PDQ Physiology - part 4 pps

ere length typically ranges between 1.5 and 2.2 µm, contraction to relaxation. Myocytes are coupled to one another by a net-like collagen matrix. Differences from skeletal muscle. Cardiac muscle is striated muscle. Its contractile proteins are actin and myosin, and its regulatory proteins are tropomyosin and troponin-T, -C, and -I. Its microanatomy differs from that of skeletal muscle in that it has (1) only one or two centrally located nuclei as opposed to the several nuclei of skeletal muscle cells; (2) extensive cross connections between adjacent fibers (see Figure 6–3); (3) gap junctions between adjacent cells (gap junctions are a part of the intercalated discs) (see Figure 6–3); and (4) fewer but larger T-tubules (one per z-line). Transverse tubular system. Ventricular myocytes have a well-developed system of sarcolemmal invaginations (T-tubules) that penetrate into the muscle fiber and course between myofibrils. They are so numerous that they constitute 40 to 50% of the surface area in ventricular myocytes. By contrast, in atrial myocytes, the T-tubules make up only 10 to 20% of the surface area. Several membrane proteins are localized preferentially in the T-tubules. Particular examples are the 3Na + /Ca ++ exchanger and L-type Ca ++ channels. Chapter 6 Cardiovascular Physiology 159 Lungs Brain Upper torso Liver Spleen GI tract Kidney Lower torso Portal vein Hepatic artery RV RA LA LV 5 L/min 5 % } 20 % 25 % 15 % Bronchi Coronary artery Figure 6–1 Schematic of the cardiovascular system. Resting cardiac output in humans is near 5 L/min, and its approximate distribution to different tissues is indicated. Sarcoplasmic reticulum (SR). The SR is an intracellular network of membrane-lined tubules that forms a mesh around each myofibril. The SR abuts the T-tubules and sarcolemma and forms functionally important junctions at these sites. It has at least three electronmicroscopically different regions: 1. Network SR courses over the myofibrils and forms the connection among other SR parts and has a high content of Ca ++ -ATPase (adenosinetriphosphatase) and phospholamban. 2. Corbular SR is the bulges that are found in the region of the I-band (light region adjacent to the Z-line). It has a high Ca ++ content. 3. Junctional SR is found near the T-tubules, in the region of the triads. It does not make intimate contact with the T-tubules but appears to be “connected”to them by electron-dense foot processes. These are the large cytosolic domain of the SR Ca ++ release channel (ryanodine receptor). 160 PDQ PHYSIOLOGY Figure 6–2 The fibrous skeleton of the heart and gross anatomy of ventricular muscle fibers. Shortening of the fibers will reduce chamber dimension and will pull the apex toward the valve rings. A = aortic; M = mitral; P = pulmonic; T = tricuspid. excitation–activation–contraction coupling. Heart function differs from skeletal muscle function in that every cardiac myocyte contracts with each heart beat. As a result, the strength of cardiac contraction is not modulated by altering the number of contracting cells but is modulated by changes in the intrinsic contractile properties of myocytes. Cardiac Excitation Cardiac myocytes are excitable cells and are, therefore, capable of respond- ing to an appropriate stimulus with quick generation of an action potential. The stimulus normally originates from pacemaker cells in the sinoatrial (SA) node. An action potential that is spontaneously generated in one of these cells rapidly spreads through the functional syncytium and elicits action potentials in all other excitable cardiac cells. Passive transport mechanisms through ion-selective channels exert a dominant influence over short-term (0 to 300 ms) electrical behavior of cardiac cells. Ion currents. Membrane channels that are selectively conductive for Na + , Ca ++ ,or K + * are of special importance for the contraction–relaxation cycle of cardiac muscle cells. Their conductance changes result from channel activation and inactivation on a time scale of milliseconds and in an ordered sequence that results in the action potentials described later (Figures 6–4 and 6–5). The following currents contribute most significantly: • I Na : carried