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At least 163 records · Page 9Linked to original sources
PubMed1993

Endothelial dysfunction augments myogenic arteriolar constriction in hypertension.

To elucidate the underlying reason or reasons for the increased peripheral resistance in hypertension, we investigated the pressure-diameter relation--the myogenic response--of isolated, cannulated arterioles (approximately 50 microns) of cremaster muscle of 12-week-old Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), and normal Wistar (NW) rats. All arterioles constricted in response to step increases in perfusion pressure from 20 to 160 mm Hg. This constriction was, however, significantly enhanced from 60 to 160 mm Hg in arterioles of SHR compared with NW or WKY rats. For example, at 80 and 140 mm Hg, respectively, the normalized diameter (expressed as a percentage of the corresponding passive diameter of arterioles of SHR) was 11.8% and 27.6% (P < .05) less compared with those of WKY rats. Endothelium removal eliminated the enhanced pressure-induced tone in SHR. Similarly, indomethacin (10(-5) mol/L, sufficient to block prostaglandin synthesis) or SQ 29,548 (10(-6) mol/L), a thromboxane A2-prostaglandin H2 receptor blocker that inhibited vasoconstriction to the thromboxane agonist U46619, attenuated the enhanced pressure-diameter curve and reversed the blunted dilation to arachidonic acid in SHR. In contrast, the thromboxane A2 synthesis inhibitor CGS 13,080 (5 x 10(-6) mol/L) did not affect the increased pressure-induced tone or the reduced dilation to arachidonic acid in SHR. Thus, the present findings suggest that in early hypertension pressure-induced arteriolar constriction is increased. This seems to be due to an enhanced production of endothelium-derived constrictor factors, primarily prostaglandin H2.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Different mechanisms of endothelial dysfunction with aging and hypertension in rat aorta.

We analyzed the effects and mechanisms of aging in aortic endothelium and vascular smooth muscle of 12-week-old (adult) and 72-week-old (senescent) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Aortas were suspended in organ chambers filled with physiological salt solution (95% O2/5% CO2; 37 degrees C), and isometric tension was measured. In WKY, endothelium-dependent relaxations to acetylcholine were diminished with aging (P < .05); in SHR, they were reduced compared with WKY (P < .05) but unchanged with aging. The thromboxane/endoperoxide receptor antagonist SQ 30741 increased relaxations only in adult SHR. Relaxations to sodium nitroprusside were slightly enhanced with age in WKY and SHR (P < .05). Endothelium-dependent contractions to acetylcholine were unmasked by NG-nitro-L-arginine methyl ester (P < .05) and prevented by SQ 30741 or endothelium removal. In WKY, contractions increased with age. In adult SHR, marked endothelium-dependent contractions occurred (P < .05 versus WKY), which diminished with age (P = NS versus senescent WKY). The thromboxane analogue U46619 elicited similar contractions in adult and senescent WKY and adult SHR, whereas responses in senescent SHR were weaker (P < .05). In WKY and SHR, contractions to norepinephrine were similar and unaltered by aging. In WKY, contractions to endothelin-1 remained unaffected by aging. Adult SHR exhibited contractions to endothelin-1 comparable to those in WKY, whereas senescent SHR contracted less (P < .05). Bosentan, a combined endothelin-A/endothelin-B receptor antagonist, inhibited endothelin-1 markedly, especially in SHR (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Leukocyte-induced acute endothelial dysfunction in middle cerebral artery in rabbits. Response to aggregating platelets.

BACKGROUND AND PURPOSE: Recent evidence suggests a possible role for leukocytes in angiospastic reactions of large cerebral arteries. This study examined the effect of activation of endogenous circulating leukocytes on endothelium-dependent relaxation in the middle cerebral artery in rabbits. METHODS: Leukocytes were activated by rapid injection of either 40 micrograms/kg phorbol 12-myristate 13-acetate, or 0.2 mg/kg N-formyl-methionyl-leucylphenylalanine into the left carotid artery. Control rabbits received an equal volume of vehicle. Concentration-dependent isometric tension responses of the left and right middle cerebral artery to the dilators acetylcholine, ADP, sodium nitroprusside, or calcium ionophore (A23187), as well as to aggregating platelets, were compared in vitro in control animals and in animals killed 10 minutes after the injection of leukocyte activators in normal and leukocyte-depleted rabbits. RESULTS: In the control animals there was no significant difference in the reactivity of the left and right middle cerebral arteries. The injection of the leukocyte activators led to enhanced contractile responses to aggregating platelets and a significant reduction in the endothelium-dependent relaxation in response to acetylcholine, ADP, and A23187 in the left middle cerebral artery (the injected side), whereas the effect of an endothelium-independent dilator sodium nitroprusside remained unchanged. In leukocyte-depleted rabbits the injection of either of the leukocyte activators used did not induce significant changes in the reactivity of the left middle cerebral artery. CONCLUSIONS: Intravascular leukocyte activation appears to induce an acute disturbance of the endothelium-dependent relaxation. Under these conditions, platelet activation might result in marked angiospastic reactions of large cerebral arteries.

