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PubMed1982

High uric acid and urea clearance in cirrhosis secondary to increased "effective vascular volume".

Since urea and uric acid clearance are affected by the effective intravascular volume, we measured the fractional urea and uric acid excretion in cirrhosis. High urea and uric acid clearances were observed in 30 and 55 percent, respectively, of 20 consecutive cirrhotic patients with normal renal function. In seven patients with a high fractional uric acid excretion, 5 mg of isosorbide dinitrate every four hours for 24 hours induced a significant increase in the serum uric acid level (from 3.7 +/- 0.8 mg/dl to 4.4 +/- 0.8 mg/dl; less than 0.001) with a concomitant decrease in the fractional uric acid excretion (from 14.0 +/- 3.2 percent to 8.8 +/- 3.1 percent; less than 0.02). During the same test, the blood urea level increased from 3.3 +/- 1.1 mmol/liter to 4.1 +/- 1.2 mmol/liter (p less than 0.005) with a decrease in fractional excretion from 51 +/- 4.5 percent to 39 +/- 5 percent (p less than 0.001). The oral intake of sulfinpyrazone in six of these patients induced a normal uricosuric response. In two cirrhotic patients with ascites, 40 mg of furosemide associated with a 24-hour severe water restriction was also shown to normalize the high fractional excretion of both urea and uric acid. In nine patients with ascites, we observed a significant increase in blood urea and uric acid concentration despite the absence of change in creatinine clearance once ascites was removed by diuretics. On the basis of these findings, we believe that the high fractional excretion of both urea and uric acid frequently observed in cirrhosis is related to an increase in the effective vascular volume.

Blood Volume↗

PubMed1999

Neurogenic regulation of basal tone of coronary artery with mild atherosclerosis in humans: observation using two-dimensional intravascular ultrasound.

The purpose of this study was to assess the role of the autonomic nervous system in the regulation of basal coronary artery tone in normal and atherosclerotic plaque segments by using intravascular ultrasound in humans. In each of 21 patients, a short-axis image at one site of coronary artery was imaged by means of a 3.2F, 30-MHz intravascular ultrasound before and after intracoronary administration of 2 mg isosorbide dinitrate (ISDN). The authors identified the perimeters of the vessel wall segments with normal or atherosclerotic plaque on ultrasound images and evaluated the basal tone in each segment as a percent increase in each perimeter produced by ISDN. Using heart rate variability analysis for 512 seconds recorded immediately before ISDN administration, they evaluated cardiac sympathetic and vagal activities at rest as the integrated power of fast Fourier transform (FFT) spectrum for the low-frequency (LF: 0.04 to 0.15 Hz), and high-frequency (HF: 0.15 to 0.4 Hz) components, respectively. Of 29 segments examined by ultrasound, 16 were normal and 13 were atherosclerotic plaque. In all 29 segments, ISDN produced an increase in the perimeter of the vessel wall. At the normal 16 segments, the increase in perimeter by ISDN exhibited a significant correlation to the power of HF (r = 0.749, p = 0.0008) but no significant correlation to LF. At 13 plaque segments, however, no significant correlation between the response to ISDN and autonomic nerve activity was observed. In conclusion, the basal tone of normal coronary arterial wall segment is closely related to parasympathetic nerve, whereas the relation is impaired in mild atherosclerotic segments.

Aged↗

PubMed1991

[Effects of antianginal drugs on left ventricular diastolic filling in patients with ischemic heart disease].

To study the acute effects of isosorbide dinitrate (ISDN), nifedipine, propranolol and placebo on left ventricular diastolic filling in patients with myocardial ischemia, we repetitively performed exercise radionuclide angiography (RNA) following random assignment of each drug in 12 patients with effort angina pectoris, and 5 normal controls. Left ventricular time activity curves were constructed using computer technique. We obtained changes of hemodynamic parameters such as endodiastolic volume, systemic vascular resistance and ejection fraction. The peak filling rate (PFR), and filling rate in the first third of the diastolic period (1/3 FR) were used as the indexes of LV diastolic filling. 1/3 FR remained unchanged during peak exercise by the patients, while it increased significantly in normal controls. After administration of ISDN and nifedipine, 1/3 FR increased significantly during peak exercise by the patients. Especially after nifedipine, 1/3 FR improved significantly compared with the improvement after ISDN, although these two drugs had the same effects on systolic function. These findings showed that 1/3 FR was reliable as an indicator of LV diastolic filling in ischemic heart disease, and nifedipine improved LV diastolic filling not only by improving ischemic changes in myocardium but also by it's direct effect on left ventricular relaxation.

