Neurons of the median preoptic nucleus contribute to chronic angiotensin II-salt induced hypertension in the rat.

Experiments were designed to test the hypothesis that median preoptic (MnPO) neurons are necessary for the full hypertensive response to chronic angiotensin II (AngII) in rats consuming a high salt diet. The MnPO is implicated in many of the physiologic actions of AngII, primarily acting as a downstream nucleus to AngII binding at circumventricular organs such as the organum vasculosum of the lamina terminalis (OVLT). We have previously shown a prominent effect of lesion of the OVLT on the chronic hypertensive effects of AngII in rats consuming high salt. Additionally, we have shown that lesion of the MnPO attenuated the hypertensive response to chronic intravenous infusion of AngII in rats. However, whether MnPO neurons or fibers of passage contribute to this response is not clear. Male Sprague Dawley rats were randomly assigned to either sham (SHAM; n = 8) or ibotenic acid lesion of the MnPO (MnPOx; n = 6). In the MnPOx group, 200 nl of ibotenic acid in phosphate buffer saline (5 µg/µl) was injected into each of 3 predetermined coordinates targeted at the entire MnPO. After a week of recovery, rats were instrumented with radiotelemetric pressure transducers, provided 2.0% NaCl diet and distilled water ad libitum and given another week to recover. After 3 days of baseline measurements, osmotic minipumps were implanted subcutaneously in all rats for administration of AngII at a rate of 150 ng/kg/min. Blood pressure measurements were made for 14 days after minipump implantation. By day 7 of AngII treatment, blood pressure responses appeared to plateau in both groups while the hypertensive response was markedly attenuated in MnPOx rats (MnPOx, 122 ± 6 mmHg; SHAM, 143 ± 8 mmHg). These results support the hypothesis that neurons of the MnPO are involved in the central pathway mediating the chronic hypertensive effects of AngII in rats consuming a high salt diet.

Role of the median preoptic nucleus in the chronic hypotensive effect of losartan in sodium-replete normal rats.

1. We have shown previously that the chronic hypotensive effect of the angiotensin II AT1 receptor antagonist losartan is mediated, in part, by the subfornical organ (SFO). However, the neural pathway(s) mediating this central effect of losartan downstream from the SFO has not been completely elucidated. 2. The present study was designed to test the hypothesis that the median preoptic nucleus (MnPO) is a crucial part of the neural pathway necessary for the chronic hypotensive effect of losartan. To test this hypothesis, male Sprague-Dawley rats were subjected to either Sham or electrolytic lesion of the MnPO (MnPOx). Rats were instrumented with radiotelemetric transducers and aortic flow probes for the continuous measurement of mean arterial pressure (MAP) and heart rate and cardiac output (CO), respectively. Total peripheral resistance (TPR) was calculated as MAP/CO. After 3 days of baseline measurements, rats were infused intraperitoneally with losartan (10 mg/kg per day) via an osmotic minipump at a rate of 5 microL/min. 3. The data revealed that, by Day 9 of losartan treatment, MAP had decreased 34 +/- 2 mmHg in MnPOx rats (n = 9), whereas the MAP of Sham-lesioned rats (n = 8) had only decreased 24 +/- 3 mmHg. These findings were accompanied by a greater decrease in TPR in MnPOx compared with Sham rats (-0.464 vs-0.237 mmHg/mL per min, respectively), whereas CO remained unchanged throughout the study protocol. 4. These results do not support the hypothesis that an intact MnPO is necessary to mediate the full chronic hypotensive effect of losartan in normal rats. Instead, they appear to suggest that the MnPO may play an important role in buffering the profound hypotension induced by losartan.

Role of the median preoptic nucleus in chronic angiotensin II-induced hypertension.

Several lines of evidence implicate the median preoptic nucleus (MnPO) as a downstream site of activation following binding of angiotensin II (ANG II) at the subfornical organ and organum vasculosum of the lamina terminalis. We have shown previously that electrolytic lesion of the MnPO attenuated the increased blood pressure response to chronic intravenous infusion of ANG II. However, whether MnPO neurons or fibers that pass through this region contribute to this response is not clear. In the present study, to distinguish the relative importance of MnPO neurons from fibers of passage in the hypertensive response to chronic ANG II administration, male Sprague Dawley rats were randomly assigned to either sham (iSHAM) or ibotenic acid lesion of the MnPO (iMnPOx). In the iMnPOx group, 200 nl of ibotenic acid in phosphate buffer saline (5 microg/microl) was injected into each of 3 predetermined coordinates targeted at the entire MnPO. After a week of recovery, rats were instrumented with venous catheters, and radiotelemetric transducers for the intravenous administration of ANG II and the measurement of mean arterial pressure (MAP) and heart rate, respectively. Rats were given another week to recover. iSHAM and iMnPOx animals were then infused with saline (7 ml 0.9% NaCl/day) for 3 days as a control period, followed by 10 consecutive days of intravenous ANG II infusion (10 ng kg(-1) min(-1)), and finally a recovery period similar to control. Throughout the protocol, a 0.4% NaCl diet and distilled water were provided ad libitum. By day 8 of ANG II infusion, MAP had increased 54+/-2 mm Hg in iSHAM rats (n=8). The hypertensive response to ANG II was significantly attenuated in the iMnPOx rats (n=9), in which MAP had only increased 29+/-3 mm Hg. These results support the hypothesis that neurons of the MnPO are involved in the central neural pathway mediating the chronic hypertensive effects of ANG II.

