism, although its actual physiological importance remains undetermined.

Atrial natriuretic factor and cyclic guanosine 3',5'-monophosphate in vascular smooth muscle.

To elucidate the molecular mechanism of the vascular action of atrial natriuretic factor (ANF), we investigated the effects of synthetic ANF and sodium nitroprusside on the levels of intracellular cyclic nucleotides and prostacyclin (measured as its stable metabolite 6-keto-prostaglandin F1 alpha) in cultured vascular smooth muscle cells from rat mesenteric artery and, in some experiments, from rat renal artery. Both ANF and sodium nitroprusside increased intracellular cyclic guanosine 3',5'-monophosphate (cGMP) levels in a dose-dependent manner but did not affect cyclic adenosine 3',5'-monophosphate levels or 6-keto-prostaglandin F1 alpha synthesis. The stimulatory effect of ANF and sodium nitroprusside on cGMP levels were additive. Neither the deprivation of extracellular Ca2+ nor calcium entry blockers affected ANF-stimulated cGMP levels. Preincubation of ANF or sodium nitroprusside with kallikrein attenuated only the effect of ANF on cGMP levels. The effect of kallikrein was abolished by serine protease inhibitors. In contrast, the oxidant methylene blue inhibited the effect of sodium nitroprusside on cGMP levels, but not that of ANF. The stimulatory effect of ANF on cGMP levels was greater in cells from renal artery than in those from mesenteric artery. These results in cultured vascular smooth muscle cells further support the hypothesis that cGMP mediates the vasorelaxant action of ANF.

Interaction between atrial natriuretic peptide and the renin angiotensin aldosterone system. Endogenous antagonists.

The biologic actions of the cardiac peptide hormone atrial natriuretic peptide (ANP) of vasorelaxation, diuresis and natriuresis, suppression of aldosterone, vasopressin release, and thirst are the opposite of those of the renin angiotensin system. This close relationship is further strengthened by the complementary localization of their receptors in the brain, adrenal gland, vasculature, and kidney. In many physiologic situations including postural changes, volume expansion, water immersion, high altitude, and lower body negative pressure, the plasma levels of ANP and angiotensin II change inversely. In congestive heart failure, renin and aldosterone levels may initially be suppressed by high levels of ANP. Similarly the low renin levels associated with increasing age and with elderly hypertensive patients, may be the result of the elevation of plasma ANP that occurs with aging. ANP may thus be the endogenous antagonist of the renin angiotensin aldosterone system. These two opposing systems allow fine-tuning of volume and pressure by the body.

Effects of benidipine, a calcium antagonist, on urinary kallikrein excretion and renal impairment in experimental diabetes.

OBJECTIVE: To assess the long-term effects of different antihypertensive agents on urinary protein excretion and kallikrein excretion in diabetic rats with renal impairment. METHODS: Uninephrectomized streptozotocin diabetic Wistar-Kyoto rats were randomly assigned to receive vehicle, a calcium antagonist (benidipine) or an angiotensin converting enzyme inhibitor (captopril) for up to 12 weeks. Active kallikrein was determined by its kininogenase activity, and generated kinins were measured by radioimmunoassay. Total kallikrein was also determined by measuring kininogenase activity after inactive kallikrein had been activated with trypsin. RESULTS: Urinary protein excretion increased significantly in diabetic rats compared with non-diabetic rats. Urinary active kallikrein excretion was significantly reduced in diabetic rats, whereas urinary total kallikrein excretion was unchanged, resulting in a reduced percentage of active to total kallikrein compared with that in non-diabetic rats. Benidipine and captopril reduced blood pressure and attenuated the development of diabetic renal impairment in a similar manner. However, only benidipine attenuated the decreases in urinary active kallikrein excretion and the ratio of active to total kallikrein in diabetic rats. CONCLUSIONS: Although pathophysiological relevance of impaired urinary kallikrein activation to the development of diabetic renal impairment remains to be determined, our result might suggest a new mechanism by which calcium antagonists protect the kidney from diabetic renal impairment.

Effects of troglitazone and temocapril in spontaneously hypertensive rats with chronic renal failure.

