Centrally acting antihypertensive agents of the first generation such as clondine and -methyldopa have been used to treat hypertensive patients for three decades .These agents reduce sympathetic drive directly, mainly by an action on the brain stem that was originally thought to involve activation of central 2 – adrenoceptors. Although peripheral mechanisms such as activation of the presynaptic 2- adrenoceptors may also centribute to a small extent. However, the use of clonidine and other agents with high affinity for 2-adrenoceptors as guanfacine had serious difficulties in being readily accepted for the treatment of hypertension because of the side effects like sedation, dry mouth and rebound hypertension. Clonidine has roughly equivalent affinity for imidazoline receptors and 2- adrenoceptors, and it appears that, it is the latter that are mainly responsible for the unwanted side effects. Second generation of centrally antihypertensive agents such as rilmenidine and moxonidine were developed with greater affinity for imidazoline receptors than for 2-adrenoceptors. Rilmenidine is an oxazoline rather than an imidazoline,so, it is less potent than clonidine but it has 30-fold greater selectivity for imidazoline receptors than clonidine.
The lower affinity of rilmenidine for 2- adrenoceptors has also been suggested to be the reason for their lesser sedative and other adverse effects. This, in combination with its effectiveness in lowering blood pressure and its longer half-life, has made it much more therapeutically useful. The present study was performed in- vivo & in –vitro in order to characterize the cardiovascular, renal, metabolic and analgesic effects of rilmenidine versus that of clonidine. Moreover, this study aimed to estimate the sedative effect of rilmenidine versus that of clonidine.
24 rats were used to estimate the effects of acute administration of rilmenidine (0.01 , 0.3 and 1 mg/ kg I.V) on blood pressure and heart rate versus clonidine. Rats were divided into four equal groups. Control group (group 1), RAO hypertensive group (group 11), RAO hypertensive group treated with rilmenidine (group III) and RAO hypertensive group treated with clonidine (group IV). It was found that, at the equipotent doses; both rilmenidine & clonidne induced a transient significant elevation of blood pressure followed by long-lasting hypotension and bradycardia.
Yohimbine administration to hypertensive rats 15 minutes prior to rilmenidine administration significantly reduced the hypotensive effects of rilmenidine whereas it abolished the hypotensive effect of clonidine. Furthermore, chronic rilmenidine and clonidine administration induced significant reduction of blood pressure.
Another 24 rats were used for demonstrating the possible cardioprotective effects of rilmenidine versus clonidine in isoprenaline induced chronic heart failure, divided into 4 groups, (1) control normal rats, (2) isoprenaline (75, 150 mg/kg I.P on 2 consecutive days) induced chronic heart failure (ICHF) (3). Rilmenidine treated (1 mg/kg/day) ICHF group and (4) clonidine treated (ICHF group).
The present study revealed that, daily I.P administration of equipotent doses of rilmenidine or clonidine to isoprenaline induced chronic heart failure induced significant change of blood pressure, compared with control normal rats which is insignificant with heart failure group, significant reduction of heart rate, significant increase in renal blood flow and significant amelioration of the histopathological changes in the cardiac tissues induced by isoprenalin with no significant difference between rilmenidine and clonidine in this respect.
In regarding to the prophylactic effect of rilmenidine and clonidine against STZ and RAO induced diabetic nephropathy in rats. The results showed that, daily administration of either rilmenidine or clonidine at equipotent doses had favorable effects on blood pressure, fasting blood glucose level and urine albumin. There were a significant reduction of these parameters in groups treated with rilmenidine or clonidine compared with diabetic nephropathy non treated group. Moreover, histopathological examination of kidney tissues sowed significant improvement in the form of reduction of basement membrane thickening & infiltration of inflammatory cells.
The present study extended to estimate the effects of rilmenidine and clonidine on lipid parameters and insulin sensitivity in fructose induced insulin resistance. It was found that both rilmenidine and clonidine prevented the elevation of blood pressure, fasting blood glucose level with non significant difference, and prevented the elevation of total cholesterol level which is more significant in the rilmenidine treated group. Compared with clonidine treated group. However, rilmenidine was found to induce significant elevation of triglycerides compared with clonidine treated group. Significant improvement insulin sensitivity was noted with either of them with in significant difference.
The present study demonstrated that, rilmenidine in different doses up to 10 m/kg I.P had non significant effect on sleeping time induced by pentobarbitone 30 mg/kg I.P), compared with control and clonidine treated groups.
On the other hand, in the present study acute rilmenidine or clonidine was found to provide potent antinociceptive efficacy in control of acute pain with non significant difference.
Regarding the in-vitro results, both rilmenidine and clonidine produced dose related inhibition of the force of contraction of the isolated perfused rabbit’s heart. This inhibition was not abolished by neither muscrinic nor nicotinic receptor antagonists suggesting a direct effect of rilmenidine and clonidine on isolated rabbit’s heart.
In addition, it was found that rilmenidine and clonidine produced dose related contraction of isolated rabbit aortic strip. This effect is more likely to be through receptor stimulation because phentolamine is effective antagonist for both rilmenidine and clonidine.
Lastly, in the present work demonstrated that, either rilmenidine or clonidine induced significant inhibition of isolated rabbit jejunum.
This effect is more likely to be through postsynaptic 2 – adrenoceptor stimulation because yohimbine was more effective antagonist than prazosin indicating the higher selectivity of rilmenidine and clonidine for postsynaptic 2- adrenoceptor than 1 subtype.
In conclusion, rilmenidine is a centrally acting antihypertensive dreg with high efficacy, has analgesic effect and no sedative effect. In CHF it decreased blood pressure, heart rate, increased renal blood flow and attenuated histopathological changes.
Moreover, rilmenidine could be a drug of choice in diabetic hypertensive cases as it significantly lowered of blood pressure and urine albumin which is the hall mark in nephropathy. In insulin resistance it significantly decreased blood glucose level and improved insulin sensitivity. However, there is still controversy about its effect on lipid parameters as it significantly decreased total cholesterol and increased triglyceride.
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