Dietary structured lipids and phytosteryl esters: blood lipids and cardiovascular status in spontaneously hypertensive rats.

This study examined the dietary effects of enzymatically modified sesame oil with caprylic acid (structured lipids, SL) and phytosteryl esters (PE) on blood lipid profiles and cardiovascular parameters of spontaneously hypertensive rats (SHR) fed high-fat and high-cholesterol (HFHC) diets. The dietary groups were: normal diet (control), sesame oil (SO), SL, SO fortified with PE (SOP), and SL fortified with PE (SLP). After 9 weeks of feeding, the body weights, liver weights, and liver weight/body weight ratios in all HFHC-fed groups were higher than controls. Plasma total and LDL cholesterol levels in all HFHC-fed groups were similar to one another but higher than those in controls. Plasma HDL cholesterol levels in rats fed SOP and SLP were higher than those in controls or rats fed SO and SL. Plasma HDL/total cholesterol ratios in rats fed SOP and SLP were similar to those in controls and were higher than those in rats fed SO and SL. There was no difference in plasma lipid profiles between rats fed SO and SL. Arterial blood pressures (BP) in conscious HFHC-fed rats were similar to those in controls whereas heart rates (HR) in all HFHC-fed groups were similar to one another but were higher than that in controls. These findings demonstrate that (1) the dietary effects of SL on plasma lipid profiles and resting BP and HR are similar to those of SO, (2) PE had positive effects on plasma lipid profiles, and (3) 9-week intake of SL and PE did not have pronounced effects on resting BP but induced tachycardia in SHR.

Flavin adenine dinucleotide may release preformed stores of nitrosyl factors from the vascular endothelium of conscious rats.

This study determined whether flavin adenine dinucleotide (FAD) may elicit vasodilation in conscious rats via release of preformed endothelium-derived nitrosyl factors. Injections 1-6 (inj(1-6)) of FAD (2.5 micromol/kg, IV) elicited pronounced and equivalent vasodilator responses in saline-treated rats. Inj(1) of FAD elicited pronounced vasodilation in L-NAME-treated rats pretreated with the nitric oxide (NO) synthesis inhibitor, NG-nitro-L-arginine (L-NAME; 50 micromol/kg, IV), whereas Inj(2-6) elicited progressively smaller responses such that inj(6) elicited minor responses. The vasodilator responses elicited by the endothelium-dependent agonist, acetylcholine, were markedly attenuated in L-NAME-treated rats that had received inj(1-6) of FAD but not in saline-treated rats that had received inj(1-6) of FAD. The vasodilator actions of L-S-nitrosocysteine and the NO donor, sodium nitroprusside, were not diminished after the injections of FAD in saline- or in L-NAME-treated rats. Binding studies demonstrated that the densities of muscarinic M3 receptors were increased in thoracic aorta endothelium of rats treated with L-NAME + inj(1-6) of saline or L-NAME + inj(1-6) of FAD as compared to rats treated with saline + inj(1-6) of saline or saline + inj(1-6) of FAD. The progressive loss of response to injections of FAD in L-NAME-treated rats coupled with the loss of response to acetylcholine suggests that FAD elicits the use-dependent depletion of vesicular pools of nitrosyl factors in endothelial cells that cannot be replenished in the absence of NO synthesis.

Dietary effects of structured lipids and phytosteryl esters on cardiovascular function in spontaneously hypertensive rats.

This study examined the dietary effects of sesame oil (SO)-based structured lipids (SL) and phytosteryl esters (PE) on cardiovascular function in conscious spontaneously hypertensive rats (SHR) fed high-fat (HF) diets (20% w/w fat). The dietary groups were as follows: normal diet (4.5% w/w fat), SO, SO fortified with PE (SOP), SL, and SL fortified with PE (SLP). Mean arterial blood pressures were similar in all groups, whereas resting heart rates (HR) were higher in all HF-fed groups. The pressor responses to the alpha1-adrenoceptor agonist, phenylephrine (5 microg/kg), were similar in all groups. However, the pressor responses to phenylephrine (10 microg/kg) were diminished in SO- or SL-fed SHR, whereas they were not diminished in SOP- or SLP-fed SHR. The depressor responses elicited by the nitric oxide (NO) donor, sodium nitroprusside (5 and 10 microg/kg), were not diminished in HF-fed rats. Baroreflex-mediated changes in HR were variously decreased in the HF-fed groups, and this decrease tended to be greater in SOP and SLP than in SO and SL groups. The depressor and tachycardic responses elicited by the beta-adrenoceptor agonist, isoproterenol, were equivalent in all groups. The depressor responses elicited by the endothelium-dependent agonist, acetylcholine (0.1 microg/kg), and the hypertension elicited by the NO synthesis inhibitor, NG-nitro-L-arginine methylester (25 micromol/kg), were similar in all groups. These findings demonstrate that (1) HF diets increase resting HR and impair baroreflex function in SHR, whereas they do not obviously affect endothelium-dependent vasodilation, and (2) fortification with PE may be deleterious to cardiovascular function (eg, baroreflex activity) in SHR.

