Method optimization to assess endothelial function in females-duration of glyceryl trinitrate effect

Pulse-wave analysis (PWA) combined with pharmacological challenges has recently been used as a method to measure endothelial function. This involved administration of glyceryl trinitrate (GTN), followed by salbutamol as endothelium-independent and -dependent vasodilators, respectively. The duration of GTN effect needs to be established before the administration of salbutamol. Baseline augmentation index (AIx) and pulse-wave velocity (PWV) measurements were taken in 11 healthy female subjects (mean age 23.27 +/- 3.66 years). Sublingual GTN 0.5 mg was administered for 3 min, followed by AIx and PWV measurements every 5 min till 20 min and then every 10 min until 40 min post-GTN. Maximum change in AIx post-GTN was at 3 min with a mean change from the baseline of -17.86% +/- 4.40% (p < 0.001). There were no significant changes noted after 30 and 40 min with mean change being -0.82% +/- 2.61% and 0.14% +/- 3.20%, respectively (p > 0.05). Significant changes in PWV were noted at 5 and 10 min with the mean change of -0.33 +/- 0.36 m/s and -0.33 +/- 0.35 m/s, respectively (p = 0.01). There were no further changes noted at 15 min and thereafter (p > 0.05). A duration of at least 30 min after GTN is required for AIx and PWV values to reach their baseline. Thus, the administration of salbutamol should be given only after 30 min of sublingual GTN for the assessment of endothelial function.     

Effects of salbutamol and glyceryl trinitrate on large arterial stiffness are similar between patients with hypertension and adults with normal blood pressure

AIMS: Endothelial function is characteristically impaired in patients with hypertension. Endothelial function was assessed in men and women with hypertension using a recently described, non-invasive method. METHODS: Twenty patients and 20 controls received salbutamol 400 microg and glyceryl trinitrate (GTN) 500 microg in a two-way randomized, single-blind study. Effects on augmentation index (AIx) were assessed using pulse wave analysis (PWA). RESULTS: Responses (absolute AIx reduction and 95% confidence interval) to salbutamol were 8.4% (6.2, 10.6) and 8.3% (7.0, 9.6) in patients and controls, respectively, and those to GTN were 13.6% (10.8, 16.4) and 15.5% (13.0, 17.0), respectively. CONCLUSIONS: Systemic arterial responses to endothelium-dependent and -independent vasodilators are preserved in patients with mild, uncomplicated hypertension, indicating normal large arterial endothelial function.     

Comparative effects of glyceryl trinitrate and amyl nitrite on pulse wave reflection and augmentation index

AIMS: The influence of vasodilators on augmentation index (AIx) offers a simple, rapid and noninvasive method of evaluating vascular function. Glyceryl trinitrate (GTN) is widely used as an endothelium-independent vasodilator, although other nitrates that are shorter acting may have advantages in clinical studies. The aim of this study was to compare the effects of two short-acting nitrates, GTN and amyl nitrite, which have differing pharmacodynamic profiles. METHODS: Twenty-one healthy volunteers (15 male; mean age 35 years, range 21-56 years) attended on three occasions and received sublingual GTN (0.5 mg for 3 min), inhaled amyl nitrite (0.2 ml inhaled for 30 s), or no treatment in a randomized cross-over design. Haemodynamic responses of AIx, blood pressure and thoracic bioimpedance (heart rate, cardiac index) were assessed by measurement at baseline, every 60 s for the first 5 min, and then every 5 min for a further 55 min. RESULTS: AIx was reduced by amyl nitrite (peak effect -9 +/- 2% at 1 min, P < 0.002) and GTN (peak effect -12 +/- 3% at 4 min, P < 0.05). Compared with amyl nitrite, the onset and offset of action of GTN was slower. Amyl nitrite initially increased heart rate by 27 +/- 4% (P < 0.001) and cardiac index by 13 +/- 3% (P < 0.001) whereas GTN had no significant effect (P > 0.05). Neither agent affected blood pressure. CONCLUSIONS: GTN causes a slower and more sustained reduction in AIx than amyl nitrite. Although amyl nitrite causes a more rapid fall and recovery in AIx, it induces a reflex tachycardia that may limit interpretation of the initial (1 min) but not later (2 min) changes in AIx. The prolonged offset of GTN suggests that a sufficient washout period must be included when making repeated measures or when assessing the subsequent effects of other agents.     

