Jacobs Journal of Community Medicine

Impact of Oxide of Nitrogen in the Management of Acute Coronary Syndrome at Tamale Teaching Hospital (TTH)

Abdallah Iddrisu Yahaya
Department Of Medicine And Allied Science, University For Development Studies, UDS, Head Of Chest Unit, Tamale Teaching Hospital (TTH), Ghana,, Central African Republic

Published on: 2019-05-17

Abstract

Keywords

Oxide of Nitrogen,Acute Coronary Syndrome,Hospital

Introduction

Acute Coronary Syndrome “This is an absolute medical emergency. Something dramatic, right this minute is going on in the arteries that is hurting the blood flow to the heart,” said Ann Bolger, M.D., a cardiologist at San Francisco General Hospital and a member of the American Heart Association’s Council on Clinical Cardiology. The blockage can be sudden and complete, or it can come and go – clot, break open, and then clot again. “In either case, the heart tissue is dying, even if it’s just a few cells or a whole big section of the heart,” Bolger said. Doctors use the broad term regularly, but usually only among themselves and in the medical literature. “It’s like describing a North American state rather than just saying Texas,” Bolger said. “I don’t think too many doctors say, ‘You’re having an acute coronary syndrome.’ They say, ‘You’re having a heart attack.’”

What Are The Symptoms?

Chest pain or discomfort may immediately signal to you that something’s wrong with your heart. Other symptoms, however, may leave you unsure of what’s wrong. Take note of these common signs of an acute coronary syndrome:

1. Chest pain or discomfort, which may involve pressure, tightness or fullness

2. Pain or discomfort in one or both arms, the jaw, neck, back or stomach

3. Shortness of breath

4. Feeling dizzy or lightheaded

5. Nausea

6. Sweating

These symptoms should be taken seriously. If you experience chest pain or other symptoms, immediately. “People are in denial and they’re sitting there thinking, ‘This can’t really be happening to me,’” Bolger said. “We want them to feel entitled to. They’re not being alarmist.” Chest pain caused by acute coronary syndromes can come on suddenly, as is the case with a heart attack. Other times, the pain can be unpredictable or get worse even with rest, both hallmark symptoms of unstable angina. People who experience chronic chest pain resulting from years of cholesterol buildup in their arteries can develop an acute coronary syndrome if a blood clot forms on top of the plaque buildup.

How Is It Diagnosed And Treated?

To determine what’s causing your symptoms, a doctor will take a careful medical history and give you a physical examination. If the doctor suspects an acute coronary syndrome, the following tests will be performed:

  1. A blood test can show evidence that heart cells are dying.(Cardiac Triponin)
  2. An electrocardiogram (ECG or EKG) can diagnose an acute coronary syndrome by measuring the heart’s electrical activity.

If tests confirm blood flow to the heart has been blocked, doctors will work quickly to reopen the artery. “Minute by minute, the heart is accumulating irreversible damage. So time is myocardium – myocardium being the heart muscle itself,” Bolger said. At San Francisco General Hospital, the goal is to have the artery reopened within an hour of the patient entering the hospital, Bolger said. Generally, patients do best when the artery is reopened within four hours of the first symptoms. Treatment for acute coronary syndrome includes medicines and a procedure known as angioplasty, during which doctors inflate a small balloon to open the artery. View an illustration of coronary arteries. A stent, a wire mesh tube, may be permanently placed in the artery to keep it open. For hospitals not equipped to do angioplasty quickly, drugs may be used to dissolve blood clots, but more hospitals are making the procedure available in a timely manner, Bolger said.

Am I At Risk?

Acute coronary syndromes, just like heart failure and stroke, are much more likely in people who have certain risk factors. These include:

1. Smoking

2. High blood pressure

3. High blood cholesterol

4. Diabetes

5. Physical inactivity

6. Being overweight or obese

7. A family history of chest pain, heart disease or stroke

Your primary care doctor can help you understand your personal risk and what you can do about it. “[The phy- 3 sician] should also be the one to say, ‘By the way, if you ever have any of these symptoms, I want you to,’” Bolger said. “If someone has told you that in advance, you’re much more likely to do it.”

