Angiotensin II Type 1 receptor blockade protects endothelium-derived hyperpolarising factor-mediated relaxation in a rat model of monoarthritis.

AIMS: Rheumatoid arthritis (RA) is associated with high cardiovascular mortality. Impaired endothelial cell (EC) function and elevated angiotensin II levels may be central to the link between vascular dysfunction and RA. Here we investigated the action of angiotensin type 1 receptor (AT1R) blockade on endothelium-dependent relaxation of the isolated saphenous artery in a rat model of monoarthritis. MAIN METHODS: Adjuvant arthritis was induced in rats with and without prophylactic losartan (AT1R antagonist) treatment. Vehicle-treated rats were used as controls. Wire myography was employed to investigate EC function of isolated rings of saphenous artery. KEY FINDINGS: EC-dependent relaxation in arteries from non-inflamed control rats was mediated by both nitric oxide (NO) and endothelium-derived hyperpolarising factor (EDHF) with the EDHF response dependent principally on functional myoendothelial gap junctions. While NO-dependent relaxation remained unaffected, the EDHF-mediated response was abolished in arteries from arthritic rats (P<0.001), however, substantial protection (approximately 50%) of the EDHF-relaxation was found in arthritic rats treated with losartan (P<0.01). Thus, the attenuated EDHF response found in the saphenous artery of arthritic rats was significantly reversed by AT1R blockade. SIGNIFICANCE: These results suggest a key role for the angiotensin system in the EC dysfunction found in chronic joint inflammation and highlights AT1R as a potential therapeutic target to redress the vascular impairment and mortality associated with RA.

Pharmacodynamic study on acute hypotensive activities of Carissa carandas extract in normal rats.

This study aims to evaluate the effect of Carissa carandas extract on cardiovascular function of normal rats. Intravenous bolus injection of this extract in the doses of 5 mg kg(-1)_-45 mg kg(-1), produced dose dependent reduction in arterial blood pressure (p<0.001). The 45mg/kg dose caused a 50.75% ± 2.71 decrease in MABP which was highly significant with P value < 0.0005 when compared with its controls. Significant reduction in heart rate frequency was observed after CC injection at a dose of 45 mg kg-1 (p<0.001). The results were comparable with Acetylcholine 10(-4) M. The receptor activity performed for which Atropine 10(-4)M was administered I.V. and then the extract (45mg/kg) was administered. A highly Non Significant fall in Mean Arterial Blood pressure was observed 1.51% ± 0.22 (P>0.05). It was concluded that the Carissa carandas Ethanol extract possess potent acute hypotensive effect in normal rats. It stimulates the muscarinic receptors located on the endothelial cells of the vasculature. This stimulation results in the release of endothelial-derived relaxing factors (EDRFs) or nitric oxide that diffuses to vasculature smooth muscles and causes their relaxation.

Dietary probucol preserves endothelium-dependent relaxation of arteriovenous fistula in hypercholesterolemic rabbits.

BACKGROUND: Shear stress caused by arteriovenous fistula (AVF) enhances endothelium-dependent relaxation (EDR) but oxidized low-density lipoprotein (ox- LDL) counteracts its effect. Probucol, a lipid soluble antioxidant, may preserve EDR of AVF by limiting oxidation of LDL. METHODS: Twenty New Zealand rabbits, fed with 2% cholesterol chow for 4 weeks, underwent AVF. They were then divided into two groups: continuing with 2% cholesterol chow alone (group I) and 2% cholesterol chow with 1% probucol supplement (group II). Another 10, fed regular chow, were assigned to the control (group III). The levels of cholesterol and LDL were measured. Segments of the AVF afferent arteries were harvested to check intimal thickness, and endothelium-dependent and independent relaxations, after 4 weeks dietary treatment had been completed. RESULTS: Both cholesterol and LDL levels were significantly elevated after 4 weeks of cholesterol feeding. These profiles reached higher levels at 8 weeks in group I and were less increased in group II. The intimal hyperplasia ratio was 48% in group I, 34% in group II and 24% in group III. Maximal EDR response to either acetylcholine or receptor-independent calcium ionophore A23187 in group II was greater than that in group I (66 +/- 1.9% versus 38 +/- 1.2%, p = 0.02; 76 +/- 2.4% versus 30 +/- 0.8%, p = 0.01) and not different from that in group III (74 +/- 2.4%, 84 +/- 3.7%). There was no similar difference of denuded arterial rings among the three groups (76 +/- 3.2%, 78 +/- 3.7%, 82 +/- 4.1%). CONCLUSION: Cholesterol can limit EDR of AVF and produce vulnerability to early occlusion and thrombosis. Probucol supplement under hyperlipidemia status preserves EDR and not endothelium-independent relaxation.