Aged↗

PubMed2006

Comparison of the prognostic value of SPECT after nitrate administration and metabolic imaging by PET in patients with ischaemic left ventricular dysfunction.

PURPOSE: We compared the prognostic value of 99mTc-tetrofosmin single-photon emission computed tomography (SPECT) after nitrate administration and positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) in patients with ischaemic left ventricular (LV) dysfunction. METHODS: Eighty-nine patients with previous myocardial infarction and LV dysfunction (LV ejection fraction 33 +/- 10%) underwent 99mTc-tetrofosmin SPECT under control conditions (baseline) and after sublingual administration of 10 mg of isosorbide dinitrate (nitrate). Within 1 week, all patients underwent PET imaging with 18F-FDG. Four patients were excluded because of inadequate FDG uptake caused by severe diabetes. Follow-up data were obtained by phone contact with patients and by review of hospital or physicians' records. Cardiac death, myocardial infarction and late revascularisation for unstable angina were considered as events. Follow-up data were not available in three patients. Follow-up was 96% complete at a mean period of 29 +/- 19 months. RESULTS: At baseline SPECT, 59 (72%) patients had evidence of viable myocardium, while 23 did not. Of these latter patients, 12 (52%) demonstrated viable myocardium after nitrate and 13 (56%) had preserved metabolic activity. Cardiac events (cardiac death, myocardial infarction and late revascularisation for unstable angina) occurred in 24 (29%) patients. Event-free survival was similar in patients with and patients without viable myocardium at baseline SPECT (p = 0.8). In contrast, event-free survival was lower in patients with viable myocardium at nitrate SPECT and PET compared to those without viable myocardium (both p<0.05). CONCLUSION: In patients with ischaemic LV dysfunction, the prognostic value of SPECT imaging after nitrate is comparable to that of PET metabolic imaging.

Female↗

PubMed1991

Influence of balloon size and stenosis morphology on immediate and delayed elastic recoil after percutaneous transluminal coronary angioplasty.

After successful coronary angioplasty, the minimal luminal diameter of the dilated coronary artery segment is generally smaller than the diameter of the largest balloon catheter at the maximal inflation pressure. The determinants of this phenomenon were studied in 28 patients. Biplane angiograms were obtained after intracoronary administration of isosorbide dinitrate (1 mg) before, immediately and 24 h after coronary angioplasty. Balloon and coronary luminal diameters were measured by automated contour detection. Immediately after the procedure, the difference between inflated balloon diameter and minimal luminal diameter averaged 0.93 +/- 0.43 mm for the entire group and was greater both in eccentric stenoses (1.13 +/- 0.39 vs. 0.70 +/- 0.36 mm; p less than 0.01) and after angioplasty with an oversized balloon (1.20 +/- 0.37 vs. 0.71 +/- 0.33 mm; p less than 0.005). At 24 h, the balloon - minimal luminal diameter difference was unchanged at the group level (0.86 +/- 0.38 mm, but the minimal luminal diameter increased significantly in the subgroup of coronary segments dilated with an oversized balloon (1.97 +/- 0.37 vs. 1.81 +/- 0.28 mm; p less than 0.05). Thus, the difference between the minimal diameter of a dilated coronary segment immediately after a successful coronary balloon angioplasty procedure and the maximal diameter of the inflated balloon catheter is dependent both on eccentricity of the stenosis and on the balloon/artery diameter ratio. Moreover, the increase in minimal luminal diameter 24 h after angioplasty performed with an oversized balloon suggest that in addition to elastic recoil partly reversible factors related to vessel barotrauma are involved.

Angioplasty, Balloon, Coronary↗

PubMed1986

Dose-dependent effects of isosorbide-5-mononitrate on the venous, arterial and coronary arterial system of conscious dogs.

