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Extrapulmonary tuberculosis in the transplant recipients: review of pathogenesis generic dapoxetine 60mg, diagnosis dapoxetine 60 mg, and treat- United States order 60 mg dapoxetine with amex. Human polyoma virus pyelonephritis: sonographic-pathologic correlation of 16 cases cheap dapoxetine online visa. Generalized cytomega- and occurrence of uveitis in children with idiopathic tubulointersti- lic inclusion disease. Primer: histopathology of polyomavirus- cal analysis of 26 cases and of the literature. Renal medullary calcifications: a light and with renal Fanconi syndrome: pathological and molecular charac- electron microscopic study. Irreversible acute oliguric manifestation of plasma cell dyscrasias: the role of immunoelectron renal failure: a complication of methoxyflurane anesthesia. Toxic alcohol ingestions: clinical features, diagnosis, thrombi in multiple myeloma. Tubular and inter- clinical significance of light chain proximal tubulopathy with and stitial nephrocalcinosis. Myeloma cast nephropathy: immu- purge: an unrecognized cause of chronic renal failure. Unearthing uric acid: an ancient factor with recently found significance in renal and cardiovascular disease. Crystalline nephropathy due to 2,8 Lymphoproliferative Disorders dihydroxyadeninuria: an under-recognized cause of irreversible renal failure. Crystal-induced kidney disease in 2 kidney lymphoma: a case report and review of the literature. Renal Vascular Diseases 4 Renal vascular diseases are the most common forms of renal Benign or essential hypertension is very common, espe- injury as well as the most common renal abnormalities cially in middle-age and older patients. It is a silent killer associated not these diseases, hypertension-associated injury leads the list only with renal failure but also cardiac and cerebrovascular by far. Although most patients with benign hypertension axis that has been recognized for over a century; severe or will not develop renal failure, because of the high prevalence prolonged hypertension may damage the kidneys, and of the disease, it is the leading cause of end-stage renal severely damaged kidneys, from whatever cause, may pro- disease. Malignant hypertension, by contrast, is a medical emer- Many of the vascular diseases listed below are associated gency with a high risk of irreversible renal failure, myocar- with acute or chronic renal failure and secondary forms of dial infarct, and stroke. Most also have distinctive gross findings that symptoms including headache, dizziness, and impaired allow easy recognition in a nephrectomy or at autopsy fol- vision. Ocular examination will reveal retinal hemorrhages lowing careful assessment of the vascular pole and examina- and exudates, and papilledema. Diastolic blood pressure tion of the renal surface after removal of the renal capsule. Types of renal vascular diseases are as follows: Most patients have had preexisting benign hypertension. Either type may be primary, which is most common, • Thrombotic microangiopathy or secondary to one of many possible causes. Hypertension- • Vasculitis associated renal disease may be classified as benign nephro- • Coartation of the aorta sclerosis or malignant nephrosclerosis. The renal lesions of benign hypertension have been referred There are genetic contributions as well. The kidney is uni- to by variety of names: benign nephrosclerosis, hyperten- formly contracted with weights ranging from 90 to 120 g. This disease ance due to shallow scars with intervening normal is more common in African Americans and in men, and paraenchyma. The granular compo- nent represents rounded islands of preserved renal parenchyma. The grooves or depressed red areas between the rounded islands represent shallow subcapsular scars, as illustrated in Figs. The arteries at the renal hilum are very thick- ened, which may be appreciated in the photograph Fig. The kidney on the left has a coarsely granular subcapsular sur- face; it is from an adult with a long history of hypertension. The coarse- ness of the granularity correlates with the severity of the nephrosclerosis; the more severe degrees of nephrosclerosis have a coarser appearance due to deeper scars, whereas milder degrees of nephrosclerosis have shallower scars and a finer granularity (From Zhou M, Mag-Galluzzi, editors. This subcapsular scar shows a mildly contracted glomerulus on the left with an adjacent, completely hylanized or globally sclerotic glomerulus to its right. Notice the very sclerotic and thick-walled arteriole