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PubMedDate not supplied

Rapid microbial degradation of organic nitrates in rat excreta. Re-examination of the urinary and fecal metabolite profiles of pentaerythritol tetranitrate in the rat.

The in vitro stabilities of three organic nitrates, viz. pentaerythritol tetranitrate ( PETN ), nitroglycerin (NTG), and isosorbide dinitrate (ISDN) in rat urine, and of PETN in rat feces were examined. PETN , NTG, and ISDN degraded completely in rat urine following incubation for 24 hr at either 25 or 37 degrees C. Degradation of PETN , NTG, and ISDN was absent in sterilized urine under the same conditions. These data suggested that decomposition of organic nitrates in untreated urine was usually rapid and extensive, and was primarily of microbial origin. Stability of these organic nitrates could also be maintained when urine samples were stored in packed ice. Rapid and extensive microbial degradation of PETN was also found in rat fecal homogenates, suggesting the possibility of organic nitrate metabolism by intestinal microflora. The metabolic profiles of PETN in rat urine and feces following intra-arterial and oral dosing of this organic nitrate were then re-examined. The data confirmed a previous finding that in vivo PETN excretion in urine was minimal. However, contrary to data which showed about 8% fecal recovery after oral dosing, our results suggested a smaller (2%) fecal PETN recovery with oral dosing. It appeared likely then that unabsorbed PETN might be further metabolized by gut flora.

Administration, Oral↗
PubMed1998

High-dose nitrates in the immediate management of unstable angina: optimal dosage, route of administration, and therapeutic goals.

Nitrates are commonly used for rapid relief of ischemia in the initial management of unstable angina. However, their optimal dosage, route of administration, and therapeutic goals have not been fully established. This study was conducted to determine the optimal dosage and mode of administration (intravenous bolus versus sublingual spray) of nitrates and the therapeutic goals of their use in the immediate management of unstable angina. In a single-center prospective trial, 72 consecutive patients with unstable angina accompanied by typical ST-segment depression on electrocardiogram were randomly assigned to receive isosorbide dinitrate either as repeated intravenous boluses or as sublingual sprays while being delivered to the hospital by a mobile intensive care unit. Optimal nitrate dosage was tailored to pain relief while monitoring mean blood pressure reduction to an optimal range (5% to 20%) without dosage restriction. The mean nitrate dosage needed for ischemia control during the first hour of treatment was 7.8 +/- 3.8 mg. Optimal blood pressure reduction was achieved by significantly more intravenously treated patients than sublingually treated patients (68% v 41%, P = .037). Intravenously treated patients also experienced a more pronounced therapeutic effect, as assessed by reduction in chest pain score (67% v 39%, P = .0004) and decrease in ST-segment depressions (57% v 27%, P = .004). These results show that higher doses of nitrates than previously recommended are required for ischemia control during the initial management of unstable angina. The use of repeated intravenous boluses is safe and more easily controlled and, therefore, more efficacious than sublingual sprays in inducing the maximal anti-ischemic effect while avoiding significant hypotension.

Administration, Sublingual↗
PubMed1998

Short- and long-term effects of molsidomine retard and molsidomine nonretard on exercise capacity and clinical status in patients with stable angina: a multicenter randomized double-blind crossover placebo-controlled trial.

A multicenter, randomized, double-blind, crossover, placebo-controlled study was conducted in 90 isosorbide dinitrate responders showing stable angina to compare the efficacy of molsidomine retard, 8 mg b.i.d., with that of molsidomine, 4 mg t.i.d., for 6 weeks. Total work performance (workload x min) was significantly improved, compared with baseline and placebo until 8 and 12 h after molsidomine and molsidomine retard administration, respectively. ST-segment depression decreased significantly under the two treatments at 60 W as well as at maximal exercise. The rate-pressure product (heart rate x systolic blood pressure) decreased and increased significantly at submaximal and maximal exercise level, respectively. All these effects remained significant after 6-week treatment, with only the ST segment showing a nonsignificant tendency to improvement at maximal work. The frequency of anginal attacks and of sublingual nitroderivative-tablets consumption decreased significantly with molsidomine, 4 mg, and molsidomine retard, 8 mg. However, overall results showed that the latter form reduces myocardial ischemia more efficiently at submaximal exercise level, has a more prolonged effect on exercise tolerance, and maintains it at a somewhat higher level after 6-week treatment.

