Handelsman: This is very interesting. A comment you made in passing about pharyngeal receptors prompted me to think of some experiments. It would be interesting to see in humans given £uid via a nasogastric tube whether you would see this phenomenon or not — in other words, whether you could localize the effect to the pharynx. The second issue is whether chemical sympathectomy via 6-hydroxydopamine would have effects like this in animals. It would also be interesting to deliver the water into the stomach, bypassing the pharynx, or actually allow the subject to drink the water, and then suck it out of the stomach as quickly as it is drunk.

Robertson: Studies on rats have been done. I believe they were not sympathectomized. There were some observations of increases in blood pressure with water ingestion. It was more prominent with water than with fluid with Na+ in it. The question about pharyngeal receptors is very important, and I don't have an answer for that. It would be a wonderful study to do. Our current studies are focused on blowing up a balloon in the stomach to observe the effect of stretch. As you know, there are osmoreceptors in the liver also that might detect small changes in the diluteness of bloodflow from the liver. I don't know any other purpose for those osmoreceptors.

Veldhuis: It would have to involve more specific receptors, because just passage of food may not be relevant. I was thinking of the simple sugar experiment. It has been a clinical adage that bad hiccups can be sometimes suppressed by swallowing some granulated sugar irritating the glossopharangyeal nerve.

Laron: Your data on the orthostatic shift are extremely interesting. Elderly people drink less, so they are relatively dry. They are more prone to have arteriovascular incidents. If you take out so much £uid they could have more plugging of small arteries. What is the practical application of this? We know that if people don't move, they get more osteoporosis. How do you meet the needs of the population we are discussing here?

Robertson: That is a good point. There are data indicating there are more heart attacks in the early hours of the morning, soon after people have woken up. The main reason cited for this is stress, although other factors may be involved. But the constituents of the blood are concentrated by standing. Although 12—15% increase in concentration might not seem much, it is certainly possible that a 12% increase in the platelet count might make blood clots in the heart more likely.

Laron: Would you say that elderly people should drink more before standing up?

Robertson: We view water as potentially a very dangerous drug! Seriously, though, we do ask people who have these rare autonomic disorders not to drink water after about 9 p.m. unless they are really thirsty. In some of these patients with dysautonomia, water can raise blood pressure by 90 mmHg, and if this occurs before they go to bed, the resulting hypertension could be deleterious.

Burger: Is the difference between oral versus intravenous fluid load in any way explicable by the speed at which the plasma compartment is expanded by the two routes?

Robertson: I wish I had a better way to do that experiment. In addition to the problem you have identified there is another: dextrose has its own tendency to lower blood pressure by calling out some of the gastrointestinal hormones that may themselves be vasodilatory. On the other hand, if we gave saline, this wouldn't be a fair test of water either. We tried to spread the saline out over an hour. We wish we could have just looked at volume.

Carroll: Could you do an isotope dilution study and look at the rate of entry of that water volume into the circulation?

Roberston: We need to do that. Although the haematocrit didn't change, the fluid could be distributed both intracellularly and extracellularly.

Carroll: It is probably not operating through blood volume changes, but rather through some sort of reflex.

Elahi: We have done some studies where we have infused hypertonic saline in young and old volunteers. There are great changes in atrial natriuretic peptide (ANP). It is delayed in the elderly. We did the opposite experiments in which we used half normal saline. There is very little change in the elderly. Do you have any information about brain ANP with respect to age?

Haus: In the elderly, there is a shift in urine excretion from daytime to night. This is not a function of the enlarging prostate because it occurs just as much in women as in men (Haus et al 1988). Do you have any explanation for this?

Robertson: It is in part circadian, because it isn't just supine posture that is responsible.

Haus: Other solutes in the urine such as adrenaline and noradrenaline do not shift. Their circadian rhythm remains unchanged in its timing and is dissociated from that in urinary volume excretion (Haus et al 1988).

Robertson: I don't have the answer, though there is a substantial literature about this.

Haus: The blood viscosity is higher in the morning, which may be one of the factors contributing to the morning incidence of myocardial infarction. The number of circulating granulocytes peaks in the late afternoon. Granulocytes and lymphocytes show high amplitude circadian rhythms. The number of circulating platelets peaks in the afternoon, but the amplitude of their rhythm is relatively small (Haus 1996). In contrast, platelet aggregation and adhesion peak in the morning (Haus et al 1990). This may be responsible for some of the cardiovascular and cerebrovascular accidents occurring at that time. Also, the plasminogen activator inhibitor (PAI), which determines the overall activity of the fibrinolytic system peaks in the morning decreasing the activity of the fibrinolytic component of the haemostatic system (Andreotti & Patti 1997).

Robertson: I don't know whether we really have data that will address the postural effects on platelets. For example, remember these changes in fluid occur over 10-15 minutes. It may be that acutely standing up in the morning could significantly increase the number of platelets within 10 minutes. This may be separate from the circadian variation.

Haus: The change in position may increase the function of platelets probably more than their number. Tofler et al (1987) studied platelet aggregation and found a rise with the change from recumbent to upright position which paralleled the rise in plasma catecholamines. We studied clinically healthy subjects in the morning while still lying down and during the day after 30 minutes in recumbent position and found the rise in platelet adhesion and aggregation (Haus et al 1990) a little earlier than Tofler et al (1987).

Robertson: The postural changes could induce additional changes on top of that.

Bjorntorp: As you mentioned, this work has practical clinical and research implications. Most blood sampling is done with the patient lying down, but some is when the patient is sitting. How long does it take before you reach equilibrium after lying down?

Robertson: I think it is 30 minutes to equilibrium in either change of posture. When I was an intern, patients would walk into the emergency room, get screening blood work and be admitted. Then they would become supine. In those days we didn't watch our testing too much, and the next day another blood test would show a 4% fall in the haematocrit, and it would appear that the patient had lost a unit of blood. As an intern, I was frequently pushed by my resident physician to find out where the patient was bleeding. We were probably observing this volume shift.

Veldhuis: We learned this in our General Clinical Research Center. If the nurses call you for a slightly low haematocrit, have the patient walk about for 30 minutes and repeat the blood count: it will typically be normal.

Bjorntorp: What about sitting?

Robertson: I don't have data on sitting.

Prior: We need to find out, because this is the posture in which most samples are obtained.

Miiller: Would it be worthwhile testing this water role in Parkinsonian patients: many of them have a natural orthostatic hypotension. There are data showing that the noradrenergic innervation of the heart of these patients is decreased (Goldstein et al 2000). In your data you show that there is a blockade of dopamine ^-hydroxylase which will involve an increase in the dopaminergic tone.

Robertson: We recorded our findings about water in the literature about 18 months ago. Then, investigators in France gave water to patients with Parkinson's disease and did not see any effect. I haven't yet gone back and looked at Tennessee Parkinson's disease patients.

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