Pathophysiology

In those who have ACS, atheroma rupture is most commonly found 60% when compared to atheroma erosion (30%), thus causes the formation of thrombus which block the coronary arteries. Plaque rupture is responsible for 60% in ST elevated myocardial infarction (STEMI) while plaque erosion is responsible for 30% if the STEMI and vice versa for Non ST elevated myocardial infarction (NSTEMI). In plaque rupture, the content of the plaque are lipid rich, collagen poor, with abundant inflammation which is macrophage predominant, and covered with a thin fibrous cap. Meanwhile, in plaque erosion, the plaque is rich with extracellular matrix, proteoglycan, glycosaminoglycan, but without fibrous caps, no inflammatory cells, and no large lipid core. After the coronary arteries are unblocked, there is a risk of reperfusion injury due spreading inflammatory mediators throughout the body. An investigation is still underway on the role of Cyclophilin#Cyclophilin D in reducing the reperfusion injury.

Prediction scores

The ACI-TIPI score can be used to aid diagnosis; using seven variables from the admission record, this score predicts crudely which patients are likely to have myocardial ischemia [1]. For example, according to a randomized controlled trial, males having chest pain with normal or non-diagnostic ECG are at higher risk for having acute coronary syndrome than women [2]. In this study, the sensitivity was 65.2% and specificity was 44%. This particular study had an 8.4% prevalence of acute coronary syndrome, which means the positive predictive value of being a male with chest pain and having coronary syndrome is 9.6% and negative predictive value is 93.2%.

In a second cohort study, exercise electrocardiography was similarly found to be a poor predictor of acute coronary syndrome at follow-up [3]. Of the patients who had a coronary event at 6 years of follow up, 47% had a negative ECG at the start of the study. With an average follow up of 2.21 years the receiver operating characteristic curves gave resting ECG a score of 0.72 and exercise ECG a score of 0.74.

There are not only prediction scores for diagnosis of ACS, but also prognosis. Most notably, the GRACE ACS Risk and Mortality score helps diagnose, and based upon that score predicts mortality rate of a given patient. It takes into account both clinical (blood pressure, heart rate, EKG findings) and medical history in its scoring system.

Prevention

Acute coronary syndrome often reflects a degree of damage to the coronaries by atherosclerosis. Primary prevention of atherosclerosis is controlling the risk factors: healthy eating, exercise, treatment for hypertension and diabetes, avoiding smoking and controlling cholesterol levels; in patients with significant risk factors, aspirin has been shown to reduce the risk of cardiovascular events. Secondary prevention is discussed in myocardial infarction. After a ban on smoking in all enclosed public places was introduced in Scotland in March 2006, there was a 17% reduction in hospital admissions for acute coronary syndrome. 67% of the decrease occurred in non-smoker

Background of the Research

Urban populations in the developing world are growing rapidly and at an accelerating rate. Rural-to-urban transitions are often associated with marked changes in behavior and lifestyle, such as diminished physical activity, sedentary employment, poorer dietary habits, and increased psychosocial stress. In part because of these emerging risk factors, over 80% of the global burden of cardiovascular disease (CVD) has now shifted to low- and middle-income countries. While proper screening and preventive strategies have reduced CVD in high-income countries, individuals at risk in the developing world are much less likely to be identified and treated, because of poor infrastructure, inadequate resources, and a lack of awareness regarding CVD and its symptoms in general.

