disputerer for ph.d.-graden i helsevitenskap og vil offentlig forsvare avhandlingen:
“Guanylate cyclase activators and stimulators. Potential cardiovascular therapeutics, with special focus on the right ventricle.”
Opptak av disputasen vil være tilgjengelig i et døgn.
Populærvitenskapelig sammendrag av avhandlingen:
Nitric oxide, NO, is an important vasodilator that is instrumental to the regulation of healthy circulation. Dysregulation of NO or its effector sites contributes to cardiovascular disease. Several therapeutic approaches to cardiovascular conditions are directed at normalizing NO-effects. In many cases, however, the principal mechanism through which NO normally works, the enzyme soluble guanylate cyclase, has lost its ability to interact with NO, and measures to increase NO-levels will no longer result in vasodilation. In patients with lung disease, the lack of NO-effect on lung arteries may result in high lung blood pressure and failure of the right heart.
Direct stimulation or activation of soluble guanylate cyclase is a different way of inducing effects normally expected by NO-stimulation. In this thesis, we have investigated one soluble guanylate cyclase stimulator, Riociguat and one soluble guanylate cyclase activator, Cinaciguat. The difference between these is that Riociguat by mechanism is expected to exert its effects in concert with NO, while Cinaguat works independently of NO.
Of special interest is the potential selective effect of Riociguat and Cinaciguat in the lung vasculature. Such selectivity could make these medications interesting therapeutics for right ventricular failure.
Both medications have proved to be potent vasodilators and are already studied both in pathological animal models and in patient studies. We wanted to further characterize the principal effects of these medications independent of pathology and during different levels of NO-stimulation. Riociguat and Cinaciguat were therefore given independently to healthy pigs together with medication to increase and decrease NO-levels.
Our experiments confirmed that both Riociguat and Cinaciguat dilate arteries in healthy animals, but without any selectivity for the lung arteries. The direct cardiac effects are minor. No major effect on veins could be discerned. Importantly, while Riociguat acts in concert with NO and is modulated by NO-tone, Cinaciguat works independent of the NO-system and blocks the normal effects of NO and is, therefore, more prone to give hypotension than Riociguat.
Rinociguat and Cinaciguat are both potent substances to induce NO-associated effects. The lack of pulmonary selectivity in our healthy animal model shows that there are no principal isolated effects on lung vessels, but rather at generalized vasodilatory effect. This might be different during pathological states, and other studies have shown such selectivity during pulmonary disease.
Further studies are warranted to establish in which pathological conditions these medications will yield the desired dilatation of lung vessels without inducing unacceptable blood pressure in the rest of the body.
Professor Truls Myrmel, Institutt for klinisk medisin, Det helsevitenskapelige fakultet, UiT Norges arktiske universitet.
Professor Ole-Jakob How, Institutt for medisinsk biologi, Det helsevitenskapelige fakultet, UiT Norges arktiske universitet.
Adjungerad biträdande professor Søren Berg, Linkøpings Universitet, Sverige - 1. opponent.
Førsteamanuensis Stig Urheim, Universitetet i Bergen - 2. opponent.
Professor Marit Solbu, Institutt for klinisk medisin, Det helsevitenskapelige fakultet, UiT Norges arktiske universitet – leder av komité.
Førsteamanuensis Åsa Birna Birgisdottir, Institutt for klinisk medisin, Det helsevitenskapelige fakultet, UiT Norges arktiske universitet