Clinical and experimental pharmacology & physiology
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Clin. Exp. Pharmacol. Physiol. · Jan 2008
Comparative StudyEffects of dipeptidyl peptidase iv inhibition on arterial blood pressure.
1. The aim of the present study was to determine whether inhibition of dipeptidyl peptidase IV (DPP IV) elevates arterial blood pressure and whether any such effect is dependent on genetic background, the sympathetic nervous system and Y(1) receptors. The rationale behind this study was that: (i) neuropeptide (NP) Y(1-36) and peptide YY(1-36) (PYY(1-36)) are endogenous Y(1) receptor agonists and are metabolised by DPP IV to NPY(3-36) and PYY(3-36), which are not Y(1) but rather selective Y(2) receptor agonists; (ii) Y(1) receptors mediate vasoconstriction, whereas Y(2) receptors have little effect on vascular tone; (iii) vaso-constrictor effect of the Y(1) receptor is enhanced in spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) rats; and (iv) NPY(1-36) is released from sympathetic nerve terminals. 2. ⋯ Unlike the results in genetically hypertensive animals, in normotensive WKY rats pretreated with captopril (30 mg/kg, i.v.; MABP = 81 +/- 4 mmHg; n = 6), or hydralazine (5 mg/kg, i.p.; MABP = 63 +/- 4 mmHg; n = 4) or chlorisondamine (10 mg/kg, s.c.; MABP = 63 +/- 4 mmHg; n = 5), P32/98 did not affect arterial blood pressure. 8. We conclude that, in genetically susceptible animals, inhibition of DPP IV increases arterial blood pressure via Y(1) receptors when elevated blood pressure is reduced with antihypertensive drugs provided that the sympathetic nervous system is functional. The results suggest vigilance because DPP IV inhibitors are used more widely in hypertensive patients treated with antihypertensive drugs.
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Clin. Exp. Pharmacol. Physiol. · Jan 2008
Hyperoxia confers myocardial protection in mechanically ventilated rats through the generation of free radicals and opening of mitochondrial ATP-sensitive potassium channels.
1. One hour exposure to hyperoxia has been shown previously to limit a subsequent ischaemia-reperfusion injury in spontaneously breathing rats. We tested the cardioprotective effect of a shorter period of hyperoxia during mechanical ventilation and the possible contribution of reactive oxygen species (ROS) and mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels. 2. ⋯ When rats were pretreated either with NAC before hyperoxic ventilation or with K(ATP) channel blockers before ischaemia, myocardial protection was abolished. 4. Hyperoxic mechanical ventilation, prior to ischaemia, reduces myocardial reperfusion injury. This is likely to occur through the induction of oxidative stress, which leads to myocyte mitoKATP channel opening.
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Clin. Exp. Pharmacol. Physiol. · Jan 2008
Comparative StudyOral mitemcinal (GM-611), an erythromycin-derived prokinetic, accelerates normal and experimentally delayed gastric emptying in conscious dogs.
1. We examined effects of orally administered mitemcinal, an erythromycin-derived motilin agonist, on gastric emptying and antroduodenal motility in conscious normal dogs and conscious dogs with experimentally delayed gastric emptying. For comparison, we also examined the effects of orally administered cisapride. 2. ⋯ Cisapride (3 mg/kg) restored the indices to roughly prevagotomy levels, but none of the increases was significant. Mitemcinal, at a dose of 0.25 mg/kg, also stimulated antroduodenal motility. 6. Because delayed gastric emptying is the basic characteristic of gastroparesis, the fact that mitemcinal accelerated gastric emptying in dogs with normal and delayed gastric emptying much more robustly than cisapride adds to the evidence that mitemcinal is likely to be useful for the treatment of patients with gastroparesis.
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Clin. Exp. Pharmacol. Physiol. · Nov 2007
Actions of the endocannabinoid transport inhibitor AM404 in neuropathic and inflammatory pain models.
1. Although cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central cannabinoid CB(1) receptor-mediated motor and psychotropic side-effects. The actions of endocannabinoids, such as anandamide, are terminated by uptake and subsequent intracellular enzymatic degradation. ⋯ The effect of AM404 in the PNL model was abolished by coapplication with the selective cannabinoid CB(1) receptor antagonist AM251 (1 mg/kg). AM404 did not produce a reduction in motor performance in either the PNL or CFA models. 4. These findings suggest that acute administration of AM404 reduces allodynia in a neuropathic pain model via cannabinoid CB(1) receptor activation, without causing the undesirable motor disruption associated with cannabinoid receptor agonists.
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Clin. Exp. Pharmacol. Physiol. · Nov 2007
Low coronary driving pressure is associated with subendocardial remodelling and left ventricular dysfunction in aortocaval fistula.
1. The role of haemodynamic changes in left ventricular remodelling has been poorly investigated, especially in the context of volume overload cardiac hypertrophy. Low diastolic blood pressure and high left ventricular filling pressure are expected to affect coronary driving pressure negatively and thereby put in jeopardy subendocardial perfusion in particular. ⋯ Otherwise, MPO activity and levels of tumour necrosis factor-alpha and IL-10 were similar in both groups. Final coronary driving pressure correlated with both the expression and activity of MMP-2. 4. Low coronary driving pressure early in the course of ACF determines SE damage and, by this mechanism, interferes negatively in left ventricular function.