Withdrawal of intravenous glyceryl trinitrate: absence of rebound phenomena with transition to oral isosorbide dinitrate

1. Glyceryl trinitrate (GTN) is frequently infused intravenously as a component of the management of acute coronary syndromes (ACS). Abrupt cessation of GTN infusion after periods of more than 24 h administration often induces rebound vasoconstriction reflecting 'pseudotolerance'; this is also the basis of the 'zero hour phenomenon' during chronic nitrate therapy. The efficacy of oral nitrate regimens to prevent vasoconstriction following cessation of intravenous GTN has not been previously examined. Therefore, we investigated the effects of transition from intravenous GTN to oral isosorbide dinitrate (ISDN) on a parameter of apparent arterial stiffness in patients with ACS. 2. The effects of GTN infusion at 5 microg/min on augmentation index (AIx) were quantified in patients (n = 10) with stable angina pectoris in order to establish the magnitude of effect on apparent arterial stiffness. 3. This infusion rate of GTN reduced AIx from 23 +/- 10% (SD) to 3 +/- 14% (SD) (P < 0.01). The effect of transition from GTN infusion of greater than 24 h duration to ISDN (10 mg tds) were examined in patients (n = 16) with ACS (unstable angina/non-Q-wave myocardial infarction). No patient developed recurrent angina during the 24 h following cessation of GTN infusion. The level of AIx was 8 +/- 4% (SD) prior to GTN cessation and fell to 5 +/- 6% (SD) on ISDN (P = 0.05). 4. Thus, in patients treated for ACS, transition from intravenous GTN to low dose oral ISDN is associated with an incremental vasodilatation and no evidence of 'rebound' ischaemia.     

Effects of glutathione S-transferase inhibitors on nitroglycerin action in pig isolated coronary arteries

1. The present study was designed to clarify the role of glutathione S-transferase (GST) in the vasorelaxation response and development of tolerance to nitroglycerin (GTN) using GST inhibitors. 2. In pig isolated coronary arteries, GST activity was significantly changed to 77 and 82, or 69% of the control level (100%) following treatment with bromosulphophthalein (BSP; 10-3 and 10-4 mol/L) or ethacrynic acid (ETA; 10-4 mol/L), both GST inhibitors, respectively, but not following treatment with 10-3 and 10-4 mol/L GTN (GST activity 97 and 98% of control, respectively). 3. In KCl-contracted coronary artery strips pre-incubated with 10-5 and 10-4 mol/L GTN, 10-4 and 10-3 mol/L BSP or 10-4 mol/L ETA, concentration-dependent relaxations produced by GTN were significantly decreased compared with control. 4. 8-Bromo cGMP (8-Br-cGMP), a membrane-permeable cGMP analogue, produced concentration-dependent relaxations in GTN-pretreated arterial strips that were identical to control responses. However, there was weak but significant decrease in concentration-dependent relaxations in response to 8-Br-cGMP in BSP- and ETA-pretreated arteries. 5. The cGMP content in coronary arteries was significantly increased with GTN, GTN + BSP or GTN + ETA to similar high levels compared with control. 6. The results of the present study show that BSP and ETA decrease GTN- and 8-Br-cGMP-induced vasorelaxation, but have no effect on the GTN-induced increase in cGMP content in coronary arteries, suggesting a possibility that the GST inhibitors may have depressant actions on GTN- and 8-Br-cGMP-induced vasorelaxation through direct inhibition of the vasorelaxation of vascular smooth muscle themselves, in addition to having inhibitory effects GST activity.     

The involvement of the release of nitric oxide in the pharmacological activity of the new furoxan derivative CHF 2363.