The fastest rate of urbanization worldwide is occurring in sub-Saharan Africa, driven by high fertility rates and rapid industrialization [4]. The transition from pre-in- 4 dustrial to industrialized economies has initiated an epidemiological transition from illnesses related to malnutrition, childbirth, and infection, towards chronic, non-communicable diseases, such as CVD. However, the epidemiological transition in sub-Saharan Africa is still in its early stages. As a consequence, diseases such as HIV and malaria continue to strain limited resources and dominate the public consciousness, while CVD and its often-subclinical symptoms are overlooked. Thus, populations are becoming older and more vulnerable to CVD at a time when surveillance capacities remain poor and skilled health workers scarce.

Our knowledge of CVD epidemiology in sub-Saharan Africa is incomplete [5]. Early surveys (pre-1990) revealed that risk factors such as hypertension and diabetes were rare, fueling the hypothesis that CVD is not of substantial public health interest. More recently, this view has begun to change. Nonetheless, variation in study designs and the diversity of the populations being studied have generated an often-confusing picture. While some reports suggest that the proportion of disease burden attributed to CVD in sub-Saharan Africa may still be relatively low (primarily on account of persistent infectious disease-related mortality), the average age of death from CVD is the youngest in the world. Thus, all the makings of a CVD epidemic are in place, as both life expectancy and urban populations increase.

Much of our understanding of CVD risk is based on studies of European populations, despite the fact that both the prevalence of risk factors and their relation to CVD endpoints differ among ethnic groups. Existing risk assessment algorithms, such as the Framingham score, may consequently be prone to error when applied globally. Moreover, while such algorithms are typically calculated separately for males and females, the effect of sex on CVD incidence and risk profile can also vary with culture and ethnicity [6,7]. Indeed, sex-specific effects appear to be more pronounced in the developing world, perhaps owing to differences in cultural practices and social behavior [8-10]

Given these heterogeneities of CVD risk profiles by sex, environment, and population, a multifactorial approach to CVD assessment and intervention is essential. Here, we describe how major CVD risk factors, including dyslipidemia, hypertension, obesity, and diabetes, are distributed among urban and rural Ghanaian men and women from a single ethnic group. In addition to the conventional CVD risk factors, we also assess plasma levels of two fibrinolysis ally active enzymes that may provide deeper insight into CVD risk and pathophysiology [11], plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA). PAI-1 impedes the removal of thrombi from the vascular system by binding to and neutralizing t-PA’s thrombolytic properties, such that high circulating PAI-1 increases the risk of thromboembolic events [12,13], while also playing a role in atherosclerosis [14]. Our overriding goal is to evaluate the prevalence of CVD risk factors in the region and to understand some of the conditions that may give rise to them, establishing a baseline for future comparisons and setting guidelines for appropriate recommendations.

Literature Review

Organic nitrates still are one of the most important drug classes used in the treatment of an acute coronary syndrome and stable coronary artery disease as well as acute and chronic congestive heart failure. The mechanism of vasodilatation comprises the release of nitric oxide. Which in turn activates soluble granulates cyclase and lowers the intracellular calcium content leading to relaxation of vascular smooth muscle. Recent research has demonstrated that highly reactive nitrates, such as nitroglycerin (or glyceryl trinitrate) and pentaerthrity l tetra nitrate (PETN) are bioactivated by aldehyde dehydrogenase 2 (ALDH-2), an enzyme located in mitochondria. The enzyme, which bioactivates mono- and denigrates is not yet identified. Despite being effective in the acute treatment of patients, its longterm efficacy is limited by the development of tolerance to nitrates and of endothelial dysfunction. Both of these side effects of nitrate therapy are due to increased production of reactive oxygen species. This review focuses on new aspects of the process of bioactivation of organic nitrates, the conception of oxidative stress of endothelial dysfunction and of the development of tolerance and their therapeutic consequences. Also discussed are more recent findings on nitric oxide donors such as molsidomine, PETN and the combination treatment of isosorbide denigrate and hydralazine of patients with coronary artery disease and chronic heart failure [4].