Hemodynamic responses elicited by systemic injections of flavin adenine dinucleotide in anesthetized rats.

Flavin adenine dinucleotide (FAD) elicits an endothelium-dependent vasodilation in isolated rat mesenteric beds via activation of P2Y-purinoceptors. The aims of this study were to characterize the hemodynamic responses elicited by systemic injections of FAD and flavin mononucleotide (FMN) in anesthetized rats and to determine the role of nitric oxide synthase (NOS), cyclooxygenase, P2Y/P2X-purinoceptors, and muscarinic receptor in these responses. FAD (0.05-1.0 micromol/kg, iv) elicited dose-dependent decreases in heart rate (HR), mean arterial blood pressure (MAP), and hindquarter vascular resistance (HQR), whereas it elicited an initial increase and then a decrease in mesenteric (MR) vascular resistance. The FAD-induced responses were not affected by the P2Y/P2X-purinoceptor antagonist suramin, the muscarinic receptor antagonist methyl-atropine, or the cyclooxygenase inhibitor indomethacin. The vasodilator actions of FAD were unaffected by the NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME), whereas the bradycardia elicited by higher doses of FAD were diminished by L-NAME. FMN did not elicit hemodynamic responses in the absence or presence of L-NAME. In summary, FAD-induced bradycardia depends, in part, on the activation of NOS, whereas the vasodilator actions of FAD are not obviously due to newly synthesized nitrosyl factors. These findings and those in our companion manuscript support the concepts that the adenine moiety confers biological activity to FAD, which releases preformed pools of nitrosyl factors.

Differential effects of peroxynitrite on the function of arginine vasopressin V(1a) receptors and alpha(1)-adrenoceptors in vivo.

OBJECTIVE: The aim of this study was to provide evidence that peroxynitrite may differentially affect the function of arginine vasopressin (AVP) V(1a) receptors and alpha(1)-adrenoceptors in vascular smooth muscle of the rat METHODS: The vasoconstrictor responses elicited by AVP, or the alpha(1)-adrenoceptor agonist, phenylephrine, were determined in anesthetized rats before and after injections of (i) peroxynitrite, the thiol chelator, para-hydroxymercurobenzoic acid (PHMBA), or the electron acceptor, nitroblue tetrazolium (NBT). The ability of the reducing agent, glutathione, to reverse the loss of response to phenylephrine and AVP in peroxynitrite-treated rats was also examined. RESULTS: The AVP-induced responses were suppressed 10-20 min but not 60-70 min after the administration of peroxynitrite. Glutathione reversed the above loss of response to AVP at 10-20 min. The responses elicited by phenylephrine were suppressed 10-20 min and 60-70 min after administration of peroxynitrite. Glutathione did not reverse the above losses of response to phenylephrine. In addition, the vasoconstrictor actions of AVP and phenylephrine were markedly suppressed after administration of PHMBA or nitroblue tetrazolium. CONCLUSIONS: The above findings provide evidence that exogenously administered peroxynitrite may differentially affect the function of AVP V(1a) receptors and alpha(1)-adrenoceptors in vascular smooth muscle of the rat. The possibility that peroxynitrite impairs AVP V(1a) receptor function by transient oxidation events whereas peroxynitrite impairs alpha(1)-adrenoceptor function by transient oxidation and permanent nitration events will be discussed.

Differential effects of ouabain on the vasodilator actions of nitric oxide and S-nitrosothiols in vivo: relevance to the identity of EDRF/EDHF.

