A. A. Khraibi

Atrial natriuretic peptide and C-type natriuretic peptide in spontaneously hypertensive rats and their vasorelaxing actions in vitro.

The present study determined circulating concentrations of atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) and also investigated the vasorelaxing action of ANP and CNP on isolated contracted aorta. We also defined the vasorelaxing action of a novel and newly synthesized 27-amino acid chimera of ANP and CNP termed vasonatrin peptide (VNP), which we compared with ANP and CNP in WKY rats and SHR. Plasma and urinary cyclic GMP and sodium excretion were also investigated. Plasma ANP was increased in SHR in contrast to no change in circulating CNP. Plasma and urinary cyclic GMP and sodium excretion were no different between WKY rats and SHR. In WKY rats maximal relaxations to VNP in aortic rings without endothelium were greater than those to ANP and CNP. In SHR aortic rings the potency of VNP relaxation was preserved, the actions of ANP were enhanced, and the actions of CNP were markedly impaired. In association with these vasorelaxing actions, these data suggest that (1) circulating CNP is not different in SHR and WKY rats, but the aortic relaxing action of CNP is markedly impaired in SHR; (2) endogenous plasma ANP is significantly increased in SHR without associated increases in plasma or urinary cyclic GMP; (3) there is an increase in aortic relaxation to exogenous ANP in SHR; and (4) VNP has a potent endothelium-independent aortic relaxing action in both WKY rats and SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Sulfhydryl group donors potentiate the hypotensive effect of acetylcholine in rats.

Nitric oxide mediates the vasodilator and hypotensive responses of acetylcholine infusion. It has been reported that nitric oxide could be protected from free radical destruction by forming an S-nitrosothiol compound. Furthermore, sulfhydryl donors such as N-acetylcysteine or thiosalicylic acid enhance nitric oxide production from nitroglycerin. Consequently, the hypotensive effect of intravenous acetylcholine infusion might be potentiated during the simultaneous administration of sulfhydryl donors. The objective of the present study was to test in Okamoto spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (1) whether the hypotensive effect of acetylcholine (10 micrograms/kg per minute) was affected by the simultaneous administration of N-acetylcysteine (10 micrograms/kg per minute) or thiosalicylic acid (10 micrograms/kg per minute), and (2) whether NG-nitro-L-arginine-methyl ester (100 micrograms/kg per minute) administration was able to reverse the changes induced by acetylcholine plus N-acetylcysteine or acetylcholine plus thiosalicylic acid. The administration of acetylcholine reduced (P < .05) mean arterial pressure in WKY rats (13 +/- 2%) and SHR (14 +/- 2%) without affecting urine flow rate, urinary sodium excretion, and glomerular filtration rate. In the presence of N-acetylcysteine, the acetylcholine-induced reduction in mean arterial pressure was potentiated (P < .05) in WKY rats (24 +/- 4%) and SHR (20 +/- 2%). These changes in mean arterial pressure were accompanied by significant reductions in urine flow rate and urinary sodium excretion in WKY rats, as well as in glomerular filtration rate in SHR.2

Catecholamine release and excretion in rats with immunologically induced preganglionic sympathectomy.

Abstract: Plasma and urinary catecholamines were quantified to assess global sympathoadrenal function in rats with preganglionic lesions caused by antibodies to acetyl‐cholinesterase (AChE). Rats were given intravenous injections of normal mouse IgG or murine monoclonal anti‐acetylcholinesterase IgG (1.5 mg). Five or 16 days afterward, basal blood samples were taken through indwelling arterial cannulae. A few hours later, the rats were immobilized for 10 min in padded restrainers, and another blood sample was drawn. HPLC determinations showed low basal levels of norepinephrine and epinephrine (<0.2 ng/ml in all rat plasma samples). In control rats, immobilization stress increased levels of plasma catecholamines up to 35‐fold. In rats tested 5 days after injection of antibody, the norepinephrine response was much smaller (15% of control), and (he epinephrine response was nearly abolished (5% of control). There was some recovery at 16 days after antibody treatment, but stress‐induced catecholamine release was still markedly impaired. Reduced stress‐induced release: was not accompanied by major changes in tissue epinephrine or norepinephrine (heart, spleen, adrenal glands, and brain), although adrenal dopamine content dropped by 60%. Urinary excretion was studied in parallel experiments to gain insight into the effects of AChE anti‐bodies on basal sympathoadrenal activity. Epinephrine, norepinephrine, dopamine, and selected metabolites were quantified in 24‐h urine samples collected at frequent intervals for 30 days after antibody injection. No statistically gnificant changes were detected in the urinary output of dopamine, 3‐methoxytyramine, normetanephrine, or 3‐methoixy‐4‐hydroxyphenylglycol. On the other hand, epinephrine and norepinephrine output increased sharply at the time of antibody injection and then fell significantly below control levels. Norepinephrine output returned to normal after 2 weeks, but epinephrine output remained depressed. These results are consistent with previous evidence of widespread and persistent antibody‐mediated βmade to the preganglionic sympathetic system.