As concluded by Adeagbo et al 2002, cyclooxygenase-2 is constitutively expressed in rat aortic endothelial and smooth muscle cells and NS-398 modulates aortic contractions principally through an action on endothelial cyclooxygenase-2. The data strongly suggest that cyclooxygenase-2, in concert with endothelium- derived nitric oxide, regulate the Ca2+ pump function in rat aorta. The data suggest that this no steroidal anti-inflammatory drug directly inhibits the leakage (released) of Ca2+ from the sarcoplasmic reticulum in an endothehum derived nitric oxide-dependent manner. This assertion is supported by our finding that exposure of endothelium-denuded, or L-NAME-treated aortic rings to sodium nitrite restores NS-398 effectiveness in blocking contractions elicited by cyclopiazonic acid and norepinephrine (see Table 2). Since sodium nitrite generates nitric oxide at physiological pH such as prevails in our experimental conditions, or at acidic pH (Modin et al, 2001), it can be deduced from the present study that endothelium-derived nitric oxide influences Ca2+ release/ uptake into sarcoplasmic reticulum. This deduction is compatible with the possibility that NS-398 May inhibit the production of an endothelial cyclooxygenase-2-mediated product that facilitates aortic contractility through the regulation of Ca2+ homeostasis by the sarcoplasmic reticulum. Connolly et al. (1998) attributed the blockade of rat aortic contractions by nimesulide, a compound chemically related to NS-398 to inhibition of the production of the production of an endogenous facilitator of vascular contractions [4].

Methodology

Cross Sectional Approach, Analysis of secondary data, adopted from my previews thesis entitled: A selective cyclooxygenase-2 blocker acutely inhibits receptor-mediated contractions of rat aorta: role of endothelium in 29th October, 2002. Multiple case studies on the male and female wards of internal medicine department, Retrospective analysis of records of patients of Acute Coronary Syndrome- at T.T.H.

Progression of Atherosclerotic Plaque: Role of Inflammation

Once the endothelium has been damaged, the inflammatory cells, especially monocytes, migrate into the sub endothelium by binding to endothelial adhesion molecules; once in the sub endothelium, they undergo differentiation, becoming macrophages. Macrophages digest oxidized low-density lipoprotein (LDL) that has also penetrated the arterial wall, transforming into foam cells and causing the formation of fatty streaks. The activated macrophages release chemo attractants and cytokines (eg, monocyte chemo attractant protein 1, tumor necrosis factor α, and interleukins) that perpetuate the process by recruiting additional macrophages and vascular smooth muscle cells (which synthesize extracellular matrix components) at the site of the plaque. Macrophages also elaborate matrix metalloproteinase, enzymes that digest the extracellular matrix and lead to plaque disruption.3 The ratio between smooth muscle cells and macrophages plays an important role in plaque vulnerability and the propensity for rupture. Although plaque rupture may result in ACS, more often, in fact in 99% of cases, it is clinically silent.7 The rate of progression of atherosclerotic lesions is variable, nonlinear, and unpredictable.

Therapeutic Goals and Approaches for ACS

The severity of findings on coronary angiography and angioscopy parallels the clinical severity of ACS. Although only white clots are found in patients with UA/ NSTEMI,33 red clots form in patients with STEMI.34 The differences in the underlying pathophysiology of UA/ NSTEMI and STEMI call for different therapeutic goals and approaches. In UA/NSTEMI, the goal of antithrombotic therapy is to prevent further thrombosis and to allow endogenous fibrinolysis to dissolve the thrombus and reduce the degree of coronary stenosis35-39; revascularization is frequently used to increase blood flow and prevent reclusion or recurrent ischemia.40 In contrast, in STEMI, the infarct-related artery is usually totally occluded, and immediate pharmacological or catheter-based reperfusion is the initial approach, with the goal of obtaining normal coronary blood flow.41 Other therapies, such as anti-ischemic and lipid-lowering therapies, are used in all cases to stabilize plaques over the long term.