1. The mechanism of action and the pharmacological effects of the new furoxan derivative, CHF 2363 (4-ethoxy-3-phenylsulphonylfuroxan), were investigated. 2. Pre-incubation of CHF 2363 with human platelet-rich plasma produced a concentration-dependent inhibition of the platelet aggregation induced by collagen, adenosine diphosphate (ADP) and platelet activating factor (PAF). The test compound was about 5 times more potent than sodium nitroprusside. 3-Isobutyl-1-methyl-xanthine (IBMX) potentiated the antiaggregating effect of CHF 2363. 3. CHF 2363 was a potent inhibitor of rubbed endothelium rabbit aortic ring contraction induced by noradrenaline. Comparison of IC50 values showed that CHF 2363 was as potent as glyceryl trinitrate (GTN). 4. Increasing concentrations of CHF 2363 elevated platelet guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels. Adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were unaffected. 5. Oxyhaemoglobin reduced all the pharmacological actions of the test compound. Moreover, CHF 2363 concentration-dependently released nitric oxide (NO) in platelet-rich plasma. The NO release was correlated to its ability to increase platelet cyclic GMP levels. 6. After exposure of rat aortic strips to supramaximal concentrations of GTN (550 microM), the vasorelaxant activity of CHF 2363 did not change, although that of GTN decreased about 55 fold. 7. It has been concluded that the new furoxan derivative CHF 2363 exerts a potent antiaggregating and vasorelaxant activity via NO release and increase of cyclic GMP levels. No in vitro cross tolerance between GTN and CHF 2363 was observed.     

Influence of ALDH2 Glu504Lys polymorphism on nitroglycerin response in chronic heart failure and involvement of Calcitonin Gene Related Peptide (CGRP)

Objective: The aim of this study was to investigate whether the neuropeptide calcitonin gene related peptide (CGRP) contributes to nitroglycerin (GTN) response in patients with chronic heart failure (CHF) and the association with the mitochondrial ldehyde dehydrogenase-2 (ALDH2) Glu504Lys (ALDH2*2) polymorphism. Methods: This is a 2-period, placebo-controlled clinical study. An intravenous infusion of saline followed by GTN (20 μg/min), each for 2 hours, respectively, was given to 49 stable CHF patients. Blood pressure (BP), heart rate (HR) and respiratory rate (RR) were measured at baseline, at 10 min, 30 min, 1.0 h, 1.5 h, and 2.0 h after initiation of saline infusion and initiation of GTN therapy. Blood samples were drawn for the determination of plasma CGRP for 49 patients at baseline, and at 2.0 h after initiation of saline and GTN infusion, respectively. Global clinical status of the patients was evaluated. Left ventricular ejection (LVEF), left ventricular end-diastolic volume (LVEDV), stroke volume (SV) and cardiac output (CO) were measured with 2D echocardiography with Simpson's biplane method (Pillip HP sonos 5500) by the same investigator at baseline and at 2.0 h after initiation of saline and GTN infusion. Results: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and left ventricular end-diastolic volume (LVEDV) were decreased, while left ventricular ejection fraction (LVEF) was increased at the end of GTN infusion (p < 0.001, respectively). Saline infusion showed no hemodynamic effects. At the end of GTN infusion, ALDH2*1/*1 homozygous patients showed higher degrees of both the absolute decrease in SBP (DSBP) (p < 0.001) and increase in LVEF (p < 0.001) than carriers of the ALDH2*2 allele. Mean plasma concentration of CGRP was increased after GTN infusion (p < 0.001), but not changed after saline infusion (p > 0.05). Changes in plasma concentration of CGRP correlated positively with the improvement in LVEF (r = 0.400, p = 0.004), while correlated negatively with changes in SBP (r = -0.300, p = 0.036) and LVEDV (r = -0.290, p = 0.043). Conclusions: ALDH2*2 polymorphism is associated with contributions of CGRP to GTN response in CHF patients.     

Role of superoxide dismutase in in vivo and in vitro nitrate tolerance.

