Fluid Balance: Adenosine, ADH, and Histamine

1. Fluid Balance:
Adenosine, ADH, and Histamine
Group #11: Robin Yi, Dave Mun, Chia Jung Wu
Symposia Presentation
T/TH Manely Yafeh

2. Introduction
Why Fluid Balance?
● Allows for efficient examination of drug
effects on vasculature
What we hope to accomplish:
● To obtain practical results that can be
explained through expected pathways

3. Common Uses
● Adenosine
○ regulation of coronary blood flow
○ anti-inflammatory properties
● ADH
○ regulation of blood pressure
○ increased water retention
● Histamine
○ immune response
○ gastric regulation
○ NT in the brain

4. Methods
Fig 1. Isometric Transducer used to determine rate of weight change

5. Predicting Drip Rate:
Ohm's Law & Resistance
Resistance = (8ηL)/(Πr4)
(η = Viscosity, L = Length, r = Radius)
Ohm's Law: Q = ΔP/R
(Q = Flow, ΔP = Hydrostatic pressure difference, R = Resistance)
● ↑R = ↓ in Q = ↓ drip rate
● ↓R = ↑ in Q = ↑ drip rate

6. Predicting Rate of Weight Change:
Starling's Equation
Φ = K[(Pc+Πi) – (Pi+Πc)]
(out) (in)
where:
Φ = Filtrate flow across capillary
K = Filtration coefficient
Pc = Capillary hydrostatic pressure Φ
Πi = Interstitial osmotic pressure -Φ +Φ
Pi = Interstitial hydrostatic pressure
Πc = Capillary osmotic pressure
Capillary
Fig 2. Filtrate flow into and out of a capillary

7. Adenosine Receptors
Fig 3. Major Receptors of Adenosine. "adenosine 1." Herbalzym. 2010. Web. 13 Mar. 2012. <http:
//www.herbalzym.com/2012/01/caffeine-competitively-inhibits-different-adenosine-receptors/>.

8. Adenosine - Gs Pathway
Fig 4. Gs Pathway. "Cyclic AMP pathways in myometrial tissue." BMC Pregnancy and Childbirth. 2007. Web. 14 Mar.
2012. <http://www.biomedcentral.com/1471-2393/7/S1/S10/figure/F1>

9. Adenosine Pathway Effects
● Activating PKA
○ K+ channels: repolarization and decreases strength
of contraction
○ Myosin Light Chain Phosphatase: dephosphorylates
myosin & causes relaxation.
● Decreasing Ca2+
○ SERCA: returns Ca2+ to SR
○ NCX: exchanges 3 Na+ for Ca2+

10. Adenosine: Vasodilator
● Adenosine causes coronary vasodilation
○ Vasodilation ↑ radius of blood vessels (R=(8ηL)/
(Πr4)), so ↓resistance.
■ ↓resistance ↑ flow rate (Q=ΔP/R)
■ Expected to increase drip rate
○ Vasodilation ↑ Pc (Φ = K[(Pc+Πi) – (Pi+Πc)])
■ ↑ Pc = ↑ filtrate flow across capillaries
■ Expected to increase rate of weight change

11. Results for Adenosine
● Drip Rate: increased (19 to 21 drips/min)
● Rate of Weight Change: increased (-0.0233
to +0.0584 g/min)

12. ADH Pathway - Gq Coupled Receptor
ADH V1 Receptor ⇒ ↑ Cytosolic [Ca2+]
↳ ↑ Smooth Muscle Contraction
Fig 5. Shih, Michael and Croston, Glenn. Activation of PKC through G protein coupled receptor. Graphic. BioCartaWeb. 12 Mar
2012. <http://www.biocarta.com/pathfiles/h_pkcPathway.gif>

13. ADH: Vasoconstriction
● Systemic vasoconstriction results in decreased fluid
hydrostatic pressure, (Pc), in the capillaries
Fig 6. MacDonald, Matthew. Your Temperature Control System. 2009. Graphic. Immaterial.fr Web. 14 Mar 2012.
Adapted for use. <http://librairie.immateriel.fr/baw/9780596801748/tagoreillycom20090720oreillyimages310768.png.
jpg>

14. ADH: Vasoconstriction
● Site-specific vasoconstriction can result in increased
OR decreased capillary Pc, depending on whether the
site of constriction is pre- or post-capillary
Fig 7. Mc-Graw Hill Corporation. Effect of Vasoconstriction on Blood Pressure. Graphic. Wikispaces. Web. 14 Mar
2012. <http://humanphysiology2011.wikispaces.com/file/view/the_effects_of_casoconstriction_on_blood_pressure..jpg>

15. ADH Pathway Effects - Weight Loss
● As Pc (capillary hydrostatic pressure) decreases as a
result of systemic vasoconstriction, according to
Starling's Law:
Φ = K[(Pc+Πi) – (Pi+Πc)]
As Pc ↓, Φ ↓. Vasoconstriction therefore results in
increasing filtrate leaving the interstitial tissues and
and entering the capillaries. This results in the frog
losing weight, as frog filtrate exits the frog.

