Vaclav Hampl, PhD

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RESEARCH INTERESTS

In general, I work in the field of pulmonary circulation and its disorder, pulmonary hypertension. More specifically, I am interested in the main physiological regulator of the pulmonary vascular tone, hypoxia, and in the role of an endogenous vasodilator, nitric oxide. I am also intrigued by the developmental aspects of the pulmonary circulation, especially what happens at around the time of birth.

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METHODS

The main tool I've been using for my research is the isolated perfused rat lung. In addition, sometimes I also measure pulmonary hemodynamics in intact, anesthetized rats, or changes in tension of isolated pulmonary arteries. Pulmonary hypertension is usually induced by a chronic exposure to hypoxia (about 10% O₂ for 3-4 weeks), but sometimes an injection of an alkaloid monocrotaline is also used.

Some additional techniques are mentioned in the section describing my recent results.

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SOME RESULTS

Permanent effects of perinatal adverse stimuli

The most profound changes of the pulmonary circulation occur at the time of birth. We found that adverse influences (such as hypoxia), afflicting pulmonary vessels at around the time of birth, have permanent consequences on the function of these vessels, unlike the same stimulus acting during adulthood (the effect of which is reversible).

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Role of nitric oxide (NO) in the normal and hypertensive pulmonary circulation

NO is a simple gas and an ubiquitous and important endogenous vasodilator produced by the endothelial cells. In most vessels of the body, a certain amount of NO is produced continuously, thus preventing the vascular tone from being too high. There were speculations that reduction of high baseline NO production in the pulmonary circulation is responsible for the development of the pulmonary hypertension. We found that this is not the case. The basal NO synthesis in the healthy lung endothelium is minimal and is increased (rather than decreased) in acute and chronic hypoxic pulmonary hypertension. Pulmonary hypertension thus cannot be explained as an NO deficiency syndrome.

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Mechanism of nitric oxide-induced pulmonary vasodilation

Nitric oxide (NO) and its intracellular second messenger cause pulmonary vasodilation (among other mechanisms) by activation of calcium-dependent potassium channels (through a cGMP-dependent protein kinase) and the resulting membrane hyperpolarization. Media of the pulmonary arteries consist of three populations of smooth muscle cells, which differ in their sensitivity to NO.

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Experimental therapy for pulmonary hypertension

Pulmonary hypertension is a severely disabling and often fatal disorder with no effective treatment currently available. We found that, unlike chronic infusion of nitric oxide (NO) solution, repeated inhalations of aerosolized NO donor reduce established pulmonary hypertension in rats.

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Mechanisms of pulmonary hypertension induced by anorectic drugs

Some appetite suppressants, such as aminorex, fenfluramine, and dexfenfluramine, can cause severe pulmonary hypertension. Their mechanism of action was unclear. We found that they inhibit potassium channels in the cell membrane of the smooth muscle cells of resistance pulmonary arteries, causing membrane depolarization and vasoconstriction. Our data also suggest that the reason why only some of the patients taking appetite suppressants suffer from primary pulmonary hypertension might be a preexisting pulmonary endothelial dysfunction.

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Hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction is an important regulator of pulmonary vascular tone and blood oxygenation. We found that a certain subpopulation of pulmonary vascular smooth muscle responds to hypoxia with reduced transmembrane potassium current, leading to depolarization and vasoconstriction. The effect of hypoxia on pulmonary vascular tone can be mimicked by a clinically used respiratory stimulant, almitrine.

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Methodology

One of the arginine analogs, commonly used as an inhibitors of nitric oxide biosynthesis, N^G-monomethyl-L-arginine (L-NMMA), is not suitable for this purpose because it is actually a partial agonist for NO synthesis. Dithionite, frequently used in studies of hypoxic pulmonary vasoconstriction, is not suitable for this purpose because - unlike hypoxia - it elicits a massive outburst of radical production. The main site of nitric oxide production into the human breath is the nose.

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current WORK

We finished a study showing that appetite suppressant, dexfenfluramine, transiently elevates intracellular calcium levels in the pulmonary artery smooth muscle cells, which is a known signal for vasoconstriction.

We found that antibodies against the Kv1.5 potassium channel reduced the increase in intracellular calcium, caused in pulmonary artery smooth muscle cells by hypoxia, and reduced hypoxic pulmonary vasoconstriction in isolated lungs. This indicates that the Kv1.5 channel is important in the mechanism of hypoxic pulmonary vasoconstriction.

We are now working on the hypothesis that normal pulmonary vessels do not respond to increased flow by vasoconstriction (unlike for example renal or brain vessels), but they do in pulmonary hypertension, making it more serious.

I am preparing some studies in perfused human placental cotyledon. If it goes well, I will post it here.

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JUST A BIT OF SOME PERSONAL STUFF:

Since 1988 I have my dear wife Alice. She is a psychologist and a manager of a company "Centrum Dohody" specializing in conflict resolution and trainings. Our son Jakub was born in 1989 in Czechoslovakia (just a few months before the end of communism in this country). Our daughter Marta Caroline was born in 1993 in Minneapolis, Minnesota, where we spent 5 unforgettable years, made some of our best friends, and where we love to return. Alice and I also have had a great time with the Worldwide Marriage Encounter. Since 2002 we have agreat little daughter Nikki. I like skiing, hiking, white-water canoeing, travel, and music (my notes on places I had visited in the Czech Republic are offered here as a possible inspiration). On those few occasions when I had a chance to try it I also loved speed-boating and water skiing. Occasionally, I do some computer graphics and desktop publishing (e.g. cover page of FASEB Journal vol. 9, number 2, February 1995) as my hobby. Occasionally, I do some interpreting (Czech - English).

CONTACT:

Address: Department of Physiology 2nd Medical School Charles University Plzenska 130/221 150 00 Prague 5 Czech Republic

SOME OF THE LINKS I FIND USEFUL