Early Assessment

The symptoms of UA/NSTEMI and STEMI are similar, and differentiating the two requires medical evaluation and 12-lead electrocardiography (ECG). The 2007 guidelines for managing UA/NSTEMI, released by the American College of Cardiology (ACC) and the American Heart Association (AHA), state that patients with symptoms suggestive of ACS should be instructed to call 9-1-1 and should be referred to a facility that has capabilities for 12-lead ECG recording, biomarker determination, and evaluation by a physician (eg, an emergency department [ED]).42 Patients who have previously been given a prescription for nitroglycerin should be instructed to promptly take 1 dose of nitroglycerin sublingually for chest discomfort or pain. If no relief occurs, or if symptoms worsen 5 minutes after 1 dose of nitroglycerin has been taken, the patient should immediately call 9-1-1.42 Patients at increased risk of ACS, such as those with known coronary artery disease (CAD), peripheral vascular disease, cerebral vascular disease, diabetes, or a 10-year Framingham risk of CAD of 20% or higher, should be targeted by health care professionals and should be educated about recognizing the symptoms of ACS and calling 9-1-1 promptly if such symptoms occur.

Western blot analysis for cyclooxygenase-2

Western immunoblotting analyses were performed in order to determine the locus (endothelium and/or vascular smooth muscle cells) of cyclooxygenase-2 protein expression in rat aortic vessels. Total cellular proteins were obtained by glass-glass homogenization of freshly isolated, to react selectively with cyclooxygenase-2, but not cyclooxygenase-l (Zimmermann et al., 1999).Blots were subsequently incubated with horseradish peroxidase-conjugated goat anti-mouse secondary antibody (l: 10,000 dilution; Bio-Rad). Signal detection was facilitated with enhanced chemiluminescence (ECL, Amersham). Proteins extracted from normal rat testes and lipopolysaccharide-treated rat kidney were used as positive controls for cyclooxygenase-l and -2, respectively. Specific signals were analyzed using a densitometer (Personal Densitometer SI, Molecular Dynamics) and the ImageQuant software (Molecular Dynamics) and compared using paired Hest. A P-value less than 0.05 was considered as significant.

Figure 1: Effect of NS-398 on responses initiated by norepinephrine in endothelium-intact (+ ENDO; left panel) or endothelium-denuded (-ENDO; right panel) rat aortic rings. The PSS bathing the tissues contained cycloheximide (CHX, 10 1-1M). In both panels, (O) represents responses to norepinephrine alone, while (O), (A) and represent responses to norepinephrine in the presence of l, 3 and 10 BM NS-398, respectively. Each data point on the graphs represents the mean ± S.E.M., n=8; *** and *** denote statistical differences (P<0.05) between Emax of control and treated tissues to norepinephrine.

Figure 2: Effect of NS-398 on responses initiated by 5-hydroxyfiyptamine (5-HT) in endothelium-intact (+ENDO; left panel) or endothelium-denuded (-ENDO; right panel) rat aortic rings. The tissue bathing PSS contained cycloheximide (CHX, 10 In both panels, (O) represents responses to 5-HT alone, while (O), (A) and represent responses to 5-HT in the presence of l, 3 and 10 HM NS-398, respectively. Each data point on the graphs represents the mean ± S.E.M., n=8; * and ** denote statistical differences (P<0.05) between 5-HT Emax of control and treated tissues.

Figure 3: Effects of NS-398 on contractions of rat aortic rings initiated by KCI or NaF (5 mg; insert). Each data point on the graphs represents the mean ± containing (mmol/l): Tris-HCl (pH 7.5) 50, ethylenediaminetetraacetic acid (EDTA) 5, ethyleneglycol-bis(ß-aminoethyl) acid (EGTA) 10, benzamidine 10 and sodium orthovanadate 1; and (in phenylmcthylsulfonyl fluoride (PMSF) 50, aprotinin 10, leupeptin 10, pepstatin A 10 and P-mercaptoethanol 0.3%. Protein concentrations were determined using the method of Bradford (Bio-Rad). Protein samples (60 ktg/lane) were electrophoresed in 10% polyacrylamide/SDS gels and transferred by electroblotting onto nitrocellulose membranes.