by rapidly activating and inactivating, voltage-gated Na + channels; contains a small noninactivating component (the slow Na + current). Inactivated Na + channels become available for reactivation only after the membrane has been repolarized. Thus, the long duration of the cardiac action potential imposes a long refractory period on cardiac myocytes and prevents tetanization. • I f : the pacemaker current; a nonselective cation current composed mostly of Na + . Unlike most voltage-gated channels, which are closed at resting membrane potential and open on depolarization, the channel carrying I f opens on hyperpolarization, and this “funny” behavior has given it the designation “f.” I f is directly modulated by cyclic adenosine monophosphate (cAMP) and is, therefore, increased by β 1 -adrenocep- tor activation. • I C-T : carried by voltage-gated T-type Ca ++ channels (blocked by nickel). • I C-L : carried by voltage-gated L-type Ca ++ channels (blocked by dihydropyridine). 162 PDQ PHYSIOLOGY *At least 12 different K + channels have so far been identified in myocytes. Their expres- sion varies greatly in different regions of the heart, and this variation leads to regional differences in action-potential profile. • I K1 : one of several inward rectifier K + currents. Inwardly rectifying channels are highly conductive in the inward direction when the membrane potential is negative to the K + equilibrium potential. They are poorly conductive in the outward direction when the membrane potential is more positive than the K + equilibrium potential. The channel is not voltage gated; it has only two transmembrane domains, in contrast to the six transmembrane domains that characterize voltage-gated channels. • I K(Ach) :a K + current that is carried through an inwardly rectifying channel in pacemaking tissue and atrial myocytes. The channel is directly coupled to a G protein. It mediates approximately 50% of the negative chronotropic effect of vagal stimulation. • I KATP : links membrane potential to cellular metabolic status. K AT P channels are inhibited by physiologic levels of adenosine triphosphate (ATP) and open when [ATP] decreases. • I 3Na/2K : is the outward current arising from the ubiquitous 3Na + -2K + membrane pump. Pacemaker cells. Pacemaker cells are concentrated in the sinoatrial (SA) node, the atrioventricular (AV) node, the bundle of His, and Purkinje fibers. Sinus rhythm is normally driven by SA node cells because they are the earliest to depolarize. Pacemaker cells differ from other myocytes in that they do not have a stable membrane potential in diastole (see Figure 6–4). After they have repolarized to the maximum diastolic potential, their membrane potential gradually depolarizes, and an action potential is generated when Ca ++ influx increases explosively. The instability of diastolic potential arises mostly from (1) the absence of the inwardly rectifying K + channel, I K1 , the major diastolic stabiliz- ing current; and (2) the presence of a mixed Na + /K + pacemaker channel, I f . The slope of the diastolic potential in pacemaker cells is determined by the imbalance between I f and I K(Ach) , the acetylcholine-sensitive K + channel. Modulation of SA-node pacemaker rate: Sinoatrial nodal cells have a high basal level of cyclic adenosine monophosphate (cAMP), and this level can be increased by β-adrenergic activation and decreased by muscarinic activation of guanylate cyclase. Sympathetic stimulation increases intracellular cAMP. This has a direct, stimulatory effect on the pacemaker current I f and also increases I Ca-L by pro- moting phosphorylation of the channel. Parasympathetic stimulation slows pacemaker frequency by muscarinic mechanisms that include membrane hyperpolarization, inhibition of I Ca-L as a result of kinase C–dependent inhibition of channel phosphorylation, decreased cAMP by virtue of the action of cyclic guanosine monophosphate (cGMP)-dependent phosphodi- esterase, and activation of I K(Ach) . Chapter 6 Cardiovascular Physiology 165 Myocytes. The action potential is the result of exquisitely tuned ion currents that are activated and deactivated at different intervals. Figure 6–5 shows the ion currents dominating each phase of the action