at the top and the severe fibrointimal thicken- Fig. Also present are thickened arterioles and interstitial fibrosis with a mild lymphoid infiltrate. Shown is a glomerulus undergoing ischemic obsolescence secondary to hypertension and associated vas- cular disease. The glomerulus shows capillary loop wrinkling and col- lapse, often referred to as ischemic wrinkling or ischemic obsolescence. Between the medial smooth muscle cells, electron-dense hyaline material has filled in sites of smooth muscle loss. The evolution of hypertensive injury and small arteries in hypertension and diabetes from a normal to a sclerotic glomerulus begins with capillary loop wrinkling and collapse, visible in the upper half of this glomerulus. The completely sclerotic glomerulus due to hypertension appears as a bland featureless eosinophilic mass on hematoxylin and eosin stain. In the acute lesions, there is necrosis of endothelium, vascular smooth muscle, and In malignant hypertension, there is severe injury to arteries, mesangial cells with fibrin deposition and red blood cell arterioles, and glomeruli. Grossly, the kidney may be smaller extravasation, a lesion known as acute thrombotic microan- than normal from preexistent benign nephrosclerosis or giopathy. In the chronic lesions, the thrombotic and necrotiz- enlarged from interstitial edema due to acute injury. The ing lesions organize or heal, resulting in concentric subcapsular surface may show petechial hemorrhages or fibrointimal thickening of arteries and hyperplastic arteri- even acute infarcts. Microscopically, thrombotic microan- oles, and either glomerular ischemic collapse or glomerular giopathy is present with lesions that range from acute to capillary loop duplication. The arteriole on the left shows luminal thrombosis with red cell extravasation and fragmentation. Although arteries often are involved, in this field the adjacent artery shows chronic hypertensive damage with prominent fibrointimal thickening but no thrombotic changes Fig. In the center, the afferent arteriole is thrombosed, extending into several capillary loops. The second glomerulus, on the right, shows severe capillary loop thom- bosis with red cell fragmentation. Few discernable nuclei are present, indicating endothelial cell and mesangial cell necrosis 152 4 Renal Vascular Diseases Fig. This field shows both acute an abundant pale-staining ground substance, a finding referred to as thrombotic lesions and an organizing lesion. In this trichrome-stained sample, the cell extravasation in the artery at the bottom and the arteriole in the severely thickened intima contains fragmented red blood cells and its center. Both are severely damaged, with little remaining discernable lumen is markedly reduced. The associated glomerulus is undergoing ischemic col- intima and are likely producing matrix proteins. The large artery at the top right shows replication of its internal stain elastic lamina and marked intimal thickening rich in ground substance. This interlobular artery shows a more advanced stage or early resolution with impressive Fig. The thrombosis has resolved, leaving behind microangiopathy often shows prominent deposition of both immuno- no residual fibrin or red cell fragments. The severely thickened intima globulin M (IgM) and fibrin in the thrombotic arterial and arteriolar contains abundant ground substance with sparce cellularity. The most common cause is aortic atheroscle- rotic disease affecting the ostia of the main renal artery. This is usually a dis- ease of older adults, with a male predominance, and is a complication of prolonged smoking, hypertension, and hyperlipidemia. The second most common cause of chronic renal artery stenosis is fibromuscular dysplasia of the renal arteries.

In the case of ingestion of 100 mg 13C-urea in 50 mL water with no test meal after a 6-h fasting discount 90 mg dapoxetine with amex, the earliest optimal time for discriminating H order dapoxetine 60 mg mastercard. Another study involving 202 patients showed no significant difference between the conventional tests (75 mg 13C-urea in 50 mL water) with or without a test meal (200 mL 0 cheap 60 mg dapoxetine. Citric acid slows gastric emptying and thus increases the contact between the bacterial urease and the substrate [124 buy 60 mg dapoxetine with amex, 125 ]. A further modification incorporating endoscopy showed highly accurate diagnosis of H. However, this tech- nique requires a lot of patient preparation, including an oral intake of 80 mg dimeth- ylpolysiloxane to remove adherent gastric mucus 