Blocker Pretreatment Research Articles

Evaluation of the Modulation of P-glycoprotein (P-gp) on the Intraocular Disposition of its Substrate in Rabbits

Purpose: To evaluate the functional role of P-gp and ocular tissue distribution of intravitreally injected Rhodamine-123 (Rho-123) in the presence of P-gp specific blocker (GF 120918) in normal as well as rifampicin-fed rabbits using microdialysis and direct sampling technique. Methods: Intravitreal pharmacokinetics of Rho-123 were conducted in male New Zealand albino rabbits. Direct sampling and microdialysis were employed to study the disposition of Rho-123 in normal as well as rifampicin-fed conditions. Control animals received Rho-123 at the concentration of 350 ng in PBS (0.05 ml) intravitreally, and the blocker-treated group received GF 120918 intravenously at the dose of 3.5 mg/kg 30 min prior to intravitreal injection of Rho-123. In case of direct sampling, four eyes were enucleated at different time points, and ocular tissues and humors were stored at –86°C until analysis by HPLC with fluorescence detection. Results: In direct sampling, the blocker group showed significant increase (2.6 fold) in the mean vitreous concentration of Rho-123. Other tissues like ret-choroid, iris, and cornea also showed significant increase in their mean concentration. Microdialysis did not significantly predict the changes observed with direct sampling. Rifampicin-fed rabbits showed a vitreous pharmacokinetic profile comparable with non-fed (control) animals, and the pharmacokinetic parameters were unaffected by the blocker pretreatment. Conclusion: Intravenously injected blocker significantly altered the ocular disposition of intravitreally injected P-gp substrate. Rifampicin pretreatment did not upregulate P-gp transporters of the retina to the extent to affect the intravitreal kinetics of Rho-123 significantly.

Angiotensin II receptor blockade blocker pre-treatment largely prevents injury from gradual renal ablation in rats

Reduction in renal mass in rats results in progressive proteinuria, hypertension, focal-segmental glomerulosclerosis (FSG), atrophy of tubules (AT), and interstitial expansion. We reported that slow reduction of renal tissue in rats (slow ablation) ending in the removal of 1.5 kidneys is associated, over the next six months, with higher albumin excretion rates (AER) and accelerated development of FSG lesions compared to sudden equivalent renal mass reduction. It was hypothesised that slow reduction of nephron numbers allows for a process of conditioning of residual nephrons that increases their susceptibility to subsequent injury. To test this idea we treated Münich-Wistar rats with the angiotensin receptor blocker (ARB) losartan for six weeks during the gradual staged surgical removal of 1.5 kidneys, and compared them to sham operated controls, and parallel groups untreated by losartan. Despite discontinuation of losartan over the subsequent six months, ARB pre-treatment completely prevented proteinuria and hypertension in these slow renal ablation rats. ARB pre-treatment also largely prevented the subsequent development of FSG, AT, and interstitial expansion in these animals. Both losartan-treated and untreated renal ablation groups had glomerular enlargement and compensatory hyperfiltration and this was uninfluenced by losartan. Temporary ARB administration during gradual renal mass reduction resulted in long-term prevention of hypertension and albuminuria and greatly reduced FSG and tubular and interstitial lesions. We hypothesise that the preconditioning of residual nephrons in the gradual ablation model which facilitates their subsequent injury, is blunted by renin-angiotensin system blockade.