We assessed whether pharmacological inhibition of CuZn-superoxide dismutase (SOD) mimics the molecular mechanism of either in vitro or in vivo nitrovasodilator tolerance. In endothelium-intact aortic rings from in vivo tolerant rabbits the GTN- and acetylcholine (ACh)-induced maximal relaxation was attenuated by 36 and 23%, respectively. In vitro treatment of control rings with GTN (1 h 10 microM) similarly attenuated the vasorelaxant response to GTN, but not to ACh. Formation of superoxide radicals (*O2-) in endothelium-intact rings (lucigenin-chemiluminescence) increased 2.5 fold in in vivo tolerance, but significantly decreased in in vitro tolerance. The membrane associated NADH oxidase activity was increased 2.5 fold in homogenates of in vivo tolerant aortae, but was not changed in in vitro tolerant aorta. Conversely, SOD activity and protein expression was halved in in vivo tolerance, but SOD activity was not altered by in vitro tolerance. The *O2- scavenger tiron (10 mM) effectively restored the vasorelaxant response to GTN in in vivo tolerant aortic rings, but not the reduced response to GTN in in vitro tolerant rings. Pretreatment (1 h) of vessels with diethyldithiocarbamate (DETC; 10 mM) attenuated vasorelaxant responses to GTN and ACh, increased vascular *O2- production, and inhibited SOD activity in vessel homogenates to a similar degree as observed in in vivo tolerance. DETC-treatment of in vivo-tolerant vessels induced an additional increase in *O2- production. Increased *O2- production in in vivo nitrate tolerant aorta is associated with activation of vascular NADH oxidase and inactivation of CuZnSOD. Therefore, in vivo tolerance can be mimicked by in vitro inhibition of CuZnSOD, but not by in vitro exposure to GTN, which does not affect vascular *O2- production, NADH oxidase and CuZnSOD.     

The reproducibility and effect on non-specific airway responsiveness of inhaled prostaglandin D2 and leukotriene D4 in asthmatic subjects.

1. Mast cell mediators PGD2 and LTD4 may play important roles in asthma pathogenesis. There is little information on the repeatability of inhalation challenge with these agonists in the laboratory. 2. We assessed the repeatability of inhalation challenges using PGD2 and LTD4 in two groups of 10 asthmatic volunteers. Non-specific bronchial responsiveness was assessed by histamine inhalation challenges. 3. Using the Bland-Altman method, we found the coefficient of repeatability to be 1.2 doubling doses for LTD4 and 2.1 for PGD2 at a 1 week interval. Repeatability for histamine inhalation challenge over the same time period was similar at 1.4 and 2.1 doubling doses respectively. 4. Non-specific bronchial responsiveness following LTD4 challenge decreased significantly, mean PD20FEV1 increasing from 169 nmol on day 1 to 278 nmol on day 3 (P = 0.001), before returning to baseline levels. 5. A progressive decrease in non-specific bronchial responsiveness occurred following PGD2 challenge. Baseline PD20FEV1 was 195 nmol, increasing to 238 nmol by day 3 (NS) and 313 nmol by day 8 (P = 0.016). 6. PGD2 inhalation challenges performed a week apart are less reproducible than LTD4 challenges, possibly as a result of significant changes in histamine bronchial responsiveness. Our findings allow accurate power calculations to be made for studies to assess new pharmacological antagonists to these mediators.     

Oxidative stress and mitochondrial aldehyde dehydrogenase activity: a comparison of pentaerythritol tetranitrate with other organic nitrates

Mitochondrial aldehyde dehydrogenase (ALDH-2) was recently identified to be essential for the bioactivation of glyceryl trinitrate (GTN). Here we assessed whether other organic nitrates are bioactivated by a similar mechanism. The ALDH-2 inhibitor benomyl reduced the vasodilator potency, but not the efficacy, of GTN, pentaerythritol tetranitrate (PETN), and pentaerythritol trinitrate in phenylephrine-constricted rat aorta, whereas vasodilator responses to isosorbide dinitrate, isosorbide-5-mononitrate, pentaerythritol dinitrate, pentaerythritol mononitrate, and the endothelium-dependent vasodilator acetylcholine were not affected. Likewise, benomyl decreased GTN- and PETN-elicited phosphorylation of the cGMP-activated protein kinase substrate vasodilator-stimulated phosphoprotein (VASP) but not that elicited by other nitrates. The vasodilator potency of organic nitrates correlated with their potency to inhibit ALDH-2 dehydrogenase activity in mitochondria from rat heart and increase mitochondrial superoxide formation, as detected by chemiluminescence. In contrast, mitochondrial ALDH-2 esterase activity was not affected by PETN and its metabolites, whereas it was inhibited by benomyl, GTN applied in vitro and in vivo, and some sulfhydryl oxidants. The bioactivation-related metabolism of GTN to glyceryl-1,2-dinitrate by isolated RAW macrophages was reduced by the ALDH-2 inhibitors benomyl and daidzin, as well as by GTN at concentrations >1 microM. We conclude that mitochondrial ALDH-2, specifically its esterase activity, is required for the bioactivation of the organic nitrates with high vasodilator potency, such as GTN and PETN, but not for the less potent nitrates. It is interesting that ALDH-2 esterase activity was inhibited by GTN only, not by the other nitrates tested. This difference might explain why GTN elicits mitochondrial superoxide formation and nitrate tolerance with the highest potency.     