10 min before the endoscopy, along with an oral intake of 200 mg lidocaine to anesthetize the pharyngeal areas, and intramuscular injection of 20 mg scopolamine butylbromide 5 min before the endoscopy [ 127]. The 13C-urea breath test is not affected by bleeding peptic ulcers while the rapid urease test shows significantly decreased sensitivity in this condition [ 128]. One drawback with the 13C-urea breath test is that dubious or false-negative results often occur in patients on antisecretory medications, for example, H2-blockers. This problem can be resolved by taking the 13C-urea in a tablet formulation supple- mented with citric acid [117 ]. The commonly accepted method is using 75 mg 13C-urea with breath samples taken at baseline, 20 and 30 min. Because of some overlap, defining a gray zone seems to be appropri- ate in this age group [130]. The breath test has been shown to have excellent sensi- tivity and specificity for confirmation of eradication of H. The diagnostic specificity (95%) and sensitivity (100%) have also been shown to be comparable to histology, rapid urease test, and 22 S. A fatty test meal and 50 mg 13C-urea with breath sampled at 30 min have been shown to give the best sensitivity (98%) and specificity (98%) in a multicenter study [133 ]. A granulated powder containing 75 mg 13C-urea, citric acid, aspartate, and mannitol is provided within the kit for preparing the oral dose. The claimed sensitivity and specificity are 95% (Metabolic Solution Web site, 2011). The test can be administered in the doc- tor’s office, clinic, or patient service center. The patient is also required not to have anything in his/her mouth 1 h prior to the testing. Each 3 g dose of the Pranactin-Citric powder is supplied in a pouch containing 75 mg 13C-urea, citric acid, aspartame, and mannitol. The second breath sample is then collected 15 min after the dose by blowing into the second collection bag. The post-dose breath collection is set at 30 min, and the sensitivity and specificity are claimed to be 98 and 95%, respectively (Package insert, 2011). Further prospective clinical studies are needed to validate the clinical usefulness of this biomarker in diagnosis and monitoring of Aspergillus infection [ 139]. Conclusions In summary, urea breath tests are intended to detect active infections. Newer assay formats and instruments are much simpler, more cost effective, more user friendly, and thus may provide suitable alter- native choices for clinical diagnosis of microbial infections. Malfertheiner P, Schultze V, Rosenkranz B et al (2008) Safety and immunogenicity of an intramuscular Helicobacter pylori vaccine in noninfected volunteers: a phase I study. Ibrahim-Granet O, Philippe B, Boleti H et al (2003) Phagocytosis and intracellular fate of Aspergillus fumigatus conidia in alveolar macrophages. Daly P, Kavanagh K (2001) Pulmonary aspergillosis: clinical presentation, diagnosis and therapy. Vaira D, Holton J, Menegatti M et al (1999) New immunological assays for the diagnosis of Helicobacter pylori infection. Guarner J, Kalach N, Elitsur Y, Koletzko S (2010) Helicobacter pylori diagnostic tests in children: review of the literature from 1999 to 2009. Agha-Amiri K, Mainz D, Peitz U, Kahl S, Leodolter A, Malfertheiner P (1999) Evaluation of an enzyme immunoassay for detecting Helicobacter pylori antigens in human stool samples. Agha-Amiri K, Peitz U, Mainz D, Kahl S, Leodolter A, Malfertheiner P (2001) A novel immunoassay based on monoclonal antibodies for the detection of Helicobacter pylori anti- gens in human stool. Suzuki N, Wakasugi M, Nakaya S et al (2002) Catalase, a specific antigen in the feces of human subjects infected with Helicobacter pylori. Suzuki N, Wakasugi M, Nakaya S et al (2002) Production and application of new monoclonal antibodies specific for a fecal Helicobacter pylori antigen. Huizinga M, Stevens E, Berrens L (1985) Detection of class-specific antibodies against Aspergillus fumigatus antigens in various pulmonary diseases. Odabasi Z, Mattiuzzi G, Estey E et al (2004) Beta-D-glucan as a diagnostic adjunct for inva- sive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Sulahian A, Boutboul F, Ribaud P, Leblanc T, Lacroix C, Derouin F (2001) Value of antigen detection using an enzyme immunoassay in the diagnosis and prediction of invasive aspergil- losis in two adult and pediatric hematology units during a 4-year prospective study. Pazos C, Ponton J, Del Palacio A (2005) Contribution of (1- > 3)-beta-d-glucan chromogenic assay to diagnosis and therapeutic monitoring of invasive