Isosorbide-5-mononitrate (IS-5-MN), the main metabolite of isosorbide dinitrate shows antianginal efficacy and is being used increasingly as a drug for practical therapy. In conscious dogs we therefore measured the effects of increasing doses of IS-5-MN on hemodynamic parameters and the diameter of the circumflex artery. We found a dose dependent reduction of the mean right atrial pressure, the systolic blood pressure and a dilatation of the circumflex artery. For all three parameters threshold dosages were between 0.01 and 0.03 mg/kg. On the contrary peripheral and coronary resistance did not change at doses less than or equal to 0.3 mg/kg. The heart rate was significantly increased only at doses above 1 mg/kg and the diastolic blood pressure also showed a tendency to fall only at doses above 1 mg/kg. Cardiac output and coronary flow were not significantly altered over the entire dose range investigated, with the exception of a transient rise in coronary blood flow after the injection of 2.5 mg/kg IS-5-MN. From our results we can deduce that in the low dose range reduction of preload and dilatation of large arteries are the main effects of IS-5-MN. In contrast, no reduction of the coronary or peripheral resistance is to be expected.

Animals↗

PubMed2000

Isosorbide-2-mononitrate reduces the consequences of myocardial ischaemia, including arrhythmia severity: implications for preconditioning.

The effects of the intracoronary administration of isosorbide-2-mononitrate (ISMN; 3 microg kg(-1) min(-1)), a major metabolite of isosorbide dinitrate, were examined in chloralose-urethane anaesthetized dogs before and during a 25 min, acute occlusion of the left anterior descending coronary artery. The only significant haemodynamic effects of ISMN administration were a slight (-11 +/- 2 mmHg) decrease in arterial blood pressure and a decrease (< 12%) in diastolic coronary vascular resistance. Coronary occlusion in the presence of ISMN led to a markedly reduced incidence and severity of ventricular arrhythmias compared to those in control, saline-infused dogs. There were fewer ectopic beats (62 +/- 35 versus 202 +/- 72; p < 0.05), a lower incidence (25% versus 75%; p < 0.05) and number of episodes (0.7 +/- 0.4 versus 4.3 +/- 2.1; p < 0.05) of ventricular tachycardia and fewer dogs fibrillated during the ischaemic period (17% versus 82%; p < 0.05). More dogs given ISMN survived the combined ischaemia-reperfusion insult (50% versus 0%; p < 0.05). Changes in ST-segment elevation (recorded by epicardial electrodes) and in the degree of inhomogeneity of electrical activation within the ischaemic area were much less pronounced throughout the occlusion period in dogs given ISMN. These results add weight to the hypothesis that the previously reported antiarrhythmic effects of ischaemic preconditioning, and of the intracoronary administration of nicorandil, involve nitric oxide.

Animals↗

PubMed2003

Does nitric oxide mediate the vasodilator activity of nitroglycerin?

Nitroglycerin (glyceryl trinitrate, GTN) relaxes blood vessels primarily via activation of the soluble guanylyl cyclase (sGC)/cGMP/cGMP-dependent protein kinase (cGK-I) pathway. Although the precise mechanism of sGC activation by GTN in the vascular wall is unknown, the mediatory role of nitric oxide (NO) has been postulated. We tested the GTN/NO hypothesis in different types of isolated rat and rabbit blood vessels using two novel approaches: (1) EPR spin trapping using colloid Fe(DETC)2 and (2) analysis of cGK-I-dependent phosphorylation of the vasodilator-stimulated phosphoprotein at Ser239 (P-VASP). For comparison, another organic nitrate, isosorbide dinitrate (ISDN), and endothelium-dependent vasodilator, calcium ionophore A23187, were tested. We found a marked discrepancy between GTN's strong vasoactivity (vasodilation and augmentation of P-VASP) and its poor NO donor properties. In aortas precontracted with phenylephrine, GTN, ISDN, and A23187 induced nearly full relaxations (>80%) and doubling of vascular P-VASP content at concentrations of 100 nmol/L, 100 micromol/L, and 1 micromol/L, respectively. GTN applied in vasorelaxant concentrations (10 to 1000 nmol/L) did not significantly increase the basal vascular NO production, in contrast to ISDN and A23187. The absence of GTN-derived NO was confirmed in rabbit vena cava and renal artery. A significant increase in vascular NO formation was observed only at suprapharmacological GTN concentrations (>10 micromol/L). The concentration dependency of NO formation from GTN was comparable to that of ISDN, although the latter exhibits 100-folds lower vasorelaxant potency. We conclude that GTN activates the sGC/cGMP/cGK-I pathway and induces vasorelaxation without intermediacy of the free radical NO. The full text of this article is available online at http://www.circresaha.org.

