Setting Of Endothelial Dysfunction Research Articles

Endothelial Aquaporins and Hypomethylation: Potential Implications for Atherosclerosis and Cardiovascular Disease.

Aquaporins (AQPs) are transmembrane channels that facilitate water and glycerol permeation through cell membranes. Recently, the water channel AQP1 was suggested to contribute to endothelial homeostasis and cardiovascular health. Less is known about endothelial aquaglyceroporins expression and its implication in cardiovascular disease (CVD). We have previously used cultured human endothelial cells under a hypomethylating environment to study endothelial dysfunction and activation, a phenotype implicated in the establishment of atherosclerosis and CVD. Here, we used the same cell model to investigate aquaporin’s expression and function in healthy or pro-atherogenic phenotype. We first confirmed key features of endothelium dysfunction and activation in our cell model, including an augmented endothelial transmigration under hypomethylation. Subsequently, we found AQP1 and AQP3 to be the most predominant AQPs accounting for water and glycerol fluxes, respectively, in the healthy endothelium. Moreover, endothelial hypomethylation led to decreased levels of AQP1 and impaired water permeability without affecting AQP3 and glycerol permeability. Furthermore, TNF-α treatment-induced AQP1 downregulation suggesting that the inflammatory NF-κB signaling pathway mediates AQP1 transcriptional repression in a pro-atherogenic endothelium, a possibility that warrants further investigation. In conclusion, our results add further support to AQP1 as a candidate player in the setting of endothelial dysfunction and CVD.

PARP inhibition in leukocytes diminishes inflammation via effects on integrins/cytoskeleton and protects the blood-brain barrier.

BackgroundBlood-brain barrier (BBB) dysfunction/disruption followed by leukocyte infiltration into the brain causes neuroinflammation and contributes to morbidity in multiple sclerosis, encephalitis, traumatic brain injury, and stroke. The identification of pathways that decreases the inflammatory potential of leukocytes would prevent such injury. Poly(ADP-ribose) polymerase 1 (PARP) controls various genes via its interaction with myriad transcription factors. Selective PARP inhibitors have appeared lately as potent anti-inflammatory tools. Their effects are outside the recognized PARP functions in DNA repair and transcriptional regulation. In this study, we explored the idea that selective inhibition of PARP in leukocytes would diminish their engagement of the brain endothelium.MethodsCerebral vascular changes and leukocyte-endothelium interactions were surveyed by intravital videomicroscopy utilizing a novel in vivo model of localized aseptic meningitis when TNFα was introduced intracerebrally in wild-type (PARP+/+) and PARP-deficient (PARP−/−) mice. The effects of selective PARP inhibition on primary human monocytes ability to adhere to or migrate across the BBB were also tested in vitro, employing primary human brain microvascular endothelial cells (BMVEC) as an in vitro model of the BBB.ResultsPARP suppression in monocytes diminished their adhesion to and migration across BBB in vitro models and prevented barrier injury. In monocytes, PARP inactivation decreased conformational activation of integrins that plays a key role in their tissue infiltration. Such changes were mediated by suppression of activation of small Rho GTPases and cytoskeletal rearrangements in monocytes. In vitro observations were confirmed in vivo showing diminished leukocyte-endothelial interaction after selective PARP suppression in leukocytes accompanied by BBB protection. PARP knockout animals demonstrated a substantial diminution of inflammatory responses in brain microvasculature and a decrease in BBB permeability.ConclusionsThese results suggest PARP inhibition in leukocytes as a novel approach to BBB protection in the setting of endothelial dysfunction caused by inflammation-induced leukocyte engagement.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0729-x) contains supplementary material, which is available to authorized users.

Does Aldosterone Play a Significant Role for Regulation of Vascular Tone?