potential. Upstroke (phase 0): When a suitable stimulus depolarizes the membrane to the gating voltage for fast Na + channels (I Na ), they are activated, and the membrane potential rapidly moves toward the Na + equilibrium potential. Channels carrying I Ca-T, the transient Ca ++ current, are activated at E m more positive than –50 to –65mV. At E m more positive than –40mV, channels carrying I Ca-L, the long-last- ing Ca ++ current, are activated and remain activated in phases 1 and 2. The excitation propagates to adjacent myocytes at a velocity of 0.3 to 0.5 m/s through myocytes and 1 to 3 m/s through Purkinje fibers. Early rapid repolarization (phase 1): At the peak of the upstroke, E m reaches between +20 and +40 mV and then undergoes rapid partial repolarization. The major contributors are (1) inactivation of I Ca-T and most of I Na and (2) activation of I to . This creates the “notch” near the peak of the action potential and determines the plateau potential and, thereby,the magnitude and time course of currents that flow during the plateau phase. The plateau (phase 2): The plateau arises from a delicate balance between depolarizing and repolarizing currents. The major depolarizing influence is I Ca-L, carried through channels that were opened during phase 0. Repo- larizing currents arise from the K + currents K ur ,K r , and K p (see Figure 6–5). Late rapid repolarization (phase 3): The plateau terminates partly because K r and K s increase their respective conductance and partly because I Ca-L decays when the L-type channels carrying it are inactivated by processes dependent on time, voltage, and intracellular [Ca ++ ]. Repolarization then occurs rapidly because of the dominant influence of outward K + currents, mainly I Kr ,I Ks, and I K1 . As the membrane potential approaches its resting value, K + currents diminish as the electrochemical gradient for K + decreases and the 3Na + -2K + pump current gains in relative importance. Diastole (phase 4): Nonpacemaker cells maintain a stable resting membrane potential because of an exact balance between depolarizing and repolarizing currents. The significant depolarizing currents are I NaCaX and a Na + leakage current because the electrochemical gradient for Na + is steep and the Na + channels do not inactivate completely. The significant repolarizing currents are I K1 and I 3Na/2K , the current resulting from active 3Na + , 2K + pumping (capable of taking E m down to –150 mV). I KATP becomes significant only when cytosolic [ATP] is low. 166 PDQ PHYSIOLOGY The conducting system of the heart. The SA node is electrically coupled by way of gap junctions to a specialized conduction system that consists of the AV node, bundle of His, and Purkinje fibers. This system, in turn, is coupled to myocytes by gap junctions and, therefore, rapidly conducts electrical activity to all parts of the heart and ensures that large numbers of cells depolarize in synchrony. The spread of depolarization along relatively fixed, predetermined paths ensures that the orientation of the electric field with respect to the body surface changes little from beat to beat. Generation of the electrocardiogram. Whenever a sufficiently large number of cardiac cells undergo synchronized depolarization and repolarization, the resulting electrical activity can be detected as potential differences between any two points on the body surface. This results in bipolar lead electrocardiograms (ECGs), such as leads I, II, III, and others, as dictated by specific needs. It is also conventional to record ECGs at several surface points, not with reference to one other surface point but with reference to a point that is derived electronically by the recording apparatus from voltages measured at two or three other surface points. This results in unipolar ECGs.