The objective of this experiment was to determine whether bilateral renal denervation (RD) prevents the elevation of blood pressure and cardiac hypertrophy characteristically induced by chronic exposure to cold. Four groups (nine male rats each) were used. The kidneys of two groups were bilaterally denervated, while the remaining two groups were sham operated. Systolic blood pressures of the four groups, measured indirectly from the tail, did not differ significantly during the control period and following RD. At this time, 1 RD and 1 sham-operated group was exposed to cold (5 degrees C, 41 degrees F). The remaining RD and sham-operated groups were kept at 25 degrees C. Blood pressure of the cold-exposed, sham-operated group increased significantly during the 1st week of cold exposure (125 +/- 2 mmHg; 1 mmHg = 133.3 Pa), and rose to 139 +/- 4 mmHg by the 5th week, whereas the blood pressure of the RD group exposed to cold remained at the control level (116 +/- 2 mmHg). Both RD and sham-operated cold-exposed groups developed cardiac hypertrophy with significantly increased resting heart rates compared with controls kept at 25 degrees C. Plasma renin activities and renal norepinephrine content of kidneys of both RD groups at 7 weeks after RD were significantly less than those of sham-operated controls, confirming that renal nerves had been severed. Thus, RD prevented the elevation of blood pressure induced by chronic exposure to cold but had no significant effect on cardiac hypertrophy.
The induction of Fos-like immunoreactivity (FLI) was used to determine the brain localization affected by b-casomorphin-7 (b-CM7). Peripheral administration of human b-CM7 at different doses (5, 10 and 30 mg/kg, IV for 1 hour) to rats induced moderate to strong FLI in discrete brain regions including the nucleus accumbens, caudate putamen, ventral tegmental and median raphe nucleus, and orbitofrontal, prefrontal, parietal, temporal, occipital and entorhinal cortex. All of the above areas have been shown to be altered either functionally or anatomically in patients with schizophrenia, and most have been shown to be functionally abnormal in autism. Some of these brain areas are originators or components of dopaminergic, serotoninergic and GABA-ergic pathways, suggesting that b-CM7 can affect the function of all of these systems. The role of some other affected areas in emotional and motivated behavior, social adaptation, hallucinations and delusions suggests that b-CM7, which was found in high concentration in the CSF, blood and urine of patients with either schizophrenia or autism, may be relevant to schizophrenia and autism. Induction of FLI in the above brain areas by a moderate dose (10 mg/kg) of b-CM7 was attenuated significantly, or blocked, by pretreatment with naloxone (2 mg/kg, IP). It is concluded that human b-CM7 can cross the blood-brain barrier, activate opioid receptors and affect brain regions similar to those affected by schizophrenia and autism.
The aim of this study was to test our hypotheses that AT1A receptors play a role in the pathogenesis of cold-induced hypertension (CIH) and in the cold-induced increase in drinking responses to ANG II. Two groups of wild-type (WT) and two groups of AT1A receptor gene knockout (AT1A-KO) mice were used (6/group). Blood pressures (BP) of the four groups were similar during the control period at room temperature (25 degrees C). After the control period, one group of WT and one group of AT1A-KO mice were exposed to cold (5 degrees C), while the remaining groups were kept at 25 degrees C. BP of the cold-exposed WT group elevated significantly within 1 wk of exposure to cold and increased gradually to a maximum level by week 5. However, there was only a slight increase in BP of the cold-exposed AT1A-KO group. The maximal cold-induced increase in BP (DeltaBP) is significantly less in AT1A-KO group (11 +/- 3 mmHg) than in WT group (49 +/- 6 mmHg), indicating that AT1A receptor deficiency attenuates cold-induced elevation of BP. Interestingly, both WT and AT1A-KO mice developed cardiac and renal hypertrophy to the same extent. AT1A-KO caused a significant increase in urine and plasma levels of nitric oxide (NO), indicating that the renin-angiotensin system inhibits NO formation probably via AT1A receptors. Cold exposure inhibited endothelial NO synthase protein expressions and decreased urine and plasma levels of NO, which may be mediated partially by AT1A receptors. AT1A-KO completely abolished the cold-induced increase in drinking responses to ANG II. We conclude that 1) AT1A receptors play an essential role in the pathogenesis of CIH but not cardiac hypertrophy; 2) the role of AT1A receptors in CIH may be mediated partially by its inhibitory effect on the NO system; and 3) cold-induced increase in drinking response to ANG II is mediated by AT1A receptors.
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