Effect of moxonidine versus clonidine and lisinopril on blood pressure and expression of renin gene in two kidney/one clip [2K/1 C] hypertensive rats

It has been suggested that imidazoline receptors rather than alpha-2 adrenoceptors are implicated in the sympathoinhibitory action of centrally acting antihypertensive drugs. I[1] Imdazoline receptors [I[1]Rs] are important for regulation of sympathetic drive. They are concentrated in the rostral ventrolateral medulla [RVLM], a part of the brainstem vasomotor center. The control of arterial blood pressure is mainly regulated via the sympathetic and angiotensin/ aldosterone cascades. The purpose of the present study was focused to assess the effect of oral administration and abrupt withdrawal of moxonidine versus clonidine and lisinopril on systolic pressure, to investigate the role of moxonidine versus clonidine and lisinopril on plasma noradrenaline level and plasma renin activity and to determine the genometric effect of moxonidine versus clonidine and lisinopril oral administration on renin gene expression in 2K1C renovascular hypertensive rats. Rats were made hypertensive with a clip on the left renal artery. The operation was conducted under light ether anesthesia. Three weeks after renal clipping. 2 series of experiments on male rats were conducted to evaluate the effect of the test drugs on the following parameters. 1- Effect of oral administration of the test drugs for a period of three weeks on the systolic pressure in 2K1C hypertensive rats measured via indirect rat-tail method. 2-Biochemical tests to estimate plasma norepiphrine level and plasma renin activity. 3- Renin gene expression measured by quantified RT-PCR. All test drugs elicited a remarkable significant reduction in systolic pressure of renovascular hypertensive rats. Discontinued administration of moxonidine did not trigger rebound hypertension observed with clonidine. These findings suggest that both imidazoline receptors and alpha 2- adrenoceptors are involved in the central antihypertensive effect of moxonidine, but that activation of imidazoline receptors is more important for its renal sympathinhibitory action. Additionally imidazoline derivatives and ACEIs are very effective agents for treatment of renovascular hypertension. The antihypertensive effect of moxonidine was accompanied by decrease in plasma norepinephrine, renin levels and renin gene expression in the renal tissue. Whereas lisinopril decreased plasma norepinephrine level but increased plasma renin activity in parallel with renin gene expression compared to the untreated 2K1C hypertensive control. The data presented in this report indicate that moxonidine is an orally effective antiypertensive agent in 2KIC hypertensive rats without an accompanying rebound hypertension on abrupt dicontinuation of the drug, which makes it advantageous over clonidine. Moxonidine therefore allies antihypertensive efficacy with excellent tolerance without triggering central side-effects as moxonidine selectively binds at therapeutic doses to I[1] imidazoline receptors. ACEI, lisinopril produced a significantly pronounced reduction in systolic pressure in 2K1C hypertensive rats. Lisinopril may be of greater benefit in management of renovascular hypertension. In light of these findings moxonidine represents a unique profile among centrally acting antihypertensive agents. Moxonidine offers an advantageous hemodynamic activity over clonidine and lisinopril and probably it exerts its strong antihypertensive effect through its affinity for I[1] imidazoline receptors rather than alpha[2] adrenergic receptors

Effect of benzodiazepines [Diazepam, bromazepam and clonazepam], Sodium valproate and phenytoin on acetyl choline content in various areas of the brain in rats

The effect of three members of benzodiazepines [diazepam, bromazepam and clonazepam] and two antiepileptic drugs [sodium valproate and phenytoin] on the content of acetyl choline [ACh] in the whole rat's brain and its different areas has been investigated. A.Ch. was determined by the toad's rectus abdominis muscle bioassay [Richter and Crossland, 1949]. The five drugs given either in acute schedule for 24 hours or as short term medication for five days, produced very highly significant increase in A.Ch. content both in whole rat's brain and its different areas. The increase of A.Ch. in whole rat's brain was [+ 114% and +89%] by diazepam, [+ 129% and + 100%] by bromazepam, [+ 50% and +24%] by phenytoin, [+ 17% and +24%] by sodium valproate and [+ 2% and +31%] by clonazepam for 24 hours and five days respectively. The effect of diazepam and bromazepam was more profound than sodium valproate and phenytoin in thalamus and hypothalamus and hind brain; [+ 275% and +509%] and [+ 93% and +129%] and [+ 100% and +139%] by bromazepam. In contrast, the effect of phenytoin and sodium valproate was more pronounced than the benzodiazepine members in the cerebral cortex and midbrain; [+ 160% and +115%], [+ 100% and + 111%] and [+ 80% and +157%] by sodium valproate