(Leads aV R ,aV L ,aV F and precordial leads V 1 to V 6 are typical unipolar leads.) Electrocardiogram traces show deflections that are typically identified as “waves” labeled P, Q, R, S, and T. As shown in Figure 6–6, P corresponds to atrial depolarization, Q to very early septal depolarization, R to ventricular depolarization, and S to late ventricular depolarization. T is inscribed by ventricular repolarization. Cardiac vectors. The relationship between instantaneous cardiac electrophysiologic events and ECG traces is best understood in terms of cardiac vectors (some prefer the term “electrical dipoles”) and their projections onto a geometric line that connects the end points of individual leads (see Figure 6–6). Depolarization vector: As each cell depolarizes, its membrane potential changes from a normally negative value to a slightly positive value. Hence, the process of cardiac depolarization can be imagined as a wave of positiv- ity sweeping over the tissue and can, with the help of the following con- ventions, be represented by a depolarization vector: Depolarization is represented by an arrow that is identified with a “+” sign at its head. The direction of the arrow is the same as the direction in which the depolarization wave moves through the tissue. The length of the arrow is directly proportional to the number of cardiac cells that are depolarizing at that instant. If a series of depolarization vectors is drawn, each representing the spa- tially averaged cardiac electrical activity at that instant, depolarization of the Chapter 6 Cardiovascular Physiology 167 Repolarization vector: Repolarization events, such as the T-wave of the ECG, can be similarly derived by the application of the concept of a repolarization vector. Repolarization is represented by an arrow that is identified with a “–” sign at its head. The direction of the arrow is the same as the direction in which the repolarization wave moves through the tissue and returns cell membrane potentials to their negative, resting value. The usefulness of the vector concept is that it allows us to derive whether a given cardiac electrical event will appear in any one lead as an upward or downward deflection or yield no deflection at all. The first step in the determination is to draw the right-angle projection of the vector onto the line that connects the end points of the lead of interest (see Figure 6–6). An upward deflection will be observed in the lead if the head of a depolarization vector (+) points toward the “+” end of the lead or the head of a repolarization vector (-) points to the “–” end of the lead. The opposite alignments of projection and lead lines will result in downward deflections. If a cardiac vector points to a lead line at right angles, there will be no deflection for that event in that lead (for example, there is often no Q wave in lead II) (see Figure 6–6). Mechanical Activity of the Heart Excitation–activation–contraction coupling. The events of excitation– activation–contraction coupling link the electrical activities of the myocyte to the force-generating actin–myosin reaction by which pressure is developed. Each cycle of cardiac mechanical activity is initiated when the concentration of intracellular ionized calcium rises from its resting value of 50 to 100 nM to a peak of about 1,200 nM. Sources of Ca ++ . Voltage-activated channels. Most of the calcium that enters the myocyte at the start of an action potential is carried by I Ca-L (Figure 6–7). It provides no more than 10% of the total Ca ++ needed for a maximal contraction but performs the crucial function of providing the trigger that releases calcium from intracellular, SR stores. The magnitude of I Ca-L is a significant regulator of SR Ca ++ release and correlates closely with contraction strength. Sarcoplasmic reticulum. This membrane-lined structure is filled with a Ca ++ -rich fluid and supplies most of the Ca ++ that binds to troponin in each heart beat. The primary release mechanism is calcium-triggered calcium release. It involves both L-type Ca ++ channels in the sarcolemma of the T- tubules and a Ca ++ -release channel in the abutting SR. The large cytosolic domain of each SR Ca ++ release channel (ryanodine receptor) is closely apposed to an L-type Ca ++ channel (dihydropyridine Chapter 6 Cardiovascular Physiology 169 As described above (under Ion Currents), NaCaX normally operates in the Na + -in/Ca ++ -out mode throughout the cardiac cycle. However, when there are changes in the equilibrium potential for Na + (for example, during tachycardia) or in the resting membrane potential, the difference between E NaCaX and E