Adult↗
PubMed2000

[Clinical aspects of trimetazidine (preductal) administration as an antianginal drug].

AIM: To study antianginal effectiveness of trimetazidine (TMS) in monotherapy and combined antianginal therapy; to design approaches to prediction of its effect. MATERIAL AND METHODS: An open cross-over randomised trial enrolled 29 anginal patients. They were given a single TMS dose (60 mg) and its effect was compared to that of placebo, propranolol, verapamil, isosorbide dinitrate, nifedipine). The effect was estimated by an increment of bicycle exercise (BE) duration necessary to depress ST segment by 1 mm. 10 patients retained signs of myocardial ischemia at BE though they were treated with specially selected antianginal drugs. In them, we assessed additional benefit of adjuvant TMS. The drugs were tried under acute test and one-month treatment. RESULTS: In acute test a significant antianginal effects of TMS were registered against the placebo. Differences in efficiency of the antianginal drugs were insignificant. The addition of TMS to the selected drugs gave rise to the trend to prolongation of time to ST segment depression by 1 mm. We found a strong correlation between TMS efficiency in acute pharmacological test and in long-term administration. This enables using BE for prediction of long-term effect of the drug. CONCLUSION: TMS has a significant antianginal effect. It is especially beneficial in cases of insufficient effectiveness of conventional antianginal drugs or when their use is problematic because of marked disturbances of hemodynamics.

Administration, Oral↗
PubMed1985

Isosorbide-5-mononitrate--effective monotherapy in chronic stable angina.

Isosorbide-5-mononitrate (ISMN) is not subject to first-pass metabolism and has more predictable blood concentrations than isosorbide dinitrate. In order to evaluate its efficacy as monotherapy in patients with chronic stable angina, 14 patients were studied. All had angiographically proven coronary artery disease and were limited by angina on a treadmill exercise test. After a 2-week placebo period ISMN was administered in a single-blind fashion with the dosage being titrated at 2-week intervals. The dosage increments were 20 mg once daily, 20 mg twice daily, 40 mg once daily and 40 mg twice daily. Patients were assessed subjectively by anginal attack rate and glyceryl trinitrate (GTN) consumption and objectively by treadmill exercise testing at 12 hours post dosage. ISMN increased the exercise ability significantly on all dosage regimes. However, a significant reduction in ST depression occurred only with the twice-daily regime. The increased exercise performance was associated with a significant decrease in anginal attack rate and GTN consumption from the 20 mg b.i.d. increment. ISMN is an effective antianginal agent with a more favourable profile in twice-daily dosage. Whilst no significant differences emerged between 20 mg and 40 mg twice daily, individual variation occurred, indicating a need for dosage flexibility.

Administration, Oral↗
PubMed1995

[Coronary artery caliber is not adapted to myocardial oxygen demand in hypertensive patients with angiographically normal coronary arteries].

