Posttranslational modification of angiotensin II by pyridoxal-5'-phosphate as a new drug approach against high blood pressure

Introduction: Although hypertension is a worldwide health problem, treatment options in low-income countries are still limited. This results in high mortality. Therefore, the development of new therapeutic drugs that are affordable and accessible to everyone is still an urgent need. Since angiotensin II is one of the essential vasoconstrictive peptides in the human organism, we analysed the impact of its posttranslational modification to pyruvamide-angiotensin II by pyridoxal-5'-phosphate on blood pressure. Pyridoxal-5'-phosphate is a less expensive vitamin B₆ derivative and therefore could be a novel, cost-effective drug for the treatment of hypertension.

Methods: The posttranslational modification of angiotensin II to pyruvamide-angiotensin II by pyridoxal-5'-phosphate was investigated in vitro by mass spectrometry. Calcium ion influx into vascular smooth muscle cells treated with angiotensin II or pyruvamide-angiotensin II, respectively, was also investigated in vitro. In ex vivo experiments, the vasoconstrictive effect of angiotensin II and pyruvamide-angiotensin II, respectively, was analysed by using the bioassay of the isolated perfused rat kidneys. Furthermore, angiotensin II and pyruvamide-angiotensin II were investigated in in vivo experiments. Both, Wistar Kyoto rats and spontaneously hypertensive rats were treated with pyridoxal-5'-phosphate by using mini-osmotic pumps, and the blood pressure was measured time-dependently.

Results: Angiotensin II, incubated with pyridoxal-5'-phosphate, was posttranslationally modified to pyruvamide-angiotensin II. In vascular smooth muscle cells, the calcium ion influx after stimulation with pyruvamide-angiotensin II was significantly decreased compared to angiotensin II. The perfusion pressure of isolated perfused rat kidney increased less by pyruvamide-angiotensin II than by unmodified angiotensin II. The systolic and diastolic blood pressure of spontaneously hypertensive rats treated with pyridoxal-5'-phosphate decreased after three days of treatment significantly. The blood pressure of Wistar Kyoto rats treated with angiotensin II increased to hypertensive values, while the blood pressure of Wistar Kyoto rats co-treated with angiotensin II and pyridoxal-5'-phosphate was not increased.

Conclusions: Pyridoxal-5'-phosphate significantly decreased blood pressure and might be a cost-effective drug for hypertension treatment. Respectively, an increased pyridoxal-5'-phosphate intake recommendation in the form of vitamin B₆ intake might have a decreasing effect on blood pressure in the hypertensive population.