sq-29548 and Body-Weight

Obese individuals exhibit impaired functional vasodilation and exercise performance. We have demonstrated in obese Zucker rats (OZ), a model of morbid obesity, that insulin resistance impairs functional vasodilation via an increased thromboxane receptor (TP)-mediated vasoconstriction. Chronic treadmill exercise training improves functional vasodilation in the spinotrapezius muscle of the OZ, but the mechanisms responsible for the improvement in functional vasodilation are not clear. Based on evidence that exercise training improves insulin resistance, we hypothesized that, in the OZ, exercise training increases functional vasodilation and exercise capability due to decreases TP-mediated vasoconstriction associated with improved insulin sensitivity. Six-week-old lean Zucker rats (LZ) and OZ were exercised on a treadmill (24 m/min, 30 min/day, 5 days/wk) for 6 wk. An oral glucose tolerance test was performed at the end of the training period. We measured functional vasodilation in both exercise trained (spinotrapezius) and nonexercise trained (cremaster) muscles to determine whether the improved functional vasodilation following exercise training in OZ is due to a systemic improved insulin resistance. Compared with LZ, the sedentary OZ exhibited impairments in glucose tolerance and functional vasodilation in both muscles. The TP antagonist SQ-29548 improved the vasodilator responses in the sedentary OZ with no effect in the LZ. Exercising training of the LZ increased the functional vasodilation in spinotrapezius muscle, with no effect in the cremaster muscle. Exercising training of the OZ improved glucose tolerance, along with increased functional vasodilation, in both the spinotrapezius and cremaster muscles. SQ-29548 treatment had no effect on the vasodilator responses in either cremaster or spinotrapezius muscles of the exercise-trained OZ. These results suggest that, in the OZ, there is a global effect of exercising training to improve insulin resistance and increase functional vasodilation via a decreased TP-mediated vasoconstriction.

Topics: Analysis of Variance; Animals; Arachidonic Acid; Blood Glucose; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Eating; Electric Stimulation; Exercise Therapy; Fatty Acids, Unsaturated; Glucose Tolerance Test; Hydrazines; Insulin Resistance; Male; Muscle, Skeletal; Obesity, Morbid; Oxygen Consumption; Rats; Rats, Zucker; Receptors, Thromboxane; Recovery of Function; Time Factors; Vasoconstriction; Vasodilation

We previously showed that testosterone, administered in vivo, increases the tone of cerebral arteries. A possible underlying mechanism is increased vasoconstriction through the thromboxane A2 (TxA2) pathway. Therefore, we investigated the effect of chronic testosterone treatment (4 wk) on TxA2 synthase levels and the contribution of TxA2 to vascular tone in rat middle cerebral arteries (MCAs). Using immunofluorescence and confocal microscopy, we demonstrated that TxA2 synthase is present in MCA segments in both smooth muscle and endothelial layers. Using Western blot analysis, we found that TxA2 synthase protein levels are higher in cerebral vessel homogenates from testosterone-treated orchiectomized (ORX + T) rats compared with orchiectomized (ORX) control animals. Functional consequences of changes in cerebrovascular TxA2 synthase were determined using cannulated, pressurized MCA segments in vitro. Constrictor responses to the TxA2 mimetic U-46619 were not different between the ORX + T and ORX groups. However, dilator responses to either the selective TxA2 synthase inhibitor furegrelate or the TxA2-endoperoxide receptor (TP) antagonist SQ-29548 were greater in the ORX + T compared with ORX group. In endothelium-denuded arteries, the dilation to furegrelate was attenuated in both the ORX and ORX + T groups, and the difference between the groups was abolished. These data suggest that chronic testosterone treatment enhances TxA2-mediated tone in rat cerebral arteries by increasing endothelial TxA2 synthesis without altering the TP receptors mediating constriction. The effect of in vivo testosterone on cerebrovascular TxA2 synthase, observed here after chronic hormone administration, may contribute to the risk of vasospasm and thrombosis related to cerebrovascular disease.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Androgens; Animals; Benzofurans; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Enzyme Inhibitors; Fatty Acids, Unsaturated; Hydrazines; Male; Middle Cerebral Artery; Orchiectomy; Rats; Rats, Inbred F344; Receptors, Thromboxane; Testosterone; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Differences in the acetylcholine (ACh)-induced endothelium-dependent relaxation and hyperpolarization of the mesenteric arteries of Wistar Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) were studied. Relaxation was impaired in preparations from SHRSP and tendency to reverse the relaxation was observed at high concentrations of ACh in these preparations. Relaxation was partly blocked by NG-nitro-L-arginine (L-NOARG, 100 microM) and, in the presence of L-NOARG, tendency to reverse the relaxation was observed in response to higher concentrations of ACh, even in preparations from WKY. The relaxation remaining in the presence of L-NOARG was also smaller in preparations from SHRSP. The tendency to reverse the relaxation observed at higher concentrations of ACh in preparations from SHRSP or WKY in the presence of L-NOARG were abolished by indomethacin (10 microM). Elevating the K+ concentration of the incubation medium decreased relaxation in the presence of both indomethacin and L-NOARG. Relaxation in the presence of L-NOARG and indomethacin was reduced by the application of both apamin (5 microM) and charybdotoxin (0.1 microM). This suggests that the relaxation induced by ACh is brought about by both endothelium-derived relaxing factor (EDRF, nitric oxide (NO)) and hyperpolarizing factor (EDHF), which activates Ca2+-sensitive K+ channels. Electrophysiological measurement revealed that ACh induced endothelium-dependent hyperpolarization of the smooth muscle of both preparations in the presence of L-NOARG and indomethacin; the hyperpolarization being smaller in the preparation from SHRSP than that from WKY. These results suggest that the release of both NO and EDHF is reduced in preparations from SHRSP. In addition, indomethacin-sensitive endothelium-derived contracting factor (EDCF) is released from both preparations; the release being increased in preparations from SHRSP.

