Mahmoud M. Mohy El-Din

Testosterone facilitates the baroreceptor control of reflex bradycardia: role of cardiac sympathetic and parasympathetic components.

Reported clinical and experimental findings have shown that baroreflex control of heart rate is attenuated in women compared with men. This study investigated whether the sexual dimorphism in baroreflex function relates to the ability of the male hormone testosterone to facilitate baroreflex responsiveness. Relative contributions of the vagal and sympathetic autonomic components to testosterone modulation of baroreflex function were also investigated. Baroreflex curves relating changes in heart rate to increases or decreases in blood pressure evoked by phenylephrine and sodium nitroprusside, respectively, were constructed in sham-operated rats and castrated rats with and without testosterone replacement. Slope of the curves was taken as an index of baroreflex sensitivity (BRS PE and BRS NP ). Castration (for 10 days) significantly reduced plasma testosterone levels and attenuated reflex bradycardia, as indicated by significantly smaller BRS PE in castrated rats compared with values in sham-operated rats (−0.85 ± 0.07 vs. −1.51 ± 0.10 beats/min per mm Hg). Testosterone replacement in castrated rats restored plasma testosterone and BRS PE to levels similar to those of sham-operated rats. Muscarinic blockade by atropine caused 55% reduction in BRS PE in sham-operated rats, an effect that was significantly (p < 0.05) attenuated in castrated rats and restored to intact levels after testosterone supplementation. &bgr;-Adrenergic blockade by propranolol caused slight and insignificant decreases in BRS PE . Castration and testosterone supplementation had no effect on BRS NP , ruling out a modulatory effect of testosterone on reflex tachycardia. These data provide the first experimental evidence of a favorable role for testosterone in baroreceptor control of reflex bradycardia. Further, baroreflex modulation by testosterone appears to be autonomically mediated and involves an enhancement of cardiomotor vagal activity.

Testosterone depletion contributes to cyclosporine-induced chronic impairment of acetylcholine renovascular relaxations

The immunosuppressant drug cyclosporine causes nephrotoxicity mainly via alterations of renovascular reactivity. This study investigated whether this effect of cyclosporine is modulated by the male gonadal hormone testosterone. The endothelium-dependent and -independent relaxations evoked by acetylcholine and sodium nitroprusside, respectively, were evaluated in phenylephrine-preconstricted isolated perfused kidneys obtained from sham-operated, castrated, and testosterone-replaced castrated (CAS+T) male rats in the absence and presence of cyclosporine. Compared with sham-operated values, short-term (10 days) castration or cyclosporine treatment caused significant and equivalent reductions in plasma testosterone levels and vasorelaxant responses to acetylcholine. Treatment of castrated rats with cyclosporine caused no further attenuation of acetylcholine relaxations. Testosterone replacement of castrated (CAS+T) or cyclosporine-treated castrated (CAS+CyA+T) rats restored plasma testosterone and acetylcholine relaxations to near-sham-operated levels. On the other hand, castration caused significant increases in nitroprusside relaxations versus no effect for cyclosporine. The relaxant responses to nitroprusside in castrated rats were restored to sham-operated levels after testosterone replacement. Plasma urea and creatinine were not affected by castration but were significantly increased by cyclosporine. These findings suggest that testosterone exerts directionally opposite modulatory effects on endothelium-dependent and -independent renal relaxations. Further, the results demonstrate that testosterone depletion may contribute, at least partly, to the inhibitory effect of cyclosporine on renovascular endothelial function. These data are clinically important because endothelial dysfunction contributes to vascular abnormalities associating cyclosporine therapy.

