Cardiac Signaling Pathways and Vascular Signaling Pathways III

Question 1

Describe the myogenic response

Answer 1

• The myogenic response is a feedback mechanism designed to maintain constant flow despite changes in pressure.
• Mechanism is intrinsic to VSMCs—occurs in denervated vessels and is independent of vascular endothelium.
o Stretch causes VSMC contraction by opening stretch-activated ion channels, which depolarize the VSMC, thereby ↑intracellular Ca2+ via L-type Ca2+ channels

Question 2

Describe how nitric oxide regulates vascular smooth muscle tone

Answer 2

o Many humoral regulators (ie ACh) stimulate activity of nitric oxide synthase (NOS) in vascular endothelial cells. Nitric oxide readily diffuses across the endothelial and vascular smooth muscle cell membranes. In VSMCs, NO activates guanylate cyclase→↑cGMP. cGMP activates PKG→↓intracellular Ca2+ via activation of SERCA and inhibition of L-type Ca2+ channels. ↓Ca2+ concentration causes relaxation of the VSMC (vasodilation).

• –NOS is highly susceptible to cardiovascular disease risk factors (oxidative stress, cigarette smoke)
• –Basal release of NO helps set resting vascular tone (↓NO→↑BP)
• –NO is anti-atherosclerotic and inhibits many steps in the development of plaques and ↓NO is associated with greatly increased risk for atherosclerosis.
• –Hypertensive patients often have ↓NO, which worsens there condition.

Question 3

Describe how endothelin regulates vascular smooth muscle tone

Answer 3

o Endothelin is a potent vasoconstrictor produced by the vascular endothelium.
o Endothelin binds to ET receptors, GPCRs primarily coupled to Gq. Endothelin response is similar to the a-adrenergic response, but the time course is different.
—Endothelin has both transient effects and longer lasting effects

Question 4

Renin-Angiotensin-aldosterone system:

Answer 4

critical system for regulation of blood volume, mediated by the kidney

Question 5

Renin:

Answer 5

released into circulation by the juxtoglomerular cells when stimulated by (1) sympathetic stimulation of JG cells; (2) decreased blood pressure in the renal artery; and (3) decreased sodium reabsorption in the kidney.
o Renin cleaves the circulating inactive protein angiotensinogen to angiotensin I (AI)—another inactive precursor.
o AI is then cleaved by angiotensin converting enzyme (ACE) to form the active peptide, angiotensin II (AII).

Question 6

ACE:

Answer 6

important therapeutic target for treatment of hypertension and heart failure—ACE inhibitors.

Question 7

Direct effects of AII:

Answer 7

AII is a potent systemic vasoconstrictor which acts via binding to GPCRs on VSMCs.

Question 8

Indirect effects of AII:

Answer 8

(1) stimulates sympathetic activity→↑vasoconstriction; (2) ↑aldosterone release from adrenal cortex; (3) stimulates release of endothelin from vascular endothelium→↑vasoconstriction; and (4) stimulates release of ADH from the pituitary.

Question 9

Aldosterone:

Answer 9

promotes sodium and water reabsorption in the kidney→↑blood volume→↑blood pressure.

Question 10

Anti-Diuretic Hormone (ADH—arginine vasopressin):

Answer 10

formed in hypothalamus, released by pituitary. ↑water reabsorption in the kidney; ↑peripheral vasoconstriction during systemic shock.