Neuroactive Steroids Protect Retinal Tissue through σ1 Receptors

The term ‘neuroactive steroids’ has been adopted for steroids, including 17β-oestradiol and dehydroepiandrosteronesulphate (DHEA-S), that might alter neuronal excitability through the cell surface through interaction with specific neurotransmitter receptors. It has been shown [1] that administration of 17β-oestradiol exerts protective effects against ischaemic damage in rat retina. Recently, we demonstrated [2] that 17β-oestradiol and DHEA-S inhibit biochemical changes induced by ischaemia injury in rat retina and that these effects were antagonized by σ1 receptor blocker pre-treatment. More recently, we showed [3] that neuroactive steroids protect retinal pigment epithelium against oxidative stress and that this effect was blocked by pretreatment with σ1 receptor antagonist. The mechanism by which neuroactive steroids exert these protective effects remains unclear. A direct interaction between neuroactive steroids and σ1 receptors has been hypothesized from the finding that several steroids inhibit the binding of σ1 receptor radioligands in vitro and in vivo [4]. σ1 Receptors are a unique class of non-opioid, non-phencyclidine-binding sites heterogeneously distributed in the nervous system and in peripheral organs that may serve as receptors for any, as yet unidentified, endogenous ligand. Recently, the presence of σ1 receptors in rat Muller cells, rat ganglion cells and human retinal pigment epithelial cells have been demonstrated [5], in spite of the functional role of σ1 receptors not yet being clearly determined. The present study was designed to determine whether 17β-oestradiol and DHEA-S protect rat retinal tissue against ischaemia/reperfusion damage and whether σ1 receptors are involved in the mechanism of action.

Angiotensin II receptor blockade blocker pre-treatment largely prevents injury from gradual renal ablation in rats

Angiotensin II receptor blockade blocker pre-treatment largely prevents injury from gradual renal ablation in rats

Contribution of Nitric Oxide and Sensory Transmitters to Non-adrenergic, Non-cholinergic Innervation of Nasal Blood Vessels

The possible contribution of a non-adrenergic, non-cholinergic (NANC) vasodilator mechanism in human nasal mucosa was studied using an in vitro muscle tension measuring technique. Strips of the nasal mucosa were suspended in a Magnus tube filled with Krebs solution and aerated with 95% O 2 . Isometric changes in tension were detected on administration of various drugs under electric stimulation and recorded with a transducer. The relaxing reaction under electrical train pulse stimulation with pretreatment of blockers of the autonomic nerves was suppressed by nitric oxide synthase inhibitor (L-NAME) and antagonists to the receptors of sensory nerve transmitters (Spantide, hCGRP8-37). This result suggests that nitric oxide, substance P and CGRP may be mediators in the NANC inhibitory nerve system.

Calcium channel blockers do not enhance increases in plasma potassium after succinylcholine in humans

Study Objective: To determine whether chronic calcium channel blocker therapy exaggerates the rise in plasma potassium concentration ([K +]) after succinylcholine administration. Design: Prospective clinical study. Setting: University and Veterans Affairs hospitals. Patients: 36 ASA physical status III and IV male patients: 21 patients taking chronic calcium channel blockers and 15 patients not receiving calcium channel blockers, all of whom were scheduled for inpatient surgical procedures with general anesthesia. Interventions: In all patients, anesthesia was induced with high-dose opioids plus a sedative-hypnotic, and intubation was facilitated with 1 to 1.5 mg/kg succinylcholine without nondepolarizing neuromuscular blocker pretreatment. Measurements and Main Results: Plasma [K +] was measured prior to induction and 1, 3, 5, 8, 11, and 15 minutes after succinylcholine was administered. A modest average peak rise of 0.5 mEq/L in plasma [K +] was observed, but there were no differences between patients who were or were not receiving calcium channel blockers. Conclusions: Patients receiving chronic calcium channel blocker therapy are at no greater risk of hyperkalemia after succinylcholine than those not taking such medications.

Endothelin 3 (ET3) stimulates the hypothalamic-pituitary-adrenal axis mainly by corticotropin-releasing-hormone (CRH)