Blots were incubated with either a goat anti-human cyclooxygenase-l polyclonal antibody (0.6 pg/ml; Santa Cruz Biotechnology) or an anti-rat cyclooxygenase-2 monoclonal antibody (0.5 ltg/ml; Transduction Laboratories). The anti-rat cyclooxygenase-2 has been shown to react selectively with, but not cyclooxygenase-l (Zimmermann et al.,

Drugs

Norepinephrine bitartrate, 5-hydroxytryptamine maleate, sodium fluoride, acetylcholine bromide, cycloheximide, cyclopiazonic acid, dexamethasone, No-nitro-L-arginine methyl ester (I-NAME), No-nitro-D-arginine methyl ester (D-NAME) and sodium nitrite were purchased from Sigma, St. Louis, MO. NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl)-methane sulfonamide) was purchased from Cayman Chem., Ann Arbor, MI. Celecoxib (celebrex) and 5,5dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl2(51/)-furanone) or L-75286() were obtained courtesy of Dr. Leonardo Calvino and Merck Res. Labs. , Rahway, NJ, respectively. With the exception of stock solutions of norepinephrine and 5-HT which were prepared in 0.1 M hydrochloric acid and diluted as desired with distilled water, all other compounds were dissolved in dimethyl sulfoxide.

Data analysis

Results are expressed as means ± S.E.M. Statistical significance was assessed using the one-way analysis of variance (ANOVA) statistical program, and the difference between mean values were considered significant when P<0.05. pD2 values, defined as negative logEC50 (ECso; i.e., effective concentration of agonist required to produce 50% maximal response), were determined from concentration-response curves which were fitted using a sigmoidal regression with variable slope for each agonist in the absence or presence of NS-398. All analyses were performed using GraphPad Prism (GraphPad Software, San Diego, 

Results

Effect of NS-398 on vascular contractile responses

Norepinephrine (0.001-3 11M) initiated contractions of endothelium-intact aortic ring segments and NS-398 (l -10 PIM), but not its vehicle, dimethylsulfoxide, concentration dependently antagonized the contractions. NS-398 significantly decreased norepinephrine pD2 values at 3 and 10 klM (Table 1), and markedly suppressed the Emax responses at all concentrations tested (Fig. l). 5-HT (0.1-30 BM) also concentration-dependently contracted isolated aortic rings and the responses were antagonized by NS-398 (Fig. 2).As with norepinephrine, NS-398 caused significant (P<0.05) suppression of 5-HT Em ax at all concentrations of the compound used in our study. Emax values for 5-HT were more profoundly suppressed (80.8+5.4% and 93.9+2.2%) compared to norepinephrine (42.2+3.7% and 60.2+3.6%) at 3 and 10 klM NS-398, respectively. However, contractions initiated by KCI (10-100 rnM) and also by

Figure 5: Influence of a nitric oxide synthesis inhibitor L-NAME (right panel) and its inactive isomer, D-NAME (left panel), on attenuation of norepinephrine contractions by NS-398 in endothelium-intact (+ ENDO) rat aortic rings. The tissue bathing PSS also contained cycloheximide (CHX, 10 11M). In both panels, (O) represents responses to norepinephrine alone, while (O), (A) and (a) represent responses to norepinephrine in the presence of l, 3 and 10 klM NS-398, respectively. Each data point on the graphs represents the mean ± S.E.M., n=6; *** and *** denote statistical differences (P<0.05) between Emax of control.

5 mM sodium fluoride (NaF) were relatively unaffected by NS-398.