Animals↗

PubMed1984

Pharmacokinetic aspects of isosorbide-5-mononitrate in dogs.

The aim of this study was to determine pharmacokinetic data of isosorbide-5-mononitrate (IS-5-MN) in dogs and to correlate them with the hemodynamic effects of this drug. Beagle dogs (n = 7) were given 3 mg/kg of IS-5-MN, the main metabolite of isosorbide-dinitrate, by i.v. injection and oral administration. At defined times blood samples were withdrawn from the vena cava caudalis for assaying IS-5-MN. In the experiments with oral administration the decrease in systolic blood pressure was monitored as a measure of hemodynamic response. The pharmacokinetic parameters were calculated from the plasma concentrations on the basis of an open two-compartment model. The half-life for the distribution phase was about 6 min, for the elimination phase about 1.5 hr. The latter is about one-third of that obtained in man. From the comparison of the areas under the curve, a bioavailability of 71.5% was estimated. In a second series of investigation dogs were given five different doses of IS-5-MN orally (3.125-50 mg/dog). These experiments showed a rise in the peak plasma concentration and the area under the curve proportional to the dose, whereas the terminal half-life did not differ markedly. A close correlation has been found in both series of investigations between the log concentration and the decrease in blood pressure. The minimum plasma concentration for a hemodynamic effect was estimated to be 100 ng/ml.

Administration, Oral↗

PubMedDate not supplied

Tc-99m tetrofosmin tomography after nitrate administration in patients with ischemic left ventricular dysfunction: relation to metabolic imaging by PET.

BACKGROUND: In patients with ischemic left ventricular (LV) dysfunction, myocardial perfusion imaging after nitrate administration may improve the identification of dysfunctional but viable myocardium. This study was designed to assess the relationship between tetrofosmin uptake after nitrate administration and metabolic activity as assessed by positron emission tomography (PET) in patients with ischemic LV dysfunction. METHODS AND RESULTS: Thirty-six patients with chronic myocardial infarction and LV dysfunction (ejection fraction, 35% +/- 6%) underwent resting technetium 99m tetrofosmin single photon emission computed tomography (SPECT) imaging under control conditions (baseline) and after sublingual administration of 10 mg isosorbide dinitrate. Within 1 week, all patients underwent metabolic PET imaging with fluorine 18-fluorodeoxyglucose. Tetrofosmin uptake and metabolic activity were measured in 13 segments/patient. Regional LV function was assessed in corresponding segments by echocardiography. On baseline tetrofosmin imaging, 53 (40%) of the 131 akinetic or dyskinetic segments had reduced (<55% of peak activity) tracer uptake. Of these segments, 14 (26%) showed enhanced tetrofosmin uptake after nitrate administration (>/=10% vs baseline) and the remaining 38 (74%) did not change. The sensitivity and specificity of baseline tetrofosmin SPECT for detecting preserved metabolic activity were 69% and 86%, respectively. After nitrate administration, the sensitivity was higher (81%, P <.05 vs baseline) whereas the specificity was not different (86%, P = not significant). Concordance between tetrofosmin SPECT and PET in differentiating viable and necrotic myocardium was observed in 94 (72%) of the 131 akinetic or dyskinetic segments at baseline (kappa = 0.35) and in 108 segments (82%) after nitrate administration (kappa = 0.53). CONCLUSIONS: After nitrate administration, tetrofosmin uptake in dysfunctional segments correlated with metabolic activity as assessed by fluorodeoxyglucose PET imaging better than baseline. Thus tetrofosmin SPECT after nitrate administration may improve the identification of ischemic but still viable myocardium in patients with chronic ischemic LV dysfunction.

Adult↗

PubMed1984

Effects of intraaortic balloon pumping on acute myocardial infarction in 64 cases of cardiogenic shock, severe heart failure and mechanical heart failure.