16. ADH Pathway Effects - Drip Rate
● As vasoconstriction decreases the radius of
the blood vessels, resistance increases
according to the equation:
Resistance = (8ηL)/(Πr4)
(η = Viscosity, L = Length, r = Radius)
● As resistance increases, Ohm's Law states:
Q = ΔP/R
(Q = Flow, ΔP = Hydrostatic pressure difference, R = Resistance)
Therefore as resistance ↑, flow (and drip rate) decrease.

17. ADH Results
● Expected rate of weight gain to decrease
○ Results: -0.015 g/min: decrease in weight/min ✔
● Expected drip rate to decrease
○ Results: -2 drips/min: decrease in drip rate ✔
Drug effects were in agreement with expected
effects of frog Gq coupled ADH receptors and
suggest vasoconstriction as means of effect

18. Clinical applications of ADH
● Treatment of Cardiac Arrest Resuscitation
○ Improvement in coronary perfusion pressure
● Treatment of Shock
○ Dramatically increases blood pressure

19. Abnormal applications of ADH
● Syndrome of Inappropriate ADH (SIADH)
○ ADH hypersecretion
○ Hyponatremia - increased water retention and
sodium loss
■ Headache, nausea, vomiting, and in severe
cases, convulsions or coma

20. Histamine: H2R Gs Signaling Pathway
Figure 8. Gs Signaling Pathway (Refer to Figure 4 for more In-depth look)
↑ cAMP = ↑ PKA = ↓ Ca++ ⇒ Smooth Muscle Relaxation
Mario Malerba, et al. <http://www.sciencedirect.com/science/article/pii/S1359644611004168>

21. Histamine: H1R in Endothelial Cells
↑ cGMP and PKG activity
⇒ ↑ Vasodilation
Figure 9. GPCR Nitric Oxide; Vasodilation via Endothelial cells (ACh has similar effects to Histamine in smooth muscle cells)
Conugrave, Arthur, et al. <http://ajpgi.physiology.org/content/291/5/G753.full>

22. Histamine: Vasodilation
● Histamine causes vasodilation
○ Both H1R and H2R
○ ↑ Radius of Arteriole = ↓ Resistance.
■ Resistance = (8ηL)/(Πr4)
○ ↓ Resistance = ↑ Flow
■ Ohm's Law: Q = ΔP/R
● EXPECTED RESULTS: Increase in Drip Rate
● OBSERVED RESULTS: +4 increase in Drip
Rate

23. Histamine: Weight Loss
● In humans:
○ Histamine receptors on arterioles are primary cause
of vasodilation
○ EXPECTED RESULTS: Weight gain
● In experiment (in frog):
○ OBSERVED RESULTS: Weight loss (-0.0996 g/min)
○ Hypothesis:
■ Frog's primary cause of vasodilation due to
density of receptors in venules (not arterioles)

24. Histamine in Frogs: Starling's Law
● Φ = K[(Pc+Πi) – (Pi+Πc)]
● Vasodilation of arterial end = ↑ Pc
● Vasodilation of venous end = ↓ Pc
Dilation of venous
end > dilation of
arteriole end
↳ NET ↓ Pc = -Φ
⇒ Filtrate influx
(interstistial ⇒ capillary)
Figure 10. Fluid movement in between capillaries and interstitial tissue.
Cambell & Reece, 6th Ed. <http://www.biog1105-1106.org/demos/105/unit7/fluidexchange.html>

25. Conclusion
Adenosine ADH Histamine
Pathway GPCR (Gs) GPCR (Gq) GPCR (Gs & NO
production)
Vasodilator/ Vasodilator Vasoconstrictor Vasodilator
Vasoconstrictor?
Drip Rate Increased Decreased Increased
Rate of Weight Increased Decreased Decreased
Change

26. Histamine: Conclusions
● Drip rate results were as expected
○ Histamine receptor functions are similar in human
and frog vasculature
● Weight change results were NOT as
expected
○ Histamine receptor location and density (in
vasculature) differ in humans and frogs