Short-Term Intravenous Milrinone for Severe Congestive Heart Failure: The Good,Bad, and Not so Good

We evaluated the overall hemodynamic and clinical effects, beneficial and deleterious, of short-term intravenous milrinone in the management of severe congestive heart failure (CHF). Numerous hemodynamic measurements were obtained in 24 patients (mean age 65 yrs) with advanced, severe CHF (New York Heart Association class IV, ejection fraction 24 ± 5%), including 3 with concomitant clinical sepsis. Hemodynamic data were recorded at baseline and after a bolus of intravenous milrinone 50 μg/kg and maintenance infusion based on creatinine clearance at 0.5, 3, 24 and 48 hours. Cardiac index increased and pulmonary capillary wedge pressure decreased significantly (p<0.001; 2.07 ± 0.36 to 3.6 ± 0.36 L/min/m² and 20.6 ± 4.0 to 13.5 ± 2.8 mm Hg, respectively) in 24 patients 0.5 hour after initiation of therapy. These favorable hemodynamic responses, including significant decreases in systemic vascular resistance index and right atrial pressure, were sustained throughout the 48-hour study in 19 patients (79%). Severe hypotension occurred in three patients with superimposed sepsis as the result of exaggerated vasodilatation. One patient had recurrent ventricular tachycardia and another tolerance to milrinone. In two patients, excessive decline in preload and fall in cardiac index were reversed with volume expansion. Intravenous milrinone offered significant short-term hemodynamic benefits in most patients with severe CHF.     

Acute effects of vitamin C on platelet responsiveness to nitric oxide donors and endothelial function in patients with chronic heart failure

Chronic heart failure (CHF) is characterized by a prothrombotic state, which may relate to increased platelet aggregability, endothelial dysfunction, and increased oxidative stress. We investigated the effect of vitamin C in CHF on ex vivo platelet aggregation and platelet responsiveness to the anti-aggregatory effects of the nitric oxide (NO) donors glyceryl trinitrate (GTN) and sodium nitroprusside (SNP). We also examined parameters of oxidative stress and endothelial function in patients. In this double-blind, randomized, crossover study vitamin C (2 g) or placebo was given intravenously to 10 patients with CHF. We measured adenosine 5-diphosphate (ADP)-induced platelet aggregation, flow-mediated dilatation (FMD) in the brachial artery using ultrasonic wall-tracking, and plasma levels of lipid-derived free radicals using electron paramagnetic resonance spectroscopy. Vitamin C did not affect ex vivo platelet aggregability but enhanced the inhibition of platelet aggregation by SNP (62.7+/-10.2 to 82.7+/-4.8%, p = 0.03) and tended to increase responses to GTN (40.5+/-9.0 to 53.4+/-7.3, p = 0.06). The effect of vitamin C on platelet responsiveness to the antiaggregatory effects of SNP was inversely related to basal response to SNP (r = -0.9, p < 0.01); a similar trend was observed with GTN (r = -0.6, p = 0.1). Vitamin C also increased FMD (1.9+/-0.6 to 5.8+/-1.5%, p = 0.02) and reduced plasma lipid-derived free radicals by 49+/-19% (p < 0.05). In patients with CHF acute intravenous administration of vitamin C enhances platelet responsiveness to the anti-aggregatory effects of NO donors and improves endothelial function, suggesting a potential role for vitamin C as a therapeutic agent in CHF.     