OBJECTIVES: This study examined the role of Na+/K+-ATPase in the vasodilator actions of nitric oxide (NO), S-nitrosothiols and the endothelium-dependent agonist, acetylcholine. METHODS: The vasodilator responses elicited by intravenous injections of (i) the NO-donors, sodium nitroprusside and MAHMA NONOate, (ii) the S-nitrosothiols, L-S-nitrosocysteine and S-nitrosocoenzyme A, and (iii) acetylcholine, in urethane-anesthetized rats. RESULTS: The NO-donors, S-nitrosothiols and acetylcholine elicited dose-dependent depressor responses and reductions in hindquarter (HQR) and mesenteric (MR) vascular resistances. The depressor responses and associated reductions in HQR elicited by NO-donors were markedly attenuated after injection of ouabain. In contrast, the depressor responses and reductions in HQR elicited by the S-nitrosothiols and acetylcholine were not affected. The reductions in MR elicited by all vasodilator agents were exaggerated after injection of ouabain. Finally, the decomposition of sodium nitroprusside, MAHMA NONOate, L-S-nitrosocysteine and S-nitrosocoenzyme A to NO upon addition to rat blood or vascular preparations was not affected by ouabain. CONCLUSION: This study demonstrates that ouabain has opposing effects on NO-mediated vasodilation in resistance arteries in the hindquarter and mesenteric beds of the rat. The similarity of effects of ouabain on the vasodilator actions of acetylcholine, L-S-nitrosocysteine and S-nitrosocoenzyme A as opposed to the NO-donors supports the possibility that endothelium-derived relaxing factor released by acetylcholine in resistance arteries is an S-nitrosothiol.

ACE inhibition restores the vasodilator potency of the endothelium-derived relaxing factor, L-S-nitrosocysteine, in conscious Spontaneously Hypertensive rats.

OBJECTIVE: The major aim of this study was to determine whether the angiotensin converting enzyme (ACE) inhibitors, captopril or enalapril, restore the diminished vasodilator potency of the endothelium-dependent agonist, acetylcholine (ACh), and the endothelium-derived relaxing factor (EDRF), L-S-nitrosocysteine (L-SNC), in conscious Spontaneously Hypertensive (SH) rats. METHODS: The hemodynamic responses elicited by i.v. injections of ACh, L-SNC, and nitric oxide donors such as MAHMA NONOate, were determined in SH rats treated for 7 days with captopril, enalapril, or the direct vasodilator hydralazine. The effects of captopril, enalapril or hydralazine on oxidant stress levels in blood serum and aorta of WKY and SH rats were also determined. RESULTS: Captopril, enalapril and hydralazine elicited equivalent falls in mean arterial pressure and systemic vascular resistances in SH rats. ACh- and L-SNC-induced vasodilation were increased in captopril- or enalapril-treated SH rats such that the responses were equal to those in normotensive Wistar Kyoto rats. The attenuated responses of ACh and L-SNC in SH rats were not improved by hydralazine. The vasodilator effects of MAHMA NONOate, which were substantially augmented in SH rats, were not affected by captopril, enalapril or hydralazine. The levels of oxidant stress were markedly reduced in captopril- or enalapril-treated but not hydralazine-treated SH rats. CONCLUSIONS: The finding that the ACE inhibitors improved the vasodilator potencies of L-SNC and the EDRF released by ACh in SH rats, suggests that the diminished vasodilator potency of these compounds was due to augmented ACE activity, which increased oxidant stress levels. This study provides the first evidence to support the concept that ACE inhibition lowers arterial pressure in SH rats, at least in part, by restoring the vasodilator potency of endothelium-derived L-SNC.

The vasodilator potency of the endothelium-derived relaxing factor, L-S-nitrosocysteine, is impaired in conscious spontaneously hypertensive rats.

OBJECTIVE: This study compared the hemodynamic responses elicited by the endothelium-derived relaxing factor (EDRF), L-S-nitrosocysteine (L-SNC), the non-prostanoid EDRF released by acetylcholine (ACh) and nitric oxide (NO)-donors such as MAHMA NONOate, in conscious spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats. METHODS: The depressor and/or vasodilator responses elicited by intravenous injections of ACh, L-SNC and MAHMA NONOate were determined in adult WKY and SH rats before and after intravenous injection of the NO synthesis inhibitor, N(G)-nitro-L-arginine methylester (L-NAME), or the cyclooxygenase inhibitor, indomethacin. RESULTS: The responses elicited by ACh and L-SNC were smaller in SH than in WKY rats whereas the responses elicited by MAHMA NONOate were augmented in SH rats. The ACh-induced responses were not diminished after injection of L-NAME in WKY or SH rats. Indomethacin did not affect the responses to any of the vasodilator agents in WKY or SH rats. Addition of L-SNC to whole blood or thoracic aortae from SH rats yielded similar amounts of NO to those of WKY rats. CONCLUSIONS: The vasodilator potencies of ACh and L-SNC were diminished whereas that of NO was augmented in SH rats. The loss of potency of L-SNC in SH rats was not obviously due to differences in decomposition to NO or the overactivity of cyclooxygenase factors. This study provides the first evidence that diminished endothelium-dependent vasodilation in SH rats may involve a loss of vasodilator potency of endogenous L-SNC.