Resting myocardial oxygen demand and corresponding coronary blood flow are main determinants of large coronary artery dimensions in humans. To examine the adaptation of epicardial coronary arteries to the increased myocardial oxygen demand, myocardial blood flow, in hypertensive patients, diameters of proximal and distal left anterior descending coronary artery (pLAD and dLAD), and proximal circumflex artery (CX) were determined in 15 untreated hypertensive patients and in 10 control subjects by quantitative angiography. All patients had total cholesterol < or = 5.40 mmol/l, LDL-cholesterol < or = 3.35 mmol/l, and angiographically normal coronary arteries. Measurements were made at base and after 2 mg intracoronary isosorbide dinitrate (ISDN) in order to obtain maximal dimensions of vessels. Coronary flow velocity was measured in distal left anterior descending coronary artery by Doppler. Results show that despite higher rate-pressure product in hypertensive patients, the diameters of the coronary segments were similar in control subjects and in hypertensive patients at base (3.53 +/- 0.84 vs 3.76 +/- 0.48 mm for pLAD; 2.55 +/- 0.50 vs 2.49 +/- 0.52 mm for dLAD; 2.92 +/- 0.40 vs 2.78 +/- 0.83 mm for CX, respectively). After intracoronary ISDN, diameters were also comparable between the 2 groups (4.54 +/- 0.86 vs 4.58 +/- 0.60 mm for pLAD; 3.35 +/- 0.58 vs 3.22 +/- 0.61 mm for dLAD; 3.47 +/- 0.56 vs 3.53 +/- 1.01 mm for CX, respectively). Conversely, coronary flow velocity was significantly higher in hypertensive patients at base (10.72 +/- 2.20 vs 6.48 +/- 2.01 cm/s; p < 0.001) and after ISDN (6.59 +/- 2.62 vs 3.72 +/- 0.87 cm/s; p < 0.001). Despite an elevated myocardial oxygen demand, large coronary artery dimensions are not increased in hypertensive patients resulting in an elevated coronary flow velocity that may increase longitudinal shear stress at the endothelial surface. This might be an important determinant in the pathogenesis of atherosclerosis in hypertensive patients.

Adaptation, Physiological↗
PubMed2002

Penile erectile responses to cavernous nerve stimulation in rats are not affected by nitrate tolerance.

The aim of this study was to elucidate whether penile erection induced by electrical stimulation of the cavernous nerve was affected in male rats with nitrate tolerance. Nitrate tolerance to nitroglycerin was induced by oral administration of isosorbide dinitrate (ISDN) at 1000 mg/kg to rats, once or twice a day for 5 or 6 days. The rats were anesthetized with sodium pentobarbital 18-24 h after the last dosing with ISDN or its vehicle. Penile erection induced by electrical stimulation was monitored by measuring the penile diameter sonomicrometrically. After measurement of the penile erectile response, nitroglycerin (3-300 microg/kg) was intravenously (i.v.) injected into eight rats treated with the vehicle or ISDN to examine its hypotensive effect. In the vehicle-treated rats, the maximal developed penile diameter (D-max) and the duration of penile erection (T50%, period of time from the maximum erection to its 50% decline) produced by electrical stimulation were 509+/-47 microm and 14.2+/-1.7 s, respectively. On the other hand, neither D-max nor T50% in ISDN-treated rats (509+/-36 microm and 13.1+/-1.3 s, respectively) was different from those in the vehicle-treated rats. However, the hypotensive effects of i.v. injected nitroglycerin were significantly attenuated in the ISDN-treated group as compared with the vehicle-treated group. It is concluded that nitrate tolerance fails to influence penile erection induced by cavernous nerve electrical stimulation in rats.

Animals↗
PubMed1991

Chronopharmacology of oral nitrates in healthy subjects.

The pharmacokinetics and the hemodynamic effects (blood pressure, heart rate) of oral organic nitrates have been investigated in healthy subjects after oral single-dose application either in the morning or in the evening. Isosorbide-5-monitrate (IS-5-MN, 60 mg) was administered as an immediate-release tablet or as a slow-release formulation. Isosorbide dinitrate (ISDN, 20 mg) was ingested as an immediate-release tablet. After administration of IS-5-MN as an immediate-release tablet, the drug was more rapidly absorbed in the morning (tmax of 0.9 h) than in the evening (tmax of 2.1 h). The rapid absorption led to more pronounced effects in the morning, at which time maximum drug concentrations occurred at the same time as peak effects were observed. After evening administration, however, peak effects were in advance of the maximum drug concentrations. No chronokinetics were observed after application of the slow-release formulation of IS-5-MN. In accordance with the results of the immediate-release formulation, peak effects of the slow-release preparation occurred significantly earlier than peak drug concentrations after evening than after morning dosing. ISDN bioavailability was higher after morning than after evening administration and hemodynamic effects were more pronounced in the evening than in the morning. These results show that daily variations in pharmacokinetics and/or hemodynamic effects can be observed with oral nitrates. In addition, galenic formulation can influence the time-specified pharmacokinetics of IS-5-MN.