A Novel COX‐2 Inhibitor Pyrazole Derivative Proven Effective as an Anti‐Inflammatory and Analgesic Drug

The introduction of new COX-2 inhibitors with high efficacy and enhanced safety profile would be a great achievement in the development of anti-inflammatory drugs. This study was designed to screen and assess the anti-inflammatory and analgesic activities as well as some of the expected side effects of some pyrazole derivatives, newly synthesized as potential COX-2 inhibitors at the Faculty of Pharmacy, Alexandria University and compared to indomethacin and celecoxib. Twelve compounds were screened for their anti-inflammatory activity using carrageenan-induced paw oedema and cotton pellet granuloma tests. On the basis of their apparent anti-inflammatory activity, four compounds with different substitutions were selected for the evaluation of their analgesic activity using the formalin-induced hyperalgesia and hot-plate tests. Compound AD 532, ((4-(3-(4-Methylphenyl)-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide)), showed very promising results. In the single-dose and subchronic toxicity studies, compound AD 532 showed no ulcerogenic effect and produced minimal effects on renal function. Furthermore, compound AD 532 was a less potent inhibitor of COX-2 in vitro than celecoxib, which may indicate lower potential cardiovascular toxicity. It is concluded that compound AD 532 appears to be a promising and safe option for the management of chronic inflammatory conditions. This study recommends more in-depth investigation into the therapeutic effects and toxicity profile of this compound including its cardiovascular toxicity.

Regional and endothelial differences in cyclosporine attenuation of adenosine receptor-mediated vasorelaxations.

Abstract: The present study investigated the acute effects of the immunosuppressant drug cyclosporine A on vasorelaxations evoked via activation of adenosine receptors in the phenylephrine-preconstricted rat perfused kidney and isolated aorta. The roles of endothelial relaxing factors in this interaction were also evaluated. The adenosine analogue 5′-N-ethylcarboxamidoadenosine (NECA; kidney, 6 × 10−9−1 × 10−7 mol; aorta, 1 × 10−9−1 × 10−5 M) elicited dose-dependent vasorelaxations. In the perfused kidney, NECA responses were similarly and significantly attenuated by NG-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor) or tetraethylammonium (K+ channel blocker) versus no effect for diclophenac (cyclooxygenase inhibitor). NECA relaxations in the aorta were reduced by the three inhibitors; the reduction in the response evoked by the highest dose of NECA (1 × 10−5 M) amounted to 37.7 ± 2.0% (L-NAME), 19.8 ± 1.7% (tetraethylammonium), and 29.4 ± 1.1% (diclophenac). A combination of the three inhibitors almost abolished NECA relaxations in the two preparations. Cyclosporine (2 μM) reduced NECA relaxations in the two preparations. In the aorta, cyclosporine attenuation of NECA responses was significantly reduced after exposure to L-NAME or diclophenac but not tetraethyl-ammonium, suggesting selective involvement of nitric oxide and vasodilator prostanoids in the interaction. In contrast, the cyclosporine attenuation of NECA responses in the kidney was reduced by L-NAME or tetraethylammonium. L-arginine, a nitric oxide substrate, partially restored NECA relaxations in cyclosporine-treated preparations. These findings demonstrate that cyclosporine attenuates endothelium-dependent vasorelaxations elicited via activation of adenosine receptors and highlight the interesting possibility that the relative contribution of the endothelial relaxing factors to cyclosporine-NECA interaction is largely region dependent.

Blockade of endothelin ETA, but not thromboxane, receptors offsets the cyclosporine-evoked hypertension and interrelated baroreflex and vascular dysfunctions

