and Improve Diastolic Distensibility, In Vivo
Below a study suggesting that sildenafil (Viagra) and B-Type Natriuretic=20
Peptide (BNP) can relax heart muscle and improve diastolic heart=20
failure. At the bottom also reports by ScienceDaily and MailOnline.
The study was on dogs. There is an an ongoing study with sildenafil on=20
humans -
"Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes=20
and Exercise Ability in People With Diastolic Heart Failure (The RELAX=20
Study)" NCT00763867.
http://clinicaltrials.gov/ct2/show/NCT00763867
In seminars, Paul Cheney has presented data indicating that diastolic=20
dysfunction is prevalent in ME, although his data has not been=20
published. Julia Newton, David J. Newton, Faisel Khan, Kunihisa Miwa,=20
Masatoshi Fujita among others have published data suggesting ME patients=20
have a small heart, low cardiac output and stiff arteries.
/Kasper Ezelius, Sweden
----
Circulation. 2011; 124: 2882-2891 Published online before print December=20
5, 2011, doi: 10.1161/=E2=80=8BCIRCULATIONAHA.111.048520
K. Bishu, N. Hamdani, S. F. Mohammed, M. Kruger, T. Ohtani, O. Ogut, F.=20
V. Brozovich, J. C. Burnett, W. A. Linke, M. M. Redfield.
Sildenafil and B-Type Natriuretic Peptide Acutely Phosphorylate Titin=20
and Improve Diastolic Distensibility In Vivo.
Abstract: http://circ.ahajournals.org/content/124/25/2882.abstract
Full: http://circ.ahajournals.org/content/124/25/2882.full
PDF: http://circ.ahajournals.org/content/124/25/2882.full.pdf
Abstract
Background=E2=80=94In vitro studies suggest that phosphorylation of titin=
=20
reduces myocyte/myofiber stiffness. Titin can be phosphorylated by=20
cGMP-activated protein kinase. Intracellular cGMP production is=20
stimulated by B-type natriuretic peptide (BNP) and degraded by=20
phosphodiesterases, including phosphodiesterase-5A. We hypothesized that=20
a phosphodiesterase-5A inhibitor (sildenafil) alone or in combination=20
with BNP would increase left ventricular diastolic distensibility by=20
phosphorylating titin.
Methods and Results=E2=80=94Eight elderly dogs with experimental hyperten=
sion=20
and 4 young normal dogs underwent measurement of the end-diastolic=20
pressure-volume relationship during caval occlusion at baseline, after=20
sildenafil, and BNP infusion. To assess diastolic distensibility=20
independently of load/extrinsic forces, the end-diastolic volume at a=20
common end-diastolic pressure on the sequential end-diastolic=20
pressure-volume relationships was measured (left ventricular=20
capacitance). In a separate group of dogs (n=3D7 old hypertensive and 7=20
young normal), serial full-thickness left ventricular biopsies were=20
harvested from the beating heart during identical infusions to measure=20
myofilament protein phosphorylation. Plasma cGMP increased with=20
sildenafil and further with BNP (7.31=C2=B12.37 to 26.9=C2=B110.3 to 70.3=
=C2=B18.1=20
pmol/mL; P<0.001). Left ventricular diastolic capacitance increased with=20
sildenafil and further with BNP (51.4=C2=B116.9 to 53.7=C2=B116.8 to 60.0=
=C2=B119.4 mL;=20
P<0.001). Changes were similar in old hypertensive and young normal=20
dogs. There were no effects on phosphorylation of troponin I, troponin=20
T, phospholamban, or myosin light chain-1 or -2. Titin phosphorylation=20
increased with sildenafil and BNP, whereas titin-based cardiomyocyte=20
stiffness decreased.
Conclusion=E2=80=94Short-term cGMP-enhancing treatment with sildenafil an=
d BNP=20
improves left ventricular diastolic distensibility in vivo, in part by=20
phosphorylating titin.
----
ScienceDaily (Dec. 23, 2011)
Viagra Against Heart Failure: Researchers Throw Light On the Mechanism
http://www.sciencedaily.com/releases/2011/12/111223091451.htm
How sildenafil, the active ingredient in Viagra, can alleviate heart=20
problems is reported by Bochum's researchers in cooperation with=20
colleagues from the Mayo Clinic in Rochester (Minnesota) in the journal=20
Circulation. They studied dogs with diastolic heart failure, a condition=20
in which the heart chamber does not sufficiently fill with blood. The=20
scientists showed that sildenafil makes stiffened cardiac walls more=20
elastic again. The drug activates an enzyme that causes the giant=20
protein titin in the myocardial cells to relax.