Besides the well-known renal effects of aldosterone, the hormone is now known to have direct vascular effects. Clinical observations underline substantial adverse effects of aldosterone on cardiovascular function. The source of systemic circulating aldosterone is the adrenal gland zona glomerulosa cells through stimulus-secretion coupling involving depolarization, opening of L- and T-type calcium channels and aldosterone synthase activation. Local formation and release in peripheral tissues such as perivascular fat is recognized. Where does aldosterone affect the vasculature? Mineralocorticoid receptors (MRs) are present in endothelial and vascular smooth muscle cells, and MR-independent pathways are also involved. The vascular effects of aldosterone are complex, both concentration and temporal and spatial aspects are relevant. The acute response includes vasodilation through endothelial nitric oxide formation and vasoconstrictor effects through endothelial-contracting cyclooxygenase-derived factors and a changed calcium handling. The response to aldosterone can change within the same blood vessels depending on the exposure time and status of the endothelium. Chronic responses involve changed levels of reactive oxygen radicals, endothelial Na-influx and smooth muscle calcium channel expression. Furthermore, perivascular cells for example mast cells have also been suggested to participate in the chronic response. Moreover, the vascular effect of aldosterone depends on the status of the endothelium which is likely the cause of the very different responses to aldosterone and MR treatment observed in human studies going from increased to decreased flow depending on whether the patient had prior cardiovascular disease with endothelial dysfunction or not. A preponderance of constrictor versus dilator responses to aldosterone could therefore be involved in the detrimental vascular actions of the hormone in the setting of endothelial dysfunction and contribute to explain the beneficial action of MR blockers on blood pressure and target organ injury.

Diverse Functions of Endothelial NO Synthases System: NO and EDH.

:Endothelium-dependent relaxations are predominantly regulated by nitric oxide (NO) in large conduit arteries and by endothelium-dependent hyperpolarization (EDH) in small resistance vessels. Although the nature of EDH factors varies depending on species and vascular beds, we have previously demonstrated that endothelial NO synthases (eNOS)-derived hydrogen peroxide (H2O2) is an EDH factor in animals and humans. This vessel size-dependent contribution of NO and EDH is, at least in part, attributable to the diverse roles of endothelial NOSs system; in large conduit arteries, eNOS mainly serves as a NO-generating system to elicit soluble guanylate cyclase–cyclic guanosine monophosphate-mediated relaxations, whereas in small resistance vessels, it serves as a superoxide-generating system to cause EDH/H2O2-mediated relaxations. Endothelial caveolin-1 may play an important role for the diverse roles of NOSs. Although reactive oxygen species are generally regarded harmful, the physiological roles of H2O2 have attracted much attention as accumulating evidence has shown that endothelium-derived H2O2 contributes to cardiovascular homeostasis. The diverse functions of endothelial NOSs system with NO and EDH/H2O2 could account for a compensatory mechanism in the setting of endothelial dysfunction. In this review, we will briefly summarize the current knowledge on the diverse functions of endothelial NOSs system: NO and EDH/H2O2.

Induction of Haemeoxygenase-1 Improves FFA-Induced Endothelial Dysfunction in Rat Aorta

Background: The induction of haemeoxygenase-1 (HO-1) exerts beneficial effects in the setting of endothelial dysfunction in obesity. High free fatty acid (FFA) levels are a common feature of obesity and are the primary cause of endothelial dysfunction. The objective of our study was to explore the effects of HO-1 induction on FFA-induced endothelial dysfunction in rats. Methods: Rats received FFA treatment with either cobalt protoporphyrin (CoPP) to induce HO-1 or stannous protoporphyrin (SnPP) to inhibit HO-1. Endothelial function was determined by measuring endothelium-dependent vasodilatation (EDV). Nitric oxide (NO) production, superoxide production and nuclear factor <smlcap>(NF)-</smlcap>κ<smlcap>B </smlcap>expression in the aorta were each determined. The levels of adenosine monophosphate (AMP)-activated kinase (AMPK) and endothelial nitric oxide synthase (eNOS) expression in endothelial cells were determined via Western blotting. Results: Induction of HO-1 by CoPP decreased circulating FFA, high-sensitivity C-reactive protein and malondialdehyde levels and increased serum adiponectin and glutathione levels compared with the FFA group (P<0.05). High FFA levels resulted in EDV impairment, which was improved by HO-1 induction (P<0.05). Induction of HO-1 increased NO levels and reduced aortic superoxide production and <smlcap>NF-</smlcap>κ<smlcap>B </smlcap>expression compared with the FFA group. The FFA group exhibited decreased AMPK expression and eNOS phosphorylation, both of which were enhanced via HO-1 induction (P<0.05). The beneficial effects of CoPP on EDV were partially attenuated in vitro in the presence of inhibitors of AMPK, phosphatidylinositol 3-kinase (PI3K), and eNOS. Conclusions: HO-1 induction with CoPP improves FFA-induced endothelial dysfunction in the rat aorta. The protective mechanism appears to be related to the activation of the AMPK-PI3K-eNOS pathway as a result of increased adiponectin levels as well as decreased inflammation and oxidative stress.