aspergillosis in neutropenic adult patients: a comparison with serial screening for circulating galactomannan. Rickerts V, Mousset S, Lambrecht E et al (2007) Comparison of histopathological analysis, culture, and polymerase chain reaction assays to detect invasive mold infections from biopsy specimens. Cao W, Duan Y (2006) Breath analysis: potential for clinical diagnosis and exposure assess- ment. Phillips M (1997) Method for the collection and assay of volatile organic compounds in breath. Hyspler R, Crhova S, Gasparic J, Zadak Z, Cizkova M, Balasova V (2000) Determination of isoprene in human expired breath using solid-phase microextraction and gas chromatogra- phy-mass spectrometry. Phillips M, Greenberg J (1992) Ion-trap detection of volatile organic compounds in alveolar breath. Bazzoli F, Zagari M, Fossi S et al (1997) Urea breath tests for the detection of Helicobacter pylori infection. Ozturk E, Yesilova Z, Ilgan S, Ozguven M, Dagalp K (2009) Performance of acidified 14C-urea capsule breath test during pantoprazole and ranitidine treatment. Rollan A, Giancaspero R, Arrese M et al (1997) Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection after antibiotic treatment. Ozturk E, Yesilova Z, Ilgan S et al (2003) A new, practical, low-dose 14C-urea breath test for the diagnosis of Helicobacter pylori infection: clinical validation and comparison with the standard method. Gunnarsson M, Leide-Svegborn S, Stenstrom K et al (2002) No radiation protection reasons for restrictions on 14C urea breath tests in children. Ohara S, Kato M, Saito M et al (2004) Comparison between a new 13C-urea breath test, using a film-coated tablet, and the conventional 13C-urea breath test for the detection of Helicobacter pylori infection. Oksanen A, Bergstrom M, Sjostedt S, Gad A, Hammarlund B, Seensalu R (1997) Accurate detection of Helicobacter pylori infection with a simplified 13C urea breath test. Isomoto H, Inoue K, Mizuta Y et al (2003) Validation of endoscopic 13C-urea breath test with nondispersive infrared spectrometric analysis in the management of Helicobacter pylori infection. Kato M, Saito M, Fukuda S et al (2004) 13C-Urea breath test, using a new compact nondis- persive isotope-selective infrared spectrophotometer: comparison with mass spectrometry. Shirin H, Kenet G, Shevah O et al (2001) Evaluation of a novel continuous real time (13)C urea breath analyser for Helicobacter pylori. Hamlet A, Stage L, Lonroth H, Cahlin C, Nystrom C, Pettersson A (1999) A novel tablet- based 13C urea breath test for Helicobacter pylori with enhanced performance during acid suppression therapy. Gatta L, Vakil N, Ricci C et al (2003) A rapid, low-dose, 13C-urea tablet for the detection of Helicobacter pylori infection before and after treatment. Kopacova M, Bures J, Vorisek V et al (2005) Comparison of different protocols for 13C-urea breath test for the diagnosis of Helicobacter pylori infection in healthy volunteers. Suto H, Azuma T, Ito S et al (1999) Evaluation of endoscopic 13C-urea breath test for assess- ment of Helicobacter pylori eradication. Zevit N, Niv Y, Shirin H, Shamir R (2011) Age and gender differences in urea breath test results. Kindermann A, Demmelmair H, Koletzko B, Krauss-Etschmann S, Wiebecke B, Koletzko S (2000) Influence of age on 13C-urea breath test results in children. Yoshimura N, Tajiri H, Sawada A et al (2001) A 13C-urea breath test in children with Helicobacter pylori infection: assessment of eradication therapy and follow-up after treat- ment.

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Peripheral vasoconstriction to preserve venous return and systemic blood pressure is another compensatory mechanism generic dapoxetine 90 mg mastercard. Myocardial ischemia may occur because of the tachycardia and reduced coronary perfusion pressure generic 60 mg dapoxetine with mastercard. Clinically generic dapoxetine 60mg, awake patients present with dyspnea dapoxetine 90 mg otc, orthopnea, tachycardia, paradoxical pulse, and hypotension, but the intubated, sedated, and mechanically ventilated patient in the postoperative care unit following cardiac surgery may have varied clinical and hemodynamic presentations. In the cardiac surgical patient the diagnosis of tamponade should be considered whenever hemodynamic deterioration or signs of low cardiac output occur. In postoperative cardiac patients, the pericardium is no longer intact, and loculated areas of clot may compress only one chamber, causing isolated increases in filling pressure (i. The existing extracardiac compression augments the