Role of Nitric Oxide in the Effect of Nebivolol

Role of Nitric Oxide in the Effect of Nebivolol ORIGINAL RTICLE ROLE OF NITRIC OXIDE IN THE EFFECT OF NEBIVOLOL ON ISOLATED TRACHEAL MUSCLE OF GUINEA PIG Asma Shaukat, Naila Abrar*, Ayesha Naureen**, Muhammad Nawaz*** Background: The use of beta blockers is limited by their ability to produce bronchospasm in asthmatics. Third generation ÃŽ ²-blockers like Nebivolol may show better tolerability because they may augment the release of nitric oxide (NO) from endothelial cells. However the involvement of NO in the respiratory effect of Nebivolol remains controversial. The present study, carried out on isolated tracheal muscle strips of guinea pigs, was designed to explore this controversy. Method: Varying concentration of histamine ranging from 10‑7 M to 10‑3 M were used to plot a concentration response curve on the isolated tracheal muscle strips of guinea pig and was used as a control. The same concentration response curve was plotted in presence of a fixed concentration of Nebivolol 106 M and then again in presence of a fixed concentration of L-Nitro Arginine Methyl Ester (L-NAME) 104 M and Nebivolol 106 M together in a series of experiments using six sets of isolated tracheal muscle strips in each case. Results: Nebivolol did not produce any significant shift in the concentration response curve while in the presence of L-NAME, Nebivolol shifted the histamine concentration response curve upwards and to the left. Conclusion: Nebivolol does not augment the histamine induced contraction of respiratory smooth muscle of guinea pig but in the presence of Nitric Oxide inhibitor L-NAME a significant augmentation of the same curve occurs, indicating a role of NO in the sparing of respiratory smooth muscle by Nebivolol. Keywords: Nebivolol, L-NAME, Concentration response curve, Tracheal muscle INTRODUCTION Pulmonary diseases with bronchial hyperactivity can be worsened or even precipitated by ÃŽ ²2 adrenoceptor blockage more commonly seen with non-selective ÃŽ ²-blockers.1 Nebivolol is a third generation à ¯Ã‚ Ã‚ ¢-blocker which may have advantage over classical à ¯Ã‚ Ã‚ ¢-lockers due to its sparing effect on tracheal muscle attributed to its ability to augment the release of NO from endothelial cells.2,3 The potent effects of NO on vascular smooth muscle and its presence in major conducting airways raises the possibility that it could contribute to the regulation of airway smooth muscle tone.4 However, the involvement of NO in the sparing effect of nebivolol on respiratory muscle is still controversial. Dal Negro et al, and Clini et al have reported in their in vivo study that single daily dose of nebivolol does not affect the production of exhaled NO in patients with mild to moderate asthma.5,6 Still there are some studies which report that increase in NO release by nebivolol may contribute to its respiratory effects.1,7 All the aforementioned review of literature therefore reveals the fact that there is no consensus on the role of NO in the respiratory effects of nebivolol and needs further elucidation. The present study was therefore aimed to explore the role of nitric oxide in modulating the effect of nebivolol on tracheal muscle of guinea pig. MATERIAL AND METHODS The present study has been conducted on the isolated tracheal smooth muscle of 24 guinea pigs (male and female) of Dunkin Hartley variety weighing 500 to 600 grams. Ethics Committee approval of the protocol was obtained. The animals were housed at animal house of Army Medical College, Rawalpindi at room temperature, and were given tap water ad libitum and were fed with a standard diet. Krebs Henseleit solution was used as the nutrient solution the composition of which per 1000 ml is: NaCl 118.2 mM, KCl 4.7 mM, MgSO4.7H2O 1.2 mM, CaCl2 2.5 mM, KH2PO4 1.3 mM, NaHCO3 25.0 mM, Dextrose 11.7 mM. Solutions of all drugs were prepared in the distilled water except for nebivolol the solution of which was prepared