Administration, Oral↗
PubMedDate not supplied

Acute hemodynamic response to vasodilators in primary pulmonary hypertension.

Acute hemodynamic effects of high flow oxygen (O2) inhalation, sublingual isosorbide dinitrate (ISDN), intravenous aminophylline (AMN) and sublingual nifedipine (NIF) were studied in 32 patients with primary pulmonary hypertension (PPH). In 30 out of 32 patients the basal ratio of pulmonary to systemic vascular resistance (Rp/Rs) was > 0.5 (mean = 0.77 +/- 0.20). Oxygen caused significant decrease in the mean resistance ratio to 0.68 +/- 0.20 (p = 0.005). ISDN, AMN and NIF caused increase in the resistance ratio to 0.79 +/- 0.26; 0.78 +/- 0.26; and 0.80 +/- 0.23 respectively. O2, ISDN, AMN and NIF caused a fall of Rp/Rs in 21 (65.6%), 10 (31.2%), 10(31.2%) and 9(28.1%) patients respectively. Thus, of the four drugs tested high flow O2 inhalation resulted in fall of Rp/Rs in two thirds of patients whereas ISDN, AMN and NIF caused a mean rise in Rp/Rs. One third of patients did respond acutely to the latter three drugs. Acute hemodynamic studies are useful before prescribing vasodilators in patients with PPH since more of the commonly used drugs like ISDN, AMN, NIF could have detrimental hemodynamic responses in some patients. However, great caution should be exercised before performing hemodynamic study as the procedure has definite mortality and morbidity.

Administration, Sublingual↗
PubMed1999

Stimulant effect of nitric oxide generator and roxatidine on mucin biosynthesis of rat gastric oxyntic mucosa.

Although the involvement of nitric oxide (NO) in an increasing gastric mucus metabolism has been reported, information on whether or not its activation is limited to the specific mucus-producing cells is lacking. In this paper, we report the effect of the exogenous NO-donor, isosorbide dinitrate (ISDN), and second-generation histamine H2 receptor antagonist roxatidine (2-acetoxy-N-(3-[m-(1-piperidinylmethyl)phenoxy]propyl)acetamide hydrochloride) which is demonstrated to accelerate the mucin metabolism mediated by endogenous NO, on the mucin biosynthesis in distinct sites and layers of the rat gastric mucosa using an organ culture technique. Radiolabeled mucin was obtained from the tissue of full-thickness and the deep corpus layer, and the antrum of the rat stomach incubated for 5 hr with [3H]glucosamine(GlcN) in vitro. With the addition of ISDN to the culture medium, 3H-labeled mucin in the full-thickness corpus mucosa increased to 124-145% of the control (p<0.05), but not in the antrum. This stimulation of the mucin synthesis disappeared by the removal treatment of the surface mucous cell layer which has immunoreactivity of neuronal NO synthase. Similarly, roxatidine stimulated the mucin biosynthesis in the full-thickness corpus mucosa, but not in the gland mucous cell layer. These results suggest that the stimulation of the mucin biosynthesis mediated by NO is restricted to the surface mucous cells of the rat gastric oxyntic mucosa.

Animals↗
PubMed1994

[The benefit 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 4 treatment states: control, sublingual isosorbide dinitrate (ISDN; 5 and 15 mg), oral captopril (50-200 mg daily) and during combined therapy with captopril and ISDN. Captopril produced a fall in mean arterial pressure (p < 0.01) from 81 +/- 14 to 72 +/- 13 mm Hg and a rise in stroke index from 30 +/- 5 to 35 +/- 91/min/m2 (p < 0.05), while LV ejection fraction increased from 18 +/- 5 to 21 +/- 7% (p < 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 < 0.05), a fall in systemic (p < 0.05) and pulmonary vascular resistance (p < 0.01) and a rise in cardiac (p < 0.01) and stroke work index (p < 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.

Acute Disease↗
PubMed2005

Low serum bilirubin levels are independently and inversely related to impaired flow-mediated vasodilation and increased carotid intima-media thickness in both men and women.

