The agonists of imidazoline I-1 receptors (I-1R) are widely used to lower blood pressure. It has been indicated that guanidinium derivatives show an ability to activate imidazoline receptors. Also, allantoin has a chemical stricture similar to guanidinium derivatives. Thus, it is of special interest to characterize the effect of allantoin on I-1R. In conscious male spontaneous hypertensive rats (SHRs), mean blood pressure (MBP) was recorded using the tail-cuff method. Furthermore, the hemodynamic analyses in catheterized rats were applied to measure the actions of allantoin in vivo. Allantoin decreased blood pressures in SHRs at 30 minutes, as the most effective time. Also, this antihypertensive action was shown in a dose-dependent manner from SHRs treated with allantoin. Moreover, in anesthetized rats, allantoin inhibited cardiac contractility and heart rate as showing in hemodynamic
Neurotransmitters after binding to specific receptors are known to involve in the regulation of cardiovascular functions, especially the arterial blood pressure. In this regulation, noradrenaline, acetylcholine, serotonin, angiotensin II, and g-amino-butyric acid are widely introduced as the central regulators of blood pressure [
Allantoin is known rich contained in in yam (
The presence of imidazoline receptors in brain seems to be related to the central regulation of blood pressure [
Twelve-week-old male Wistar rats and spontaneously hypertensive rats (SHR), weighing from 250 to 300 g, were obtained from the Animal Center of National Cheng Kung University Medical College. The rats were housed individually in plastic cages under standard laboratory conditions. They were kept under a 12 h light/dark cycle and had free access to food and water. All experiments were performed under anesthesia with 2% isoflurane, and all efforts were made to minimize the animals’ suffering. The animal experiments were approved and conducted in accordance with local institutional guidelines for the care and use of laboratory animals, and the experiments conformed to the Guide for the Care and Use of Laboratory Animals as well as the guidelines of the Animal Welfare Act.
Animals were randomly assigned into four groups: (I) the control group (
After treatment of allantoin, the rats were placed into a holder for the determination of the mean blood pressure (MBP) using a noninvasive tail-cuff monitor (MK2000; Muromachi Kikai, Tokyo, Japan). The values for each animal were determined in triplicate.
Then, the rats were anesthetized and cannulated in the right femoral artery with polyethylene catheters (PE-50). Mean arterial pressure (MAP) and heart rate (HR) were recorded using a polygraph (MP35, BIOPAC, Goleta, Calif.). The rat’s trachea was intubated for artificial ventilation (Small Animal Ventilator Model 683, Harvard Apparatus, Holliston, Mass.) at 50 breaths/min with a tidal volume of 8 mL/kg and a positive end expiratory pressure of 5 cm H2O. After incision into the rat’s chest at the third intercostal space to expose the heart, a small section (1 cm long) of the ascending aorta was freed from the connective tissue. A Transonic Flowprobe (2.5PSB923, Transonic System Inc., Ithaca, N.Y.) was implanted around the root of the ascending aorta and connected to a Transonic transit-time blood flowmeter (T403, Transonic System Inc.). The MAP, HR, and blood flow were record for further analysis.
Temporary pacing leads were used for the short-term study and were placed in the right atrium and RV apex. A venogram image in 2 different angulations (left anterior oblique 30° and anteroposterior) was obtained to determine the anatomy of the coronary sinus venous system. An LV pacing electrode (IX-214; iWorx Systems, Inc., Dover, NH, USA) was placed either in the free wall region via the lateral or posterior vein or in the anterior region via the great cardiac vein. After femoral artery and venous puncture using the Seldinger technique [
Results were expressed as mean ± SE of each group. Statistical analysis was carried out using ANOVA analysis and the Newman-Keuls post hoc analysis. Statistical significance was set as
We investigated the most effective time point of allantoin using the intravenous injection of allantoin into SHRs for 0–120 minutes at the dose of 0.5 mg/kg according to previous study [
Antihypertensive action of allantoin in spontaneous hypertensive rats (SHRs). Time course (a) and dose-dependent (b) decrease of mean blood pressure (MBP) induced by allantoin in conscious spontaneously hypertensive rats (SHRs). Data represent the mean ± SEM of eight animals (
In order to clarify that allantoin may produce antihypertensive effect through central I-1R, we measured the MAP and HR in normal rats. The MAP and HR were markedly decreased after injection of allantoin (Figure
Effects of allantoin on mean arterial pressure (MAP) and heart rate (HR) in rats. The representative picture shows the change in MAP and HR caused by allantoin in anesthetized rats. HR and MAP were recorded in anesthetized rats treated with allantoin or cotreatment with efaroxan. The changes in MAP (a) and HR (b) were recorded at 30 min after injection of allantoin. All values are presented as mean ± SEM (
The
Effects of allantoin on cardiac performance in anesthetized rats. The effects of coadministration of allantoin and/or efaroxan were investigated in the anesthetized rats. The changes in hemodynamic
The peripheral blood flow was markedly increased by allantoin (0.5 mg/kg, i.v.) after treatment for 30 min in the anesthetized rats, compared with the vehicle-treated control. However, as shown in Figure
Effects of allantoin on peripheral blood flow in anesthetized rats. The effects of allantoin or cotreatment with efaroxan were investigated in the anesthetized rats. The changes in peripheral blood flow were recorded at 30 min after injection of allantoin. All values are presented as mean ± SEM (
In the present study, we found that allantoin induced a dose-dependent reduction of MBP in SHRs at 30 minutes later, the most effective time point. In anesthetized rats, the heart rate, mean arterial pressure, and cardiac contraction (
Imidazoline I1-receptors (I1-IRs) are known to be expressed in the rostral ventrolateral medulla (RVLM) of nucleus tract solitary (NTS) that seems essential for the sympathoinhibitory action of clonidine-, rilmenidine-, and moxonidine-like antihypertensive agents [
Imidazoline receptors (I-Rs) have been introduced to play a role in the regulation of cardiovascular function [
It is generally recognized that both human and experimental hypertension are mainly characterized by the higher intravascular pressure due to constriction of vascular smooth muscle cells (VSMCs) in arteries, and this behavior, known as myogenic tone, is a key element of hypertension [
Allantoin is nature-identical, safe, and nontoxic [
Allantoin has been mentioned to improve lipid metabolism in high fat diet- (HFD-) fed mice [
According to the obtained data, we suggest that allantoin may act as central antihypertensive agent through activation of imidazoline I-1 receptor for decrease of mean arterial pressure, heart rate, and cardiac contractility. Also, increase of the peripheral blood flow by allantoin shows the lowering of total peripheral resistance in rats. Thus, allantoin has the potential to develop as a new central antihypertensive agent in the future.
The authors declare that they have no conflict of interests.
Mei-Fen Chen and Jo-Ting Tsai contributed equally to this work.
The authors thank Professor King-Pong Lin for his kind support and direction in this study.