in Dimethyl sulphoxide since nebivolol is highly lipophilic and insoluble in water.8 The trachea was obtained from guinea pigs and preserved in Kreb’s solution. Rings, 2–3 mm wide were formed from it and cut into strips by a longitudinal cut on the ventral side opposite to the smooth muscle. The strip was then suspended in a tissue bath of 50 ml capacity, containing Kreb’s solution at 37  ºC and was aerated with oxygen continuously. Its one end was attached to the oxygen tube while the other end was connected to an isometric force displacement transducer. The tissue was equilibrated for 45 minutes against an imposed tension of two grams. A tension of one gram was applied to the tracheal strip continuously throughout the experiments.9 The trachealis muscle activity was recorded through the transducer on 4-channel oscillograph by adding different concentrations of histamine, i.e., 10-7 to 103 M with an interval of 10 minutes between each concentration. Six experiments were performed and the mean response for each concentration was worked out. A c oncentration response curve was obtained by plotting the percent contraction against the logarithm of concentrations. In the second group tracheal muscle strips were pretreated with fixed dose of nebivolol (106 M) for 15 minutes while in third group trachea was pretreated with L-NAME (104 M) for 15 minutes and then the same procedure was followed for different concentrations of histamine.10 In the fourth group the tracheal muscle was first pretreated with fixed concentration of L-NAME for 15 minutes followed by nebivolol again for 15 minutes. Then the same procedure was followed. The results have been expressed as Mean ±SEM using Microsoft Excel. The differences between the observations were considered significant if the p-value was less than 0.05 by using Student’s t-test. RESULTS Group-1 was taken as the control group and percent response with 103 M in group-1 was taken as 100% and responses with other concentrations were compared with it (Table-1). Table-1: Comparison of Group 1 with Group 2 Table-2: Comparison of Group 1 with Group 3 Table-3: Comparison of Group 2 with Group 4 DISCUSSION From the above findings, it is inferred that nebivolol has no significant effect on histamine-induced contractions of tracheal smooth muscle. These findings support the results of in vivo study whereby nebivolol, both acutely or chronically administered, did not affect airway responsiveness to inhaled histamine in rabbits.7 Similar findings have been reported in other in vivo studies. In a study conducted by De Clerck et al., (1989) it was reported that nebivolol decreased heart rate without significantly increasing pulmonary reactivity to histamine. 11 In this study some aspects concerned with the mechanisms that may be responsible for the lack of bronchoconstrictor effect of nebivolol on tracheal smooth muscle were explored. There may be many possible mechanisms which can explain the sparing effect of nebivolol. It is the most selective à ¯Ã‚ Ã‚ ¢1-adrenoceptor antagonist currently available for clinical use; its à ¯Ã‚ Ã‚ ¢1 selectivity is 3.5 times more than bisoprolol which was previously considered as the most cardioselective à ¯Ã‚ Ã‚ ¢ blocker. Beta 1 receptor selectivity is an important determinant of less incidence of bronchoconstriction and other adverse effects seen with cardioselective à ¯Ã‚ Ã‚ ¢ blockers.3 However several in vivo and in vitro studies have shown that cardioselective blockers such as atenolol and metoprolol do increase airway hyperresponsiveness, though to a lesser extent. De Clerck et al, (1989) compared the bronchoconstrictor effects of atenolol, nebivolol and propranolol in guinea pigs and they reported that bronchoconstriction was greatest with propranolol followed by atenolol while nebivolol had sparing effect.11 So the different effect of nebivolol can not be fully explained by its à ¯Ã‚ Ã‚ ¢1 selectivity.7 Another possible mechanism is that