respiration-induced ventricular interdependence and affects the diastolic filling of the two ventricles differently. The opposite effects 2743 take place during mechanical exhalation when the effects of positive ventilation dissipate. The selected anesthetics drugs should preserve the compensatory mechanisms that sustain forward flow. Drugs with vasodilator (either venous or arteriolar) or myocardial depressant properties should be avoided in patients with serious hemodynamic compromise and dosages of any induction agent should be appropriately reduced. Ketamine, because of its sympathomimetic effects, may be helpful in preserving heart rate and blood pressure response. It is not, however, a panacea and can induce hypotension in patients under maximal sympathetic stress. If on reopening the chest there is minimal fluid or if the patient shows little improvement, a thorough search for other causes of inadequate cardiac performance, such as clotted or kinked grafts, myocardial ischemia, or valve malfunction, is indicated. Pain Management Early awakening and extubation have brought the problem of postoperative pain management in cardiac surgery into focus. The standard practice has been intravenous opioids given as needed followed by conversion to oral pain medications. However, the quest is on to find an ideal postoperative pain management technique to complement the goal of early extubation and maximize patient satisfaction. In cardiac patients with severe pain associated with sternal fractures due to the sternal retraction device during internal mammary harvest, epidural analgesia has been shown to be safe and effective and results in improved postoperative pulmonary function. The best way to understand the impact of a congenital defect and how anesthetic agents will interact with this defect is to envision the path blood must follow to maintain flow to the pulmonary arteries and aorta. Table 39-21 classifies various types of lesions by their physiologic impact; however, it must be remembered that there is often more than one defect present. Preoperative Evaluation History In infancy, heart failure usually becomes manifest through feeding difficulties, easy fatigability, vomiting, lethargy, and labored breathing. In the older child, heart failure causes easy fatigability, shortness of breath, and dyspnea on exertion. The previous surgical procedures may be key to understanding the patient’s anatomy. Physical Examination The physical examination of a child should seek signs and symptoms of poorly compensated congenital cardiac lesions. These children most often present with failure to thrive, which could be due to pulmonary hypertension and/or poor peripheral oxygenation and organ perfusion. The physical examination should seek to discover other signs of congestive heart failure, such as irritability, diaphoresis, tachycardia, rales, jugular venous distention, and hepatomegaly. Clinical examination of extremities should include evaluation of cyanosis, clubbing, edema, pulse volume, and blood pressure. In children with Blalock–Taussig shunts (subclavian artery to pulmonary artery), upper extremity pulses may be absent or reduced on the side of the shunt. Auscultation of the heart in these patients can reveal different types of murmurs depending on the lesions (Table 39-22). Polycythemia results as a consequence of bone marrow stimulation (via release of erythropoietin from the kidneys) from arterial desaturation. Increased red cell mass can lead to hyperviscosity, peripheral sludging, and reduced oxygen delivery. Sludging is augmented by dehydration from preoperative fasting and by hypothermia from low ambient operating room temperatures. In patients with hematocrit above 70%, consideration should be given to preoperative electrophoresis if symptomatic hyperviscosity is present. Cyanotic children with low hematocrit may exhibit hypoxic spells more readily than if the hematocrit were normal. Polycythemia can induce a low-grade disseminated intravascular coagulation with activation of fibrinolysis, degranulation of platelets, and consumption of coagulation factors. Newborns often have inadequate liver-dependent coagulation factors because of immaturity of hepatic function. Platelet count, prothrombin time, and partial thromboplastin time should be evaluated. Infants, particularly those with congestive heart failure, are also at risk for both hypoglycemia and hypocalcemia. Children who have undergone major cardiac procedures earlier in their lives may have been exposed to blood or blood products and are at increased