OBJECTIVE: The insulin resistance state is common in humans and animals with chronic renal failure. We investigated the effects of troglitazone, an insulin sensitizer, on blood pressure and nephropathy in the remnant kidney model of spontaneously hypertensive rats (SHR). METHODS: Eight-week-old male SHR were subjected to five-sixth nephrectomy. At the age of 10 weeks, the rats were randomly allocated to groups that received troglitazone (70 mg/kg per day); the angiotensin converting enzyme inhibitor temocapril (10 mg/kg per day); troglitazone (70 mg/kg per day) plus temocapril (10 mg/kg per day), or a vehicle alone as an untreated control group. Systolic blood pressure (SBP) and urinary protein excretion were measured every 2 weeks. At the age of 22 weeks, biochemical measurements and histological examination were performed. RESULTS: Blood glucose, glycosylated hemoglobin and body weight were similar in the four groups. SBP, serum creatinine and glomerular sclerosis index were significantly reduced in all treated groups compared with those in the control group. Urinary protein excretion, glomerular volume and aortic media thickness were significantly decreased in temocapril-treated rats and troglitazone plus temocapril-treated rats compared with those in control rats. Although antihypertensive effects of troglitazone were minute compared with those of temocapril or troglitazone plus temocapril, there was no significant difference between the glomerular sclerosis indices in these three drug-treated groups. CONCLUSIONS: The results suggest that troglitazone has renoprotective effects in this rat model. These effects might be due to the inhibition of growth factors rather than to the minute hypotensive effect, although the mechanism remains to be elucidated.

Renal kallikrein activity in spontaneously hypertensive rats.

To assess possible roles of the renal kallikrein-kinin system in the development of spontaneous hypertension, we determined daily excretion of urinary total and active kallikrein in 6-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats for up to 2 weeks. We also evaluated the effect of aprotinin, a reversible inhibitor of kallikrein and other serine proteases, on the development of hypertension in the 6-week-old SHR on ordinary intakes of sodium or on sodium loading with 1% NaCl for up to 2 weeks. Active kallikrein was determined by its kininogenase activity, and the generated kinins were radio-immunologically measured. Total kallikrein was also determined by measuring kininogenase activity after inactive kallikrein had been activated with trypsin (200 micrograms/ml). Urinary active kallikrein excretion was significantly reduced in 7-week-old SHR (1.5 +/- 0.2 microgram/day compared to 2.8 +/- 0.3 micrograms/day in WKY, P less than 0.05) and in 8-week-old SHR (1.6 +/- 0.2 microgram/day compared to 3.2 +/- 0.4 micrograms/day in WKY, P less than 0.01). Urinary total kallikrein excretion was also reduced in the 7- and 8-week-old SHR whereas the ratio of active to total kallikrein did not change. In addition, renal contents of total and active kallikrein were significantly lower in the 8-week-old SHR than in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of angiotensin converting enzyme induction and inhibition using quantitative in vitro autoradiography: tissue selective induction after chronic lisinopril treatment.

Angiotensin converting enzyme (ACE) inhibitors lead to induction of ACE in animals and humans. This complicates the use of ACE enzymatic activity as an index of inhibition in plasma or tissues after chronic administration of ACE inhibitors. We have, therefore, developed a method for ACE measurement by in vitro autoradiography using an 125I-labelled inhibitor to quantitate total ACE and the concentration of free (not inhibited) ACE in tissues after prolonged administration of ACE inhibitors to rats. Measurements made on unprocessed tissue sections reflect residual free ACE activity in the presence of the unlabelled inhibitor. In a parallel series of adjacent sections, the ACE inhibitor is dissociated from the enzyme by reversibly denaturing the enzyme by zinc chelation. This is followed by reconstitution of the active enzyme by zinc ion replacement and measuring total enzyme concentration. This technique permits measurement of the extent of ACE inhibition and induction. This method was evaluated in tissues of rats following chronic oral administration of lisinopril (10 mg/kg per day) for 2 weeks. The pattern of ACE inhibition was similar to that seen in our previous acute studies. However, induction of ACE was found to be organ specific; plasma total ACE increased 1.75-fold and total ACE in the lung increased by 30% compared with untreated animals, but there was no demonstrable change in total ACE concentration in the kidney, adrenal or aorta. Despite this, during chronic treatment with lisinopril, ACE activity in all of these organs was inhibited with low levels of free ACE.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive and renal-protective effects of losartan in streptozotocin diabetic rats.

