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

Insulin resistance and hyperinsulinemia: independent relation to left ventricular mass in humans

Hyperinsulinemia and insulin resistance may contribute to the development of cardiac hypertrophy which is a major cardiovascular risk factor. In humans, however, the evidence is inconclusive. Antihypertensive drugs have different effects on insulin metabolism, sensitivity, and on left ventricular mass [LVM]. To study the association between LVM and insulin resistance as well as some other cardiovascular risk factors. Also, to compare the effects of two drugs [Atenolol, lisinopril], which have different effects on insulin sensitivity on LVM. The study included four groups: Group [I] control group included 10 healthy lean females aged 35.7+3.4 years. Group [II] included 28 obese normotensive female patients aged 35.39+3.9 1 years, body mass index [BMI] 36.18+3.93 Kg/m2. Group [III] included 28 newly diagnosed obese hypertensive female patients aged 35.85+ 7.8 years, BMI 39.34+4.12 Kg/m2. Group [IV] included 28 newly diagnosed lean hypertensive female patients aged 34.36+4.45 years, BMI 22.98+1.60 Kg/m2. Patients in groups III and IV were randomized to treatment with atenolol or lisinopril [14 patients in each group]. The following parameters were assessed BMI, WHR, systolic and diastolic blood pressure, fasting plasma glucose and insulin, fasting insulin resistance index [FIRI], LVM and left ventricular mass index [LVMI]. Obese and hypertensive patients had significant increase in insulin resistance, LVM and LVMI compared to controls [P<0.05]. Abdominal obesity as repesented by WHR, was directly associated with insulin resistance, LVM, and LVMI [r = 0.749, P<0.001; r = 0.523,P<0.O01; r = 0.656, P<0.001 respectively]. LVM was positively correlated with systolic and diastolic blood pressure, BMI. WHR, and insulin resistance [r = 0.749, P<0.001; r = 0.639, P<0.001; r = 0.224, P = 0.041, r = 0.523, P<0.001; r = 0.509, P<0.001 respectively]. After adjustment for systemic blood pressure and obesity, LVM was independently associated with insulin resistance [P<0.001]; Lisinopril, but not atenolol was associated with favorable effect on insulin resistance and led to more significant regression of LVM in lean [P<0.001] and obese [p = 0:004] hypertesnive patients. LVM has a positive independent correlation with hyperinsulinemia and insulin resistance. Hyperinsulinemia has independent role in promoting left ventricular hypertrophy. Agents and maneuvers which improve insulin sensitivity might be beneficial in management of left ventricular hypertrnphy and other deleterious effects of hyperinsulinemia