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Viagra relatives may shrink abnormally large hearts
Viagra relatives may shrink abnormally large
heartsCompounds related to Viagra, which is already in clinical trials to prevent heart failure, may also
counter the disease in a different way, according to a study published online today in the journal
. The results hold promise for the design of a new drug class and for its potential use
in combination with Viagra or beta blockers.
, which affects about 5.7 million Americans, the heart gradually loses the ability to pumpwith enough force to supply the body with blood. One reason for lost pumping strength is the mass death of cells seen in many heart diseases (e.g. heart attack). Fewer remaining muscle cells must thenpush around the same amount of blood, and hard working muscles grow. Unlike the healthy bulging of anathlete's bicep, abnormal muscle growth (pathogenic walls, slows the heartbeat and causes potentially fatal arrhythmias. Hypertrophy is a major risk factor forthe development of heart failure as well.
Recent efforts to reverse hypertrophy include a clinical trial, sponsored by Viagra manufacturer Pfizer, andthe National Heart, Lung, and Blood Institute (NHLBI), looking at whether Viagra (sildenafil) can treatmoderate heart failure and reduce hypertrophy. Along with increasing blood flow in arteries, Viagrainterferes with phosphodiesterases (PDEs), enzymes that break down the messenger molecule called cyclicguanosine monophosphate (cGMP), which would otherwise "put the brakes on" heart muscle cell growth.
Viagra shuts down the PDE5 family in particular, one of 11 PDE families in the body and that include morethan 50 individual enzymes. They have proven to be famously good drug targets because each has a uniquestructure, tissue distribution and role, allowing them to be precisely targeted by drugs for fewer side effects.
In the just-published experiments in heart muscle cells and live mice, researchers found that members of asecond PDE family, particularly the PDE1a enzyme, also break up cGMP to control hypertrophy, but not inthe same way as Viagra.
Where PDE5 breaks down cyclic nucleotides in response to the vital signaling molecule nitric oxide (NO),PDE1 affects cyclic nucleotide pathways sensitive to Calcium (Ca2+), another major player in cardiacdisease, according to the authors.
"Our results suggest that a PDE1a inhibitor alone can shut down abnormal cardiac growth, and whencombined with Viagra or beta blockers, may do so in more than one way," said Chen Yan, Ph.D., associateprofessor within the Aab Cardiovascular Research Institute (CVRI) at the University of Rochester MedicalCenter, and corresponding author for the study. "We found a new drug target, that if interfered with,prevents hypertrophy, and where compounds already exist that interfere with it. The compounds used in thestudy were experimental, but we are already developing drug candidates based on the discovery."
Whether combination treatments featuring PDE1 inhibitors will have value in heart failure will not becomeclear until further animal studies are completed, Yan said. Both PDE1 inhibitors and Viagra lower bloodpressure, and may or may not lower it too much in combination. Viagra cannot be used with nitroglycerinfor this reason. On the other hand, some patients with heart failure cannot use beta blockers, which alsoreduce hypertrophy, because the drugs make already weak hearts pump with less vigor. Combining betablockers with PDE1 inhibitors could potentially enable heart failure patients to take less beta blocker,protecting the contractile power of their heart muscle cells while still averting hypertrophy.
PDEs, by degrading cGMP, control the strength of its signal. Normally, cGMP-dependent signalingsuppresses abnormal growth in heart cells by restraining Ca2+ signals that drive hypertrophy. The researchteam believes that PDE signaling unbalanced by long-term strain on heart muscle distorts the "crosstalk"between Ca2+ and cGMP to promote abnormal growth. Past studies had shown at least five PDE families,PDE1-5, are present in the human heart, of which PDE1 and PDE5 are most responsible for limiting cGMPsupply. Going into the current study, no one knew whether the PDE1 family was involved in hypertrophy.
Yan and colleagues found that levels of PDE1a were significantly increased in heart muscle cells in animaland individual cell models of hypertrophy. The study also confirmed that PDE1a inhibition reducesabnormal growth in heart muscle cells through their effect on cGMP.
PDE1 inhibitor IC86340 was found to reduce by at least 75 percent abnormal growth in studies of isolatedrat heart muscle cells in the face of a chemical known to cause hypertrophy (phenylephrine). Yan hadpublished in previous papers that IC86340 could inhibit the PDE1 family, but no one had ever used it tocounter hypertrophy. In live mice, the study drug significantly reduced hypertrophy over control mice whenboth were exposed to the well established hypertrophic agent, isoproterenol.
Yan's team also found that the combination of IC86340 and Viagra in studies of isolated heart muscle cellseliminated hypertrophy to a greater degree than either compound alone. Cell growth was measured bytechniques that captured each cell's protein production (more protein equals more growth) and the size ofcells in terms of their surface area. Studies already underway are looking at the effect on hypertrophy inlive mice with the genes for various PDE1 enzymes removed.
Along with Yan, efforts at the University of Rochester Medical Center were led by Clint Miller, MasayoshiOikawa, Yujun Cai, Haodong Xu, Burns Blaxall and Jun-ichi Abe within the CVRI; Andrew Wojtovichand David Nagel in the Departments of Pharmacology and Physiology; and by Xiangbin Xu and Jian-DongLi in the Department of Microbiology and Immunology. Also leading the effort were Vince Florio ofOmeris Corp. in Seattle; Sergei Rybalkin and Joseph Beavo in the Department of Pharmacology at theUniversity of Washington and Yiu-Fai Chen in the Department of Medicine at the University of Alabama atBirmingham. This work was supported by the American Heart Association and the National Institutes ofHealth (NIH).
Also moving forward, Yan's lab is focused on revealing the role of various PDE enzymes in atherosclerosisand hypertension as well as in heart failure.
"Almost every signaling molecule involved in PDE-regulated hypertrophy in the heart - including nitricoxide, calcium and angiotensin II - are at the core of regulating blood pressure and disease-related structuralchanges in arteries," Yan said. "PDE1a levels appear to influence those pathways in return, which createsthe potential for PDE1 inhibitors that treat both hypertrophy in the hypertension and atherosclerosis."
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