Describe the physiological factors that affect pulmonary arterial pressure (65% of marks). Write short notes on the use of inhaled nitric oxide as a pulmonary vasodilator (35% of marks).
Pressure in a system is generated by the interaction between flow and resistance. A structured
approach to defining and describing the many factors that influence fluid flow and resistance
was required to score well. Poiseuille’s law describes the determinants of resistance to laminar
fluid flow and provides a useful answer structure. It is also necessary to describe factors that
determine flow. This includes factors that determine venous return, as well right and left heart
output.
A standard structured answer to the pharmacology of nitric oxide enabled concise and high
scoring answering of this question.
Though this question appears to have asked for factors which influence pulmonary arterial pressure, judging by the college answer what they really wanted was a discussion of pressure in general hydrodynamic terms. "A structured approach to defining and describing the many factors that influence fluid flow and resistance was required to score well", the examiners said. Poiseuille’s law was brought up. It is therefore somewhat weird that specifically pulmonary pressure was asked about in the question, as this might have misled the trainees and sent them into a pointless discussion of hypoxic pulmonary vasoconstriction and suchlike. What follows, therefore, is an effort to explore the factors which affect the pressure of any fluid travelling any vessel, but with an attempt to flavour the discussion with factors which are uniquely pulmonary.
Thus:
Now, as to nitric oxide:
Name | Nitric oxide |
Class | Inhaled pulmonary vasodilator |
Chemistry | A free radical with the formula NO |
Routes of administration | Administered as par tof inspired gas mixture, usually as an admixture fraction measured in tens of ppm, via a proprietary system (INOMax) |
Absorption | Absorbs rapidly into the systemic circulation via the lungs |
Solubility | As it dissociates in water, nitric oxide produces nitric acid (HNO3) which has a pKa of -1.3 |
Distribution | VOD is impossible to measure, but is potentially very large. NO reacts with oxygen and water to produce nitrogen dioxide and nitrites, which then bind to haemoglobin and produce either nitrosylhaemoglobin or methaemoglobin, i.e. it can be described as "highly protein bound". |
Target receptor | Soluble guanylyl cyclase (which is induced by NO) |
Mechanism of action | Inhibits vasoconstriction by increasing the amount of cyclic GMP (cGMP) in the cytosol, thus decreasing the amount of cytosolic calcium ions available to sustain smooth muscle contraction |
Metabolism | One way or another, nitric oxide ends up as methaemoglobin and nitrate. Either it reacts with lung water, becoming nitrite (which reacts with oxyhemoglobin and generates methaemoglobin and nitrate) or it combines directly with oxyhaemoglobin, with the same results. If it encounters hypoxic blood, it can combine with deoxyhaemoglobin to create nitrosyl-haemoglobin, which then rapidly becomes methaemoglobin when it contacts oxygen. |
Elimination | Nitrates are eliminated mainly in urine whereas methaemoglobin is metabolised in several hours into haemoglobin by endogenic reductases. The nitrates excreted in urine represent over 70% of the inhaled NO dose. |
Time course of action | Onset of effect is seen within seconds |
Clinical effects | Apart from pulmonary vasodilation, there is methemoglobinaemia, hypotension (maybe some of it does leak into the systemic circulation, or maybe this the effect of depressed LV function, rebound hypoxia after abrupt withdrawal, thrombocytopenia (in as many as 10% of patients) and increased susceptibility to pulmonary infections probably due to NO2 formation and associated lung injury. |
Single best reference for further information | TGA (AusPAR) product information |
West, J. B., and C. T. Dollery. "Distribution of blood flow and the pressure-flow relations of the whole lung." Journal of Applied Physiology 20.2 (1965): 175-183.
Sobin, Sidney S., et al. "Elasticity of the pulmonary alveolar microvascular sheet in the cat." Circulation Research 30.4 (1972): 440-450.
Johnson Jr, R. L., and C. C. Hsia. "Functional recruitment of pulmonary capillaries." Journal of Applied Physiology 76.4 (1994): 1405-1407.
Hanson, WENDY L., et al. "Site of recruitment in the pulmonary microcirculation." Journal of Applied Physiology 66.5 (1989): 2079-2083.
Conhaim, R. L., and B. A. Harms. "Perfusion of alveolar septa in isolated rat lungs in zone 1." Journal of Applied Physiology 75.2 (1993): 704-711.
Konig, M. F., JOHN M. Lucocq, and EWALD R. Weibel. "Demonstration of pulmonary vascular perfusion by electron and light microscopy." Journal of applied physiology 75.4 (1993): 1877-1883.
Carlin, J. I., et al. "Recruitment of lung diffusing capacity with exercise before and after pneumonectomy in dogs." Journal of applied physiology 70.1 (1991): 135-142.
Godbey, PATRICIA S., et al. "Effect of capillary pressure and lung distension on capillary recruitment." Journal of Applied Physiology 79.4 (1995): 1142-1147.
SIMMONS, DANIEL H., et al. "Relation between lung volume and pulmonary vascular resistance." Circulation Research 9.2 (1961): 465-471.
Thomas JR, Lewis J., Zora J. Griffo, and Albert Roos. "Effect of negative-pressure inflation of the lung on pulmonary vascular resistance." Journal of applied physiology 16.3 (1961): 451-456.