Of the patients treated in the CCU of Nippon Medical School for acute myocardial infarction in the past 5 years and 8 months, 44 with cardiogenic shock, 11 with severe heart failure, 7 with ventricular septal perforation and 2 with mitral regurgitation were treated by IABP. The peak effect of IABP on the hemodynamics of patients with cardiogenic shock was noted 24 hours after starting on IABP. When hemodynamics were compared between surviving and dead groups, there was a significant difference in stroke volume index between the two groups. When left ventricular function was compared between them, it was suggested that patients whose left ventricular function does not respond to IABP for 48 hours or longer are more likely to die than responders. Twenty-four of 44 patients became independent of IABP, but no more than 13 patients (30%) survived for 6 months or longer. Isosorbide dinitrate (ISDN) was combined with IABP in 7 patients who had a persistence of heart failure in spite of IABP. Combination therapy with IABP and ISDN elicited a significant increase in cardiac index, a significant decrease in pulmonary capillary wedge pressure, mean pulmonary arterial pressure and total peripheral resistance and a pronounced improvement in left ventricular function, and all 7 patients became independent of IABP. In the patients with acute myocardial infarction complicated with ventricular septal perforation, the mean systolic arterial pressure was 87.7 +/- 8.3 mmHg, mean pulmonary capillary wedge pressure, 20.3 +/- 7.4 mmHg and pulmonary-to-systemic flow ratio, 3.12 +/- 0.95 before starting on IABP. When the hemodynamics at 3 hours of IABP were compared to the pre-IABP values, the right atrial pressure, pulmonary capillary wedge pressure and pulmonary-to-systemic flow ratio had a tendency to decline, but the changes were not statistically significant, except for the peak arterial pressure which showed a significant elevation at 3 hours of IABP. Three of the 7 patients became dependent on IABP, and 2 of the 3 patients were saved by emergency operation.

Aged↗

PubMed1995

Limitation of myocardial infarct size by nicorandil after sustained ischemia in pigs.

Nicorandil is a compound with hybrid properties of nitrates and adenosine triphosphate (ATP)-sensitive potassium channel (KATP) opening. The effects of nicorandil and isosorbide dinitrate (ISDN) were investigated in a model of 60-min coronary occlusion/180-min reperfusion in open chest pigs. Three groups of 10 pigs were randomly assessed to receive saline or equihypotensive doses of nicorandil or ISDN. Drug infusion was started at 30 min of ischemia and continued throughout reperfusion. Area at risk (AAR) and infarcted area (IA) were assessed by monastral blue dye-triphenyltetrazolium dual staining technique and calculated by planimetry. Myeloperoxidase concentration (MPO) in the non-ischemic area and in the IA was assessed as an index of presence of neutrophils. Measurements of reduced glutathione (GSH), oxidized glutathione (GSSG), lipofuscine, and malondialdehyde were performed on coronary vein blood as indexes of oxidative stress. IA, as a percentage of AAR, was 78 +/- 10% after saline, 61 +/- 12% after N (p < 0.05 vs. saline), and 69 +/- 14% after ISDN (not significant vs. saline). Cardiac output and left ventricular dP/dt were depressed during coronary occlusion in all groups and their recovery during reperfusion was earlier in the nicorandil group. In the saline group, MPO was increased in the IA compared to the nonischemic area (78 +/- 63 vs. 21 +/- 21 micrograms/mg prot, p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2005

Quantitative coronary angiogram analysis: nifedipine retard versus angiotensin-converting enzyme inhibitors (JMIC-B side arm study).

This study was performed to compare the effects of nifedipine retard and angiotensin-converting enzyme (ACE) inhibitors on the progression of coronary atherosclerosis by means of quantitative coronary angiogram. Coronary angiogram was performed before the start of the study and during the 3-year treatment period. This study was conducted on the assumption that possible coronary vasodilation, which may be caused by nifedipine, was excluded by administration of sufficient isosorbide dinitrate. The changes from the baseline in the minimum lumen diameter of the coronary artery in all measured segments were negligible in the nifedipine group (+0.02+/-0.27 mm; P=0.543), whereas they were significantly reduced in the ACE inhibitor group (-0.12+/-0.27 mm; P<0.001), with a significant difference observed between the groups (P=0.002). The number of progressors in the nifedipine group was significantly lower than that in the ACE inhibitor group (P=0.019), and there was also a significant difference between the groups in the number of patients in whom > or =1 lesion developed after treatment (P=0.040). However, the changes of minimum lumen diameter stratified by baseline percent diameter stenosis demonstrated that progression of coronary atherosclerosis was suppressed in the nifedipine group for lesions with a percent diameter stenosis of < or =40 but was suppressed in both groups for those with a percent diameter stenosis of > or =41. This study suggests that nifedipine retard and ACE inhibitors may be effective in suppression of progression of coronary atherosclerosis, and that nifedipine in particular may be effective for mild to moderate stenosis.