REST can become much smaller in diastole and might reverse in systole. The effect of this would be reduced Ca ++ extrusion in diastole and might be inward Ca ++ transport in systole. Uptake and removal of Ca ++ . Ca ++ removal is required for relaxation. It is mostly an active process that resides in ATP-dependent Ca ++ pumps and partly a passive process residing in NaCaX. Ca ++ pumps are located in both the sarcolemma and the membrane that lines the SR. They differ slightly in size and mostly in the mechanisms by which they are controlled. Sarcolemmal Ca ++ pump. Sarcoplasmic reticulum Ca ++ uptake is fast enough to account for the observed rate of relaxation in the healthy myocardium. Concurrent passive movements of Cl – and phosphates maintain electroneutrality across the SR membrane. The pump is normally inhibited by high [Ca ++ ] within the SR and by phospholamban. Phospho- lamban inhibition is removed and both Ca ++ sensitivity and rate of Ca ++ transport are increased when phospholamban is phosphorylated by either cAMP or Ca ++ -calmodulin–dependent protein kinase.As a result, both sympathetic activation and elevated cytosolic [Ca ++ ] will stimulate SR Ca ++ uptake and, thereby, promote myocardial relaxation (lusitropy). Normally, cytosolic [Ca ++ ] is the more important determinant. Phosphorylation of phospholamban increases the Ca ++ content of the SR and, thus, favors Ca ++ retention within the myocyte over Ca ++ efflux across the plasmalemma. This enhances cardiac contractility. A number of phosphatases can dephosphorylate phospholamban. Ca ++ that has been taken up into the SR is mostly stored in the free, ionized form. Some of it is bound to a number of Ca ++ -binding proteins, the most important of which is calsequestrin. Plasmalemmal Ca ++ pump. This pump is larger than the SR pump because it incorporates within its C-terminal portion the sequences that have formed the separate regulatory protein, phospholamban, in the SR Ca ++ pump. Active plasmalemmal efflux is not stimulated by cAMP. It is normally inhibited by the C-terminal portion of the transporter and is disinhibited when a Ca ++ -calmodulin complex binds directly to the C-terminal end. This provides a feedback mechanism by which elevated [Ca ++ ] i stimulates Ca ++ efflux. Chapter 6 Cardiovascular Physiology 171 Cytosolic [Ca ++ ] and force development. In the resting, diastolic state, cytosolic [Ca ++ ] is near 100 nM and, as described more fully in Chapter 2, the physical conformation of troponin–tropomyosin either blocks the actin–myosin cross-bridge formation or permits only weakly attached, non–force-generating cross-bridges. In this state, cross-bridge cycling and force generation are inhibited. When cytosolic [Ca ++ ] rises from its resting value to nearly 1,000 nM, interaction of free intracellular Ca ++ with the Ca ++ -specific binding site on troponin-C initiates the cascade in which protein constituents undergo changes of conformation and state. These changes release steric hindrance and switch weakly bound cross-bridges to a state from which they can generate force provided that ATP is present and can be hydrolyzed to provide energy. (See Chap- ter 2 for more details.) Mechanical work is performed when neighboring Z- lines are pulled toward each other as described by the sliding filament model. Cardiac muscle metabolism. Adenosine triphosphate synthesis. Myocytes require ATP and generate it by two distinct processes: (1) glycolysis in the cytosol and (2) oxidative phosphorylation in the mitochondria. Whereas fetal and neonatal hearts depend mostly on glycolysis, the adult, healthy, normoxic heart depends mostly on a nonglycolytic pathway that occurs inside the mitochondria and begins with acetyl coenzyme A (acetyl CoA) and includes the Krebs cycle, electron transport chain, and oxidative phosphorylation. Glycolysis converts glucose to two molecules of pyruvate and yields two molecules of ATP. In the well-oxygenated heart, 34 additional ATPs can be extracted by the nonglycolytic path after conversion of both pyruvates to acetyl CoA (catalyzed by the pyruvate dehydrogynase complex inside the mitochondria). Between 60 and 70% of the adult myocardial energy requirement is met by the metabolism of free fatty acids to acetyl CoA and the subsequent formation of ATP by the nonglycolytic path. There are five significant steps (Figure 6–8): 1. Fatty acids enter the myocardial cell by saturable, carrier-mediated processes. Catalyzed by acyl CoA synthetase, they become activated to fatty acyl CoA. 2. Fatty acyl CoA is shuttled across the mitochondrial membrane by reversible coupling to carnitine. 