No abstract

Activation of central kappa opioid receptors (KOR) has been demonstrated to produce marked free water diuresis with a concurrent increase in renal sympathetic nerve activity (RSNA). This study investigated the cardiovascular (CV) and renal effects evoked by central activation of KOR in two lamina terminalis sites, the median preoptic area (MPA) and anterolateral division of the bed nuclei of the stria terminalis (BST). Rats anesthetized with urethane alpha-chloralose were instrumented to record mean arterial pressure, heart rate, RSNA, and urine output (V). Rats were infused with isotonic saline (25 μL/min) and urine samples were collected during two 10-min control periods and six consecutive 10-min experimental periods following microinjection of vehicle, U50-448H (U50, KOR agonist) alone or norbinaltorphimine (nor-BNI, KOR antagonist) plus U50. Microinjection of U50 into the BST increased V (peak at 30 min, 84.8 ± 12.9 μL/min) as compared to its respective control, vehicle, or nor-BNI plus U50. This diuretic effect occurred without any significant changes in CV parameters, RSNA, or urinary sodium excretion. In contrast, U50 injection into the MPA significantly increased RSNA (peak at 20 mins: 129 ± 9.9) without increasing the other parameters. This study demonstrated novel sites through which activation of KOR selectively increases V and RSNA. The ability of U50 to increase V without affecting sodium excretion and RSNA raises the possibility that LT neurons could be an important substrate through which drugs targeting KOR could selectively facilitate water excretion in sodium-retaining diseases such as congestive heart failure.

Central kappa opioid receptor (KOR) activation produces a marked increase in renal sympathetic nerve activity with a concurrent free water diuresis in conscious rats. However, the role of KOR in the angiotensin II high salt diet (AngII) mediated hypertension model is yet to be determined. This study examines cFOS expression in several brain regions of AngII rats as compared to normal rats. In addition, cFos expression in these brain regions was examined following intracerebroventricular (ICV) microinjection of norbinaltorphimine (Nor‐BNI; 1 μg/5μl), a selective KOR antagonist. Alternate sets of forebrain sections were processed for c‐Fos using a commercially available antibody. Sections were also double labeled with vasopressin to anatomically define specific brain regions. Fos expression was significantly increased in several lamina terminalis and hypothalamic sites. ICV nor‐BNI produced significant decreases in cFos staining in the PVN (AngII, 106 ± 12; nor‐BNI 62 ± 7; P < .01) and OVLT (AngII, 132 ± 7; nor‐BNI 73 ± 5; P < .05). There was no significant change in urine and sodium excretion in all groups. Altogether, this data provides new information concerning the role of KOR in the regulation of blood pressure Grant Funding Source: 5SC2HL104639‐03

Intracerebroventricular (ICV) administration of the opioid‐like peptide agonist, nociceptin/Orphanin FQ (N/OFQ), produces a free water diuresis in addition to marked depressor effects on cardiovascular function and renal sympathetic nerve activity (RSNA). This study examined the changes in cFos expression in forebrain regions of angiotensin II high salt diet (ANGII) hypertensive rats following ICV administration of N/OFQ or saline vehicle. Protocol: 14 days prior to the experiment day, rats were implanted with an osmotic pump filled with angiotensin II and placed on a 2% high salt diet. At the day of the experiments, animals were placed in a metabolic cage and allowed to habituate for 3 hours. Following habituation, then two 15 minutes control periods, rats were than microinjected with either saline vehicle or nociceptin. Ninety minutes after the ICV injection, animals were perfused. Alternate sets of forebrain sections were processed for cFos using a commercially available antibody (Oncogene AB‐5). Results: ANGII treatment significantly increased cFos staining in the magnocellular and parvocellular PVN, SON, PNZ, OVLT, MPA and DMH brain sites as compared to Sham rats. ICV N/OFQ produced significant decrease in c‐Fos staining in the magnocellular PVN, SON, PNZ, OVLT, MPA and DMH of ANGII rats as compared to ANGII group microinjected with saline vehicle. Together, central N/OFQ receptor activation in these forebrain regions may contribute directly to or indirectly participate in the neuropathways involved in the cardiovascular and renal effects of N/OFQ. Supported by NIH 5SC2 HL104639