Self-Nanoemulsifying Drug Delivery System Loaded with Psiadia punctulata Major Metabolites for Hypertensive Emergencies: Effect on Hemodynamics and Cardiac Conductance

Abstract

Vasodilators are an important class of antihypertensive agents. However, they have limited clinical use due to the reflex tachycardia associated with their use which masks most of its antihypertensive effect and raises cardiac risk. Chemical investigation of Psiadia punctulata afforded five major methoxylated flavonoids (1-5) three of which (1, 4, and 5) showed vasodilator activity. Linoleic acid-based self-nanoemulsifying drug delivery system (SNEDDS) was utilized to develop intravenous (IV) formulations that contain compounds 1, 4, or 5. The antihypertensive effect of the prepared SNEDDS formulations, loaded with each of the vasodilator compounds, was tested in the angiotensin-induced rat model of hypertension. Rats were subjected to real-time recording of blood hemodynamics and surface Electrocardiogram (ECG) while the pharmaceutical formulations were individually slowly injected in cumulative doses. Among the tested formulations, only that contains umuhengerin (1) and 5,3'-dihydroxy-6,7,4',5'-tetramethoxyflavone (5) showed potent antihypertensive effects. Low IV doses, from the prepared SNEDDS, containing either compound 1 or 5 showed a marked reduction in the elevated systolic blood pressure by 10 mmHg at 12 μg/kg and by more than 20 mmHg at 36 μg/kg. The developed SNEDDS formulation containing either compound 1 or 5 significantly reduced the elevated diastolic, pulse pressure, dicrotic notch pressure, and the systolic-dicrotic notch pressure difference. Moreover, both formulations decreased the ejection duration and increased the non-ejection duration while they did not affect the time to peak. Both formulations did not affect the AV conduction as appear from the lack of effect on p duration and PR intervals. Similarly, they did not affect the ventricular repolarization as no effect on QTc or JT interval. Both formulations decreased the R wave amplitude but increased the T wave amplitude. In conclusion, the careful selection of linoleic acid for the development of SNEDDS formulation rescues the vasodilating effect of P. punctulata compounds from being masked by the reflex tachycardia that is commonly associated with the decrease in peripheral resistance by most vasodilators. The prepared SNEDDS formulation could be suggested as an effective medication in the treatment of hypertensive emergencies, after clinical evaluation.

Keywords: SNEDDS; methoxy flavonoids; reflex tachycardia; umuhengerin; vasodilators.

FIGURE 1

Isolated compounds (1-5) from Psiadia punctulata.

FIGURE 2

Representative traces of blood hemodynamic invasive recording (A), before (B), and after slow intravenous injection of formulation 1 in doses of 12 (C), 24 (D) and (E) 36 μg/kg in angiotensin model of hypertensive rats.

FIGURE 3

Effect of slow intravenous injection of formulations 1 and 5 on the systolic blood pressure (SBP, A), diastolic blood pressure (DBP, B), and the heart rate (C). Data presented as mean ± standard error of 6 animals. *p < 0.05, compared with the corresponding vehicle control values; by two Way ANOVA and Bonferroni post hoc test.

FIGURE 4

Effect of slow intravenous injection of formulations 1 and 5 on the pulse pressure (A), dicrotic notch pressure (B), and the systolic blood pressure-dicrotic notch pressure difference (SDP-difference, (C). Data presented as mean ± standard error of 6 animals. *p < 0.05, compared with the corresponding vehicle control values; by two Way ANOVA and Bonferroni post hoc test.

FIGURE 5

Effect of slow intravenous injection of formulations 1 and 5 on the ejection duration (A), nonejection duration (B), and the time to peak (C). Data presented as mean ± standard error of 6 animals. *p < 0.05, compared with the corresponding vehicle control values; by two Way ANOVA and Bonferroni post hoc test.

FIGURE 6

Effect of slow intravenous injection of formulations 1 and 5 on the p wave duration (A) and PR interval (B). Data presented as mean ± standard error of 6 animals. *p < 0.05, compared with the corresponding vehicle control values; by two Way ANOVA and Bonferroni post hoc test.

FIGURE 7

Effect of slow intravenous injection of formulations 1 and 5 on the QTc interval (A) and the JT interval (B). Data presented as mean ± standard error of 6 animals. *p < 0.05, compared with the corresponding vehicle control values; by two Way ANOVA and Bonferroni post hoc test.

FIGURE 8

Effect of slow intravenous injection of formulations 1 and 5 on the R amplitude (A) and the T amplitude (B). Data presented as mean ± standard error of 6 animals. *p < 0.05, compared with the corresponding vehicle control values; by two Way ANOVA and Bonferroni post hoc test.

FIGURE 9

Effect of slow intravenous injection of formulations 1 and 5 on serum sodium (A) and potassium (B) levels. Data presented as mean ± standard error of 6 animals. *p < 0.05, compared with the corresponding vehicle control values, #p < 0.05, compared with the corresponding saline control values; by One Way ANOVA and Newman Keuls post hoc test.