the effect of nebivolol may be because of partial agonist activity at à ¯Ã‚ Ã‚ ¢2 receptors but several studies have shown that nebivolol lacks partial agonist activity at à ¯Ã‚ Ã‚ ¢2 receptors.12 Therefore, this mechanism does not seem to be plausible. Nebivolol has been reported to modulate the endogenous production of NO.1 Nitric oxide is an important endogenous bronchodilator and is generated by a family of NO synthase isoforms in the airways.13 Considering the potential role of endogenous NO in the control of airways, its role was evaluated in the effects of nebivolol. For that purpose, L-NAME which is a competitive inhibitor of nitric oxide synthase was used. In one group effect of histamine was studied on tracheal muscle strips pretreated with fixed concentrations of L-NAME (10-4M) and its curve was compared with curve of control group. The difference was statistically insignificant indicating the absence of any effect of L-NAME on histamine induced contraction of tracheal muscle. In another group, the isolated tracheal muscle of guinea pig was pretreated with fixed concentrations of L-NAME (10-4M) and nebivolol (10-6M) respectively and then the effects of histamine were studied on this tissue model. At all the concentrations of histamine contraction of tracheal muscle was augmented and the p-value was 14,15 Nitric oxide that is released may interfere with the cholinergic neurotransmission either by functional antagonism on airway smooth muscle or via pre-junctional inhibition of release of acetylcholine from cholinergic nerve terminals. These findings suggest that NO indeed has some role in the sparing effect of nebivolol on the airways. This may be due to the reason that nebivolol induced-bronchoconstriction is counter balanced by the release of NO by nebivolol which causes bronchodilation resulting in the overall sparing effect of nebivolol on the airway smooth muscle. The NO-mediated inhibition of the acetylcholine-dependent bronchoconstriction may thus contribute to explain the differences between nebivolol and other à ¯Ã‚ Ã‚ ¢-blockers on the airway responsiveness. CONCLUSION NO may be responsible for sparing effect of nebivolol on airway smooth muscle. This may be due to the reason that nebivolol like classical beta blockers induces bronchospasm which is counter balanced by the relaxant effect of nitric oxide released by nebivolol thus lacking the net effect on airway smooth muscle. REFERENCES Dal Negro R. Pulmonary effects of nebivolol. Ther Adv Cardiovas Dis 2009;3:329–34. Scheen AJ. Pharma-clinics medication of the month, nebivolol Rev Med Liege 2001;56:788–91. Bundkirchen A, Brixius K, Bà ¶lck B, Nguyen Q, Schwinger RH. Beta 1-adrenoceptor selectivity of nebivolol and bisoprolol. A comparison of [3H]CGP 12.177 and [125I]iodocyanopindolol binding studies. Eur J Pharmacol 2003;460:19–26. Matera MG. Nitric oxide and airways. Pulm Pharmacol Ther 1998;11:341–8. 5. Dal Negro RW, Tognella S, Pomari C. Once daily nebivolol does not reduce airway patency in patients with COPD and arterial hypertension. Clin Drug Invest 2002;22:361–67. 6. Clini E, Bianchi L, Pagani M, Ambrosino N.. Endogenous nitric oxide in patients with stable COAD: Correlates with severity of disease. Thorax 1998;53:881–3. Agostino BD, Gallelli L, Falciani M, Fici F, Mangrella M. Nebivolol and airway responsiveness in the rabbit. Life Sci 2001;68:2159–68. Quang TT, Rozec B, Audigane L, Gauthier C. Investigation of the different adrenoceptor targets of nebivolol enantiomers in rat thoracic aorta. Br J Pharmacol 2009;156:601–8. Gillani AH, Khan, AU, Rauf M, Ghayur MN, Siddiqui BS, WohraW, Begum S. Gastrointestinal, Selective airway and urinary bladder relaxant effect of Hyoscyamus niger are mediated through dual blockade of muscarinic receptors and Calcium channels. Fundam Clin Pharmacol 2008;22:87–9. Maffei A, Pardo AD, Carangi R, Carullo P, Poulet R, Gentile MT, Vecchione C, Lembo G. Nebivolol induces nitric oxide release in the heart through inducible nitric oxide synthase activation. Hypertension 2007;50:652–6. 