BACKGROUND: Elevated levels of low-density lipoprotein (LDL) cholesterol and its oxidative modification have been described to be involved in the process of atherogenesis. Bilirubin, an antioxidant, prevents oxidative modification of LDL and therefore may protect from atherosclerosis and coronary heart disease (CHD). Impaired brachial artery flow-mediated dilatation (FMD), which means endothelial dysfunction (ED) and carotid intima-media thickness (IMT) are predictors for the development and progression of atherosclerosis. In the present study, FMD and IMT were studied in healthy subjects with lower and higher serum bilirubin concentrations in physiological ranges. METHODS: Ninety-one healthy subjects between 25 and 45 years of age (47 with lower and 44 with higher serum bilirubin concentrations) were included in this study. Carotid IMT and brachial artery flow-mediated dilatation was measured by means of high-resolution vascular ultrasound. FMD was assessed by establishing reactive hyperemia and endothelium-independent dilatation (EID) was determined by using sublingual isosorbide dinitrate. RESULTS: EDD in subjects with lower serum bilirubin concentrations was significantly worse than in those with higher serum bilirubin concentrations (11.6+/-4.4% versus 7.2+/-4.7%, respectively, p<0.0001). EID measurements were not significantly different between the groups (16+/-5.1% versus 16.8+/-7%, respectively). In addition, carotid IMT was significantly greater in subjects with lower serum bilirubin concentrations (0.5+/-0.13 mm versus 0.42+/-0.07 mm, p<0.0001). Furthermore, FMD in women with lower serum bilirubin concentrations was significantly lower than in women with higher serum bilirubin concentrations (11.5+/-4.9% and 17.5+/-4.7%, respectively, p<0.001). Accordingly, men with lower serum bilirubin concentrations had significantly lower FMD as compared to hyperbilirubinemic ones (11.7+/-3.6% versus 16.7+/-4.8%, respectively, p=0.009). Conversely, carotid IMT was significantly greater in both women and men with lower serum bilirubin concentrations compared to the subjects with elevated serum bilirubin concentrations (0.51+/-0.08 versus 0.41+/-0.08, p<0.001; 0.55+/-0.12 versus 0.40+/-0.07, p=0.002, in women and men, respectively). CONCLUSION: The healthy subjects with lower serum bilirubin concentrations show significant ED and increased carotid IMT, which are predictors for atherosclerosis.

Administration, Sublingual↗
PubMedDate not supplied

Comparison between the effect of postextrasystolic potentiation and the effect of nitrates on left ventricular function for the differentiation between reversible and irreversible left ventricular asynergy.

In patients with coronary heart disease (CHD) it is important to differentiate between reversible and irreversible left ventricular (LV) asynergy. Therefore global and regional LV function was investigated in the postextrasystolic beat (PES) and after isosorbide dinitrate (ISDN). In 24 patients LV angiograms were performed before and after ISDN. The ejection fraction (EF) was determined in a sinus beat and in PES. Regional LV performance was measured by the shortening of the length axis and six short hemiaxes. In 12 patients with normal LV function at rest EF increased from .72 +/- .04 (+/- 1 SD) to .77 +/- .04 (P less than 0.05) after ISDN and rose further to .81 +/- .02 in the PES (P less than 0.05). In 12 patients with CHD and LV asynergy EF increased from .43 +/- .12 to .47 +/- .13 after ISDN (P less than 0.05) and rose further to .57 +/- .13 in the PES (P less than 0.02). After ISDN 23/39 asynergic axes improved, 15/39 axes did not change, 1/39 axis decreased its shortening by 12%. In the PES 26/39 axes improved, 6/39 axes did not change; 7/39 axes showed less shortening, presumably due to a systolic shift of blood into dyskinetic regions with LV scar. It is concluded: The PES affects viable myocardium more than does ISDN; the PES is easier to perform and permits a more precise distinction between reversible and irreversible LV dyskinesis.

Coronary Disease↗
PubMed1984

The effects of organic nitrates on prostacyclin biosynthesis and platelet function in humans.

