Objective-To investigate the effects of activation of the AMP-activated protein kinase (AMPK) on muscle perfusion and to elucidate the mechanisms involved. Methods and Results-In a combined approach, we studied the vasoactive actions of AMPK activator by 5-aminoimidazole-4-carboxamide-1--D-ribofuranoside (AICAR) on rat cremaster muscle resistance arteries (Ϸ100 m) ex vivo and on microvascular perfusion in the rat hindlimb in vivo. In isolated resistance arteries, AICAR increased Thr172 phosphorylation of AMPK in arteriolar endothelium, which was predominantly located in microvascular endothelium. AICAR induced vasodilation (19Ϯ4% at 2 mmol/L, PϽ0.01), which was abolished by endothelium removal, inhibition of NO synthase (with N-nitro-L-arginine), or AMPK (with compound C). Smooth muscle sensitivity to NO, determined by studying the effects of the NO donor S-nitroso-N-acetylpenicillamine (SNAP), was not affected by AICAR except at the highest dose. AICAR increased endothelial nitric oxide synthase activity, as indicated by Ser1177 phosphorylation. In vivo, infusion of AICAR markedly increased muscle microvascular blood volume (Ϸ60%, PϽ0.05), as was evidenced by contrast-enhanced ultrasound, without effects on blood pressure, femoral blood flow, or hind leg glucose uptake. Conclusion-Activation
Renal ischemia-reperfusion (I/R) results in vascular dysfunction characterized by a reduced endothelium-dependent vasodilatation and subsequently impaired blood flow. In this study, we investigated the role of Rho kinase in endothelial nitric oxide synthase (eNOS)-mediated regulation of renal blood flow and vasomotor tone in renal I/R. Male Wistar rats were subjected to 60-min bilateral clamping of the renal arteries or sham procedure. One hour before the clamping, the Rho kinase inhibitor Y27632 (1 mg/kg) was intravenously infused. After I/R, renal blood flow was measured using fluorescent microspheres. I/R resulted in a 62% decrease in renal blood flow. In contrast, the blood flow decrease in the group treated with the Rho kinase inhibitor (YI/R) was prevented. Endothelium-dependent vasodilatation of renal arcuate arteries to ACh was measured ex vivo in a pressure myograph. These experiments demonstrated that the in vivo treatment with the Rho kinase inhibitor prevented the decrease in the nitric oxide (NO)-mediated vasodilator response. In addition, after I/R renal interlobar arteries showed a decrease in phosphorylated eNOS and vasodilator-stimulated phosphoprotein, a marker for bioactive NO, which was attenuated by in vivo Rho kinase inhibition. These findings indicate that in vivo inhibition of Rho kinase in renal I/R preserves renal blood flow by improving eNOS function.
van Rodijnen WF, Korstjens IJ, Legerstee N, ter Wee PM, Tangelder GJ. Direct vasoconstrictor effect of prostaglandin E 2 on renal interlobular arteries: role of the EP3 receptor. Am J Physiol Renal Physiol 292: F1094 -F1101, 2007. First published December 5, 2006; doi:10.1152/ajprenal.00351.2005.-Evidence indicates that prostaglandin E2 (PGE2) preferentially affects preglomerular renal vessels. However, whether this is limited to small-caliber arterioles or whether larger vessels farther upstream also respond to PGE2 is currently unclear. In the present study, we first investigated the effects of PGE 2 along the preglomerular vascular tree and subsequently focused on proximal interlobular arteries (ILAs). Proximal ILAs in hydronephrotic rat kidneys as well as isolated vessels from normal kidneys constricted in response to PGE2, both under basal conditions and after the induction of vascular tone. By contrast, smaller vessels, i.e., distal ILAs and afferent arterioles, exhibited PGE2-induced vasodilation. Endothelium removal and pretreatment of single, isolated proximal ILAs with an EP1 receptor blocker (SC51322, 1 mol/l) or a thromboxane A2 receptor blocker (SQ29548, 1 mol/l) did not prevent vasoconstriction to PGE2. Furthermore, in the presence of SC51322, responses of these vessels to PGE2 and the EP1/EP3 agonist sulprostone were superimposable, indicating that PGE2-induced vasoconstriction is mediated by EP3 receptors on smooth muscle cells. Immunohistochemical staining of proximal ILAs confirmed the presence of EP3 receptor protein on these cells and the endothelium. Adding PGE2 to normal isolated kidneys induced a biphasic flow response, i.e., an initial flow increase at PGE2 concentrations Յ0.1 mol/l followed by a flow decrease at 1 mol/l PGE2. Thus our results demonstrate that PGE2 affects multiple segments of the preglomerular vascular tree in a different way. At the level of the proximal ILAs, PGE2 had a direct vasoconstrictor action mediated by EP3 receptors. interlobular arteries; vasoconstriction PGE 2 IS ONE OF the major cyclooxygenase-derived products produced by the kidney (17). The actions of PGE 2 intrarenally include both tubular and vascular effects (2). The latter are important for regulating renal function under various circumstances. So far, the effects of PGE 2 on smaller pre-and postglomerular arterioles have mainly received attention. The postglomerular efferent arterioles were found to be insensitive to PGE 2 (4, 23), while for the preglomerular afferent arterioles (AAs) and distal interlobular arteries (ILAs) most studies indicated vasodilation (4,8,23), although vasoconstriction in certain instances has been reported as well (9, 23). Whether larger vessels further upstream of the glomerulus are also sensitive to PGE 2 is currently unknown. Previous studies have demonstrated that larger preglomerular vessels constrict in response to inflammatory mediators, such as serotonin and leukotrienes (5, 19), suggesting a similar mode of action for PGE 2 .In general, the actions of PGE 2 are m...
In this study alterations are characterized which occur, in myocardial force development morphological appearance and protein composition, during the development of cardiac hypertrophy and heart failure in monocrotaline (MCT) treated rats. The transition from cardiac hypertrophy to heart failure was studied by comparing the results from control (CON) and two MCT groups (40 and 44 mg/kg body weight). The three experimental groups consisted of at least five animals each. Parameters studied were: body weight (measured daily), lung/body weight ratio, right ventricular wall volume and thickness, and force development in thin right ventricular trabeculae at 27 degrees C, using different extracellular calcium concentrations and pacing frequencies. MCT injection resulted in marked right ventricular hypertrophy and heart failure as evidenced by an up to 2-fold increase in lung/body weight ratio and a 1.7-fold increase in wall volume. The MCT groups showed a negative force-frequency relation and maximum force was up to 2-fold less than in the CON group. Protein analysis by means of one- and two-dimensional gel electrophoresis revealed a marked (7-fold) up-regulation of the slow myosin heavy chain isoform as well as a 4.5-fold increase in the content of the cytoskeletal protein desmin, whereas the mitochondrial protein ATP-synthase content was reduced. Hence MCT-induced cardiac hypertrophy and heart failure result in altered cellular calcium handling, depression of maximum force output, an increase in the economy of myocardial contraction and changes in cytoskeletal structure and energy supply.
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