The impairment of arterial baroreceptor and vasodilator functions are two major contributors to the hypertensive action of cyclosporine (CSA). In this study, in vivo and in vitro pharmacological studies were performed to investigate whether these effects of CSA are differentially modulated by endothelin and thromboxane signaling. The treatment of rats with CSA (25mg/kg/day i.p.) for 7 consecutive days caused significant increases in blood pressure (BP), attenuated reflex heart rate (HR) responses to vasopressor (phenylephrine, PE) and vasodepressor (sodium nitroprusside, SNP) agents, and reduced cumulative vasorelaxant responses elicited by acetylcholine (Ach, 1×10(-9)-1×10(-5)M) in PE-precontracted isolated aortas. These effects of CSA were blunted after concurrent i.p. administration of atrasentan (selective ETA blocker, 10mg/kg/day), but not terutroban (thromboxane receptor blocker, 10mg/kg/day). Moreover, atrasentan reversed the reductions in aortic protein expression of eNOS caused by CSA whereas terutroban was without effect. We also report that the favorable effect of atrasentan on CSA-evoked impairment in aortic Ach responsiveness disappeared in rats treated simultaneously with L-NAME (NOS inhibitor, 10mg/kg/day) but not BQ 788 (ETB receptor blocker, 0.1mg/kg/day) or indomethacin (cycloxygenase inhibitor, 5mg/kg/day). Together, the data implicate endothelin ETA receptors in baroreflex and vascular derangements which predispose to the hypertensive effect of CSA. Moreover, the facilitation of NOS, but not ETB receptors or cycloxygenase-derived prostanoids, signaling is pivotal for advantageous effect of atrasentan on the aortic CSA-Ach interaction.

Redox imbalances incite the hypertensive, baroreflex, and autonomic effects of cyclosporine in rats.

Previous studies including ours showed that cyclosporine (CSA) causes baroreflex dysfunction and hypertension. Here we tested the hypothesis that oxidative damage in central and peripheral tissues underlies the hypertensive, baroreflex and autonomic actions elicited by CSA in rats. We investigated the effects of individual and combined 7-day treatments with CSA (25 mg/kg/day, n=7) and 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol, superoxide dismutase mimetic, 100 mg/kg/day, n=7) on blood pressure, reflex heart rate responses to peripherally mediated pressor and depressor responses, and biomarkers of oxidative stress. CSA elevated blood pressure and reduced reflex bradycardic (phenylephrine) and tachycardic (sodium nitroptrusside) responses. The ability of muscarinic (atropine, 1 mg/kg i.v.) or β-adrenoceptor blockade (propranolol, 1 mg/kg i.v.) to reduce reflex heart rate responses was reduced in CSA-treated rats, suggesting the impairment by CSA of reflex cardiac autonomic control. Concurrent administration of tempol abolished CSA-induced hypertension and normalized the associated impairment in baroreflex gain and cardiac autonomic control. Tempol also reversed the CSA-induced increases in aortic and brainstem nitrite/nitrate and malondialdehyde (MDA) and decreases in aortic superoxide dismutase (SOD). These findings implicate oxidative stress in peripheral and central cardiovascular sites in the deleterious actions of CSA on blood pressure and baroreceptor control of heart rate.

Facilitation of central imidazoline I1‐site/extracellular signal‐regulated kinase/p38 mitogen‐activated protein kinase signalling mediates the hypotensive effect of ethanol in rats with acute renal failure

Background and purpose:  This study investigated the role of central sympathetic activity and related mitogen‐activated protein kinase (MAPK) signalling in the cardiovascular effects of ethanol in a model of acute renal failure (ARF).

Interruption of central neuronal pathway of imidazoline I1 receptor mediates the hypertensive effect of cyclosporine in rats.