3. Once fatty acyl CoA is inside the mitochondrion, it undergoes beta-oxi- dation at the inner surface of the mitochondrial membrane. This splits off the two-carbon fragment acetyl CoA. The remaining fatty acyl CoA, shortened by two carbons, re-enters the cycle to split off two more carbons in the form of acetyl CoA and so on. Acetyl CoA is subsequently used in the Krebs cycle. 172 PDQ PHYSIOLOGY Sustained increase in cardiac work entails increased rate of ATP utilization and requires an increase in the rate of ATP production. In the healthy heart, the linkage between the two is provided by coronary flow as follows: successive dephosphorylation of ATP produces first ADP and then adenosine monophosphate (AMP) (see Figure 6–28). In turn, AMP is broken down to adenosine or IMP (imidazole monophosphate) , depending on whether the enzyme 5ńucleotidase or AMP deam- inase predominates. Imidazole monophosphate stays within the cell and either enters one of the salvage pathways for the reclaiming of AMP or is degraded, eventually forming uric acid. Low cytosolic [ATP] or high [P i ] favor 5' nucleotidase and subsequent adenosine production.Adeno- sine can diffuse out of the myocyte, act on coronary vascular A 2 recep- tors, and lead to coronary vasodilatation and increased coronary blood flow. This supplies the O 2 needed for oxidative phosphorylation. Oxygen consumption. The O 2 consumption of the “resting” heart is about 8 mL/100g•min. Approximately 25% of that is used for basic metabolic processes, and the remainder provides energy for contraction in the following rank order: (1) development of wall tension, (2) heart rate, and (3) velocity of fiber shortening. As a result of the greater O 2 cost of tension development, cardiac O 2 consumption will increase more when there is an increase in cardiac work by increasing pressure, as opposed to increasing cardiac work by increasing cardiac output (by heart rate or stroke volume). The heart as a pump. The job of the heart is to transfer the stroke volume from the venous side to the arterial side and to match the volume transfer rate, which is equal to the cardiac output, to the oxygen needs of the entire body. The transfer is accomplished by sequential generation of wall tension in each of the four chambers. The resulting increase in chamber pressure displaces a volume in a direction that is permitted by valves controlling chamber inflow and outflow. Mitral and tricuspid valves prevent flow from ventricle to respective atrium, aortic and pulmonic valves permit flow from ventricle to aorta and pulmonary artery, respectively. The cardiac cycle. In healthy individuals, the contraction–relaxation cycle of the heart is repeated as little as 35 times per minute in extremely fit athletes at rest to as often as 200+ times per minute when those athletes exercise at maximum capacity. The resting heart rate of an adult is typically near 60 per minute, and Figure 6–9 shows the hemodynamic changes on the left side of the heart over the duration of one beat. These changes occur in the same sequence as the electrophysiologic changes (see Figure 6–6) and are considered in three sequential phases in Figure 6–9: (1) atrial contraction, (2) ventricular contraction, and (3) ventricular filling. 174 PDQ PHYSIOLOGY [...]