OBJECTIVE: To assess the renal benefits of a specific angiotensin II receptor antagonist, losartan, in diabetic rats with renal impairment. DESIGN AND METHODS: Uninephrectomized streptozotocin diabetic spontaneously hypertensive rats (SHR) were randomly assigned to receive vehicle, or to receive losartan or captopril, or both, intraperitoneally via osmotic minipumps for 8 weeks. RESULTS: Blood pressure and urinary protein excretion in the diabetic SHR increased progressively during the experimental period. Both captopril treatment and losartan treatment completely blocked the development of hypertension in diabetic SHR. Simultaneous administration of captopril and losartan did not enhance the antihypertensive effects of losartan treatment or captopril treatment. Furthermore, losartan treatment, captopril treatment and losartan + captopril treatment all significantly decreased urinary protein excretion, urinary albumin excretion and serum creatinine to the same extent. These effects were sustained for the entire experimental period and were not associated with any significant changes in body weight, urine volume, urine sugar and urinary electrolytes excretion. These results were confirmed by morphological analysis of kidneys in each group of rats. Losartan treatment, captopril treatment and losartan+captopril treatment all significantly and effectively protected against an increase in the percentage of focal glomerular sclerosis. Losartan treatment and captopril treatment both significantly attenuated the increase in heart weight: body weight ratio. The heart weight: body weight ratio in the losartan-treated group was significantly lower than in the captopril-treated group. CONCLUSIONS: These results indicate that hypertension could accelerate diabetic renal impairment and that losartan has antihypertensive and renoprotective effects in this rat model. They also suggest that the antihypertensive and renoprotective effects of captopril treatment in this rat model are caused mainly by inhibition of angiotensin II production rather than stimulation of the kallikrein-kinin system or of vasodilator prostaglandins. The difference in potency between losartan treatment and captopril treatment to attenuate the increase in heart weight: body weight ratio might partly explain the existence in the heart of angiotensin-forming pathways, which are not dependent on angiotensin converting enzyme.

Effects of sodium and angiotensin II on urinary active and inactive kallikrein in rats.

To assess possible relationships between sodium balance, angiotensin II (ANG II), and renal active and inactive kallikrein, we studied the effects of sodium loading with 1% NaCl and chronic ANG II infusion (900 micrograms/kg per day) on the urinary excretion of total and active kallikrein for 6 days in conscious rats. We determined urinary total, active and inactive kallikrein by measuring kallikrein activity using a kininogenase assay before and after treatment with trypsin (200 micrograms/ml). Sodium loading produced a sustained increase in urinary total, active and inactive kallikrein excretion. Chronic infusion of ANG II induced a sustained increase in urinary total, active and inactive kallikrein excretion in rats on a regular diet. In rats loaded with sodium, however, ANG II did not induce any further changes in urinary kallikrein excretion. Thus, the present study suggests that both sodium loading and ANG II infusion might stimulate the synthesis of renal kallikrein. In addition, it is suggested that ANG II infusion might stimulate the synthesis of kallikrein, at least partly, via the same mechanism as sodium loading does.

Effects of ouabain on blood pressure regulation in rats.

In order to test the hypothesis that a circulating inhibitor of the sodium-potassium ATPase pump may cause a concomitant rise in blood pressure and increased sodium excretion, we studied chronic effects of continuous infusion of ouabain, an inhibitor of sodium-potassium ATPase, for up to 6 days on systolic blood pressure and urinary sodium excretion in conscious rats. We also evaluated the effect of this substance in rats with hypertension induced by chronic infusion of norepinephrine. Continuous infusion of ouabain (1.2 mg/kg per day) into the jugular vein by an osmotic minipump did not induce any changes in systolic blood pressure and urinary sodium excretion in intact rats on regular diets. Furthermore it did not cause a change in systolic blood pressure in rats drinking 1% NaCl, and in unilaterally nephrectomized rats drinking 1% NaCl, when compared with vehicle-infused animals. When the same dose of ouabain was administered simultaneously with 1.8 mg/kg per day norepinephrine infused intraperitoneally by another osmotic minipump in conscious rats, systolic blood pressure rose on day 1 to only 129.3 +/- 2.8 mmHg compared with the rist to 145.0 +/- 2.0 mmHg when norepinephrine alone was infused (P less than 0.01). The antihypertensive effect of ouabain was sustained for the entire experimental period lasting for 6 days and was not associated with any changes in urinary sodium excretion. The administration of ouabain to rats made hypertensive by a 3-day infusion of norepinephrine, returned the blood pressure to control levels, and the antihypertensive effect was sustained throughout the experimental period lasting a further 3 days and was not associated with any changes in urinary sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinin and angiotensin II receptor antagonists in rats with chronic renal failure: chronic effects on cardio- and renoprotection of angiotensin converting enzyme inhibitors.