11. De Clerck F, Van Gorp L, Loots W, Janssen PA. Differential effects of nebivolol, atenolol and propranolol on heart rate and on bronchoconstrictor responses to histamine in the guinea-pig. Arch Int Pharmacodyn Ther 1989;298:230–6. Hoffman BB. Catecholamines, sympathomimetic drugs and adrenergic receptor antagonists. In: Brunton LL, Lazo JS, Parker KL (Eds). Goodman and Gillman’s. The pharmacological basis of therapeutics. 11th edition, New York: Mc GrawHill; 2006. p. 215–68. Maarsingh H, Leusink J, Zaagsma J, Meurs H. Role of the L-citrulline/L-arginine cycle in iNANC nerve-mediated nitric oxide production and airway smooth muscle relaxation in allergic asthma. Eur J Pharmacol 2006;546(1-3):171–6. Ignarro LJ. Experimental evidences of nitric oxide-dependent vasodilatory activity of nebivolol, a third generation beta-blocker. Blood Press Suppl 2004;1:2–16. Ricciardolo FL. Multiple roles of nitric oxide in the airways. Thorax 2003;58:175–82 Address for Correspondence: Dr. Asma Shaukat, Assistant Professor, Department of Pharmacology, Abbottabad International Medical College, Abbottabad, Pakistan. Res: 438, Link Road, Aram Bagh, Abbottabad, Pakistan. Tel: +92-992-331588 Email: [emailprotected]

Famous Women Pilot: Amelia Earhart Essay -- Female Pilot, Biography

Amelia Earhart is one of the most famous women pilots in our history. Her childhood wasn’t the best out of everyone’s, but she used flying as a distraction. Amelia attempted to do things that no one else would attempt and she was the first women to break many records and fly to different places. Amelia was the first woman to attempt to fly around the world even though if it meant risking her life. She changed what women pilots could do and she encouraged them to fly and become pilots. It is still a mystery till today about her disappearance. Amelia Earhart impacted women in aviation even before she disappeared on her journey around the world. Amelia’s childhood didn’t start off or end up as great as it could have been. Amelia Mary Earhart was born in Atchison, Kansas on July 24, 1897. Her parents struggled financially when she was young. It was tough for them to pay for things and that impacted their family life (â€Å"Amelia Earhart†). Amelia spent a lot of time at her grandparents house. At that time her dad, Edwin wasn’t doing well with his job and he had a bad drinking problem. Amy, Amelia’s mom and the two girls left her father. Her parents got together and tried to work things out, but it eventually didn’t (Fleming 9). While Amelia was still young, she worked as an American Red Cross nurse during World War I in Toronto, Canada. Once the war ended, Amelia went to New York to attend Columbus University and got a degree in nursing. Her nursing job was one of the many jobs Amelia had to help pay for the daily needs of the family. She paid for all the things that were r equired for her plane since her family couldn’t afford these expenses (â€Å"Amelia Earhart†). Overall, she used flying as her distraction to all of the d... ...ng the Social Significance of Scientific Discovery. Ed. Josh Lauer and Neil Schlager. Vol. 6. Detroit: Gale, 2000. 57-58. Global Issues In Context. Web. 6 Nov. 2013. Parr, Jan. Amelia Earhart: First Lady of Flight. New York: Franklin Watts, 1997. Print. Pelt, Lori Vori. Amelia Earhart: The Sky's No Limit. New York: Forge, 2005. Print. American Heroes Ser. Stone, Tanya Lee. Amelia Earhart. London: DK Pub., 2007. Print. Wagner, Heather Lehr. "'A New Career'." Amelia Earhart, Famous Flyers. Philadelphia: Chelsea House Publishers, 2003. American History Online. Facts on File, Inc. Web. 26 Novem ber 2013 Waldman, Carl, and Jon Cunningham. "Aviation and Exploration." Encyclopedia of Exploration: Places, Technologies, and Cultural Trends, Volume 2. New York: Facts On File, Inc., 2004. Modern World History Online. Facts On File, Inc. Web 6 Nov. 2013.