Poly(ADP-ribose) polymerase-1 inhibition in brain endothelium protects the blood-brain barrier under physiologic and neuroinflammatory conditions.

Blood-brain barrier (BBB) dysfunction seen in neuroinflammation contributes to mortality and morbidity in multiple sclerosis, encephalitis, traumatic brain injury, and stroke. Identification of molecular targets maintaining barrier function is of clinical relevance. We used a novel in vivo model of localized aseptic meningitis where tumor necrosis factor alpha (TNFα) was introduced intracerebrally and surveyed cerebral vascular changes and leukocyte-endothelium interactions by intravital videomicroscopy. Poly(ADP-ribose) polymerase-1 (PARP) inhibition significantly reduced leukocyte adhesion to and migration across brain endothelium in cortical microvessels. PARP inactivation diminished BBB permeability in an in vivo model of systemic inflammation. PARP suppression in primary human brain microvascular endothelial cells (BMVEC), an in vitro model of BBB, enhanced barrier integrity and augmented expression of tight junction proteins. PARP inhibition in BMVEC diminished human monocyte adhesion to TNFα-activated BMVEC (up to 65%) and migration (80-100%) across BBB models. PARP suppression decreased expression of adhesion molecules and decreased activity of GTPases (controlling BBB integrity and monocyte migration across the BBB). PARP inhibitors down-regulated expression of inflammatory genes and dampened secretion of pro-inflammatory factors increased by TNFα in BMVEC. These results point to PARP suppression as a novel approach to BBB protection in the setting of endothelial dysfunction caused by inflammation.

Contribution of sympathetic activation to coronary vasodilatation during the cold pressor test in healthy men: effect of ageing

The sympathetic nervous system is an important regulator of coronary blood flow. The cold pressor test (CPT) is a powerful sympathoexcitatory stressor. We tested the hypotheses that: (1) CPT-induced sympathetic activation elicits coronary vasodilatation in young adults that is impaired with advancing age and (2) combined α- and β-adrenergic blockade diminishes/abolishes these age-related differences. Vascular responses of the left anterior descending artery to the CPT were determined by transthoracic Doppler echocardiography before (pre-blockade) and during (post-blockade) systemic co-administration of α- and β-adrenergic antagonists in young (n = 9; 26 ± 1 years old, mean ± SEM) and older healthy men (n = 9; 66 ± 2 years old). Coronary vascular resistance (CVR; mean arterial pressure/coronary blood velocity) was used as an index of vascular tone. CPT decreased CVR (i.e. coronary vasodilatation occurred) in young ( -33 ± 6%), but not older men ( -3 ± 4%; P < 0.05 vs. young) pre-blockade. Adrenergic blockade abolished CPT-induced coronary vasodilatation in young men ( -33 ± 6% vs. 0 ± 6%, pre-blockade vs. post-blockade, respectively; P < 0.05) such that responses post-blockade mirrored those of older men ( -3 ± 4% vs. 8 ± 9%; both P > 0.05 compared to young pre-blockade). Impaired CPT-induced coronary vasodilatation could not be explained by a reduced stimulus for vasodilatation as group and condition effects persisted when CVR responses were expressed relative to myocardial oxygen demand (rate-pressure product). These data indicate that the normal coronary vascular response to sympathetic activation in young men is pronounced vasodilatation and this effect is lost with age as the result of an adrenergic mechanism. These findings may help explain how acute sympathoexcitation may precipitate angina and coronary ischaemic events, particularly in older adults.

Uncoupling of VEGF with Endothelial NO as a Potential Mechanism for Abnormal Angiogenesis in the Diabetic Nephropathy

Abnormal angiogenesis is a well characterized complication in diabetic retinopathy and is now recognized as a feature of diabetic nephropathy. The primary growth factor driving the increased angiogenesis in diabetic retinopathy and nephropathy is vascular endothelial growth factor (VEGF). While VEGF is considered an important growth factor for maintaining glomerular capillary integrity and function, increased action of VEGF in diabetic renal disease may carry adverse consequences. Studies by our group suggest that the effects of VEGF are amplified in the setting of endothelial dysfunction and low nitric oxide (NO) levels, which are a common feature in the diabetic state. The lack of NO may amplify the effects of VEGF to induce inflammation (via effects on the macrophage) and may lead to dysregulation of the vasculature, exacerbating features of diabetic renal disease. In this review, we summarize how an “uncoupling” of the VEGF-NO axis may contribute to the pathology of the diabetic kidney.