Permutt, S. "Howell JB, Proctor DF, Riley RL." Effect of lung inflation on static pressure-volume characteristics of pulmonary vessels. J Appl Physiol 16 (1961): 64-70.
Howell, J. B. L., et al. "Effect of inflation of the lung on different parts of pulmonary vascular bed." Journal of Applied Physiology 16.1 (1961): 71-76.
Kovacs, Gabor, et al. "Pulmonary vascular resistances during exercise in normal subjects: a systematic review." European Respiratory Journal 39.2 (2012): 319-328.
Glasser, Steven A., et al. "Pulmonary blood pressure and flow during atelectasis in the dog." Anesthesiology 58.3 (1983): 225-231.
Talbot, Nick P., et al. "Two temporal components within the human pulmonary vascular response to∼ 2 h of isocapnic hypoxia." Journal of applied physiology 98.3 (2005): 1125-1139.
Benumof, Jonathan L. "Mechanism of decreased blood flow to atelectatic lung." Journal of Applied Physiology 46.6 (1979): 1047-1048.
Woodson, R. Donald, David E. Raab, and D. J. Ferguson. "Pulmonary hemodynamics following acute atelectasis." American Journal of Physiology-Legacy Content 205.1 (1963): 53-56.
Lumb, Andrew B., and Peter Slinger. "Hypoxic Pulmonary VasoconstrictionPhysiology and Anesthetic Implications." Anesthesiology: The Journal of the American Society of Anesthesiologists 122.4 (2015): 932-946.
Euler, US V., and Göran Liljestrand. "Observations on the pulmonary arterial blood pressure in the cat." Acta Physiologica Scandinavica 12.4 (1946): 301-320.
Marshall, B. E., C. Marshall, and H. F. Frasch. "Control of the pulmonary circulation." Anesthesia and the Lung 1992. Springer, Dordrecht, 1992. 9-18.
Marshall, B. E., and C. Marshall. "A model for hypoxic constriction of the pulmonary circulation." J Appl Physiol 64 (1988): 68-77.
Tarry, D., and M. Powell. "Hypoxic pulmonary vasoconstriction." Bja Education 17.6 (2017): 208-213.
Duke, Helen N., and Esther M. Killick. "Pulmonary vasomotor responses of isolated perfused cat lungs to anoxia." The Journal of physiology 117.3 (1952): 303.
Staub, Norman C. "Site of hypoxic pulmonary vasoconstriction." Chest 88.4 (1985): 240S-245S.
Sommer, N., et al. "Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms." European Respiratory Journal 32.6 (2008): 1639-1651.
Davis, MICHAEL J., WILLIAM L. Joyner, and JOSEPH P. Gilmore. "Microvascular pressure distribution and responses of pulmonary allografts and cheek pouch arterioles in the hamster to oxygen." Circulation research 49.1 (1981): 125-132.
Nagasaka, Yukio, et al. "Micropuncture measurement of lung microvascular pressure profile during hypoxia in cats." Circulation research 54.1 (1984): 90-95.
Talbot, Nick P., et al. "Two temporal components within the human pulmonary vascular response to∼ 2 h of isocapnic hypoxia." Journal of applied physiology 98.3 (2005): 1125-1139.
Lam, Carolyn SP, et al. "Age-associated increases in pulmonary artery systolic pressure in the general population." Circulation 119.20 (2009): 2663.
Farrar, J. F., Jeanette Blomfield, and R. D. K. Reye. "The structure and composition of the maturing pulmonary circulation." The Journal of pathology and bacteriology 90.1 (1965): 83-96.
McCORMACK, DAVID G., and N. A. Paterson. "Loss of hypoxic pulmonary vasoconstriction in chronic pneumonia is not mediated by nitric oxide." American Journal of Physiology-Heart and Circulatory Physiology 265.5 (1993): H1523-H1528.
Hyman, A. L., and PHILIP J. Kadowitz. "Effects of alveolar and perfusion hypoxia and hypercapnia on pulmonary vascular resistance in the lamb." American Journal of Physiology-Legacy Content 228.2 (1975): 397-403.
Kiely, David G., Robert I. Cargill, and Brian J. Lipworth. "Effects of hypercapnia on hemodynamic, inotropic, lusitropic, and electrophysiologic indices in humans." Chest 109.5 (1996): 1215-1221.
Rudolph, A. M., and Stanley Yuan. "Response of the pulmonary vasculature to hypoxia and H+ ion concentration changes." The Journal of clinical investigation 45.3 (1966): 399-411.
Presberg, K. W., et al. "Distribution of pulmonary vascular resistance during lactic acid infusion in dogs." Journal of Applied Physiology 68.4 (1990): 1328-1336.
Loeppky, J. A., et al. "Effects of acid-base status on acute hypoxic pulmonary vasoconstriction and gas exchange." Journal of Applied Physiology 72.5 (1992): 1787-1797.
Zayek, M. M., et al. "Induced moderate hypothermia markedly exacerbates pulmonary hypertension and dysoxia in a neonatal piglet model of elevated pulmonary vascular resistance." Critical Care. Vol. 4. No. 1. BioMed Central, 2000.
Kummer, Wolfgang. "Pulmonary vascular innervation and its role in responses to hypoxia: size matters!." Proceedings of the American Thoracic Society 8.6 (2011): 471-476.
Hoffman, Julien IE. "Pulmonary vascular resistance and viscosity: the forgotten factor." Pediatric cardiology 32.5 (2011): 557.