Increased central sympathetic outflow secondary to afferent sympathetic excitation has been implicated in the hypertensive effect of the immunosuppressant drug cyclosporine (CSA). The present study investigated the roles of central alpha(2)-adrenoceptors and I(1)-imidazoline receptors in modulating the hypertensive action of CSA. The blood pressure (BP) response to CSA in conscious rats was assessed in the absence and presence of peripherally or centrally acting sympatholytic drugs. Also, the effect of selective pharmacologic blockade of alpha(2) or I(1) receptors by yohimbine and efaroxan, respectively, on the pressor response to CSA was evaluated. CSA (20 mg/kg i.v.) produced a rapid increase in BP that peaked (25+/-4 mm Hg) after approximately 4 min and continued for the 45 min study duration. Ganglionic (hexamethonium 20 mg/kg) or alpha(1)-adrenoceptor (prazosin 1 mg/kg) blockade reduced the pressor effect of CSA. Pressor responses to phenylephrine (alpha(1)-adrenoceptor agonist) were not affected by CSA, thereby eliminating a possible role for alterations of vascular alpha(1)-adrenoceptor responsiveness in CSA hypertension. CSA hypertension was attenuated in rats pretreated intravenously with drugs that reduce central sympathetic tone including clonidine (mixed alpha(2)/I(1)-receptor agonist, 30 microg/kg) or moxonidine (selective I(1)-receptor agonist, 100 microg/kg) in contrast to no effect for guanabenz (selective alpha(2)-receptor agonist, 30 microg/kg). Intracisternal (i.c.) administration of moxonidine also reduced CSA hypertension. Selective blockade of central I(1) (efaroxan, 0.15 microg/rat, i.c.) but not alpha(2) (yohimbine, 25 microg/5 microl/rat, i.c.) receptors abolished the hypertensive response to CSA. Together, these findings highlight that CSA elicits its hypertensive effect via disruption of central sympathoinhibitory pathways which include I(1)-imidazoline receptors.

Injectable and oral contraceptive steroids in relation to some neurotransmitters in the rat brain

Abstract The influence of both injectable and oral contraceptive steroids on brain acetylcholine and serotonin was investigated. The effects of such steroids on some brain amino adds such as tryptophan, γ-aminobutyric acid (GABA), and glutamate (Glu) levels were determined. The steroids used in the present study were the long-acting injectable medroxyprogesterone acetate (MPA) and the orally active steroids ethinyloestradiol (EE) and norethisterone acetate (NEA). Acetylcholine content of the rat brain was not altered significantly following treatment with any of the steroids used. In contrast, all types of treatment caused a significant rise in brain serotonin levels. Tryptophan concentration was similarly increased following MPA injection, administration of NEA alone, or its combination with EE. No changes were noted, however, in brain tryptophan content following the administration of EE alone. MPA injection was found to be devoid of any effect on the balance between Glu, the excitatory amino acid, and GABA, the inhibitory one. On the other hand, all the orally active steroid regimens used significantly increased the GABA content of the rat brain. Only NEA pretreatment resulted in a significant decrease in brain Glu content. Changes in these central chemical transmitters and their possible relations to both antifertility and to the untoward effects of such contraceptive measures are discussed.

Adenosinergic modulation of the imidazoline I1-receptor-dependent hypotensive effect of ethanol in acute renal failure

We reported that inhibition of central sympathetic pools of imidazoline I(1) receptors abolishes the hypotensive effect of ethanol in rats with glycerol-induced acute renal failure (ARF). This study investigated whether adenosine receptors modulate the ethanol-I(1)-receptor interaction. The effect of selective blockade of adenosine A(1), A(2A), or A(2B) receptors on hemodynamic responses to ethanol in the absence and presence of the I(1)-receptor agonist moxonidine was determined in ARF rats. Ethanol (1g/kg i.v.) decreased and increased blood pressure (BP) and heart rate (HR), respectively. Pretreatment with moxonidine abolished the hypotensive but not the tachycardic effect of ethanol. The hypotensive effect of ethanol remained unaltered after selective blockade of A(1), A(2A), or A(2B) receptors with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 8-(3-chlorostyryl) caffeine (CSC) and alloxazine, respectively. Neither was ethanol hypotension affected after inhibition of adenosine uptake by dipyridamole (DPY). Alternatively, the ability of moxonidine to abolish ethanol hypotension was still evident in presence of alloxazine whereas it disappeared or weakened in rats pretreated with CSC and DPCPX, respectively. These findings implicate adenosine A(2A) receptors in the moxonidine-evoked inhibition of the hypotensive action of ethanol. A modulatory role for adenosine A(1) site in the ethanol-I(1)-receptor interaction is also possible through as yet unidentified mechanism.