1. Regulation of Cardiovascular Activities Qiang XIA (夏强), PhD Department of Physiology Room C518, Block C, Research Building, School of Medicine Tel: 88208252 Email: xiaqiang@zju.edu.cn

2. Lecture Outline Nervous Regulation Humoral Regulation Autoregulation

3. Nervous Regulation

4. Innervation of the heart Cardiac sympathetic nerve Cardiac vagus nerve 1. 起源 origin 2. 节前纤维 preganglionic fiber 3. 外周神经节 ganglion 4. 节后纤维 postganglionic fiber 5. 支配 distribution 6. 递质 neurotransmitter

7. Cardiac sympathetic actions Positive chronotropic effect 正性变时作用 Positive dromotropic effect 正性变传导作用 Positive inotropic effect 正性变力作用

8. Cardiac mechanisms of norepinephrine

9. Mechanisms of norepinephrine —increase Na + & Ca 2+ permeability I f , phase 4 spontaneous depolarization , autorhythmicity  Ca 2+ influx (I Ca,L ) , phase 0 amplitude & velocity , conductivity  Ca 2+ influx (I Ca,L ) , Ca 2+ release , [Ca 2+ ] i , contractility  (CICR)

10. Asymmetrical innervation of sympathetic nerve

11. Cardiac parasympathetic actions Negative chronotropic effect 负性变时作用 Negative dromotropic effect 负性变传导作用 Negative inotropic effect 负性变力作用

12. Cardiac mechanisms of acetylcholine

13. Mechanisms of acetylcholine —increase K + & decrease Ca 2+ permeability K + outward , |MRP| , phase 4 spontaneous depolarization , autorhythmicity  Inhibition of Ca 2+ channel, phase 0 amplitude & velocity , conductivity  Ca 2+ influx , [Ca 2+ ] i , contractility 

14. Cardiac effect of parasympathetic stimulation

15. Vagal Maneuvers Valsalva maneuver –A maneuver in which a person tries to exhale forcibly with a closed glottis (the windpipe) so that no air exits through the mouth or nose as, for example, in strenuous coughing, straining during a bowel movement, or lifting a heavy weight. The Valsalva maneuver impedes the return of venous blood to the heart. –Named for Antonio Maria Valsalva, a renowned Italian anatomist, pathologist, physician, and surgeon (1666-1723) who first described the maneuver.

17. Physiological response in Valsalva maneuver The normal physiological response consists of 4 phases

18. Physiological response in Valsalva maneuver The normal physiological response consists of 4 phases –Initial pressure rise : On application of expiratory force, pressure rises inside the chest forcing blood out of the pulmonary circulation into the left atrium. This causes a mild rise in stroke volume. –Reduced venous return and compensation : Return of systemic blood to the heart is impeded by the pressure inside the chest. The output of the heart is reduced and stroke volume falls. This occurs from 5 to about 14 seconds in the illustration. The fall in stroke volume reflexively causes blood vessels to constrict with some rise in pressure (15 to 20 seconds). This compensation can be quite marked with pressure returning to near or even above normal, but the cardiac output and blood flow to the body remains low. During this time the pulse rate increases. –Pressure release : The pressure on the chest is released, allowing the pulmonary vessels and the aorta to re-expand causing a further initial slight fall in stroke volume (20 to 23 seconds) due to decreased left ventricular return and increased aortic volume, respectively. Venous blood can once more enter the chest and the heart, cardiac output begins to increase. –Return of cardiac output : Blood return to the heart is enhanced by the effect of entry of blood which had been dammed back, causing a rapid increase in cardiac output (24 seconds on). The stroke volume usually rises above normal before returning to a normal level. With return of blood pressure, the pulse rate returns towards normal.

20. Interaction of sympathetic and parasympathetic nerves

21. Predominance of autonomic nerves

22. Tonus 紧张 Cardiac vagal tone 心迷走紧张 Cardiac sympathetic tone 心交感紧张

23. Innervation of the blood vessels Vasoconstrictor nerve 缩血管神经 –Sympathetic vasoconstrictor nerve 交感缩血管神 经 Vasodilator nerve 舒血管神经 –Sympathetic vasodilator nerve 交感舒血管神经 –Parasympathetic vasodilator nerve 副交感舒血管 神经 –Dorsal root vasodilator nerve 脊髓背根舒血管神 经

25. Cardiovascular Center A collection of functionally similar neurons that help to regulate HR, SV, and blood vessel tone

26. Vasomotor center Located bilaterally mainly in the reticular substance of the medulla and of the lower third of the pons –Vasoconstrictor area –Vasodilator area –Cardioinhibitor area – dorsal nuclei of the vagus nerves and ambiguous nucleus –Sensory area – tractus solitarius

30. Vasomotor center

31. –Reticular substance of the pons –Mesencephalon –Diencephalon –Hypothalamus –Cerebral cortex –Cerebellum Higher cardiovascular centers

32. Baroreceptor Reflexes Arterial baroreceptors –Carotid sinus receptor –Aortic arch receptor Afferent nerves (Buffer nerves) Cardiovascular center: medulla Efferent nerves: cardiac sympathetic nerve, sympathetic constrictor nerve, vagus nerve Effector: heart & blood vessels

33. Baroreceptor neurons function as sensors in the homeostatic maintenance of MAP by constantly monitoring pressure in the aortic arch and carotid sinuses.

