Inhibition of NOS enhances pulmonary vascular changes in stroke-prone spontaneously hypertensive rats.

To determine the effects of chronic nitric oxide (NO) blockade on the pulmonary vasculature, 58-day-old spontaneously hypertensive rats of the stroke-prone substrain (SHRSP) and Wistar-Kyoto rats (WKY) received N(omega)-nitro-L-arginine (L-NNA; 15 mg. kg(-1). day(-1) orally for 8 days). Relaxation to acetylcholine (ACh) in hilar pulmonary arteries (PAs), the ratio of right ventricular (RV) to body weight (RV/BW) to assess RV hypertrophy (RVH), and the percent medial wall thickness (WT) of resistance PAs were examined. L-NNA did not alter the PA relaxation, RV/BW, or WT in WKY. Although the PA relaxation and RV/BW in control SHRSP were comparable to those in WKY, the WT was increased (31 +/- 2 vs. 19 +/- 1%). L-NNA-treated SHRSP showed two patterns: in one group, the relaxation, RV/BW, and WT were comparable to those in the control SHRSP; in the other, impaired relaxation (36 +/- 7 vs. 88 +/- 4% for WKY) was associated with an increase in WT (37 +/- 1%) and RV/BW (0. 76 +/- 0.05). Thus the abnormal pulmonary vasculature in SHRSP at <10 wk of age is not accompanied by impaired relaxation in PAs or RVH; however, impaired relaxation is associated with increased WT and RVH.

Contribution of endothelin to the acute pressor response of L-NAME in stroke-prone spontaneously hypertensive rats.

In this study, we examined whether endothelin (ET) plays a role in the short-term increase in mean arterial pressure (MAP) after nitric oxide synthase (NOS) inhibition with N(omega)-nitro-L-arginine methyl ester (L-NAME) in stroke-prone spontaneously hypertensive rats (SHRSPs). Experiments were performed by using Inactin-anesthetized male SHRSPs that were pretreated with chlorisondamine to block reflex autonomic cardiovascular effects. Injection of L-NAME (10 mg/kg, i.v.), but not D-NAME, produced rapid and marked increases (74 +/- 3 mm Hg) in MAP that were sustained for >1 h. In SHRSPs that were treated with the ET(A/B) receptor antagonist, L-754,142 (15 mg/kg + 15 mg/kg/h), L-NAME increased MAP by 45 +/- 4 mm Hg (p < 0.0001 compared with L-NAME alone). L-754,142 blocked pressor responses to big ET-1 by >90% but was without effect on pressor responses to norepinephrine. Plasma levels of ET-1 averaged 5 +/- 1 pg/ml in animals given vehicle and were slightly increased in animals given either L-NAME alone (7 +/- 2 pg/ml) or L-754,142 alone (7 +/- 2 pg/ml) but increased markedly when L-NAME and L-754,142 were given together (114 +/- 18 pg/ml). This may relate to an effect of L-754,142 to block ET-receptor-mediated clearance of ET-1. We conclude that ET plays a role in the short-term pressor response after NOS inhibition in SHRSPs.

Lack of antidiuretic activity of lanreotide in the diabetes insipidus rat.

Lanreotide is a somatostatin analog which possesses antidiuretic activity in the rat. To determine whether vasopressin participates in the antidiuretic response to lanreotide, experiments were performed with diabetes insipidus (DI) rates homozygous for vasopressin deficiency. Lanreotide significantly increased urine osmolality and decreased urine volume and free water clearance during the 2-h period after injecting 400 microgram/kg s.c. in 12 awake Wistar-Kyoto rats that were undergoing water diuresis. Although lanreotide decreased serum growth hormone levels (24.2 +/- 6.1 vs. 0.9 +/- 0.1 ng/ml, P < .01), administration of recombinant human growth hormone (1 mg/kg s.c.) did not affect the renal response. Lanreotide (200 microgram/kg s.c.) also significantly increased urine osmolality and free water reabsorption and tended to decrease urine volume in 15 water-loaded Long-Evans rats. In contrast, lanreotide (200 or 400 microgram/kg s.c.) did not affect urine osmolality, urine volume or free water clearance when administered acutely or chronically to DI rats. These results suggest that vasopressin plays a role in the renal response to lanreotide in the rat

Effect of ifetroban, a thromboxane A2 receptor antagonist, in stroke-prone spontaneously hypertensive rats.

Experiments were performed to determine the effect of chronic therapy with the potent and long-acting thromboxane (TX) A2/prostaglandin endoperoxide (TP) receptor antagonist, ifetroban, on hypertension development and the incidence of stroke in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP instrumented with radiotelemetry probes, for continuous monitoring of arterial blood pressure, were given 1% NaCl to drink and Stroke-Prone Rodent Diet and were chronically treated with ifetroban (20 mg/kg/day, n = 10) or vehicle (n = 12) starting at 16.5 weeks of age. Ifetroban did not affect blood pressure or the development of proteinuria and cerebrovascular lesions. Chronic administration of a higher dose ifetroban (40 mg/kg/day) starting at 7 weeks of age was also without effect on blood pressure and stroke in noninstrumented saline-drinking SHRSP. These results do not support a major role for TXA2 and its endoperoxide precursors in the elevation of blood pressure and the development of cerebrovascular lesions in saline-drinking SHRSP.