OBJECTIVE: To assess the potential of the kallikrein-kinin and renin-angiotensin systems in mediating the cardio- and renoprotective effects of angiotensin converting enzyme (ACE) inhibitors in rats with chronic renal failure. MATERIALS AND METHODS: Spontaneously hypertensive rats (SHR) and normotensive control Wistar-Kyoto (WKY) rats subjected to five-sixths nephrectomy were randomly assigned to treatment with vehicle, a kinin antagonist (Hoe 140) or an ACE inhibitor (cilazapril) or both drugs, intraperitoneally via osmotic minipumps for 4 weeks. In addition, the effects of a chronic infusion of a specific angiotensin receptor antagonist (losartan) alone or in combination with an ACE inhibitor (enalapril) were also investigated in nephrectomized SHR for 2 weeks. RESULTS: In nephrectomized SHR and WKY rats, cilazapril alone significantly reduced systolic blood pressure, urinary protein excretion, heart weight and serum creatinine. In nephrectomized SHR, Hoe 140 alone or cilazapril in combination with Hoe 140 (7 or 70 mu g/kg per day) induced no changes in these parameters, other than those associated with the effects of cilazapril alone. In nephrectomized WKY rats, cilazapril in combination with Hoe 140 (70 mu g/kg per day) slightly, but not significantly, attenuated the antihypertensive effect of cilazapril but did not affect the other parameters. These results were confirmed by morphological analysis of kidneys. All the drug regimens provided effective protection against an increase in focal glomerular sclerosis. Enalapril did not modify the antihypertensive and renoprotective effects of losartan in nephrectomized SHR. CONCLUSIONS: The present results indicate that the kallikrein-kinin system might not be a major factor in the cardio- and renoprotective effects of ACE inhibitors in rats with chronic renal failure.

Renal-protective effect of non-depressor dose of cicletanine in streptozotocin diabetic rats.

OBJECTIVE: To assess the renal benefits of cicletanine (CIC) in diabetic rats with renal impairment. METHODS: Hemi-nephrectomized streptozotocin-diabetic Wistar-Kyoto Izmo rats (WKYIzm) (10 weeks old) were randomly assigned to receive vehicle or a low or high dose of CIC (30 or 100 mg/kg per day, orally) for 12 weeks. RESULTS: The blood pressure was raised slightly but not significantly in this model. An anti-hypertensive effect of CIC was not significantly observed. However, the sub-depressor doses of CIC significantly and dose-dependently decreased urinary albumin excretion. These results were confirmed by morphological analysis of kidneys in each group of rats. CIC treatment significantly and effectively protected against an increase in the percentage of focal glomerular sclerosis. CIC did not affect urinary and blood glucose concentrations at either dose. CONCLUSIONS: These results suggest that CIC has a renal-protective action, which is not related to improvement of diabetes or of high blood pressure in this model. The action might be due to the reduction of intraglomerular capillary pressure, although the mechanism remains to be further investigated.

Renal protective effects of chronic exercise and antihypertensive therapy in hypertensive rats with chronic renal failure.

OBJECTIVES: Patients with chronic renal failure are restricted to mild physical activity and tend to a lack of exercise. However, there have been few reports regarding the influence of chronic exercise on the progression of renal disease. Similarly, there are few animal models concerned with the effect of exercise training on improving renal function. Therefore, we assessed the renal effects of moderate chronic treadmill exercise in a remnant kidney model of spontaneously hypertensive rats (SHR) with chronic renal failure. We also assessed the effects of exercise and antihypertensive therapy on renal function. DESIGN AND METHODS: Eight-week-old SHR were subjected to 5/6 nephrectomy by removal of the left kidney and excision of two-thirds of the right kidney. The rats were divided into four groups: (i) no exercise (Non-EX); (ii) moderate exercise with treadmill running (20 m/min, 0 grade incline for 60 min) (EX); (iii) EX with an angiotensin converting enzyme (ACE) inhibitor, enalapril (2 mg/kg per day, i.p.); and (iv) EX with an angiotensin receptor antagonist, losartan (5 mg/kg per day, i.p.), for 4 weeks. RESULTS: Chronic EX significantly attenuated the increase in proteinuria (P < 0.01) and significantly protected against increases in the index of glomerular sclerosis (IGS). Both enalapril and losartan with EX significantly decreased blood pressure (P < 0.001), and further decreased the IGS. In the stepwise multiple regression analysis, only antihypertensive drug remained in the model as a significant predictor of IGS (P < 0.0001). In contrast, exercise, antihypertensive drug and mean systolic blood pressure (weeks 1-4) remained in the model as a significant predictors of mean proteinuria (weeks 1-4) (all P < 0.0001). CONCLUSIONS: These results suggest that exercise does not worsen renal function and has renal-protective effects in this model of rats. Moreover, the antihypertensive therapy has additional renal-protective effects in this model of rats.

Localization and characterization of endothelin receptor binding sites in the rat brain visualized by in vitro autoradiography.