Ibn Battuta in China Essay

At a time when most men cover distance astride a traveling animal, 75,000 miles of travel in a span of 30 years is an amazing achievement. When asked to name this historical individual who covered such great distance during the medieval period, most will likely point a credit to Marco Polo who is the well-known traveler of his time in Hakooki. com. But somehow, another person who has traveled longer and earlier than Marco Polo has actually covered this distance and visited 44 countries throughout the world. Ibn Battuta’s travels have almost been delegated into the oblivion if the world continued seeing history through the western view. Marco Polo, being European is far known than Ibn Battuta. Even his visit to China is virtually unknown in comparison to similar books of travel written by Marco Polo despite the fact that even to this day there remains lingering, unresolved questions as to whether or not Marco Polo truly visited China. However, if the myth sounds interesting enough, it will eventually be reported as fact. In the case of Marco Polo, the man has become a mythical folk hero and when a person ascends to such lofty heights in the public’s eye, criticism, scrutiny and a healthy dose of reality will usually fall by the wayside. Marco Polo’s travels will still remain famous regardless of the controversy that surrounds his journeys and the equally lengthy debate among scholars. It will be the goal of this essay to shift scholarly and historical directions and seek to shed light on the subject by comparing Ibn Battuta to Marco Polo’s travel in China. It is not uncommon for influential people from history to be seemingly erased from the documented chronology. In the United States, history is chronicled from a western perspective with Western Europe being presented as the epicenter of the world. As such, individuals from other cultures and parts of the world are often viewed in a peripheral manner and not provided with the same depth of historical coverage. Marco Polo was a hero whose birth origins are in the Western World. Because of this, his feats are given great credibility of honor in text. In the case of Battuta, a Moroccan by descent, his achievements will not be glossed over despite spending 17 years in China in comparison to Marco Polo’s travel which could have distinguished itself in many areas such as extent of land and historicity. In order to understand the work of Ibn Battuta, one must examine his early biographical years to as to put his life’s work into a certain context. Muhammed ibn Abdullah ibn Battuta or Ibn Battuta was born in Tangier, Morocco in a Muslim family in 1304 and started his travels when he was 20 years old and lasted almost 30 years of his life according to Dunn (2004, 14). Battuta according to Francis in consequence belongs to the religious upper class of the Mohammedan community and received usual religious and scholastic education from theologians (1997:2). His travels started in 1325 when Ibn went on a pilgrimage to Mecca that continued on until he had covered 75,000 miles in Kegan (1929:1). He had stopped on most Muslim cities along his route and paid homage to holy sites in Damascus, Syria, Hebron, Jerusalem and Bethlehem in the face of many obstacles he met along the way as related in Monteil (1930:30).

Critical and Creative Thinking Essay - 676 Words

Critical and creative thinking are fundamental to human intellectual progress and artifacts thereof (Dewey, Elder, Csikszentmihalyi, Rosenman, Gero, 2012). Critical and creative thinking are considered higher levels of thought because while it is believed that critical thinker primarily uses the left-brain and a creative thinker primarily uses the right-brain, both types of thinkers tend to think outside the box, but in different ways. There is no direct link between critical and creative thinking, but they each have different dimensions of thought that are used. Critical thinking is convergent thinking, creative thinking is divergent thinking. Critical thinking is a process used when reflecting and judging ideas and efforts, whether†¦show more content†¦Creative thinkers are curious, imaginative, inventive, explorative and open minded. Almost 20 years ago, my husband of 20 years passed away. A few years later, my father passed away also. They were the only 2 men that I had known in my life, so it was an incident in my life that left gaping holes. At the time, I loved in North Carolina and that is also the place that both my late husband and father resided at the time of their deaths as well, so there were so many bad memories. I had made a decision to move 400 miles away from my children that also lived in North Carolina at the time and a large majority of other family that lived in a neighboring state. It was a huge decision to make at that time, my children were grown, but just stepping out into life good, so in order to make this decision, I had to use both critical and creative thinking in making my final deci sion. It was a difficult decision making process that I had to go through. Knowing that I needed a change, but at the same time being scared to make such a huge change in my life. I used the critical thinking process to determine answers to some of the questions I seemed to have the most difficulty in answering, such as: 1. What might happen to my children if I leave? 2. What do I know about the state/city I am moving to? 3. What will I do to afford the cost of living change? 