Mechanisms and consequences of salt sensitivity and dietary salt intake.

Investigation into the underlying mechanisms of salt sensitivity has made important advances in recent years. This review examines in particular the effects of sodium and potassium on vascular function. Sodium chloride (salt) intake promotes cutaneous lymphangiogenesis mediated through tissue macrophages and directly alters endothelial cell function, promoting increased production of transforming growth factor-β (TGF-β) and nitric oxide. In the setting of endothelial dysfunction, such as occurs with aging, diminished nitric oxide production exacerbates the vascular effects of TGF-β, promoting decreased arterial compliance and hypertension. Dietary potassium intake may serve as an important countervailing influence on the effects of salt in the vasculature. There is growing appreciation that, independently of alterations in blood pressure, dietary intake of sodium and potassium promotes functional changes in the vasculature and lymphatic system. These changes may protect against development of salt-sensitive hypertension. While salt sensitivity cannot be ascribed exclusively to these factors, perturbation of these processes promotes hypertension during high-salt intake. These studies add to the list of genetic and environmental factors that are associated with salt sensitivity, but in particular provide insight into adaptive mechanisms during high salt intake.

Therapeutic Angiogenesis in Diabetes and Hypercholesterolemia: Influence of Oxidative Stress

Despite significant improvements in the medical, percutaneous, and surgical management, numerous patients are first seen with non-revascularizable coronary artery disease (CAD). The growth of new blood vessels to improve myocardial perfusion (i.e., therapeutic angiogenesis) is an attractive treatment option for these patients. However, the successes of angiogenic therapy, observed in preclinical studies, have not been realized in clinical trials. Increasing evidence suggests that this discrepancy between animal and human studies may be due to the nature of the substrate, or the molecular and cellular environment within which the angiogenic agent acts. Antiangiogenic influences, including endothelial dysfunction, hypercholesterolemia, and diabetes, are present in virtually all patients with advanced CAD. Recent studies have better characterized the abnormalities associated with these disease states, providing novel targets for intervention. These substrate-modifying interventions can potentially enhance the response to protein-, gene-, or cell-based angiogenic therapy. In this review, we discuss key aspects of the angiogenic process and the pathophysiologic and molecular mechanisms that contribute to an impaired angiogenic response in the setting of endothelial dysfunction, hypercholesterolemia, and diabetes, with a focus on the role of oxidative stress. Last, we briefly explore substrate modifying agents that have been evaluated in preclinical and clinical studies to improve the angiogenic response.

Endothelial dysfunction—An obstacle of therapeutic angiogenesis

Due to ageing populations and improvements in survival, increasing numbers of patients suffering from ischemic cardiovascular disease are not amenable to revascularization. Hence, interests are currently focused on “therapeutic angiogenesis”, which is the clinical use of growth factors to enhance or promote the development of collateral blood vessels in ischemic tissue. Several growth factors (or genes encoding these growth factors) are now available for therapeutic vascular growth in normal and ischemic tissues. However, the successes of angiogenic therapy observed in pre-clinical studies have not been realized in clinical trials. Most animal studies demonstrating the physiologic effectiveness of angiogenic therapies have been performed in normal young animals, while clinical trials typically enroll older patients with various endothelial disruptive risk factors. The promising results of trials using endothelial function-improving strategies support the hypothesis that the decreased effectiveness of growth factor therapy due to endothelial dysfunction could be a principle reason for failure of trials using growth factors. We will have a retrospection of therapeutic angiogenesis trials and discuss the mechanisms that contribute to an impaired angiogenic response in the setting of endothelial dysfunction. We also briefly explore endothelial function-improving procedures that have the potentially therapeutic benefit of enhancing the angiogenic response.