risk of having abnormal serum antibodies to various blood antigens. Hence, samples of a child’s blood should be sent to the blood bank for possible cross-matching. Cardiac Evaluations Echocardiography delineates most of the cardiac anatomy and permits noninvasive measurement of ventricular size and function, cardiac output, and severity of valve dysfunction. Cardiac catheterization is reserved for patients with poor echocardiographic windows and when there is intervening bone or air-filled lung (e. Premedication The purpose of the premedication is to have a calm child without 2747 oversedation, loss of protective airway reflexes, or hemodynamic compromise. This will facilitate the separation of the child from the parents and ease the fear and anxiety associated with the perioperative period. Anesthetic and Intraoperative Management Inhalational agents hold a prominent place as induction as well as maintenance agents in pediatric cardiac anesthesia. Opioids are used routinely to limit the stress response in the prebypass phase of pediatric cardiac surgery. No specific relationship between opioid dose and stress response has been established. Of special note is the marked reduction in neuromuscular blocking requirements during hypothermic bypass. In neonates, modified 2748 ultrafiltration results in an elevated hematocrit, improved pulmonary compliance in the immediate postbypass period, and probably improved cerebral metabolic recovery after deep hypothermic circulatory arrest, although the long-term benefit on outcome is unclear. It is truly selective for the pulmonary vascular bed and, in addition, should improve the ventilation/perfusion matching in the lungs. The potentially detrimental effects of endotracheal intubation and positive pressure ventilation offset this advantage. Positive pressure ventilation is known to have a deleterious effect on pulmonary blood flow in patients with Fontan physiology. Resumption of pain-free spontaneous respiration does enhance hemodynamic performance in these patients. For example, caudal (epidural) opioids can be used in repair of coarctation of the aorta in the older 2749 child or ligation of a patent ductus arteriosus. The recommendation has been made that one allow 60 minutes to elapse between placement of a neuraxial block and administration of heparin, although there is no evidence to support this time interval. The pathophysiology of perioperative myocardial infarction: Facts and perspectives. The metabolic demand and oxygen supply of the heart: physiologic and clinical considerations. Endothelial and neuro-humoral control of coronary blood flow in health and disease. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2. The adequacy of subendocardial oxygen delivery: The interaction of determinants of flow, arterial oxygen content and myocardial oxygen need. Clinical and economic effects of pulmonary artery catheterization in nonemergent coronary artery bypass graft surgery. Standard versus fiberoptic pulmonary artery catheterization for cardiac surgery in the Department of Veteran Affairs: A prospective, observational, multicenter analysis. Comparison of hemodynamic, electrocardiographic, mechanical, and metabolic indicators of intraoperative myocardial ischemia in vascular surgical patients with coronary artery disease.

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This is the putative mechanism by which the bundle of Kent produces Wolff–Parkinson–White syndrome discount dapoxetine 90 mg mastercard. Two other determinants of coronary flow are vessel length and blood viscosity discount dapoxetine 60mg with visa, but these factors are relatively constant buy dapoxetine 90 mg mastercard. Resting coronary blood flow in the adult is approximately 250 mL/min (1 mL/min/g; 5% of normal adult cardiac output) dapoxetine 30 mg without a prescription. As a result, the subendocardial layer is much more susceptible to ischemia when a flow-limiting coronary stenosis, pressure-overload hypertrophy, or pronounced tachycardia is present. Coronary blood flow is also reduced when aortic diastolic pressure is low, such as occurs in severe aortic valvular insufficiency. Another important determinant of coronary blood flow is coronary vascular resistance (estimated using the ratio of coronary blood flow to perfusion pressure), which also varies substantially during the cardiac cycle. While coronary perfusion certainly changes in response to aortic, intramyocardial, and coronary venous pressures, the primary regulator of coronary blood flow is the variable resistance