Effect of renal decapsulation on lithium excretion in the presence and absence of volume expansion

The relationship between fractional sodium excretion (FENa) and fractional lithium excretion (FELi) was determined in Munich-Wistar rats with intact capsules (control, n = 16), and in rats with acute bilateral renal decapsulation (n = 16) during hydropenia and acute saline volume expansion. In response to volume expansion, the glomerular filtration rate increased significantly in both decapsulated and intact groups, but was similar in the two groups of rats at the same period. The FENa and FELi increased significantly from 0.49 +/- 0.10 and 20.09 +/- 1.76% to 1.71 +/- 0.20 and 34.14 +/- 2.82% in control rats with volume expansion. In decapsulated rats, FENa and FELi were 0.17 +/- 0.03 and 11.64 +/- 1.39% during control and increased to 1.04 +/- 0.21 and 26.23 +/- 1.17% during volume expansion. The FELi and FENa were significantly greater in control rats compared with decapsulated rats during both control and volume expansion periods. The lower FELi in bilateral renal decapsulation suggests reduced delivery of sodium from the proximal tubule.

Blockade of cytochrome P-450 epoxygenase pathway attenuates the natriuresis of NG-monomethyl-l-arginine infusion in the spontaneously hypertensive rat

Previous studies demonstrated that there is increased renal synthesis of cytochrome P-450-dependent arachidonic acid metabolites in the vasculature and tubules of the Okamoto spontaneously hypertensive rat (SHR). It has also been shown that the natriuretic response of the SHR to NG-monomethyl-L-arginine (L-NMMA) infusion is exaggerated compared with that of the normotensive Wistar-Kyoto rat. The purpose of this study was to determine the roles of cytochrome P-450 epoxygenase and cyclooxygenase pathways in the natriuresis that is observed with the systemic infusion of a high dose of L-NMMA to inhibit nitric oxide synthesis in the SHR and the Wistar-Kyoto rats. After a control clearance period of 20 minutes groups of adult SHR (n = 14) were given L-NMMA (15 mg/kg bolus followed by 500 microg/kg/min continuous infusion). In other groups of SHR either ketoconazole (0.5 mg/kg, n = 9) to inhibit the renal activity of cytochrome P-450 epoxygenase pathway or indomethacin (3 mg/kg, n = 7) to inhibit cyclooxygenase activity was administered intravenously 20 minutes before the control clearance period. After the control clearance period L-NMMA was infused as previously described. Infusion of L-NMMA in the control group of SHR resulted in a significant increase in fractional excretion of sodium (FE Na from 1.78% +/- 0.24% to 6.90% +/- 0.61%). In the ketoconazole-treated group of SHR, L-NMMA infusion resulted in a significant natriuresis (from 2.22% +/- 0.58% to 4.70% +/- 0.93%); however, the natriuretic response was significantly attenuated compared with that of the control group of SHR that received only L-NMMA (delta FE Na, 2.47% +/- 0.40% vs 5.24% +/- 0.55%). Indomethacin administration did not affect the natriuretic response to L-NMMA infusion in the SHR. In conclusion, the natriuretic response to L-NMMA infusion in the SHR is significantly attenuated by administration of ketoconazole but not indomethacin. This result suggests that the natriuretic effect of L-NMMA infusion in the SHR is mediated at least partly by cytochrome P-450 metabolites of the epoxygenase pathway.