A new mouse model resembling human diabetic nephropathy: uncoupling of VEGF with eNOS as a novel pathogenic mechanism

Diabetics develop a variety of histological abnormalities in the kidney. Early features include glomerular hypertrophy, glomerular basement membrane thickening, and mesangial expansion, whereas mesangiolysis, glomerular capillary aneurysm and nodular lesions develop in late phase. The goal of preventing diabetic nephropathy is important, but its achievement has been difficult due in part to a lack of an animal model for human diabetic nephropathy. Most animal models develop mild lesions in early phase diabetes, but not advanced lesions in late phase. Vascular endothelial growth factor (VEGF) mediates diabetic nephropathy, but its precise role remains to be determined. A complexity of VEGF function is that it is protective in nondiabetic renal diseases but is deleterious in diabetic nephropathy. Because diabetes is associated with endothelial dysfunction, we hypothesized that VEGF is deleterious in the setting of endothelial dysfunction. To test this hypothesis, we recently developed a new model of diabetic nephropathy in mice deficient in endothelial nitric oxide synthase (eNOS). Importantly, these mice developed the advanced lesions of diabetic nephropathy resembling to those in human diabetic nephropathy. In addition, these models also exhibit an uncoupling condition of VEGF with NO. In this review, we discuss our hypothesis which is that uncoupling of VEGF with NO causes advanced diabetic nephropathy.

Spermine and Endothelial Damage During Endotoxemia

Diazenolate-NO-donors like spermine-NONOate use spermine as a nitric oxide releasing carrier. As one of the naturally occurring polyamines, spermine belongs to the most potent platelet aggregation inhibitors among the polyamines. Recent publications describe a dominating role for platelets and nitric oxide in the setting of endothelial dysfunction during endotoxemia. It is unknown whether spermine as single agent, beside his function as nitric oxide releasing carrier, exerts effects on macromolecular leakage during early endotoxemia. In male Wistar rats, macromolecular efflux was determined in mesenteric postcapillary venules using intravital microscopy at baseline, 60 and 120 min after the start of the experiment. In the first part of the experiments we investigated the effects of spermine and spermine-NONOate during leukocyte-independent states of endotoxemia, using the L- and P-selectin inhibitor fucoidin to suppress leukocyte-endothelial-interaction. In the second part we investigated the effects of spermine on endothelial damage during endotoxemia without co-administration of fucoidin. Combined treatment of animals with spermine and fucoidin was as effective as treatment with spermine-NONOate and fucoidin alone. Spermine and fucoidin as single agents had no effects on macromolecular efflux during endotoxin challenge. Combined treatment of animals with spermine and fucoidin reduce macromolecular efflux to the same degree like treatment with spermine-NONOate and fucoidin. A currently unknown interaction between fucoidin and spermine leads to a significant reduction in macromolecular efflux.

Detection of retained microbubbles in carotid arteries with real-time low mechanical index imaging in the setting of endothelial dysfunction

We sought to determine if intravenously injected microbubbles would be retained by the carotid arteries (CAs) in the setting of endothelial dysfunction (ED) using a linear transducer equipped with a low mechanical index pulse sequence scheme (PSS). Microbubbles normally pass freely through large and small vessels but are retained in regions with ED. New high-frequency low mechanical index PSS can potentially be utilized to image these retained microbubbles. Intravenous albumin- and lipid-encapsulated microbubbles were administered in seven pigs while imaging the CAs before and after a 20% intralipid infusion to induce hypertriglyceridemia. The degree of microbubble retention was quantified by measuring endothelial acoustic intensity (AI) after clearance of free-flowing microbubbles. Microbubble adherence was also evaluated after selective balloon injury of the CAs. The CA diameter responses to acetylcholine were quantified. After induction of hypertriglyceridemia, adherence of albumin-encapsulated microbubbles was visually evident in all CAs, and endothelial AI increased significantly (p < 0.001 compared with baseline). The CA responses to acetylcholine went from vasodilation at baseline to vasoconstriction during hypertriglyceridemia. Endothelial AI also increased in the balloon-stretched vessels (p < 0.01 compared with uninjured vessels) after albumin-encapsulated microbubble injection, with a ring of microbubbles selectively adhering to the injured segment. This retention was not observed with lipid-encapsulated microbubbles. Scanning electron microscopy confirmed that albumin-coated microbubbles adhered to endothelial cells. Retention of intravenously injected albumin microbubbles occurs in the setting of both global and regional ED in large vessels and can be noninvasively imaged with high-frequency low mechanical index PSS.