The results of prior studies indicate that nitroglycerin stimulates prostacyclin release by cultured endothelium and by the coronary vasculature in vivo. However, the accuracy of these findings in coronary vasculature relies on plasma samples obtained from the circulation via cardiac catheters, a procedure we have shown to stimulate prostacyclin release, thereby confounding interpretation of drug action. We studied the effects of short-acting (nitroglycerin) and long-acting (isosorbide dinitrate) nitrates on a noninvasive index of prostacyclin synthesis, excretion of urinary 2,3-dinor-6-keto-PGF1 alpha. Nitroglycerin was infused into six subjects to either a maximum of 480 micrograms/min or until mean arterial pressure fell by 20 mm Hg. Urine was collected for negative ion chemical ionization gas chromatographic, mass spectrometric analysis before and during the nitroglycerin infusion and for two 2 hr periods after nitroglycerin. The peak nitroglycerin infusion rate was 387 +/- 67 micrograms/min, which caused a fall in supine blood pressure (systolic/diastolic) of 11 +/- 5/14 +/- 4 mm Hg and a 12 +/- 3 beats/min increase in heart rate. Excretion of 2,3-dinor-6-keto-PGF1 alpha (pg/mg creatinine) was unchanged from control infusion values (106 +/- 19.5) either during (123 +/- 21) or after (134 +/- 14.6; 139 +/- 36) nitroglycerin infusion. Platelet aggregation to arachidonic acid (0.33 to 1.33 microM) and epinephrine (1 to 10 microM) ex vivo was inhibited in only one subject in whom excretion of 2,3-dinor-6-keto-PGF1 alpha was unaltered. Serum thromboxane B2 was not changed by nitroglycerin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed2005

Effects of the long-term administration of nicorandil on vascular endothelial function and the progression of arteriosclerosis.

This study compared the effects of long-term administration of nicorandil and isosorbide dinitrate (ISDN) on vascular endothelial function and the progression of arteriosclerosis. Forty-two patients with ischemic heart disease were randomly allocated to receive nicorandil (N group; 15 mg/d) or ISDN (I group, 40 mg/d). Twelve normal subjects served as controls. Vascular endothelial function and the progression of arteriosclerosis (intima-media thickness, IMT), as determined by carotid vascular ultrasound, were assessed 1 week before and 3 months after drug administration. Reactive hyperemia was induced in the forearm for 5 minutes, and the percentage change in the diameter of the brachial artery (% change in flow-mediated dilation, %FMD) was calculated. FMD was significantly lower in CAD groups than in controls. The %FMD significantly decreased (7.2 +/- 1.9 to 4.2 +/- 2.8) in the I group, while rising from 6.8 +/- 1.6 to 8.0 +/- 2.0 in the N group. IMT increased by 0.036 +/- 0.015 mm in the I group but showed no significant change in the N group (-0.01 +/- 0.012 mm). Thus, ISDN deteriorates IMT and FMD, whereas a beneficial effect of nicorandil is seen on FMD with no effect on IMT. Long-term treatment with nicorandil may be desirable for prevention of cardiovascular events.

Administration, Oral↗
PubMed1992

Nitrovasodilators as a new class of ocular hypotensive agents.

Because of recent evidence indicating that hormone regulation of particulate guanylate cyclase in the eye may modulate aqueous humor dynamics, we have investigated the possibility that exogenous activators of soluble guanylate cyclase may be useful in altering intraocular pressure (IOP). A variety of nitrovasodilators known to activate guanylate cyclase were evaluated for their topical effects on IOP, outflow resistance and systemic cardiovascular parameters. In both young and older rabbits, topically applied nitroglycerin (0.003-0.1 g %) rapidly lowered IOP in a dose-dependent fashion, with a peak effect at 1 to 2 hr. Topically applied 0.1% isosorbide dinitrate, sodium nitrite, hydralazine, minoxidil and sodium nitroprusside mimicked the ocular hypotensive actions of nitroglycerin. Ipsilateral effects on IOP were greater than contralateral effects and, at the doses applied, there was little or no alteration in heart rate or systemic blood pressure, or signs of ocular irritation. Higher doses (0.5-2.0 g %) of nitroglycerin, hydralazine and sodium nitroprusside were less effective in lowering IOP. Topically applied molsidomine (0.1%), a prodrug which requires hepatic metabolism to 3-morpholino-sydnonimin hydrochloride for guanylate cyclase stimulatory activity, was ineffective in lowering IOP, whereas topical 0.1% 3-morpholino-sydnonimin hydrochloride was effective. After chronic administration, rabbits receiving nitroglycerin showed diminished ocular response, whereas repeated doses of hydralazine (56 days) did not elicit tolerance. Tonographic studies showed that topically applied nitroglycerin and hydralazine increased the facility (decreased the resistance) of aqueous humor leaving the eye. These data indicate that topically applied nitrovasodilators can effectively lower IOP at doses which have little effect on systemic blood pressure. Because these IOP-lowering effects appear to result, to a significant degree, from local actions on the eye, further investigation of these agents in conditions of elevated intraocular pressure may be warranted.