Beneficial effects of fenoldopam on systemic and regional hemodynamics in rabbits with congestive heart failure

Fenoldopam (SKF 82526 J) is a selective DA-1 receptor agonist and thus of a potential benefit for promoting afterload reduction, renal vasodilatation, and diuresis in congestive heart failure. To examine the acute effects of fenoldopam in heart failure, studies were performed in control rabbits (n = 6) and in rabbits with chronic congestive heart failure (CHF, n = 6) induced by adriamycin treatment. Cardiovascular variables and regional blood flows were determined before and after an infusion of fenoldopam (150 micrograms/kg total dose). Resting hemodynamics differed in CHF and control groups. In the CHF group, mean arterial pressure (MAP), cardiac output (CO), and stroke volume (SV) were reduced and right atrial pressure (RAP), left ventricular end-diastolic pressure (LVEDP), and total peripheral resistance (TPR) were increased. Renal blood flow was much reduced in the CHF as compared with the control group (5.1 +/- 0.8 vs. 9.1 +/- 0.6 ml/min.g, p less than 0.05). Similar falls in MAP were noted after fenoldopam in CHF (-13 +/- 2%) and control rabbits (-12 +/- 3%) due to falls in TPR. An increase in CO was observed in both groups, the rise being more pronounced in the CHF group (22 vs. 12%). Heart rate was unchanged by fenoldopam in CHF rabbits but increased in controls. After fenoldopam, CHF rabbits exhibited significantly greater increases in blood flow to each of the three vascular beds studied: renal (113 +/- 27% vs. 7 +/- 13%), mesenteric (249 +/- 60% vs. 15 +/- 19%) and cerebral (145 +/- 13% vs. 12 +/- 12%). Plasma renin and norepinephrine (NE) levels increased after fenoldopam in both control and CHF rabbits. These results show that acute administration of fenoldopam produces favourable systemic and regional hemodynamic responses in rabbits with low output heart failure. However, long-term benefit remains to be demonstrated, particularly considering the hormonal responses.     

Chronic decrease in flow contributes to heart failure-induced endothelial dysfunction in rats

Chronic heart failure (CHF) impairs endothelium-dependent, nitric oxide (NO)-mediated dilation. This decreased dilation may be partly secondary to the chronic decrease in blood flow, but this hypothesis has not yet been tested. Thus, we assessed whether a localized, chronic increase in blood flow in vivo reverses endothelial dysfunction of small arteries in rats with CHF. Two months after coronary artery ligation or sham surgery, second-order side branches of the superior mesenteric artery were ligated in order to obtain persistently elevated blood flow (HF) in the adjacent first-order side branch compared with normal vessels (NF). One month later, responses to acetylcholine and flow-mediated vasodilatation (FMD) were assessed in vitro in an arteriograph. Chronic heart failure induced a decrease in mesenteric blood flow (374 +/- 25 and 305 +/- 27 micro L/min for sham and CHF, respectively; P < 0.05). Neither CHF nor the chronic increase in flow affected the responses to acetylcholine. Chronic heart failure decreased FMD (maximal response in sham and control 34 +/- 6 and 13 +/- 4%, respectively; P < 0.05). Chronic increases in blood flow did not modify FMD in sham, but restored FMD in CHF rats (28 +/- 4%; P < 0.05 vs CHF NF). The restored response was abolished by an inhibitor of NO synthesis (N(G)-nitro-l-arginine). Chronic heart failure did not affect the abundance of mesenteric endothelial NO synthase (eNOS) mRNA. A chronic increase in flow significantly increased the abundance of eNOS mRNA in sham rats, but only moderately and non-significantly in CHF rats. Thus, endothelial dysfunction of small arteries in CHF appears to be largely the consequence of the chronic decrease in flow.     

Reduced nitric oxide release causes nitrate tolerance in the intact coronary circulation.

