Date: July 13, 1999
Interstitial Cystitis Network - Chat Log (© 1999,
Topic: The role of nitric oxide in IC
Speaker: Lori Birder, University of Pittsburgh, USA

<icnmgrjill> Welcome everyone to the ICN support group meeting for july 13, 1999. I'd like to introduce our speaker, Dr. Lori Birder. She is currently an Assistant Professor of Pharmacology at the University of Pittsburgh here in the USA. It is always a pleasure to welcome IC researchers to our chats because they help us to understand what the current research issues and findings are. In tonight's case, we're going to learn a little bit more about the physiology of IC in humans and in cats and how certain nerve functions appear to be involved in the IC disease process. Welcome, Dr. Birder!

<drbirder> Thank you very much for inviting me to the ic chat. I really appreciate being able to speak her tonight!

--------- Q&A Begins ---------

<icnmgrjill> Your research stood out to us because of your work with Nitric Oxide. So, before we actually talk about your research results, lets go over some Nitric Oxide basics for our audience.

<icnmgrjill> What is nitric oxide?

<drbirder> Nitric Oxide (NO) is naturally found in the human body. It is a neurotransmitter, which means that it helps different parts of the body communicate with each other. As a neurotransmitter, it has various actions in the body. So, for example, in the bladder, nitric oxide acts to relax the urethra and some of the muscles involved in urination.

<icnmgrjill> Why is this important to IC?

<drbirder> As we have studied lower urinary tract syndromes, particularly diseases that cause frequency and urgency, we've tried to figure out why some patients have more spasms or are unable to empty their bladder fully. In some animal studies, we learned that if nitric xxide wasn't present, more spasms occurred. So, nitric oxide is important. It plays a vital role in the relaxation needed to urinate.

<icnmgrjill> How does this relate to L-Arginine?

<drbirder> It turns out that one of the reasons why L-Arginine appears to help some bladder and IC patients because, when metabolized by the body, nitric xxide is released into the tissues. Oxygen and L-Arginine combine in body to create nitric oxide and L-citrulline.

<icnmgrjill> Can you tell us about your research studies?

<drbirder> Our research focuses on a naturally occurring form of cystitis called feline interstitial cystitis. Cats with FIC demonstrate all of the characteristics of people with IC, including most if not all of the symptoms. Therefore, cats are considered a naturally occurring animal model of IC.

My research has studied how the pathology of IC in cats influence the release of nitric oxide (NO) and the neural activity of the lower urinary tract. We evaluated how pathological conditions in IC cats and other models of bladder inflammation influence the release of chemical mediators such as NO and neural activity in the lower urinary tract. Let me say "We evaluated.."

NO is not a conventional neurotransmitter. It exists on demand and has a very short half life of just a few seconds, which makes it very hard to measure. I have shown that high levels of NO can modulate epithelial integrity and membrane function. What that means is that nitric oxide.. like other neurotransmitters. Under conditions of excessive formation.. it may be toxic and in other situations, the lack of nitric oxide, may not allow the bladder to function properly.

The urothelial epithelium functions as a selective barrier (protecting the underlying tissue from urine and other potentially toxic compounds). Damage in IC cats could result in the passage of toxic and irritating urine elements through the barrier which can result in actual changes to bladder nerves and possible damage to the bladder nerves.

Alterations in bladder epithelium have been demonstrated in IC patients too so this is helping understand what some of the interactions between nerves and the epithelium in the bladder.

<icnmgrjill> That's a good point. For those of us who read the urology journals, we've seen many recent references to IC having a strong neurological element perhaps a generalized nerve inflammation.. or some type of nerve trauma. Would it be fair to say that one of the things that could be happening in IC is that there is a low level of NO?? We see more contractions. We see the structural integrity of the epithelium damaged and, because of that, a generalized nerve sensitization process. Is that right?

<drbirder> In part, yes. That once they are sensitized, the nerve activity increases and there can be an increase in pain. If there is an increase in nerve activity and the bladder wants to contract but if there are low levels of NO in various parts of the bladder we may see incomplete emptying as one possibility.

Also.. the increase in activity can cause an increase in contraction, where the bladder always wants to contract and empty. That's called hypersensitivity, where even a small amount of urine creates contractions and the need to urinate.

In my research, we wanted to discover or measure if different parts of the bladder could actually release NO. We discovered that a number of agents caused NO to be released and we have shown that IC cats have a different release of NO than normal cats. This altered release changes the excitability of bladder nerves and it can also change the structure or function of the epithelial barrier.

<icnmgrjill> As I was scanning some of the NO research.. it was talking about how different parts of the bladder may be different sensitivities to neuro transmitters ... that the urethra was sensitive to NO2 but that the detrusor isn't. Is that correct?

<drbirder> I think in the studies that are out there.. that is true but I don't think we really don't understand the functions of the detrusor yet. We don't understand just how it functions yet

<icnmgrjill> So many mysteries. It's comforting to know that there are researchers like you asking the minute but vitally important questions. Let's take a few questions from the floor. Let's take a few questions from the floor..