Topics: Acetylcholine; Animals; Apamin; Blood Pressure; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Charybdotoxin; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; Fatty Acids, Unsaturated; Glyburide; Hydrazines; Hypertension; In Vitro Techniques; Indomethacin; Membrane Potentials; Mesenteric Arteries; Methylene Blue; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide; Nitroarginine; Nitroprusside; Potassium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Systole; Tetraethylammonium; Vasodilation; Vasodilator Agents

We performed micropuncture studies to determine the role of thromboxane A2 in the exaggerated tubuloglomerular feedback (TGF) activity in young spontaneously hypertensive rats (SHR). Glomerular function was assessed by changes in proximal tubular stop-flow pressure (SFP) produced by different rates of orthograde perfusion through Henle's loop. Seven-week-old SHR exhibited an exaggerated TGF activity compared with Wistar-Kyoto rats (WKY) during euvolemia, confirming earlier studies. During control periods, the feedback-induced maximal SFP response (DeltaSFP) was greater in SHR (18-19 vs. 12-13 mmHg in WKY), whereas basal SFP and proximal tubular free-flow pressure were similar in both strains. In one series, the thromboxane A2 agonist U-46619 was added to the tubular perfusate for a final concentration of 10(-6) M. In WKY, DeltaSFP was increased by 100% to 26 mmHg. In contrast, DeltaSFP in young SHR was unaffected by the thromboxane A2 agonist. In other animals, the thromboxane synthase inhibitor pirmagrel (50 mg/kg) was injected intravenously to inhibit thromboxane production. In SHR, pirmagrel decreased DeltaSFP by 8.5 mmHg and reduced reactivity. Less attenuation was observed in WKY; DeltaSFP was reduced by 3 mmHg, whereas reactivity was unchanged. In other studies, tubular perfusion with the thromboxane receptor inhibitor SQ-29548 (10(-6) M) reduced DeltaSFP more in SHR (7 vs. 3 mmHg in WKY) and also decreased reactivity more in SHR (2.3 vs. 0.5 mmHg. nl-1. min-1). Coperfusion of SQ-29548 and U-46619 resulted in an 85% block of the effect of U-46619 on DeltaSFP. Tubular perfusion with the agonist U-46619 during thromboxane synthase inhibition markedly enhanced DeltaSFP in both strains, with a greater effect in WKY. These results suggest that elevated levels of thromboxane A2 in young SHR contribute to the exaggerated TGF control of glomerular function in SHR during the developmental phase of hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Age Factors; Animals; Blood Pressure; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Capillaries; Enzyme Inhibitors; Fatty Acids, Unsaturated; Feedback; Hematocrit; Hydrazines; Imidazoles; Juxtaglomerular Apparatus; Kidney Tubules, Proximal; Loop of Henle; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Thromboxane A2; Vasoconstrictor Agents