We investigated the possible involvement of reduced nitric oxide (NO) formation in development of nitrate tolerance in an intact organ circulation. NO formation was measured spectrophotometrically on-line in the coronary effluent of Langendorff hearts of rabbits. Short-term (3 min) infusion of glyceryl trinitrate (GTN, 40 microM) or a sydnonimine (SIN-1, 2.3 microM), the active metabolite of molsidomine, into the coronary inflow tract resulted in a decrease in coronary vascular resistance and NO release into the coronary effluent. Pretreatment with 250 microM GTN for 30 min resulted in considerably reduced NO formation and coronary vasodilation, whereas NO release and coronary vasodilation subsequent to SIN-1 remained unchanged. In hearts pretreated with 250 microM SIN-1 for 30 min, there was no effect on GTN- or SIN-1-induced vasodilation and NO release. Studies of cyclic GMP formation in rat lung fibroblasts further indicated that GTN bioconversion rather than desensitization of the soluble guanylate cyclase is involved in GTN tolerance. These data suggest metabolic, endothelium-independent NO release from GTN during passage through the coronary circulation. This NO release is reduced in nitrate-tolerant cells and appears to be the major cause of nitrate tolerance in intact circulatory systems.     

Mechanisms of nitric oxide generation from nitroglycerin and endogenous sources during hypoxia in vivo

Nitroglycerin (GTN), often used in conditions of cardiovascular ischaemia, acts through the liberation of nitric oxide (NO) and the local concentration of NO in the tissue is responsible for any biological effect. However, little is known about the way in which the concentration of NO from GTN and other NO-donors is influenced by low oxygen tension in the target tissues. To evaluate the impact of changes in oxygen tension in the metabolism of NO-donors we measured exhaled NO in anaesthetized rabbits in vivo and expired NO and perfusate nitrite (NO(2)(-)) in buffer-perfused lungs in situ. The impact of acute hypoxia on NO formation from GTN, isosorbide-5-mononitrate (ISMN), dissolved authentic NO, NO(2)(-) and NO generated from endogenous NO-synthase (NOS) was studied in either model. Acute hypoxia drastically increased exhaled NO concentrations from all NO-donors studied, both in vivo and in the perfused lung. During similar conditions endogenous NO generation from NOS was strongly inhibited. The effects were most pronounced at less than 3% inspired oxygen. The mechanisms for the increased NO-formation during hypoxia seems to differ between GTN- and NO(2)(-)-derived NO. The former phenomenon is likely due to diminished breakdown of NO. In conclusion, hypoxic conditions preserve very high local NO concentrations generated from organic nitrates in vivo and we suggest that this might benefit preferential vasodilation in ischaemic tissue regions. Our findings point out the necessity to consider the influence of oxygen tension when studying the action of NO-donors.     

Inhibition of angiotensin converting enzyme with enalapril maleate in infants with congestive heart failure.

We studied the inhibition of angiotensin converting enzyme (ACE) in eight infants with congestive heart failure (CHF) poorly controlled with digoxin and diuretics, treated orally with 0.25 mg kg-1 enalapril maleate once a day. Baseline ACE activities were compared between these infants and control children without CHF or ACE inhibitor. Except for one infant who vomited, inhibition of ACE activity was 75.5 +/- 12.2%, 75.5 +/- 10.5% and 51.7 +/- 12.2%, at 4, 12 and 24 h after drug intake respectively. There was no correlation between postnatal age and inhibition of ACE activity. In infants with CHF, mean baseline ACE activity was significantly higher than in control infants (36.4 +/- 7.2 mu ml-1 vs 26.9 +/- 6.9 mu ml-1, P < 0.05). These results were very similar to those seen in adults.     

Comparison of the beta2-adrenoceptor selectivity of rimiterol, salbutamol and isoprenaline by the intravenous route in man.