<icnmgrjill> Our first question is from Lisa G. She has a question about herpes and whether the use of L-Arginine can create and provoke more herpes outbreaks. Is this a question you can answer?

<drbirder> L-Arginine is naturally in the body. Taking L-Arginine probably won't have an effect on an outbreak. NO is formed from larginine but it gets broken down very very fast.

There are two different kinds of NO in the bladder. One type is calcium dependent NO and there is one that is calcium independent. CNO is released and broken down very quickly. Inducible NO (the second type)

is constantly released after an infection or inflammation and is thought to be toxic. So, patients with a UTI, it is possible that they have a lot of this inducible NO but IC patients which don't have an infection have a decrease in CNO. Hold on, that's a little messy. Let me try that again

One of the things that we looked at is how IC cat patients are different from normals. We found that normal cats had normal levels of NO. We found that IC cats.. didn't have enough of the CNO and that IC cats had more than normal of the second type of NO. So.. their NO levels were much different than normal.

<icnmgrjill> Matt's mom has the second question. She says: I know that one theory of IC is that there is damage to the GAG layer. How does NO tie into that theory.. or does it?

<drbirder> That's very controversial. WE have found, not necessarily in cats, but in other animals that NO can make the barrier leaky and so that's what we're studying now.. the effect of NO on epithelial function. That's what we're looking at. We don't know how it makes it leaky. It's not really damage but it may effect "tight junctions" between the outer surface of the epithelial cells.

The epithelial barrier of the bladder works so well because the cells are normally very tight but, if NO acts to loosen this barrier, this could effect nerves which are right next to the barrier and now the nerves could be exposed to urine and other toxic substances which they may normally never see.

<icnmgrjill> The next question is from Theresa. She wants to know if there are certain dietary substances which can influence the levels of NO in the bladder and possible contribute to our ups and downs?

<drbirder> That's a good question.. and actually I dont' know the answer to that. I know that people are very interested in hormone levels and hormone levels are thought to influence NO. But I don't know enough about diet to be able to tell if that makes a difference

<icnmgrjill> Carol L has the next question. One of the "hidden" symptoms of IC that patients often don't tell their doctors because of embarrassment is that some patients experience intense clitoral sensations.. where it becomes very hyper sensitized? Could that relate?

<drbirder> I don't know. I know that its very common that NO plays a role in sexual function particularly in penile erection. That's how viagra works. It prevents the breakdown of NO but how it relates to IC.. I just don't know anything about.

You know.. I've been to a lot of IC meetings and nobody has actually brought that up but it is very intriguing. There are alot of people measuring clitoral function but I think that it would be difficult to measure pain. In general, pain is difficult to measure in an animal model so measuring clitoral sensitivity would be very difficult.

<icnmgrjill> Dr. Birder, because we pride ourselves in being very active patients. We'd like to ask you how can we become more involved in supporting research and do you have any needs that we can help with?

<drbirder> I think that you are doing a very good job of being involved perhaps not just my needs but other researchers would be to help learn more about patient experiences.. like clitoral stimulation.. that we aren't aware of. For those of us working with animals studies.. we may not hear about the issues that you talk about between yourselves. It is important to spread the word about what you are going that we can hear about it too!

<icnmgrjill> Reba has one last question. She says "I would like to spread the word on IC. What is the best way to spread the word so that important people will hear us?"

<drbirder> For example.. one of the biggest granting agencies is the NIDDK and one way to do that would be to write to Leroy Nyberg any questions or concerns that you have. He often distributes the questions to other researchers and I think that he really wants to push IC research. He frequently has requests for proposals and grants related to IC. I think he would be the one person to not only write to but to tell him that you want the information distributed to the other ic researchers funded by his institute

<drbirder> Also.. I know that they have IC meetings every other year. I don't know if you can create satellite meetings on both coasts. Funding for travelling to events for IC researchers is very low and it can be hard for some of us to travel to the other coast but it would be nice to find a way to increase the participation of researchers at these big meetings and travel funding would be one way of doing this!

--------- Q&A Ends---------

<icnmgrjill> Thank you Dr. Birder for appearing with us tonight!

<drbirder> Thank you for inviting me. I've learned quite a lot just being here tonight and I hope that I can come back!

<icnmgrjill> Consider this an open ended invitation! Please let us know if there is anything that we can do to help you.. and other researchers with your work and that includes writing letters to congress for funds or whatever need you may have! We are hear not only for patients but for researchers!

Special gratitude to Julie Halbur for coordinating this exceptional presentation.

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© 1999, The IC Network, All rights reserved. This transcript may be reproduced for personal use only. If you do so reproduce, we ask only that you give credit to the source, the IC Network, and speakers, Lori Birder and Jill Osborne. For additional use, please contact the ICN at (707)538-9442.