Endothelin binding sites in rat brain were mapped by quantitative in vitro autoradiography employing [125I]endothelin-1 as radioligand. [125I]Endothelin-1 bound with high affinity and specificity to rat cerebellar sections and was potently displaced by unlabelled endothelins (endothelin-1 greater than endothelin-2 = endothelin-3) and sarafotoxin 6B. The highest densities of endothelin binding sites were found in the cerebellum (especially Purkinje cell layer), choroid plexus and median eminence. High densities were found in the supraoptic and paraventricular hypothalamic nuclei, anterior hypothalamic area, ventromedial hypothalamic nucleus, mammillary nuclei and glomerular layer of olfactory bulb. Moderate densities were found in many thalamic nuclei, the pretectal region, interpeduncular nucleus, suprachiasmatic nucleus, raphe nuclei, tegmental nuclei, olfactory ventricle, red nucleus, subthalamic nucleus, central gray, reticular nuclei, vestibular nuclei, oculomotor and trochlear nuclei, hypoglossal nucleus, motor trigeminal nucleus, nucleus of the trapezoid body and lateral cerebellar nucleus. Low but detectable densities of endothelin binding sites were found in medial geniculate nucleus, fields of Ammon's horn, caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra, anterior commissure, internal capsule, anterior pituitary, median preoptic nucleus, septohypothalamic nucleus, superior colliculus and area postrema. These patterns were completely abolished by 1 microM unlabelled endothelin-1, -2 and -3 and sarafotoxin S6B. Brain endothelin binding sites show high affinity for endothelin-1, -2 and -3 and sarafotoxin 6B with highest affinity for endothelin-1. Endothelin binding sites show a non-vascular pattern of distribution in the brain, suggesting that the peptide may have widespread functions as a modulator of neuronal function.

Renal-protective effect of nondepressor dose of cicletanine in diabetic rats with hypertension.

We assessed the renal and cardiac benefits of cicletanine (CIC), a furopyridine derivative drug with diuretic and antihypertensive properties, in diabetic spontaneously hypertensive rats with renal impairment. Uninephrectomized streptozotocin (STZ)-diabetic spontaneously hypertensive Izmo rats (SHRIzm) (10 weeks old) were randomly assigned to receive vehicle or CIC (100 mg/kg/day, orally), and age-matched, uninephrectomized STZ diabetic Wistar-Kyoto Izmo rats (WKYIzm) were assigned to receive vehicle for up to 12 weeks. Blood pressure increased progressively in diabetic SHRIzm but not in diabetic WKYIzm. Urinary albumin excretion increased significantly in both diabetic SHRIzm and diabetic WKYIzm throughout the experiment. The antihypertensive effect of CIC was not significantly observed in diabetic SHRIzm. However, the subdepressor doses of CIC significantly decreased urinary albumin excretion, serum creatinine, and blood urea nitrogen in diabetic SHRIzm. These results were confirmed by morphological analysis of kidneys in each group of rats. The index of focal glomerular sclerosis (FGS) in diabetic SHRIzm was significantly higher than that in diabetic WKYIzm. The CIC treatment significantly and effectively protected against an increase in the index of FGS in diabetic SHRIzm. Moreover, CIC treatment significantly attenuated the increase in the heart weight to body weight ratio in diabetic SHRIzm. Treatment with CIC did not affect urinary and blood glucose concentrations at this dose. These results suggest that CIC has a renal-protective action, which is not related to improvement of diabetes or improvement of high blood pressure in diabetic rats with hypertension. The action might be due to the reduction of intraglomerular capillary pressure or protection of the renal glomerular vascular endothelial cell injury and mesangial cell injury through stimulation of PGI2 generation or elimination of free radicals, although the mechanism remains to be further investigated.

Chronic effects of synthetic endothelin on blood pressure and sodium excretion in rats.

Continuous infusion of endothelin at a rate of 60 micrograms/kg/day into the jugular vein of rats via osmotic minipumps induced a significant increase in systolic blood pressure, but did not induce any significant changes in urine volume and urinary sodium excretion, compared to those in vehicle-infused rats. When 6 mg/kg/day of benidipine, a newly developed calcium channel blocker, was administered simultaneously with 60 micrograms/kg/day of endothelin, the systolic blood pressure of conscious rats rose on Day 1 to only 137.0 +/- 2.4 mm Hg (P less than .05) compared to the rise to 163.8 +/- 4.7 mm Hg when endothelin alone was infused. The antihypertensive effect of benidipine was sustained. The present results suggest that endothelin can act as a circulating hormone. In addition, they clearly demonstrate that the calcium channel blocker attenuates the elevation of blood pressure induced by endothelin.