NROSCI-BIOSC 1070 MSNBIO 2070

1. NROSCI-BIOSC 1070MSNBIO 2070 • September 22, 2014 • Cardiovascular 5

2. Control of Blood Flow • Neural control of blood pressure • Local control of blood pressure • Hormonal control of blood pressure

3. The Baroreceptor Reflex • Baroreceptors innervate the carotid sinus and aortic arch • Carotid sinus baroreceptors course in cranial nerve IX • Aortic arch baroreceptors course in a branch of cranial nerve X

4. The Baroreceptor Reflex • When blood pressure increases, the baroreceptor terminals are stretched and the afferents fire more. • As with other types of stretch receptors, the responses of these afferents adapt to prolonged stretch. In the case of baroreceptors, this adaptation (resetting) begins within a few minutes.

5. The Baroreceptor Reflex • Increases or decreases in blood pressure induce baroreceptor-mediated changes in sympathetic and parasympathetic activity • Baroreceptor activity displays “ceiling” and “floor” effects

6. Brain Regions Mediating the Baroreceptor Reflex • RVLM Rostral Ventrolateral Medulla

7. Brain Regions Mediating the Baroreceptor Reflex • CVLM Caudal Ventrolateral Medulla

8. Some NTS neurons project directly to parasympathetic preganglionic neurons in nucleus ambiguus (a region of the caudal medullary lateral reticular formation) Neural Basis of the Baroreceptor Reflex Baroreceptor afferents terminate in nucleus tractus solitarius (NTS) in the caudal medulla.

9. The RVLM is the major region of the brainstem involved in cardio-vascular control. The RVLM projects to sympathetic pre-ganglionic neurons in the intermediolateral cell column (IML) of the thoracic spinal cord. CVLM neurons are inhibitory, and inhibit the activity of neurons in the rostral ventro-lateral medulla (RVLM) Neural Basis of the Baroreceptor Reflex NTS neurons also project to an area of the caudal ventrolateral medullary reticular formation (CVLM).

10. Baroreceptor Reflex

11. Response of RVLM Neuron to Carotid Artery Stretch 100 Blood Pressure 90 mm Hg 80 200 100 0 µV -100 -200 Neural Activity 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (sec)

13. What Happens if the Baroreceptor Reflex is Dysfunctional?

14. RVLM Neurons Integrate a Variety of Inputs • The baroreceptor reflex provides a powerful mechanism to prevent sudden increases or decreases in blood pressure. • However, additional mechanisms are needed to adjust blood pressure in the absence of perturbations. • RVLM neurons integrate inputs from many regions of the nervous system, all of which contribute to altering blood pressure.

15. Changes in Regional Perfusion During Exercise       Blood flow to different organs changes appreciably during exercise

16. Factors Adjusting Blood Flow to Different Vascular Beds • Neural control (results in some patterning) • Myogenic autoregulation (the ability of vascular smooth muscle to regulate its own activity) • Response to paracrines from surrounding tissues (major factor producing increases in blood flow to metabolically active tissues) • Hormonal control (epinephrine, vasopressin, angiotensin 2, aldosterone, atrial natriuretic factor)

17. Myogenic Autoregulation • Blood vessels automatically adjust their diameter in response to alterations in blood pressure, so that flow through the vascular bed remains constant. • Ohm’s law (Q = ΔP/R) indicates that flow and perfusion pressure are directly proportional. • As such, vascular resistance must increase in proportion to the increase in pressure to achieve autoregulation.

18. A rise in pressure stretches the wall of vascular smooth muscle cells, opening stretch-sensitive Na+ channels, thereby resulting in a depolarization of the cell. • This depolarization elicits an opening of voltage-gated Ca2+ channels on the surface, increasing Ca2+ and triggering vasoconstriction. Myogenic Autoregulation • Consequently, vessel diameter will become smaller as perfusion pressure rises. • Autoregulation provides for a constant rate of O2 delivery regardless of perfusion pressure.

19. Local control of vascular resistance is mainly controlled by the release of metabolites from tissues. • H+ from acids (e.g. lactic acid), K+, and CO2 release promotes vasodilation. • Low oxygen levels can also induce vasodilation, likely mediated by the release of adenosine from muscle cells during hypoxia. • Each factor is additive, and the accumulation of all of these chemicals during exercise promotes the extensive increases in skeletal muscle perfusion that occur. Paracrine Control of Local Blood Flow

20. Paracrine Control of Local Blood Flow • Adenosine triggers an increase in cAMP, which activates protein kinase A (PKA). • PKA phosphorylates and opens K-ATP channels, resulting in K+ efflux and hyperpolarization.