... of forcegenerating cross-bridges and the rate of cross-bridge cycling • During basal, resting conditions, only about 25 to 30% of all potential cross-bridges participate in force-generating interactions with the thin filament in any one heart beat The number can be increased by increasing cytosolic [Ca++] and by decreasing interfilament spacing At any Chapter 6 Cardiovascular Physiology 179 length is... (contractility) because of the observation that the end-systolic points of the P-V loops of a given ventricle, at a constant contractility, fall on the end-systolic P-V relationship, no matter what the initial LVEDV or the aortic diastolic pressure happens to be As a result, contractility can be assessed as the slope of the line connecting the end-systolic pressure-volume points of several loops obtained at different... Produces inflammatory mediators IL-1; VCAM, ICAM, selectins Produces growth factors VEGF; cell colony stimulating factor; insulinlike growth factor; fibroblast growth factor Synthesizes vasorelaxing agents NO; CNP; PGI2; EDHF Synthesizes vasoconstrictor agents Endothelins; Ang-II; PGH2; TXA2 Ang-II = angiotensin-II; CNP = C-type natriuretic peptide; EDHF = endothelium-derived hyperpolarizing factor;... endothelium-derived hyperpolarizing factor; ICAM = intercellular cell adhesion molecule; IL-1 = interleukin-1; LDL = low-density lipoprotein; NO = nitric oxide; PGH2, = prostaglandin H2, PGI2, = prostacyclin; TXA2 = thromboxane-A2; VCAM = vascular cell adhesion molecule; VEGF = vascular endothelial growth factor 190 PDQ PHYSIOLOGY prostacyclin (PGI2) and nitric oxide (NO) Both are synthesized in endothelial... of receptor-coupled agonists that operate through the phospholipase C path (Figure 6–18) The effector mechanism by which NO causes vascular smooth muscle relaxation involves stimulation of a soluble guanylyl cyclase in vascular smooth muscle and a consequent increase in cGMP levels L-arginine H3N + H H C C C C H OOC - H H H H H NH2 N C H2N Guanidino group L-citrulline NADPH L-arginine S-nitrosocysteine... dominant postsynaptic receptor in the vasculature is the α1-adrenoreceptor Its activation elevates [Ca++]i through the phospholipase C pathway Strong sympathetic nervous activity can co-release neuropeptide Y, ATP, dopamine, or dopamine-␤-hydroxylase with norepinephrine, and they can each influence local vascular reactions by receptor-dependent or -independent mechanisms Sympathetic nerves generally carry... most variable of the factors that determine transcapillary exchange It is influenced by arterial and venous B) A) Venule Arteriole 40 P Π 25 28 -3 8 28 20 Net = 8 Π P 29 20 8 -3 21 23 Net = 2 15 Venule Arteriole 40 P Π 15 15 28 -3 8 18 20 Net = 2 Figure 6–22 The Starling-Landis mechanism of fluid exchange across the capillary membrane Net fluid movement occurs in response to a gradient in hydrostatic... 500 nm) and forms a selective barrier against plasma lipids and lipoproteins It also secretes vasoactive substances and participates in thrombic and antithrombic activities 1 84 PDQ PHYSIOLOGY Aorta Elastic ar teries Muscular arteries Small muscular arteries Arterioles Figure 6– 14 Arterial vessels branch successively to become arterioles eventually Architecture of the Peripheral Circulation From the... in vascular endothelial cells from L-arginine is catalysed by endothelial NO synthetase (eNOS) S-nitrosocysteine and L-citrulline are synthesized in the same reaction Inducible NOS (iNOS) can also be used as a catalyst for this reaction Under some conditions, the action of iNOS on L-arginine can produce superoxide radicals instead of NO 193 Chapter 6 Cardiovascular Physiology a given species The major... C-type natriuretic peptide (CNP), (3) endothelium-derived hyperpolarizing factor (EDHF), and (4) prostacyclin (PGI2) 1 Nitric oxide: NO is a continuous regulator of resistance vessels and, hence, of arterial blood pressure Nitric oxide is a labile gas, synthesized from the terminal guanidino nitrogen atom(s) of the amino acid Larginine (Figure 6–17) The stimulus for the formation of NO can be flow-induced . by β 1 -adrenocep- tor activation. • I C-T : carried by voltage-gated T-type Ca ++ channels (blocked by nickel). • I C-L : carried by voltage-gated L-type Ca ++ channels (blocked by dihydropyridine). 162. number of force- generating cross-bridges and the rate of cross-bridge cycling. • During basal, resting conditions, only about 25 to 30% of all potential cross-bridges participate in force-generating. Endothelins; Ang-II; PGH 2 ; TXA 2 Ang-II = angiotensin-II; CNP = C-type natriuretic peptide; EDHF = endothelium-derived hyperpolarizing factor; ICAM = intercellular cell adhesion molecule; IL-1 = interleukin-1;

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