Nitroglycerin-induced coronary vasodilation is not enhanced in patients with impaired endothelium-dependent dilation

Objectives. This study was designed to determine whether enhanced sensitivity to exogenous nitrovasodilators is present in the coronary arteries of patients with impaired endothelium-dependent dilation.Background. Animal studies have demonstrated that the dilator response to exogenous nitrovasodilators is exaggerated in the setting of endothelial dysfunction (diminished nitric oxide activity). Whether such relative hyperresponsiveness to exogenous nitrates occurs and is important in humans is unknown.Methods. We assessed coronary vasomotion in 110 patients (mean [±SD] age 56 ± 10 years) by serial intracoronary infusions of acetylcholine (10−8 to 10−6 mol/liter) to test endogenous nitric oxide and nitroglycerin (40 μg) to test responses to exogenous nitrovasodilators.Results. The vasomotor response to 10−6 mol/liter of acetylcholine differed between patients with (n = 95) and those without (n = 15) normal endothelial dysfunction (−21 ± 14% vs. 12 ± 8% respectively, p < 0.001). However, neither the dilator response to nitroglycerin (21 ± 14% vs. 18 ± 13%) nor the baseline diameter differed between those with endothelial dysfunction and normal function, respectively. There was no correlation between the magnitude of the dilator response to nitroglycerin and acetylcholine. The response to nitroglycerin was decreased with increasing age (r = −0.21, p = 0.03) but was not related to any other demographic factors or to the angiographic appearance of the vessel.Conclusions. The coronary vasodilator response to nitroglycerin is not significantly enhanced in patients with impaired endothelium-dependent dilation but decreases with increasing age. This finding provides indirect evidence that basal coronary tone is not increased in patients with endothelial dysfunction and that supersensitivity to exogenous nitrates is not clinically important in humans.

Beneficial actions of nitrates in cardiovascular disease

Nitroglycerin and the long-acting nitrates have been used in cardiovascular medicine for > 100 years. Nitrates are widely utilized for the various anginal syndromes and are also used in congestive heart failure and patients with left ventricular dysfunction. The potential mechanisms for relief of myocardial ischemia with nitrates are multiple. The nitrovasodilators are a related group of drugs that result in the formation of nitric oxide (NO) within vascular smooth muscle cells. NO stimulates the enzyme guanylate cyclase, which results in increases in cyclic guanosine monophosphate and vasodilation. In the presence of atherosclerosis, endothelial dysfunction is ubiquitous and associated with decreased NO availability, probably due to increased destruction of NO by free radical anions. Nitrovasodilators, including the nitrates, supply exogenous NO to the vascular wall and improve the vasodilator state. When nitrates are administered, endothelial-dependent stimuli cause relaxation rather than constriction in the setting of endothelial dysfunction. Nitrates also have antiplatelet effects, and recent evidence confirms that these drugs decrease platelet aggregation and thrombosis formation. This may play an important role in the therapy of acute unstable myocardial ischemia, including unstable angina and myocardial infarction. Nitrate hemodynamic effects have been long known. They are primarily modulated through a decrease in myocardial work that results from smaller cardiac chambers operating with lower systolic and diastolic pressures. These changes are caused by a redistribution of the circulating blood volume away from the heart to the venous capacitance system, with a fall in venous return to the heart. The afterload or arterial effects of nitrates are also useful in decreasing myocardial oxygen consumption. Considerable evidence confirms a variety of mechanisms whereby nitrates increase coronary blood flow, including epicardial coronary artery dilation, stenosis enlargement, enhanced collateral size and flow, improvement of endothelial dysfunction, and prevention or reversal of coronary artery vasoconstriction. These effects help increase nutrient coronary blood flow to zones of myocardial ischemia. Recent data with the nitroglycerin patch confirm that myocardial ischemia is decreased after nitrate administration. Nitroprusside, another nitrovasodilator, is a commonly used intravenous agent for lowering arterial pressure and left ventricular filling pressure. This drug is highly effective for the treatment of acute or severe hypertension and congestive heart failure. However, there are data suggesting that nitroprusside may be deleterious in the presence of acute myocardial ischemia, perhaps by shunting blood away from zones of jeopardized myocardial blood flow. Therefore, nitroprusside cannot be recommended to treat myocardial ischemia; intravenous nitroglycerin should be used in this context.