Animals↗
PubMed1991

Low-dose felodipine treatment attenuates endothelial dysfunction in rabbits fed an atherogenic diet.

Loss of endothelium-dependent relaxation is an early step in atherogenesis. To test the effect of low-dose felodipine on the progression of this dysfunction, male New Zealand white rabbits were rendered hypercholesterolemic with a diet containing 0.25% cholesterol and 3% coconut oil. After a 1-month induction period on this diet, during which the rabbits were identified as low or normal responders to cholesterol, 0.46 mg/kg of felodipine (FELO) or placebo (CON) were given by gavage once daily for a further 3 months. This regimen established FELO plasma levels (14.2 +/- 1.3 nM, week 9) corresponding to therapeutic concentrations in humans and an average 13-fold increase in plasma cholesterol from below 1 mM. At the end of the treatment period, relaxation of norepinephrine (1 x 10(-8) M)-precontracted proximal thoracic aorta strips to acetylcholine (ACh: 1 x 10(-8)-1 x 10(-5) M) was determined. Cholesterol exposure was calculated as the area under the curve for serum cholesterol x time [AUC (mM x day 1)]. Despite equal cholesterol load [FELO (n = 17): 1,856 +/- 182 mM x day) and CON (n = 22): 1,851 +/- 167 mM x day], maximal relaxation to 1 x 10(-7) M ACh was well preserved in strips from FELO-treated rabbits (29.5 +/- 5.7%) but suppressed in strips from untreated rabbits (11.0 +/- 2.9%). For comparison, relaxation in strips from standard diet controls was 49.8 +/- 2.9% (n = 15). Moreover, there was a significant inverse correlation (r = -0.74) between percentage ACh relaxation and cholesterol exposure in FELO-treated rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

Comparison of the antiatherogenic effects of isradipine and ramipril in cholesterol-fed rabbits: I. Effect on progression of atherosclerosis and endothelial dysfunction.

This study was designed to compare the effects of a calcium antagonist (isradipine) and a converting enzyme inhibitor (ramipril) on progression and regression of atherosclerosis in hypercholesterolemic rabbits. Sixty rabbits in three groups were fed a 0.3% cholesterol diet for 4 weeks. After this induction period, group II received the 0.3% cholesterol diet, group III received cholesterol diet with isradipine (0.33 mg/kg/day), and group IV received cholesterol with ramipril (0.33 mg/kg/day) for 12 more weeks. A group of 20 rabbits received a standard diet throughout the study (group I). After 16 weeks, 10 rabbits were randomly chosen from each group and used in the progression study. The other rabbits were placed on a standard diet and remained on their respective drug regimen for 12 more weeks. In the progression phase of the study, ramipril significantly attenuated the percentage of aortic lesions in group IV (35 +/- 6%) as compared with group II (56 +/- 6%, p < 0.05), whereas isradipine had no effect. Acetylcholine (ACh)-induced maximum endothelium-dependent relaxations (EDR) of aortic rings were significantly reduced by the atherogenic diet to 37 +/- 4 versus 77 +/- 2% in group I (p < 0.05). Treatment with ramipril significantly improved maximum EDR to 53 +/- 3% (p < 0.05 vs. group II). Isradipine had no significant effect on impaired EDR. Aortic rings with endothelium from group II developed supersensitivity to sodium nitroprusside (SNP) and had significantly reduced basal cyclic GMP levels as compared with those of group I. Both drugs prevented development of supersensitivity to SNP and blunted the cholesterol-induced reduction in basal cyclic GMP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effect of superoxide dismutase on hemorrhagic hypotension and retransfusion-evoked middle cerebral artery endothelial dysfunction.

UNLABELLED: Middle cerebral artery rings (MCA) were prepared from control and hemorrhagic hypotension and retransfusion-subjected (HHR) cats, with or without superoxide dismutase (SOD) treatment. Two-mm-long MCA segments were suspended in organ chambers containing Krebs-Henseleit solution (37 degrees C, gassed with 95% O2-5% CO2) for isometric force measurements. HHR was produced by bleeding to 90, 70, and 50 mmHg MAP and maintained for 15 min at each level, followed by retransfusion. HHR resulted in a marked attenuation of the acetylcholine- and ATP-induced endothelium-dependent relaxations of the MCA in vitro. Relaxations induced by the nitric oxide (NO) donor SIN-1 remained unaltered. In vitro treatment of the vessels with SOD (150 U/ml), facilitated the acetylcholine-induced relaxations both in the control arteries and in the vessels after HHR. In the vessel rings from cats that received in vivo SOD (10 mg/kg initial bolus, followed by 0.1-mg/kg/min infusion) during HHR, cholinergic relaxations were more pronounced than in the HHR untreated cats. The ATP-induced relaxations, however, remained attenuated after SOD treatment, except for the highest dose (10(-5) M) that was applied. CONCLUSION: Superoxide release attenuates the endothelium-dependent relaxation by acetylcholine both in control arteries and after HHR in vitro. The protective effect of in vivo SOD treatment on cerebrovascular endothelium-dependent reactivity in cats suggests that superoxide free radicals contribute to the development of the endothelium dysfunction in MCA rings after HHR.

Acetylcholine↗