Aged↗

PubMed1988

Advantage of combined therapy with captopril and nitrates in severe congestive heart failure.

We compared the acute hemodynamic effects of captopril and nitrates in 11 patients with severe congestive heart failure and Grade IV cardiac disability. Pressures were measured using a Swan-Ganz catheter system; cardiac output and stroke index were measured by thermodilution, and left-ventricular (LV) volumes and ejection fraction were calculated simultaneously with the hemodynamic measurements from radionuclide ventriculography. Measurements were made in each of four treatment states: control, sublingual isosorbide dinitrate (ISDN) (5 and 15 mg), oral captopril (50 to 200 mg daily) and during combined therapy with captopril and ISDN. Captopril produced a fall in mean arterial pressure (P less than 0.01) from 81 +/- 14 to 72 +/- 13 mm Hg, and a rise in stroke index from 30 +/- 5 to 35 +/- 91/min per m2 (P less than 0.05), while LV ejection fraction increased from 18 +/- 5 to 21 +/- 7% (P less than 0.05). ISDN reduced mean arterial, pulmonary arterial, right-atrial and wedge pressure. The combination of captopril and ISDN produced a greater fall in mean arterial pressure, a further rise in ejection fraction to 22 +/- 8% (P less than 0.05), a fall in systemic (P less than 0.05) and pulmonary vascular resistance (P less than 0.01) and a rise in cardiac (P less than 0.01) and stroke work index (P less than 0.01), while the beneficial effects of ISDN on right-atrial, pulmonary arterial and wedge pressure were again achieved. LV contractility, assessed from end-systolic stress-shortening relations, was essentially unaltered or decreased very slightly. The study showed that combined therapy with captopril and nitrates produced acute hemodynamic benefits superior to those achieved by treatment with captopril or nitrates alone.

Blood Pressure↗

PubMed1986

Augmented platelet reactivity and thromboxane A2 production possible aggravating factors in unstable angina.

We examined platelet aggregation and plasma levels of thromboxane B2, a stable metabolite of thromboxane A2, in patients with unstable angina and correlated these platelet indices with the response to antianginal conventional therapy such as isosorbide dinitrate and calcium channel blocker. Eight of 36 patients exhibited anginal attacks more than 5 times/week in spite of the therapy, designated refractory unstable angina, associated with augmented platelet aggregation induced by arachidonate (0.3 mM, 71 +/- 3%, mean +/- SEM) and collagen (2 micrograms/ml, 72 +/- 5%), and elevated plasma levels of thromboxane B2 (350 +/- 19 pg/ml). In the remainder of the patients whose anginal attacks were effectively subsided by the therapy, platelet aggregation was much lower (arachidonate: 34 +/- 9%, collagen: 31 +/- 8%, p less than 0.01) and plasma levels of thromboxane B2 were also lower (295 +/- 12 pg/ml, p less than 0.05). To evaluate the effect of selective thromboxane A2 blockade on clinical findings and platelet reactivity in refractory unstable angina, OKY-046 (600 mg/day, p.o.) was administered to another 14 patients with refractory unstable angina in addition to the conventional therapy. We found that platelet aggregation induced by arachidonate (71 +/- 4%) and collagen 65 +/- 8%) was markedly reduced (44 +/- 7% and 24 +/- 3%, respectively, p less than 0.01) and plasma levels of thromboxane B2 (358 +/- 31 pg/ml) and thromboxane B2 production in serum (29 +/- 5 ng/ml) were also significantly reduced after OKY-046 treatment (262 +/- 21 pg/ml, p less than 0.05, and 1.4 +/- 0.2 ng/ml, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗

PubMed2004

Nitric oxide donation lowers blood pressure in adrenocorticotrophic hormone-induced hypertensive rats.