imparted by coronary vascular smooth muscle. For example, activation of the sympathetic nervous system increases coronary vascular smooth muscle tone, thereby making coronary 752 vascular resistance greater. The degree of smooth muscle stretch (myogenic factor) also influences coronary vascular tone and resistance. However, metabolic factors are the primary physiologic determinants of coronary vascular tone and myocardial perfusion. The ratio of subepicardial to subendocardial blood flow remains near unity throughout the cardiac cycle despite the differentially greater systolic compressive forces exerted on the subendocardium. The relative maintenance of subendocardial blood flow despite compression is also related to the redundancy of arteriolar and capillary anastomoses within the subendocardium. The heart normally extracts between 75% and 80% of arterial oxygen content, by far the greatest oxygen extraction of all the body’s organs. Heart rate is the primary determinant of myocardial oxygen consumption in the intact heart. Increases in myocardial contractility, preload, and afterload are also associated with greater myocardial oxygen consumption. Cardiac oxygen extraction is near maximal under resting conditions and cannot substantially increase during exercise. As a result, the primary mechanism by which myocardium is able to meets its oxygen requirements during exercise is through enhanced oxygen delivery, which is proportional to coronary blood flow when hemoglobin concentration is constant. Thus, it is not surprising that myocardial oxygen consumption is the most important determinant of coronary blood flow. For example, myocardial oxygen consumption and corresponding coronary blood flow increase by a magnitude of four- to fivefold during strenuous physical exercise. The difference between maximal and resting coronary blood flow (coronary reserve) determines the magnitude with which coronary blood flow can rise during exercise-induced increases in myocardial oxygen consumption. Coronary vascular resistance is greater in the resting, perfused heart than in the contracting heart. These data suggest that increases in coronary blood flow exceed those of perfusion pressure in response to greater myocardial oxygen consumption when the heart is contracting versus when it is quiescent. The precise mechanisms responsible for this close correlation between myocardial oxygen consumption and coronary vasomotor tone remain elusive. The factors responsible for coronary autoregulation (maintenance of coronary blood flow despite changes in perfusion pressure) and reactive hyperemia (the several-fold increase in coronary blood flow 753 above baseline after a brief period of myocardial ischemia) are also not clearly understood. Metabolic coronary vasodilation in response to enhanced myocardial oxygen consumption during exercise occurs, at least in part, as a result of enhanced local release of metabolic substrates (e. This latter effect causes a “feed-forward” vasodilation of small coronary arterioles by activating β adrenoceptors. An α adrenoceptor-13 induced vasoconstriction also occurs in larger coronary arteries during exercise. Although seemingly counterintuitive, this differential vasoconstriction of larger caliber upstream coronary arteries serves two important functions: reduction of vascular compliance and attenuation of the wide swings in coronary blood flow normally observed during the cardiac cycle. In contrast to the important role of the cardiac sympathetic nerves, parasympathetic innervation has a relatively minor direct effect on coronary blood flow regulation despite its well-known negative inotropic and chronotropic actions. The aforementioned conclusions about sympathetic nervous system control of the coronary circulation are based on alterations in the slope of the myocardial oxygen consumption–coronary venous oxygen tension relation during graded exercise in the presence of exogenous α or β adrenoceptor blockade. The β adrenoceptor appears to account for only one-fourth of the total coronary vasodilation observed during exercise-induced hyperemia, but most of this vasodilation is most likely related to local or autocrine metabolic factors that act on coronary vascular smooth muscle with or without the additional modulation by vascular endothelium. Adenine nucleotides from red blood cells or the myocardium itself may activate endothelial purinergic receptors to produce coronary vasodilation during exercise. Many factors14 have been proposed to individually or collectively modulate coronary blood