Two other chemically distinct cyclooxygenase-2-selective inhibitors, Celecoxib (1-10 HM) and compound L752860 (10-100 HM), also concentration-dependently blocked norepinephrine induced contractions. As with NS398, Celecoxib (Fig. 4) and also compound L-752860 (data not shown) decreased norepinephrine pD2 and Emax values significantly.

Discussion

Cyclooxygenase-2 is generally considered an inducible enzyme. Thus, its expression can be induced by proinllammatory cytokines, mitogens or lipopolysaccharides (Cryer and Dubois, 1998). Cyclooxygenase-2-related activity can also be enhanced by stretch-induced changes in intrinsic tone (Charente et al., 1995). The increased levels of eicosanoids associated with its induction can be suppressed by treatment with protein synthesis inhibitors such as cycloheximide and actinomycin D (Masferrer et al., 1994; Akarasereenont et al., 1995), or by glucocorticoids (Cryer and Dubois, 1998). In our current study, NS-398, the prototype cyclooxygenase-2selective inhibitor, acutely antagonized receptor-mediated contractions of rat aorta in the absence, or in the presence of protein synthesis inhibitor cycloheximide or dexamethasone. Since blockade of aortic contractions by NS-398 is acute and probably did not occur through inhibition of induced synthesis of new proteins, we hypothesize two possible targets of action for this compound in our experimental model. First, cyclooxygenase-2 proteins that are native to rat aortic tissues and thus not amenable to modulation by protein synthesis inhibition in vitro, and/or second, that NS-398 elicits a nonspecific inhibition of a signal transduction process that is common to not-epinephrine and 5-HT.

The hypothesis that aoltic tissue cyclooxygenase-2 is the target for NS-398 is attractive based on our observation that other chemically distinct inhibitors of this isozyme, namely, celecoxib and L-752860, a highly selective, tetrasubstituíed furanone cyclooxygenase-2 inhibitor

Figure 6(A): Effects of NS-398 at 3 or 10 1-1M (NS-3 and NS-10, respectively) on contractions of rat aortic rings initiated by CaC12 during priming with I ¥LM NE. (B) Bar graphs depicting the effects of DMSO, vehicle for NS-398 (20 and 60 DMS, respectively; left panel), or NS-398 itself (NS-3 and NS-IO, respectively; right panel) on aortic contractions initiated by CaCl, during priming with I BM NE. Aortic rings were bathed with Ca2+-free PSS (CF-PSS). Data plotted in each column represents the mean+S.E.M

(Riendcau et al., 1997), also inhibited receptor agonist induced contractions. We further tested the hypothesis by conducting Western blot analyses of cyclooxygenase proteins in freshly isolated aortic vessel segments. Our data show 3-fold greater expression of cyclooxygenase-2 immunoreactive proteins in endothelium intact, compared to endothelium-denuded aortic segments. This finding indicates that cyclooxygenase-2 is constitutive to both endothelium and smooth muscle cells of rat aorta. Constitutive expression of cycJooxygenase-2 has previously been demonstrated in the aorta of Wister Kyoto (WKY) rats (Garcia-Cohen et al., 2000) and in rat brain (Yamagata et al., 1993) and kidney (Harris et al., 1994; Vio et al., 1997). Bishop-Bailey et al. (1997) also found cyclooxygenase-2 mRNA in freshly prepared rat aorta with intact or disrupted endothelium. Since cyclooxygenase-2 is expressed in the aorta, our data may be interpreted to support the notion that this isozyme mediates the formation of a factor(s) that contributes to, or facilitates aortic contraction [4]. Connolly et al. (1998) suggested that cyclooxygenase-2 mediate the formation of a vasoconstrictor prostaglandin in rat aollic smooth muscle. Muscara et al. (2000) also showed cyclooxygenase-2 inhibition to reduce the scrum concentration of thromboxane B2 in hypertension.Further evidence that cyclooxygenase-2 is expressed in rat aoltic endothelium, and its product contributes to aortic contraction is shown by comparing NS-398/receptor agonist of interactions in vessels rings with/without endothelium, or treated with D- or I.-NAME to specifically determine a possible role of endothelium-derived nitric oxide. NS-398 failed to alter responsiveness to norepinephrine or 5-HT in endothelium-denuded and in L-NAME treated vessel rings

