Neuroanatomical abnormalities in a nonhuman primate model of congenital Zika virus infection.

We evaluated neuropathological consequences of fetal ZIKV exposure in rhesus monkeys, a translatable animal model for human neural development, by carrying out quantitative neuroanatomical analyses of the nearly full-term brains of fetuses infected with ZIKV and procedure-matched controls. For each animal, a complete cerebral hemisphere was evaluated using immunohistochemical (IHC) and neuroanatomical techniques to detect virus, identify affected cell types, and evaluate gross neuroanatomical abnormalities. IHC staining revealed the presence of ZIKV in the frontal lobe, which contained activated microglia and showed increased apoptosis of immature neurons. ZIKV-infected animals exhibited macrostructural changes within the visual pathway. Regional differences tracked with the developmental timing of the brain, suggesting inflammatory processes related to viral infiltration swept through the cortex, followed by a wave of cell death resulting in morphological changes. These findings may help explain why some infants born with normal sized heads during the ZIKV epidemic manifest developmental challenges as they age.

Cardiovascular effects after the intracerebroventricular administration of peptide and nonpeptide angiotensin antagonists in Dahl salt-sensitive rats.

Cardiovascular responses after the central blockade of the brain angiotensin system with peptide or nonpeptide angiotensin II analogs in conscious, freely moving hypertensive Dahl salt-sensitive (DS/JR) rats were measured. Four-week-old animals were maintained on an 8% salt diet until experimentation at 7 weeks of age. At the time of experimentation, mean arterial pressures were 176 +/- 6 mm Hg. The i.c.v. administration of 20 micrograms of the peptide analog sarcosine1, threonine8-angiotensin II (sarthran) resulted in a significant bradycardic response (approximately 17% decrease in H.R. peaking at 8 min after injection) without a significant change in blood pressure. Central administration of the AT1 antagonist losartan (10 micrograms) or of the AT2 antagonist PD 123319 (10 micrograms) was without effect. The peptide and nonpeptide analogs differed in their ability to inhibit central angiotensin II (10 ng)-induced pressor and dipsogenic responses. PD 123319 (10 micrograms) had no effect on the pressor and dipsogenic responses, whereas losartan (10 micrograms) and sarthran (20 micrograms) inhibited both responses for 85 +/- 17 and 29 +/- 3 min, respectively. The effect of preblocking either the AT1 or the AT2 receptors on the sarthran-induced bradycardia was also determined. Preblocking with either losartan (10 micrograms) or PD 123319 (10 micrograms) inhibited the bradycardic response by approximately 45%, which suggests that both receptor subtypes are involved in the central cardiovascular responses in the DS/JR rat and that, because it was attenuated by pure antagonists, the response to sarthran may be mediated by its agonist actions.(ABSTRACT TRUNCATED AT 250 WORDS)

The antihypertensive effect of acute intracerebroventricular administration of captopril in Dahl salt-sensitive rats.

The ability of centrally administered angiotensin converting enzyme (ACE) inhibitors to lower mean arterial pressure (MAP) has been demonstrated in numerous animal models of hypertension. In the present study, we assessed the effect of intracerebroventricular (i.c.v.) injection of the ACE inhibitor captopril (10 micrograms) on MAP in conscious, freely moving hypertensive inbred Dahl salt-sensitive (DS/JR) rats and their normotensive control inbred Dahl salt-resistant (DP/JR) rats. Both DS/JR and DR/JR rats were maintained on an 8% salt diet from 4 weeks of age until experimentation at 7-8 weeks of age, at which time DS/JR pressures were significantly elevated as compared to DR/JR rats (185 +/- 6 vs. 99 +/- 2 mm Hg, respectively). Following i.c.v. administration of captopril, a significant depressor response lasting for several hours was observed in DS/JR rats, with a maximum reduction of 17.6 +/- 4.1 mm Hg. The same treatment had no effect on the MAP of DR/JR rats. Mean arterial pressures in both groups were not significantly affected by i.c.v. administration of vehicle alone or by intravenous (i.v.) administration of 100 micrograms of captopril. These findings indicate that i.c.v. captopril lowers MAP in hypertensive DS/JR rats. Further studies will be necessary to elucidate the mechanism of this antihypertensive effect.

Prevention of Dahl salt-induced hypertension by chronic dietary tryptophan.

Four-week-old inbred Dahl salt-sensitive (DS/JR) and Dahl salt-resistant (DR/JR) rats were placed on an 8% salt diet with or without a supplemental 2.5% tryptophan (Trp). Blood pressures were monitored for the next 5 weeks. Urine volumes and ion concentrations were measured during the 6th week. Blood pressures of DS/JR rats on control diets elevated rapidly and markedly, whereas pressures of DS/JR rats on the Trp-supplemented diet were not significantly elevated over those of DR/JR rats. Pressures of DR/JR rats were unaffected by Trp supplementation. Urinary sodium was significantly greater in DR/JR rats compared with DS/JR rats and was unaffected by Trp supplementation. This suggests that the antihypertensive effect of Trp was not at the level of the kidney. We conclude that dietary Trp blocks the development of hypertension in DS/JR rats maintained on a high salt diet.

Effect of dietary tryptophan on the development of hypertension in the Dahl salt-sensitive rat.

Dahl salt-sensitive rats are inbred on the basis of their tendency to develop hypertension when placed on a high salt diet. The present study investigated the effects of chronic dietary tryptophan (trp) at 50 g/kg food on the development of hypertension in these animals under conditions of both normal and elevated dietary salt. Dietary trp attenuated the development of hypertension in inbred Dahl salt-sensitive (DS/JR) rats and had no effect upon the patterns of development of systolic blood pressures in the normotensive controls, the inbred Dahl salt-resistant (DR/JR) rat and the outbred parental Sprague Dawley (SD) rat. Cardiac hypertrophy, which is associated with Dahl salt-induced hypertension, was blocked by the high trp diet. Further work will be necessary to elucidate the mechanisms by which dietary trp protected against the development of hypertension and cardiac hypertrophy in DS/JR rats.