flow at the arteriolar or capillary level, including adenosine, bradykinin, nitric oxide, arterial oxygen or carbon dioxide tension, acid–base status, osmolarity, plasma electrolyte (e. For example, hypoxia or ischemia decreases arterial oxygen tension and pH concomitant with increases in carbon dioxide tension, adenosine release, and the plasma concentrations of K and Ca+ 2+. These changes collectively augment coronary blood flow during exercise, but none individually is solely responsible for this vasodilation. Adenosine receptor blockade does not alter coronary blood flow under resting conditions or during exercise. Endothelin and thromboxane A produce direct2 coronary vasoconstriction in vitro, but the precise role of these substances on the regulation of coronary blood flow in vivo has not been defined. Cardiac Myocyte Anatomy and Function Ultrastructure The heart contracts and relaxes nearly three billion times during an average lifetime, based on an average heart rate of 70 beats per minute and a life expectancy of 75 years. A review of cardiac myocyte ultrastructure provides important insights into how this remarkable feat is possible. Deep invaginations of the sarcolemma, known as transverse (T) tubules, penetrate the internal structure of the myocyte at regular intervals. The T-tubules assure rapid, simultaneous transmission of the depolarizing impulses that initiate myocyte contraction. The cardiac myocyte is densely packed with mitochondria that are responsible for production of large quantities of high-energy phosphates (e. The myofilaments within each sarcomere are arranged in parallel cross-striated bundles of thin (containing actin, tropomyosin, and the troponin complex) and thick (primarily composed of myosin and its supporting proteins) fibers. Sarcomeres are connected in 755 series and produce characteristic shortening and thickening of the long and short axes of each myocyte, respectively, during contraction. Observations from light and electron microscopy led to the definition of the sarcomere’s distinctive structural features. The “I” band represents the region of the sarcomere that contains thin filaments alone, and this band is reduced in width as the cell contracts. Each “I” band is bisected by a “Z” (from the German zuckung [twitch]) line, which delineates the border between two adjacent sarcomeres. As a result, the length of each sarcomere contains a complete “A” band and two symmetric one-half “I” bands located between “Z” lines. This “M” band is composed of thick filaments spatially constrained in a cross-sectional hexagonal matrix by myosin-binding protein C. The contractile machinery and the mitochondria that power it occupy more than 80% of the total volume of the cardiac myocyte. This observation emphasizes that mechanical function, and not new protein synthesis, is the predominant activity of the cardiac myocyte. Intercalated discs connect adjacent myocytes through the fascia adherens and desmosomes that link actin and other proteins between cells, respectively. The intercalated discs also provide a seamless electrical connection between myocytes via large, nonspecific ion channels (known as “gap junctions”) that facilitate intercellular cytosolic diffusion of ions and small molecules. Contractile Apparatus Myosin, actin, tropomyosin, and the three-protein troponin complex compose the six major components of the contractile apparatus. Enzymatic digestion of myosin divides the structure into light (containing the tail section of the complex) and heavy (composed of the globular heads and the light chains) meromyosin. The elongated tail section of the myosin complex (light meromyosin) functions as the main structural 756 support of the molecule (Fig. The globular heads of the myosin dimer contain two “hinges,” located at the junction of the distal light chains and the tail helix, that play an essential role in myofilament shortening during contraction. The myosin molecules are primarily arranged in series along the length of the thick filament, but are abutted “tail-to-tail” in the center of the thick filament. This orientation facilitates shortening of the distance between “Z” lines during contraction as the thin filaments are drawn symmetrically toward the sarcomere’s center. Figure 12-6 Schematic illustration of the myosin molecule demonstrating double helix tail, globular heads that form cross bridges with actin during contraction, two pairs of light chains, and “hinges” (cleavage sites of proteolytic enzymes) that divide the molecule into meromyosin fragments (see text).