Administration, Topical↗
PubMed1993

Nitric oxide-donating compounds stimulate electrolyte transport in the guinea pig intestine in vitro.

The role of nitric oxide (NO) as a regulator of intestinal electrolyte transport was investigated in stripped segments of guinea pig intestine mounted in Ussing chambers. Serosal application of the NO-donating compounds sodium nitroprusside or isosorbide dinitrate (in the presence of 5 microM L-cysteine) resulted in concentration-dependent increases in the short circuit current. The response to 0.5 mM nitroprusside was exhibited to the same degree in duodenum, jejunum, ileum and proximal colon, and to a lesser degree in the distal colon. The response to nitroprusside was reduced by pretreatment with either the cyclo-oxygenase inhibitor, indomethacin (45% inhibition), the 5-HT3 antagonist, BRL43694 (30% inhibition) or by incubation with chloride-free buffer (59% inhibition). There was no significant effect of the 5-HT2 receptor antagonist, LY53857, or the neural blocker, tetrodotoxin. Pretreatment of ileal segments with the NO synthase inhibitor, NG-monomethyl-L-arginine, did not significantly alter the short circuit current response to electrical field stimulation compared to controls. Exposure of ileal mucosal scrapings to sodium nitroprusside resulted in a significant increase in cGMP production. The data suggest that exogenous NO-donating compounds can modulate electrolyte transport in the guinea pig intestine in vitro. The response is cyclo-oxygenase-, 5-HT3- and chloride-dependent, and coincides with increases in mucosal cGMP. However, the role of endogenous NO in regulating electrolyte transport remains unclear.

Amino Acid Oxidoreductases↗
PubMed1987

Effect of metaraminol during acute inferior wall myocardial infarction accompanied by hypotension: preliminary study.

This study was designed to evaluate the effects of metaraminol (Aramine) in six patients with evolving acute inferior wall myocardial infarction accompanied by hypotension and warm limbs. There were 16 episodes of acute inferior wall ischemia, and the response to therapy was judged by evaluating blood pressure and ST segment and T wave abnormalities. Three patients received intravenous isosorbide dinitrate and two received streptokinase as the initial therapy. The mean ST segment elevation was significantly reduced (from 4.94 +/- 1 to 0.5 +/- 0.7 [p less than 0.0001]) after metaraminol infusion was initiated. The average T wave height also decreased (from 6.8 +/- 2 to -1.3 +/- 2.5 mm [p less than 0.0005]). The average heart rate decreased from 82 +/- 11 to 69 +/- 9 beats/min (p less than 0.05) and the mean arterial blood pressure increased from 81 +/- 12 mm Hg before metaraminol treatment to 126 +/- 8 mm Hg after treatment. All these changes occurred within a few minutes after metaraminol therapy was instituted. In 12 episodes, accelerated idioventricular rhythm appeared concomitantly with the resolution of ST segment elevation. Coronary angiography performed between 4 and 10 days after admission demonstrated significant obstruction in all infarct-related arteries, but none was totally occluded. Left ventricular function was normal in three patients and slightly hypokinetic in the inferior wall in two. These results indicate that in a selected group of patients with acute inferior myocardial infarction, metaraminol administration (in certain hemodynamic circumstances) can alleviate acute ischemia within a few minutes and thereby reduce ischemic injury.

Adult↗