vapiprost and Hypertension

The influence of the endothelium on aortic contractility to KCl 100 mM was studied during maturation and aging in normotensive Wistar and spontaneously hypertensive rats (SHR). In Wistar rats, there was no significant difference in maximal responses in the course of aging whether the endothelium was present (E+) or not (E-). A similar result was obtained in SHR E- rings. However, contraction was significantly higher in E+ rings of young (9 weeks) compared to adult and old SHR (18, 25, 36 and 72 weeks) (in mN/mm2: 34.8 +/- 3.1 versus 24.8 +/- 1.8, 16.0 +/- 2.5, 17.4 +/- 2.0 and 12.9 +/- 1.8, p<0.01). This increase remained significant in 18- compared to that of 25-, 36- and 72-week-old rats (p<0.01). No change appeared with age in noradrenaline-induced contractions of E+ rings neither in Wistar nor in SHR. A dose-dependent decrease in response to KCl was observed after an in vivo pretreatment of the young SHR with acetylsalicylic acid. Finally, blocking the TXA2/PGH2 receptor by addition of GR 32191B or ONO-3708 led to a decrease in the response of young SHR aortic rings to KCl. This study points out a decrease in the response of SHR aortic rings to a depolarizing agent during maturation. The enhanced contraction observed in young SHR seems to be the result of an increased participation of an endothelium-derived, cyclooxygenase-dependent contracting factor(s), most likely either TXA2 or PGH2. This factor might play a key role in the onset of hypertension in the spontaneously hypertensive strain.

Topics: Aging; Animals; Aorta; Aspirin; Biphenyl Compounds; Body Weight; Endothelium, Vascular; Heptanoic Acids; Hypertension; In Vitro Techniques; Muscle Contraction; Norepinephrine; Potassium Chloride; Prostaglandin Antagonists; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2

The present study evaluated the effects of miconazole, a selective inhibitor of epoxygenase activity, on renal hemodynamics and the pressure-natriuresis response of saline-drinking, uninephrectomized Lyon hypertensive (LH) and Lyon low blood pressure (LL) rats. Infusion of miconazole (final concentration, 1 micromol/L) into the renal artery had no effect on the renal function of LL rats over a range of renal perfusion pressures (RPP) from 100 to 140 mm Hg. In contrast, miconazole lowered renal vascular resistance (RVR, 17.9 +/- 1.1 v 26.3 +/- 1.5 mm Hg/mL/min/g, P < .01) and increased urinary sodium excretion (6.4 +/- 1.2 v 4.2 +/- 0.8 micromol/min/g, P < .05) in LH rats at a RPP of 140 mm Hg. To determine whether the effects of epoxyeicosatrienoic acids were dependent on activation of the thromboxane A2-prostaglandin H2 (TP) receptor, we studied the effects of a TP receptor antagonist, GR 32191B (0.1 mg/kg/min), on the renal response to an infusion of miconazole into the renal artery in LH rats. GR 32191B decreased basal RVR and prevented the dilation induced by miconazole. It did not, however, alter its natriuretic effect. The renal metabolism of arachidonic acid was also compared in LH and LL rats. The production of epoxygenase metabolites was 25% lower in microsomes prepared from the renal cortex of LH versus LL rats. Miconazole (1 micromol/L) reduced epoxygenase activity similarly, by approximately 60%, in both strains. These results suggest that endogenously formed P450 metabolites of arachidonic acid may serve as a substrate for the formation of vasoconstrictor endoperoxides that interact with TP receptors in LH rats and contribute to the enhanced renal vascular tone but not the blunted pressure-natriuresis response.

Topics: Animals; Arachidonic Acid; Biphenyl Compounds; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Hemodynamics; Heptanoic Acids; Hypertension; Kidney; Male; Miconazole; Natriuresis; Perfusion; Pressure; Rats; Receptors, Thromboxane; Reference Values

To evaluate the contribution of cytochrome P450 (CYP450) metabolites of arachidonic acid in the increased renal vascular resistance and blunted pressure-natriuresis response exhibited by Lyon hypertensive (LH) rats, the effects of an intrarenal infusion of 17-octadecynoic acid (3 microM), an inhibitor of the formation of epoxyeicosatrienoic and 20-hydroxyeicosatetraenoic acids, were compared in 8-week-old LH and low blood pressure (LL) control rats. 17-Octadecynoic acid failed to affect renal function in LL rats. In contrast, it reduced renal vascular resistance and shifted the pressure-natriuresis relationship to lower pressures in LH rats. Blockade of thromboxane-endoperoxide (TP) receptors with GR 32191B prevented the renal vasodilator response to 17-octadecynoic acid but not its natriuretic action. Miconazole (1 microM), an inhibitor of epoxygenase activity, had no effect on renal function in LH rats. These results indicate that CYP450 metabolites of arachidonic acid, likely 20-hydroxyeicosatetraenoic acid, contribute to the resetting of the pressure-natriuresis relation in LH rats and that the renal vasoconstrictor effects of 20-hydroxyeicosatetraenoic acid in LH rats may be related to activation of TP receptors.

Topics: Animals; Biphenyl Compounds; Blood Pressure; Body Weight; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Fatty Acids, Unsaturated; Heptanoic Acids; Hydroxyeicosatetraenoic Acids; Hypertension; In Vitro Techniques; Kidney; Male; Miconazole; Organ Size; Oxygenases; Rats; Receptors, Thromboxane; Renal Circulation; Systole; Vascular Resistance; Vasodilation

The influence of renal perfusion pressure (RPP) on renal functions was studied in anesthetized 8-wk-old Lyon hypertensive (LH) and normotensive (LN) rats before and after a specific blockade of prostaglandin (PG) H2-thromboxane (Tx) A2 receptors using GR-32191B. The nervous and hormonal influences on the kidneys were controlled by renal denervation, adrenalectomy, and an infusion of norepinephrine, aldosterone, hydrocortisone, and vasopressin. With the use of inflatable cuffs, RPP was varied from 100 to 125 and then to 150 mmHg. In control conditions, the renal blood flow (RBF) and glomerular filtration rate (GFR) were independent of RPP in both strains. LH kidneys differed from LN controls by an increased preglomerular vasoconstriction as indicated by a similar decrease in RBF and GFR. Moreover, the pressure-natriuresis curve was blunted in LH compared with LN kidneys. GR-32191B did not affect the renal function of LN rats. In LH kidneys, it normalized RBF and renal vascular resistance and improved GFR, whereas it had no effect on the pressure-natriuretic relationship. It is concluded that the elevated preglomerular vascular resistance that characterizes LH rats is dependent on an overstimulation of PGH2-TxA2 receptors whereas these latter are not involved in the control of pressure-natriuresis.

Topics: Analysis of Variance; Animals; Biphenyl Compounds; Glomerular Filtration Rate; Heptanoic Acids; Hypertension; Kidney; Male; Natriuresis; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Regional Blood Flow; Species Specificity