35. Characteristics of baroreceptors:  Sensitive to stretching of the vessel walls  Proportional firing rate to increased stretching  Responding to pressures ranging from 60- 180 mmHg  Receptors within the aortic arch are less sensitive than the carotid sinus receptors

37. The action potential frequency in baroreceptor neurons is represented here as being directly proportional to MAP.

38. Baroreceptor neurons deliver MAP information to the medulla oblongata’s cardiovascular control center (CVCC); the CVCC determines autonomic output to the heart. i.e., MAP is above homeostatic set point i.e., reduce cardiac output

39. Reflex pathway

40. Click here to play the Baroreceptor Reflex Control of Blood Pressure Flash Animation

41. Typical carotid sinus reflex

42. Maintaining relatively constant arterial pressure, reducing the variation in arterial pressure Physiological Significance

43. Other Cardiovascular Reflexes Click here to play the Chemoreceptor Reflex Control of Blood Pressure Flash Animation

44. Humoral Regulation Vasoconstrictor agents Vasodilator agents

45. Renin-angiotensin system

46. Juxtaglomerular cell Renin

47. –Constricts resistance vessels –Acts upon the adrenal cortex to release aldosterone –Stimulates the release of vasopressin –Facilitates norepinephrine release from sympathetic nerve endings –Stimulates thirst centers within the brain Physiological effects of angiotensin II

48. Epinephrine & Norepinephrine Sources Epinephrine---- adrenal medulla Norepinephrine---- adrenal medulla sympathetic nerves

49. Catecholamines Norepinephrine Epinephrine

50. EffectsEpinephrineNorepinephrine Receptor  -adrenoceptor++ +++  -adrenoceptor++ + Heartheart rate+ + (in vitro) － (in vivo) cardiac output+++ ± Vesselsconstriction (skin, visceral) + +++ relaxation (SM, liver) － +++ total peripheral resistance ± +++ Blood pressuresystolic +++ +++ diastolic ± ++ MAP + ++ Clinical applicationpositive inotropic pressor agent agent

52. Vasopressin (antidiuretic hormone, ADH)

54. Endothelium-derived vasoactive substances Vasodilator factors PGI 2 --prostacyclin EDRF, NO--endothelium-derived relaxing factor, nitric oxide EDHF--endothelium-dependent hyperpolarizing factor Vasoconstrictor factors Endothelin

55. Atrial natriuretic peptide (ANP) Produces natriuresis and diuresis Decreases renin release Reduces total peripheral resistance via vasodilatation Decreases heart rate, cardiac output

56. Autoregulation Definition: Intrinsic ability of an organ to maintain a constant blood flow despite changes in perfusion pressure, independent of any neural or humoral influences

59. Myogenic mechanism The myogenic mechanism is how arteries and arterioles react to an increase or decrease of blood pressure to keep the blood flow within the blood vessel constant The smooth muscle of the blood vessels reacts to the stretching of the muscle by opening ion channels, which cause the muscle to depolarize, leading to muscle contraction. This significantly reduces the volume of blood able to pass through the lumen, which reduces blood flow through the blood vessel. Alternatively when the smooth muscle in the blood vessel relaxes, the ion channels close, resulting in vasodilation of the blood vessel; this increases the rate of flow through the lumen.

60. From: http://www.umm.uni-heidelberg.de/inst/cbtm/kphys/research-schubert.html Universität Heidelberg > Fakultäten > Medizinische Fakultät Mannheim > CBTM: Kardiovaskuläre Physiologie >

61. From: AJP - Heart October 2008 vol. 295 no. 4 H1505-H1513

62. Metabolic mechanism Any intervention that results in an inadequate oxygen (nutrient) supply for the metabolic requirements of the tissues results in the formation of vasodilator substances which increase blood flow to the tissues

63. Metabolic mechanism

64. Lack of oxygen? Formation of vasodilators? Combination of both?? Metarteriole Precapillary Sphincter Capillary Relaxation of smooth muscle Increased Blood Flow

65. Metabolic mechanism Hypoxia Tissue metabolites and ions –Adenosine –Potassium ions –Carbon dioxide –Hydrogen ion –Lactic acid –Inorganic phosphate

66. The End.