Long-term normalization of blood pressure in SHR and 1-kidney 1-clip rats by synthetic precursor of stable PAF analogue without systemic effects in normotensive rats

Sergei I Malekin; Sergei V Kotelevtsev; Svetlana A Gavrilova; Olga E Fadyukova; Anna V Golubeva; Marina I Grinchenko; Vladimir B Koshelev; Yuri V Kotelevtsev; Pavel Hamet; Sergei N Orlov

doi:10.1016/j.pathophys.2010.08.001

Long-term normalization of blood pressure in SHR and 1-kidney 1-clip rats by synthetic precursor of stable PAF analogue without systemic effects in normotensive rats

Pathophysiology. 2011 Apr;18(2):151-7. doi: 10.1016/j.pathophys.2010.08.001.

Authors

Sergei I Malekin¹, Sergei V Kotelevtsev, Svetlana A Gavrilova, Olga E Fadyukova, Anna V Golubeva, Marina I Grinchenko, Vladimir B Koshelev, Yuri V Kotelevtsev, Pavel Hamet, Sergei N Orlov

Affiliation

¹ Institute of Organic Chemistry and Technology, Moscow, Russia.

PMID: 20888741
DOI: 10.1016/j.pathophys.2010.08.001

Abstract

This study characterized the actions of the newly synthesized PAF precursor 1-hexadecyl-2-alkylcarbamoyl-glycerol (HAG) on blood pressure (BP) in male spontaneously hypertensive rats (SHR), SHR-stroke prone (SHRSP) and Wistar rats with 1-kidney 1-clip (1K1C) renovascular hypertension used as experimental models of human primary and secondary hypertension. Systolic blood pressure (SBP) in the tail artery and mean arterial pressure (MAP) in the abdominal aorta were measured by tail plethysmography and invasive pressure transducer, respectively. Intravenous treatment with 1mg/kg HAG in SHR resulted in a rapid decline of MAP from 151±4 to 127±4mmHg in 50min (p<0.001) that was maintained for 24h after injection (128±5mmHg, p<0.01). We also observed a profound hypotensive effect of HAG in SHRSP but not in normotensive Wistar rats. In 1K1C rats, the magnitude of the BP decline evoked by HAG was correlated with MAP measured before drug administration (R=0.74, p<0.005). In 1K1C rats with SBP>140mmHg, 5mg/kg/48h HAG, given orally for 14 days, decreased SBP by 20-30mmHg without an increase in the death rate and other adverse effects. Thus, our results show that intravenous and oral administration of HAG led to a long-lasting reduction of BP in experimental models of primary and secondary hypertension. In contrast to PAF and its derivatives, the hypotensive action of HAG was preserved for 24h after a single administration, was absent in normotensive animals, and was not accompanied by visible side-effects, at least during 2 weeks of treatment.