1 The bronchodilating efficacy and the degree of beta2-adrenoceptor selectivity of rimiterol, salbutamol and isoprenaline were determined in seven subjects who exhibited histamine-induced bronchoconstriction. 2 Rimiterol, 0.5 (high dose) and 0.05 (low dose) mug kg-1 min-1, salbutamol, 0.3 and 0.03 mug kg-1 min-1, isoprenaline, 0.05 and 0.005 mug kg-1 min-1 and placebo were administered by a single intravenous injection over 6 min, and the protection against histamine-induced bronchoconstriction, changes in heart rate, pulse pressure and skeletal muscle tremor were measured. 3 Rimiterol (98%), salbutamol (96%) and isoprenaline (69%) protected against histamine-induced bronchoconstriction. For these ventilatory responses, there was a heart rate increase of 31.9, 24.7 and 44.3 beats/min for rimiterol, salbutamol and isoprenaline respectively. The three drugs produced similar increases in pulse pressure and tremor. 4 Significant dose-responses were obtained for all the parameters with each drug. 5 Isoprenaline was approximately 7 and 5 times as potent as rimiterol and salbutamol respectively in bronchodilator action when equimolar doses were compared. Similarly, isoprenaline was approximately 14 and 10 times as potent in increasing the heart rate as rimiterol and salbutamol respectively. 6 Rimiterol, a new beta-adrenoceptor stimulating drug, is an effective bronchodilator and has similar beta2-adrenoceptor selectivity to salbutamol when administered intravenously. The relative potencies and degrees of beta2-adrenoceptor selectivity of these drugs depend partly on their route of administration.     

Effects of beta 1- and beta 2-adrenoceptor stimulation on hemodynamics in the anesthetized rat.

The role of beta 1-adrenoceptors in mediation of vasodilatation is not clear. The microsphere technique was used to compare the effects of mixed beta-, beta 1-, and beta 2-stimulation on blood flow and conductance changes in five groups of pentobarbital-anesthetized rats: I, vehicle; II, mixed beta-stimulation; III, beta 1-stimulation; IV, beta 2-stimulation; and V, mixed beta-blockade. Isoproterenol (32 ng/kg/min) was infused into rats either without (group II) or with ICI 118,551 (beta 2-blocker, 30 micrograms/kg, group III), atenolol (beta 1-blocker, 100 micrograms/kg, group IV), or both blockers (group V), respectively. At the doses selected, ICI 118,551 shifted the dose-vasodepressor response curve of salbutamol (beta 2-agonist) to the right but had no effect on the dose-chronotropic response curve of dobutamine (beta 1-agonist), whereas atenolol shifted the dose-chronotropic response curve of dobutamine to the right and had no effect on the dose-vasodepressor response curve of salbutamol. The results show that isoproterenol increased heart rate (HR) and arterial conductances in the coronary and skeletal muscle beds but had no effects in other beds. Combined with ICI 118,551, isoproterenol caused similar increases in HR and coronary arterial conductance but markedly less increase in skeletal muscle conductance. Atenolol abolished the increase in HR by isoproterenol but did not affect the increases in coronary and muscular arterial conductances. With both blockers, isoproterenol produced no increase in coronary and skeletal muscle conductance. Therefore, both beta 1- and beta 2-adrenoceptors play a role in coronary and skeletal muscle vasodilatation.(ABSTRACT TRUNCATED AT 250 WORDS)     

血浆基础N末端B型利钠肽原水平对高龄心力衰竭患者应用左西孟旦近期临床疗效的预测价值

目的 评价基础血浆NT-proBNP水平对高龄心力衰竭患者应用左西孟旦近期临床疗效的预测价值。方法 采用前瞻性观察研究方法,28例高龄心功能分级为Ⅲ～Ⅳ级的心力衰竭患者纳入研究,在基础心衰治疗基础上加用左西孟旦,入选患者于入院时检测基础血浆NT-proBNP水平,依据其四分位数值作为界限,分为四组,并于入院24小时内及治疗后行心脏超声检查,测定左室射血分数(LVEF%),观察患者出院时心功能改善情况,计算LVEF%变化值。采用Pearson双变量相关分析评价血浆基础NT-proBNP水平与治疗前后患者LVEF%水平差值的相关性,应用双向有序分类资料线性趋势检验比较各组间整体临床状况改善程度。结果 基础血浆NT-proBNP值与左西孟旦用于心衰患者的心功能改善程度负相关,且呈线性变化趋势。心衰患者经治疗后LVEF%变化值与基础血浆NT-proBNP水平呈显著负性相关。结论 基础血浆NT-proBNP值可能成为评估预测高龄心衰患者应用左西孟旦临床疗效的手段之一。