Endothelin 3 (ET3) is a member of the novel vasoconstrictive peptide family, identified in the porcine central nervous system. The effect of ET3 on the hypothalamic-pituitary-adrenal axis in male rats was examined in vivo and in vitro. Intravenous bolus injection of 1000pmol/kg of ET3 in free moving rats caused significant increases in plasma ACTH and corticosterone levels, almost equivalent to those of 100pmol/kg of rat corticotropin-releasing hormone (rCRH). Since an iv bolus injection of ET3 1000pmol/kg did not cause significant changes in the blood pressure of anesthetized rats or the locomotor activity of free moving rats, it seems unlikely that ET3 1000pmol/kg acted as a nonspecific stressor. When ET3 (10(-11) greater than 10(-7)M) was added to cultured anterior pituitary cells, neither direct stimulation of ACTH release nor potentiation of rCRH action was noted. Although it has been shown that ET3 administered systemically probably does not cross the brain-blood-barrier, circulating ET3 may reach the brain tissues through regions lacking the tight barrier, circumventricular structures. The next studies included pretreatment of antagonists or blockers of ACTH stimulating hormones to elucidate the mechanisms of ET3 induced ACTH release. The action of ET3 was virtually abolished by pretreatment of CRH-antagonist alpha helical CRH (150 micrograms/rat icv). But pretreatment of catecholamine-blocker alpha methyl-tyrosine (100mg/kg iv), arginine vasopressin-antagonist dP-thy(Me)AVP (50 micrograms/rat iv) and prostaglandin-blocker indomethacin (3mg/rat iv) did not inhibit the action of ET3. The results indicate that ET3 may play the role of a neuropeptide and that the stimulation of the CRH-neurons is mainly responsible for activation of ACTH and corticosterone release.

Alterations in hemodynamics and Kf,c during lung mass resection.

The effects of progressive lung mass reduction on total pulmonary vascular resistance (RT), compliance (CT), arterial (Pa), venous (PV), and capillary (Pc) pressures, and the capillary filtration coefficient (Kf,c) were evaluated in whole isolated dog lungs perfused with autologous blood. RT increased (P less than 0.05) in a nonlinear fashion when mass was reduced by greater than 35% in zone 3 lungs (Pa greater than PV greater than airway pressure) perfused at constant pressure (CP, n = 9), a finding predicted by a model of rigid parallel flow channels subjected to loss of cross-sectional area. Furthermore, these findings were not altered by pretreatment with ibuprofen or diphenhydramine (n = 7). In contrast, in zone 3 lungs perfused with constant flow (CF, n = 4), RT did not increase until at least 60-75% of mass was removed. Since Pa and Pc were constant in the former group, but increased in the latter group (P less than 0.05), the attenuation of RT by CF is best explained by vascular distension. This is supported by the finding that microvascular C, as a fraction of CT, decreased significantly with CF, but not with CP. Kf,c and CT (referenced to the initial lung mass) decreased linearly with reductions in lung mass % delta Kf,c = 1.26-0.98% mass removed (r = 0.90, P less than 0.01) and % delta CT = -3.99-0.98% mass removed (r = 0.82, P less than 0.01) relationships that were not altered by blocker pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasopressin is important for restoring cardiovascular homeostasis in fetal lambs subjected to hemorrhage

To determine if the posterior pituitary hormone vasopressin is important for maintaining fetal cardiovascular homeostasis during hypovolemic stress, in seven chronically catheterized fetal lambs we induced hemorrhage of 20% of estimated blood volume in the presence and in the absence of a potent antagonist to the pressor effects of vasopressin. The study was a paired crossover design with at least 48 hours separating experiments in the same animal. Injection of the vasopressin antagonist did not alter basal fetal heart rate or arterial blood pressure, but hemorrhage of 2% of estimated fetal blood volume per minute for 10 minutes produced a greater fall in blood pressure (13 ± 2 versus 10 ± 2 torr, p < 0.05) when the blocker was present than when it was absent. Arterial blood pressure remained below control levels longer following hemorrhage when the fetuses were pretreated with the antagonist (49.7 ± 6 versus 26.6 ± 6 minutes, p < 0.01), and the integrated fall in arterial blood pressure with hemorrhage was greatest (283 ± 53 versus 169 ± 57 mm Hg · min p < 0.01) when the blocker was used. The fall in heart rate following hemorrhage was similar with and without blocker pretreatment. These results indicate that vasopressin plays a physiologic role in blood pressure regulation in fetal lambs during periods of hypovolemia.