All concepts, explanations, trials, and studies have been
re-written in plain English and may contain errors. I am
not a doctor
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Blocking Those Receptors

September 8, 2003 - Beta-blockers "block" beta-adrenergic
receptors. Such receptors exist on the surface of many cells
in the body. We are talking here of the ones on heart muscle
cells.
	Think of these receptors as locks on doors leading
into heart cells. If certain "natural" hormones get to the
receptor first, they fit the lock and unlock the door, so
the hormone gets into the cell.
	Unfortunately, in heart failure, once that "natural"
hormone gets into the cell, it tells the heart to work harder,
weakening your heart over time.
	Beta-blockers are designed to fit that same receptor
like a key. If the drug gets to it first, it enters the key
hole but doesn't tell the cell to do anything when it goes
through the door. While the drug is there, nothing else can
get through that receptor into the cell.
	The idea is to "block" as many of the heart's beta-
receptors as possible with the drug so harmful hormones have
to stand around outside till they get tired and die, never
harming your heart.
	There are also angiotensin II receptors. These are
the receptors that ARBs block. For more on ARBs and beta-
blockers, see:

http://www.chfpatients.com/ace.htm#arb
and
http://www.chfpatients.com/coreg.htm.

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Beta-receptors and angiotensin II receptors may "join" to
form receptor "complexes." This allows one "blocker" drug to
have a double effect.
	"We know that beta receptors and angiotensin 
receptors talk to  each other through the sympathetic
nervous system," said study author Liza Barki-Harrington.
"We wanted to know if they also talk to each other at the
cell level direct - receptor to receptor."
	In mice on beta-blockers, heart muscle cells
beat more weakly than expected when stimulated by angiotensin
II - a major culprit in worsening heart failure. The heart
rates of live mice on an ARB contracted also less then
expected when given the same substance that beta-blockers
block.
	So it seems that drugs which block one receptor type
also reduce activity through the other kind of receptor. This
is caused by interaction between receptors in linked pairs in
heart muscle cells. "It's like getting two drugs for the
price of one," says Barki-Harrington.
	Dr. Howard Rockman says, "It appears that the success
of these drugs in treating heart failure is from the fact
that they (affect) not just one receptor, but two."
	The "arrangement" of receptors is different in
different people and varies with the seriousness of the CHF.
A blood test could identify a patient's unique receptor
makeup, letting doctors choose the most effective meds for
that person.

ON THE TECHNICAL SIDE

These effects occur through receptor-G protein uncoupling; ie,
beta-blockers interfere with AT1R-Gq coupling, and valsartan
interferes with ßAR-Gs coupling. AT1Rs and ßARs form
constitutive complexes that are not affected by ligand
stimulation. As a result, a single receptor antagonist
effectively blocks downstream signaling of both receptors
simultaneously.

NOTE

The National Institutes of Health and the Burroughs Wellcome
Fund funded this study.

Title:   Dual Inhibition of B-Adrenergic and Angiotensin II
         Receptors by a Single Antagonist: A Functional Role for
         Receptor-Receptor Interaction In Vivo.
Authors: Liza Barki-Harrington, Louis Luttrell, Howard Rockman.
Source:  Circulation 108: 1611-1618; published online before
         print as doi:10.1161/01.CIR.0000092166.30360.78.