21. Conductance through another K+ channel, the K-IR channel, increases when extracellular K+ rises, causing hyperpolarization of the cell. • Increases in extracellular K+ due to metabolism of surrounding tissues also opens and increases K+ conductance through K-IR channels.

22. Hyperpolarization of smooth muscle causes a closing of voltage-gated Ca2+ channels, thereby resulting in relaxation of the smooth muscle. • Through these mechanisms, there is profound vasodilation of vascular smooth muscle during exercise.

23. A large number of additional paracrine factors help to precisely regulate blood flow to particular vascular beds. • One example is endothelin, which is released from damaged endothelial cells. Endothelin produces powerful vasoconstriction, which serves to reduce bleeding from damaged arteries. • Release of serotoninfrom activated platelets induces vasoconstriction to prevent blood loss. • In contrast, histaminerelease from healing tissues or mast cells promotes vasodilation. Other Paracrine Factors that Regulate Blood Flow

24. Endothelium-Derived Relaxing Factor • Vasodilation is also produced by a chemical first called “endothelium-derived relaxing factor,” which is now know to be nitric oxide (NO). • Sheer stress produced by the flowing of blood across the surface of endothelial cells opens mechanically-gated channels on the surface, including Ca2+ channels.

25. Endothelium-Derived Relaxing Factor • Ca2+ entering the endothelial cell through open channels combines with calmodulin (CM); the resulting Ca2+—CM complex activates NO synthase. • An additional mechanotransduction mechanism initiates a kinase cascade, ultimately leading to phosphorylation of NO synthase and increased production of NO.

26. Endothelium-Derived Relaxing Factor • NO diffuses from endothelial cells to adjacent smooth muscle cells. • NO produces smooth muscle relaxation by activating the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP).

27. cGMP activates an ATPase that pumps calcium out of the smooth muscle cell, thereby inhibiting interactions between actin and myosin. • Other factors besides sheer stress can also lead to NO production by endothelial cells: • Bradykinin, an agent that is released during cellular damage. • A number of products of metabolism • Parasympathetic activity acting on vessels that receive this innervation (e.g., genitalia) Endothelium-Derived Relaxing Factor

28. cGMP is rapidly broken down in vascular smooth muscle cells. • In male genitalia, the degredation of cGMP is the result of the actions of phosphodiesterase type 5 (PDE5). cGMP can be degraded via other routes in other tissues. • Drugs such as Viagra are phosphodiesterase type 5 inhibitors. • Sexual stimulation in males results in parasympathetically-mediated vasodilation in the penis, via the local release of NO from endothelial cells in the corpus cavernosum. This NO release results in an increase in cGMP in smooth muscle cells of the corpus cavernosum, which generates vasodilation, an influx of blood, and an erection. • Viagra prevents the cGMP from being rapidly degrated, so the vasodilation persists much longer than usual. Endothelium-Derived Relaxing Factor

29. Control of Blood Flow by Erythrocytes • The release of oxygen and vasodilator substances from erythrocytes are coupled: an increase in O2 release is associated with more vasodilator release. • As such, tissues utilizing a considerable amount of oxygen will receive increased blood flow, as nearby arterioles will dilate.

30. NO O2 NO2 • NO is continuosly produced by endothelial cells. Some of the NO reacts with O2 to form the nitrite anion (NO2-), which can be taken up by the erythrocytes. Control of Blood Flow by Erythrocytes • Some of the NO reacts with O2 to form the nitrite anion (NO2-), which can be taken up by the erythrocytes. The deoxygenated hemoglobin can function as a nitrite reductase that regenerates NO from nitrite.

31. As such, NO production by erythrocytes is coupled to how much oxygen they have released to surrounding tissues. Control of Blood Flow by Erythrocytes • ATP is produced in the erythrocyte by glycolysis and is released in response to off-loading of O2. How O2 dissociation from hemoglobin activates this process is still not known. The release of ATP triggers the release of NO from endothelial cells.

