Effects of N3SA Analogues on Cerebral and Peripheral Arteriolar Vasomotion in Spontaneously Hypertensive Rats

Thiazides are among the most efficacious and commonly used drugs for the treatment of hypertension. The nanomolar stabilizer N3SA binds specifically to the recently discovered thiazide-binding site of the membrane target NAPE-PLD, showing sustained arterial blood pressure-lowering effects and vasodilation in spontaneous hypertensive rats (SHRs). To further support the relation between stabilizers anchored to NAPE-PLD and their beneficial effects on hypertension, we selected compound analogues of N3SA with chemical modifications at the three target-interacting sulfonic groups, including the drug Suramin. Each compound was injected i.v in an adult SHR (systolic blood pressure of 217 ± 5 mmHg) to evaluate the frequency components contribution to cerebral and peripheral arteriolar vasomotion. We visualized the pial and rectus femoral muscle microcirculation by Epi-illumination, measuring changes in the rhythmic arteriolar diameter. Findings showed that the minor structural differences in compounds correlated with the contribution of the six different frequency components affecting the arterial tone, as well as their vasodilatory effects, in both cerebral and femoral muscle arterioles. These results provide evidence that the spectra analysis of the regulation mechanisms of vascular tone and arterial blood pressure can accurately reflect the structure–activity correlations of different analogues of an antihypertensive compound.