Adrenocorticotrophic hormone (ACTH) elevates systolic blood pressure (SBP) and lowers plasma reactive nitrogen intermediates in rats. We assessed the ability of NO donation from isosorbide dinitrate (ISDN) to prevent or reverse the hypertension caused by ACTH. In the prevention study, male Sprague Dawley rats were treated with ACTH (0.2 mg/kg/day) or saline control for 8 days, with either concurrent ISDN (100 mg/kg/day) via the drinking water or water alone. Animals receiving ISDN via the drinking water were provided with nitrate-free water for 8 hours every day. In the reversal study ISDN (100 mg/kg) or vehicle was given as a single oral dose on day 8. SBP was measured daily by the indirect tail-cuff method in conscious, restrained rats. ACTH caused a significant increase in SBP compared with saline (P < 0.0015). In the prevention study, chronic administration of ISDN (100 mg/kg/day) did not affect the SBP in either group. In the reversal study, ISDN significantly lowered SBP in ACTH-treated rats at 1 and 2.5 hours (132 +/- 3 mmHg (1 h) and 131 +/- 2 mmHg (2.5 h) versus 143 +/- 3 mmHg (0 h), P < 0.002), but not to control levels. It had no effect in control (saline treated) rats. In conclusion, the lowering of SBP by NO donation is consistent with the notion that ACTH-induced hypertension involves an impaired bioavailability or action of NO in vivo.

Adrenocorticotropic Hormone↗

PubMed1996

Difference in the enhancing effects of ultrasound on the skin permeation of polar and non-polar drugs.

The effect of ultrasound (150 kHz, 111 mW/cm2) on the permeability of isosorbide dinitrate (ISDN) and antipyrine (ANP) through excised hairless rat skin was evaluated using an Arrhenius plot. The permeability coefficients of ISDN across skin (at various temperatures) in the presence and absence of ultrasound were virtually isolinear on the Arrhenius plot. It has been suggested that the temporal increase in the ISDN flux, which was observed when ultrasound was applied in our previous study, was only a result of the thermal effect of ultrasound, i.e., an increase in the temperature of the donor solution. On the other hand, ultrasound influenced the Arrhenius plot of ANP, suggesting that the enhancement effect for ANP permeation could be not explained only by the thermal effect of ultrasound. In addition, the effective diffusion (D) and partition coefficients (K) of ISDN and ANP were estimated using their skin permeation profiles across the ultrasonic pretreated skin. The coefficients of ISDN with ultrasonic pretreatment were comparable to those without pretreatment. On the other hand, the D value of ANP with ultrasonic pretreatment was increased about 4 times by ultrasonic pretreatment, in spite of an insignificant change in the K value. These results suggest that the ultrasound used in the present study increased the effective diffusivity across the aqueous region in the stratum corneum to enhance the skin permeation of the polar compound, ANP.

Animals↗

PubMed2006

Long-term results of "chemical sphincterotomy" for chronic anal fissure: a prospective study.

INTRODUCTION: Pharmacologic anal sphincter relaxants promote fissure healing; however, their effect is transient and the risk of late recurrence remains uncertain. METHODS: From August 1997 to August 2002, patients with chronic anal fissure attending our outpatient clinic were treated with a protocol that included: topical isosorbide dinitrate, 2.5 mg, or nifedipine, 0.2 percent t.i.d., or the combination of both. Botulinum toxin 20 units was injected to the internal anal sphincter to those who failed. All the patients were contacted and interviewed during November to December 2002. RESULTS: Follow-up was a median of 47.43 +/- 13 (range, 4.7-60) months. A total of 455 patients completed the study; 323 patients (71 percent) healed at follow-up ending: 170 of the healed patients had one or more recurrences that responded to further treatment (37.4 percent), whereas 153 patients (33.6 percent) healed and had no recurrences. One hundred thirty-two patients (29 percent) did not heal and were referred to lateral sphincterotomy. Long intervals between symptoms appearance and treatment initiation decreased healing and increased recurrence rates (P = 0.03 and 0.01 respectively). CONCLUSIONS: Topical treatment is effective for patients with chronic anal fissure, at short-term and long-term periods. Because for many patients it is not a definitive treatment, it can be offered to those who are ready to receive repeated treatments. Longer intervals between symptom appearance and treatment initiation negatively affects fissure healing and recurrence rate.

Adolescent↗