4. What is the value of moving versus the value of staying? After answering those questions, I then used theShow MoreRelatedCritical and Creative Thinking2382 Words   |  10 PagesCritical and creative thinking is regaining its popularity in the global education scene. This resurgence in popularity can be attributed to the demands of the evolving economic, political, social and technological world in the 21st century. The competitiveness of the global market demands corporations to constantly innovate. To do so, corporations need employees who are able to think critically and creatively. Barren of natural resources, Singapore depends on its human population for economic survivalRead MoreCreative and Critical Thinking Essay1254 Words   |  6 PagesKnowledge is generated through critical and creative thinking. Creative thinking is something new or original that is created with value. Critical thinking is a type of thinking that questions assumptions and validates or invalidates a current belief or something that is said to be previously true. Knowledge is created through the culmination of generally accepted assumptions and creativity. How do you separate general assumptions and creativity? These two types of thinking can be easily separated inRead More The interaction of critical and creative thinking1522 Words   |  7 Pagesexperiments I used different forms of thinking, including critical and creative thinking, in order to form a hypothesis, analyze the data, and then come to a conclusion regarding results and my hypothesis. While knowledge can be formed through the interaction of critical and creative thinking, such as in my physics experiments, the statement given in the title implies that knowledge is solely generated through the interaction of critical and creative thinking. I intend to demonstrate that knowledgeRead MoreThe Importance of Critical and Creative Thinking886 Words   |  4 PagesDescribe a situation in which critical and creative thought could have been used for a better outcome. Describe why it is important to think critically and creatively in similar situations. Critical thinking to begin with is the use of those cognitive skills or strategies that increase the probability of a desirable outcome (Sternberg, Roediger, and Helpern, 2007). One of the many situations where critical thinking should have been utilized to achieve a desirable (and perhaps better) outcome wasRead MoreHow Critical And Creative Thinking2197 Words   |  9 Pagesskills, behaviour and dispositions. This will assist students to live and work successfully in the twenty-first century according to the Australian curriculum, assessment and reporting authority (ACARA, 2013). This essay will evaluate how Critical and Creative Thinking (CCT) as well as Sustainability (SUS) can be linked to pedagogical practices that are utilised in Health and Physical Education (HPE). It will provide the reader with an understanding about how the new Australian curriculum frameworkRead MoreCreative And Critical Thinking Assignment1481 Words   |  6 PagesCREATIVE AND CRITICAL THINKING ASSIGN MENT Criminal Justice year one, semester one, 2016 4) Ireland has the best managed healthcare system in the developed world. Discuss. In recent years, Ireland’s healthcare service has faced many issues and many people have been noted to criticise and point out the issues of the healthcare system. In this essay we will be discussing the healthcare system in Ireland and we will be opposing to the statement â€Å"Ireland has the best managed healthcare system inRead MoreEssay about Critical and Creative Thinking1108 Words   |  5 Pagesï » ¿ Critical and Creative Thinking COM/600 2013 Critical and Creative Thinking Critical thinking is an important and valuable skill to have. Critical thinking affects both your professional lifestyle as well as your personal lifestyle. Critical thinkers should encompass skills needed to thoroughly analyze all the variables in a problem. During critical thinking, decisions should be based upon logic, and relevant and accurate data. Problem-solving and decision making is part ofRead MoreDifferences Between Creative Thinking, Critical Thinking And Focused Thinking791 Words   |  4 Pagesbetween Creative Thinking, Critical Thinking and Focused Thinking? o Creative thinking- Going beyond the limitations and being fresh in one’s ideas, while having a generative purpose. o Critical thinking- Is evaluative in nature and analyses a particular thing. Also, this has an analytical purpose. o Focused think- thinking critically and creatively 2. Summarize the advice and what you need to do in the Four -Part Model of Critical Thinking: †¢ Reasoning- Reasoning is the foundation of critical thinkingRead MoreTok Essay: Critical and Creative Thinking1599 Words   |  7 Pagesof Knowledge 3 May 2012 TOK Essay Response: Critical and Creative Thinking Since the dawn of humanity, man has sought to gain further insight on life through attaining knowledge. Knowledge can be defined as any information gained through personal experience. The means of obtaining knowledge include four main branches: reason, perception, language, and emotion. Despite the means, all knowledge is formulated through the process of thinking. Thinking refers to the use of the mind to gain understandingRead MoreCritical And Creative Thinking : The Work Place1818 Words   |  8 PagesCritical and Creative Thinking In the Work Place Elizabeth Willis-Satele October 4, 2014, 2014 COM 600 Chad Millar Critical and Creative Thinking in the Work Place As adults, we may enter into careers that require us to use critical and creative thinking skills. In the workplace, situations such as teamwork, presentations, and crises require us to use those skills. In my previous employment, I was a crisis outreach worker working specifically with individuals who were developmentally