"We have developed a therapy in an animal model that, for the first=20
time, also raises hopes for the successful treatment of patients" says=20
Prof. Dr. Wolfgang Linke of the RUB Institute of Physiology.
"Rubber band proteins" can be influenced
Sildenafil inhibits a specific enzyme (phosphodiesterase 5 A), which=20
causes the increased formation of a messenger substance (cGMP). The=20
messenger substance activates the enzyme protein kinase G, which=20
attaches phosphate groups to certain proteins. This so-called=20
phosphorylation causes blood vessels to relax, which was why the=20
"potency pill" Viagra originally came onto the market. The Bochum and=20
Rochester researchers found that the cardiac muscle protein titin is=20
also phosphorylated through the same mechanism. "The titin molecules are=20
similar to rubber bands" explains the Bochum physiologist. "They=20
contribute decisively to the stiffness of the cardiac walls." The=20
activity of the protein kinase G causes titin to relax. This makes the=20
cardiac walls more elastic. The effect occurs within minutes of=20
administering the drug.
Heart failure drugs currently not sufficient
"Of all the patients aged over 60 who are in hospital because of a weak=20
heart, half suffer from diastolic heart failure" explains Linke.=20
"Although we know that the decreased distensibility of the cardiac walls=20
is the cause, the disease cannot be treated properly with today's=20
medicines." In the so-called "Relax" study of the Heart Failure Network,=20
the efficacy of sildenafil in people is already being tested. "If, for=20
the first time, the drug is found to have a positive effect on heart=20
failure, we would already have a molecular mechanism on hand to explain=20
the effect" says Linke.
----
Mail Online, 23rd December 2011
Viagra touted as life-saving heart treatment - after scientists find it=20
makes heart muscles LESS stiff
http://www.dailymail.co.uk/sciencetech/article-2078139/Viagra-touted-life=
-saving-heart-treatment--scientists-makes-heart-muscles-LESS-stiff.html
Alt: http://tiny.cc/6myn0
Viagra helps ailing hearts to recover in a surprising way - by making=20
them less stiff, scientists have learned.
The drug was first developed as a heart disease treatment - it's more=20
well-known use was simply a lucky side-effect.
But now it seems that it might help heart patients after all.
The impotency drug causes too-rigid heart chamber walls to become more=20
elastic.
The research explains how Viagra might benefit patients with diastolic=20
heart failure.
People with the condition have abnormally inflexible ventricles, the=20
heart's major pumping chambers, that do not fill sufficiently with blood.
This leads to blood =E2=80=98backing up=E2=80=99 in the lungs and breathi=
ng difficulties.
Scientists found that Viagra activates an enzyme that causes a protein=20
in heart muscle cells to relax.
The effect was seen in dogs with diastolic heart failure within minutes=20
of the drug being administered.
Study leader Professor Wolfgang Linke, from the Ruhr Universitat Bochum=20
in Germany, said: =E2=80=98We have developed a therapy in an animal model=
that,=20
for the first time, also raises hopes for the successful treatment of=20
patients.=E2=80=99
Viagra has a similar effect on blood vessels, which is why it was=20
originally developed as a treatment for high blood pressure and heart=20
disease.
The drug's active ingredient, sildenafil, inhibits an enzyme involved in=20
the mechanism that regulates blood flow.
However, the enzyme is slightly different in different parts of the body.
The British scientists behind Viagra found to their initial=20
disappointment that it was not a great help to patients with high blood=20
pressure. But it had a miraculous effect on men with erectile dysfunction.
The drug successfully suppressed the enzyme phosphodiesterasein the=20
penis, increasing blood flow to the organ.
Prof Linke's team found that it worked on the same enzyme in heart=20
cells. This had the effect of causing a cardiac muscle protein called=20
titin to become more elastic.
=E2=80=98The titin molecules are similar to rubber bands,=E2=80=99 said t=
he professor.=20
=E2=80=98They contribute decisively to the stiffness of cardiac walls.=E2=
=80=99
The research is published today in the journal Circulation.
Almost half of emergency patients admitted to hospital with heart=20
failure have a diastolic condition.
Diastolic heart failure affects the =E2=80=98diastole=E2=80=99 half of th=
e cardiac=20
cycle, when the heart's chambers have finished contracting and are=20
re-filling with blood.
--=20
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