Two deductions can be made from these observations:

(1) Cyclooxygenase-2, resident in vascular endothelium, serves as the target for NS-398 action. Endothelium denudation results in concomitant decrease in cyclooxygenase-2 protein expression and a loss of product(s) associated with its activity.

(2) Endothelium-derived nitric oxide (EDNO) interacts with a cyclooxygenase-2 and/or its putative product(s) to regulate aortic vascular tone.

That NS-398 did not significantly alter contractions to 1 KCI and sodium fluoride suggest that the acute effects of the compound did not involve the voltage-gated Ca channels and activation of G-proteins/phosphatase inhibition (Adeagbo and Triggle, 1991), respectively. Therefore, our alternative hypothesis that NS-398 might act to block a regulatory event common to aw-adrenoceptors and 5-HT2 receptors deserves consideration. The possible signal transduction processes that may be altered by NS-398 include the receptor-operated Ca2+channels and/or release of Ca from an intracellular binding site such as the sarcoplasmic reticulum, or even the protein kinase C/mitogen-activated protein kinases (MAPKs) pathways. We investigated the effects of NS-398 on ligand-gated Ca2+entry by conducting contraction experiments to readmission of Ca in Aortic rings bathed in Ca2 0-free PSS and primed with not-epinephrine, or 5-HT. NS-398, or its vehicle dimethylsulfoxide, did not alter Ca2+entry facilitated by norepinephrine. However, 5-HT-mediated Ca entry was significantly decreased in the presence of dimethylsulfoxide and more profoundly decreased in the presence of NS-398. Because dimethylsulfoxide and NS-398 effects were partially restored by washing, we deduced that these compounds influenced 5-HT-driven Ca2+entry into aortic smooth muscle. Our study did not examine the effects of NS-398 on protein kinase C and other cellular kinase systems.

Calcium for physiologic function such as vascular smooth muscle contraction is distributed and sequestered into many compartments within the cell. These include the inositol triphosphate (IP3)-sensitive pool stored in the sarcoplasmic reticulum, a caffeine-sensitive pool and other stores, e.g., in the mitochondria. Since receptors activated by norepinephrine and by 5-HT, and 5-HT2, respectively, are G-protein coupled and elicit contraction of rat aorta through the phospholipase C-IP3 pathway, our study focused on the SR as the probable intracellular site of action of cycloxygenasc-2 blockade with NS-398. Homeostasis of the cytosolic Ca concentration is tightly regulated by the activity of sarcoplasmic reticulum Ca2 1 -ATPase (SERCA) or Ca2 1 pump. Cyclopiazonic acid selectively inhibits the activity of this pump (Goerger et al., 1988; Seidler et al., 1989) thus promoting leakage of Ca2 1 from its sarcoplasmic reticular storage site to initiate a slow contraction of rat aortic rings.

Conclusion

The impact of organic nitrite in the combat of Acute coronary syndrome at the clinics and wards of internal medicine of the Tamale Teaching Hospital can not be over emphasized though combined therapy with interventions: such as Oxygen therapy, Fibronolytics, Anti Coagulants and thrombolytic. It is also empirical to realize that women turn to experience to realize pain at the back rather than the sub sternal in the left side of the chest. Women do not characterize it as pain but may instead report it as numbness, tingling, sensation, palpitation, indigestion or phatic rather than chest pain as in men. From the experiment on the rat author has done by Abdallah and Adebayo at University of Louisville, endothelial derived nitrite oxides also have an impact in resisting critical vaso contractions during Acute Coronary Syndrome.

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