32. Through these mechanisms, the off-loading of O2 from erythrocytes leads to local vasodilation, and thus delivery of more erythrocytes to the area utilizing O2. • During exercise, this mechanism enhances oxygen delivery to working muscle. Control of Blood Flow by Erythrocytes

33. Hormonal Control of Blood Pressure • Atrial Natriuretic Factor (Peptide) • Vasopressin (Antidiuretic Hormone) • Angiotensin II • Aldosterone

34. Atrial Natriuretic Factor (Peptide) • Atrial natriuretic factor is released from the atria when venous pressure (atrial stretch) is high. • This hormone tends to produce vasodilation. This will diminish cardiac return, and will thus decrease the workload of the heart which is overloaded with blood. • In addition, atrial natriuretic factor promotes secretion of water and salt by the kidney, to reduce blood volume.

35. Atrial Natriuretic Factor (Peptide)

36. Atrial Stretch Receptors • Both the atria and the pulmonary arteries contain stretch receptors, which are called low-pressure receptors. • These low-pressure receptors are much like arterial baroreceptors in structure, but because of their location do not sense pressure in the systemic circulation. Instead, they detect increases in pressure in the low-pressure parts of the circulation that are generated by increases in blood volume.

37. Atrial Stretch Receptors • The axons of atrial stretch receptors project to the brainstem via the vagus nerve, and synapse in nucleus tractus solitarius (NTS). • Activation of atrial stretch receptors elicits a brainstem-mediated reflex that tends to an increase heart rate and probably contractility.

38. Vasopressin • Signals from atrial stretch receptors are also transmitted to the hypothalamus, and affect the release of vasopressin. Signals from atrial stretch receptors can elicit a decrease in vasopressin release, which will in turn act on the kidney to result in lowered volume in the cardiovascular system. • Vasopressin is additionally released when the hypothalamus detects an increase in blood osmolarity, which occurs when blood volume decreases or the concentration of solutes increases.

39. Vasopressin • A large decrease in blood pressure sensed by arterial baroreceptors triggers vasopressin release. • Increased blood levels of angiotensin II induce vasopressin release.

40. Vasopressin • Increases in vasopressin result in kidney reabsorbing more water. As a consequence, blood volume increases and urine production decreases. • Drastic reductions in blood volume and blood pressure result in massive elevations in vasopressin levels, which induces vasoconstriction in some vascular beds.

41. Vasopressin

42. Posterior Pituitary Hormones • Posterior pituitary hormones are synthesized by neurons in the paraventricular and supraoptic nuclei of the hypothalamus • These hormones are released like neurotransmitters when the neurons fire • The release of the hormones is dependent on the number of neurons that fire and the rate and duration of their firing

43. What Happens if Baroreceptors are Removed? • Following baroreceptor denervation, blood pressure is highly unstable. • However, mean blood pressure remains near 100 mmHg. • A mechanism other than the baroreceptor reflex must establish the blood pressure set-point.

44. Renin-Angiotensin System • Renin converts an inactive plasma protein made by the liver, angiotensinogen, into angiotensin I. • Angiotensin I is converted by an enzyme located on the endothelium of blood vessels, called angiotensin converting enzyme (ACE), into the active form, angiotensin II. This enzyme is concentrated in blood vessels of the lung. • Angiotensin II is a very potent vasoconstrictor substance. • When blood pressure is low, special cells in the kidney called juxtaglomerular cells (JG cells) detect the condition and release a peptide called renin. • The sympathetic nervous system can also act to induce renin release.

45. Other Functions of Angiotensin II • It causes the adrenal cortex to release the hormone aldosterone, which causes the kidney to reabsorb salt and water into the blood. The net result is that blood volume is increased. • It affects the parts of the medulla that control sympathetic outflow, to increase heart rate and vasoconstriction. • It potentiates the release of NE from sympathetic terminals. • It stimulates the release of antidiuretic hormone (vasopressin) from the pituitary, which stimulates water retention and an increase in plasma volume. • It stimulates thirst, and the addition of water to the body

46. Summary of Angiotensin 2 Actions

47. Summary of Angiotensin 2 Actions

48. Not all Triggers of Ang Secretion are Equal!

49. Clinical Note Widely-prescribed anti-hypertensive mechanisms include Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin II receptor antagonists

50. Advantage of Angiotensin II Receptor Blockers Over ACE Inhibitors • AT1 receptors mediate most of the effects of Ang-II on blood pressure. • AT2 receptors are found in many tissues, including the uterus, ovary and several brain regions, but they are not known to be directly related to cardiovascular homeostasis.