An intact median preoptic nucleus is necessary for chronic angiotensin II-induced hypertension.

The median preoptic nucleus (MnPO) receives afferent input from the subfornical organ, a circumventricular organ that has been shown to be necessary in mediating the full chronic hypertensive response to angiotensin II (ANG II) administration. In addition, intravenous ANG II infusion has been shown to cause activation of a number of neurons in both the dorsal and ventral part of MnPO. Taken together, we hypothesized that the MnPO is necessary for the full hypertensive response observed during chronic ANG II-induced hypertension. To test this hypothesis, male Sprague-Dawley rats were subjected to either sham (SHAM) or electrolytic lesion of both the dorsal and ventral part of the MnPO (MnPOx). During the same surgery, rats were instrumented with venous catheters, and radiotelemetric transducers for the intravenous administration of ANG II and the measurement of blood pressure and heart rate, respectively. Rats were then given a week recovery period. After 3 days of saline control infusion, ANG II was intravenously infused (10 ngxkg(-1).min(-1)) in both sham and MnPOx animals for 10 consecutive days, and followed by 3 recovery days. By day 7 of ANG II infusion, MAP had increased 38+/-3 mm Hg in sham lesion rats (n=6), but MAP of MnPOx rats (>90% MnPO ablated; n=5) had only increased 18+/-2 mm Hg. This trend continued through day 10 of ANG II treatment. These results support the hypothesis that the MnPO is necessary for the chronic hypertensive response to ANG II administration.

Effects of a single injection of methylprednisolone acetate on serum biochemical parameters in 11 cats.

BACKGROUND: Therapeutic use of corticosteroids has been implicated in a variety of serum biochemical abnormalities in dogs; however, the effects in cats are less well characterized. OBJECTIVE: The objective of this brief communication is to report serum biochemical changes in response to methylprednisolone acetate (MPA) in adult cats. METHODS: Serum biochemical profiles were performed on 11 cats with dermatologic diseases at baseline, 3-6 days, and 16-24 days after a single intramuscular dose of 5 mg/kg MPA. RESULTS: Median serum albumin and bicarbonate concentrations and amylase activity were increased compared to baseline at both post-treatment time points; aspartate aminotransferase activity and magnesium concentration were increased at 3-6 days post-treatment only; and alkaline phosphatase activity and total calcium concentration were increased at 16-24 days post-treatment only. Median serum creatinine concentration was decreased compared to baseline at both post-treatment time points. Examination of data from individual cats revealed significant variability in serum biochemical changes in response to MPA. No adverse clinical reactions to the drug were reported. CONCLUSIONS: A single dose of MPA results in significant changes in some serum biochemical values in cats, although individual responses will vary.

Hemodynamic effects of methylprednisolone acetate administration in cats.

OBJECTIVE: To investigate the mechanisms by which corticosteroid administration may predispose cats to congestive heart failure (CHF). ANIMALS: 12 cats receiving methylprednisolone acetate (MPA) for the treatment of dermatologic disorders. PROCEDURE: The study was conducted as a repeated-measures design. Various baseline variables were measured, after which MPA (5 mg/kg, IM) was administered. The same variables were then measured at 3 to 6 days and at 16 to 24 days after MPA administration. Evaluations included physical examination, systolic blood pressure measurement, hematologic analysis, serum biochemical analysis, thoracic radiography, echocardiography, and total body water and plasma volume determination. RESULTS: MPA resulted in a substantial increase in serum glucose concentration at 3 to 6 days after administration. Concurrently, RBC count, Hct, and hemoglobin concentration as well as serum concentrations of the major extracellular electrolytes, sodium and chloride, decreased. Plasma volume increased by 13.4% (> 40% in 3 cats), whereas total body water and body weight slightly decreased. All variables returned to baseline by 16 to 24 days after MPA administration. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that MPA administration in cats causes plasma volume expansion as a result of an intra to extracellular fluid shift secondary to glucocorticoid-mediated extracellular hyperglycemia. This mechanism is analogous to the plasma volume expansion that accompanies uncontrolled diabetes mellitus in humans. Any cardiovascular disorders that impair the normal compensatory mechanisms for increased plasma volume may predispose cats to CHF following MPA administration.