BPH/2J mice are a genetic model of hypertension developed by Schlager 1 by crossing 8 normotensive strains and selecting for elevated blood pressure (BP). Normotensive BPN/3J control mice were bred concurrently by crossing randomly selected mice from the same base population. Recently, the mechanism of the hypertension has been recognized as neurogenic because ganglion blockade abolished the hypertension in BPH/2J mice.2 Furthermore, spectral analysis of BP revealed greater power in the autonomic frequency band, suggesting overactivity of the sympathetic nervous system (SNS), most prominently during the nocturnal active period.2 BPH/2J mice also display exaggerated daynight differences in BP, which are associated with greater neuronal activity in regions of the hypothalamus and amygdala known to be important for cardiovascular regulation. Given the recent success of renal sympathetic nerve ablation for the treatment of resistant hypertension, 3 the importance of renal influences on the expression of neurogenic hypertension has been highlighted. Importantly, the peripheral renin-angiotensin system (RAS) is closely linked to renal sympathetic nerve activity (RSNA) via its ability to stimulate renin secretion, 4 and also through angiotensin II-mediated facilitation of SNA. 5 However, the interaction of the kidney and renal RAS with SNS-mediated hypertension in BPH/2J mice has not been investigated thoroughly. The role of the RAS has been examined in a variety of ways in BPH/2J mice including by measurement of messenger RNA (mRNA) in tissues and various pharmacological assessments. [6][7][8][9][10] Iwao et al 8 reported normal renin activity in plasma, kidney, and submandibular gland of BPH/2J mice, although others found greater renin activity Abstract-Genetically hypertensive mice (BPH/2J) are hypertensive because of an exaggerated contribution of the sympathetic nervous system to blood pressure. We hypothesize that an additional contribution to elevated blood pressure is via sympathetically mediated activation of the intrarenal renin-angiotensin system. Our aim was to determine the contribution of the reninangiotensin system and sympathetic nervous system to hypertension in BPH/2J mice. BPH/2J and normotensive BPN/3J mice were preimplanted with radiotelemetry devices to measure blood pressure. Depressor responses to ganglion blocker pentolinium (5 mg/kg IP) in mice pretreated with the angiotensin-converting enzyme inhibitor enalaprilat (1.5 mg/kg IP) revealed a 2-fold greater sympathetic contribution to blood pressure in BPH/2J mice during the active and inactive period. However, the depressor response to enalaprilat was 4-fold greater in BPH/2J compared with BPN/3J mice, but only during the active period (P=0.01). This was associated with 1.6-fold higher renal renin messenger RNA (mRNA; P=0.02) and 0.8-fold lower abundance of micro-RNA-181a (P=0.03), identified previously as regulating human renin mRNA. Renin mRNA levels correlated positively with depressor responses to pentolinium (r=0.99; P=0.001), and BPH/2...

These findings indicate that hypertension in BPH/2J mice is associated with greater pressor responsiveness to aversive stress but not to appetitive arousal. Thus, BPH/2J hypertensive mice may be a particularly relevant model for human hypertensive patients that overrespond to daily stressors.

BPH/2J mice are a genetic model of hypertension which were selectively bred for elevated blood pressure (BP) in the 1970s alongside a normotensive strain (BPN/3J).1 Recent studies suggest that the hypertension in BPH/2J mice is caused by enhanced activation of the sympathetic nervous system (SNS) because ganglion blockade causes a greater depressor response in BPH/2J mice compared with BPN/3J controls. 2,3 Importantly, cardiovascular regulatory forebrain regions within the hypothalamus and amygdala display markedly greater neuronal activity in BPH/2J compared with BPN/3J mice during the dark-active period of the 24-hour light cycle.2 Furthermore, lesions of the medial amygdala reduced the hypertension and SNS overactivity in BPH/2J mice. 4 Thus the central nervous system seems to play a crucial role in driving the sympathetically mediated hypertension in this model.A gene array approach has been used to identify differential expression of genes in the hypothalamus between BPH/2J and BPN/3J mice. 5,6 An important finding was that expression of the orexin precursor gene (hcrt) in BPH/2J mice was more than double that of normotensive mice in early and established hypertension. Thus, hcrt could potentially contribute to the development and maintenance of BPH/2J hypertension.5 Furthermore, BPH/2J mice have ≈4-fold greater expression of the hcrt gene in the hypothalamus during the dark-active period compared with light period when mice are predominantly inactive or asleep. 6 Characteristics of the BPH/2J mouse strain, such as high BP, tachycardia, greater locomotor activity, overactivity of the SNS, 2 and exaggerated cardiovascular reactivity to stressful stimuli, 7 could all be reflective of a greater activity of the orexinergic neurons. Indeed, orexin is capable of increasing BP, heart rate (HR), and SNS activity.8 Orexinergic neurons originate in the hypothalamus and project to a wide range of brain regions, but in terms of sympathetic control of BP, the Abstract-BPH/2J mice are a genetic model of hypertension associated with an overactive sympathetic nervous system.Orexin is a neuropeptide which influences sympathetic activity and blood pressure. Orexin precursor mRNA expression is greater in hypothalamic tissue of BPH/2J compared with normotensive BPN/3J mice. To determine whether enhanced orexinergic signaling contributes to the hypertension, BPH/2J and BPN/3J mice were preimplanted with radiotelemetry probes to compare blood pressure 1 hour before and 5 hours after administration of almorexant, an orexin receptor antagonist. Mid frequency mean arterial pressure power and the depressor response to ganglion blockade were also used as indicators of sympathetic nervous system activity. Administration of almorexant at 100 (IP) and 300 mg/ kg (oral) in BPH/2J mice during the dark-active period (2 hours after lights off) markedly reduced blood pressure (−16.1±1.6 and −11.0±1.1 mm Hg, respectively; P<0.001 compared with vehicle). However, when almorexant (100 mg/ kg, IP) was administered during the light-inactive pe...

The disrupted regulation of renin synthesis caused by the renin enhancer deficit in mice is associated with a selective reduction in BP reactivity to aversive stress, which may be mediated by multiple central and peripheral mechanisms.

There is now convincing evidence from animal studies that major signals such as leptin and insulin have a sympathoexcitatory action in the hypothalamus to cause hypertension. Recent studies suggest that this may involve 'neural plasticity' within hypothalamic signalling driven by central actions of leptin mediated via activation of melanocortin receptor signalling and activation of brain neurotrophic factors. This review describes the evidence to support the contribution of the SNS to obesity related hypertension and the major metabolic and adipokine signals.

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Transglutaminase type 2 (TG2) has been reported to be a candidate gene for maturity onset diabetes of the young (MODY) because three different mutations that impair TG2 transamidase activity have been found in 3 families with MODY. TG2 null (TG2−/−) mice have been reported to be glucose intolerant and have impaired glucose-stimulated insulin secretion (GSIS). Here we rigorously evaluated the role of TG2 in glucose metabolism using independently generated murine models of genetic TG2 disruption, which show no compensatory enhanced expression of other TGs in pancreatic islets or other tissues. First, we subjected chow- or fat-fed congenic SV129 or C57BL/6 wild type (WT) and TG2−/− littermates, to oral glucose gavage. Blood glucose and serum insulin levels were similar for both genotypes. Pancreatic islets isolated from these animals and analysed in vitro for GSIS and cholinergic potentiation of GSIS, showed no significant difference between genotypes. Results from intraperitoneal glucose tolerance tests (GTTs) and insulin tolerance tests (ITTs) were similar for both genotypes. Second, we directly investigated the role of TG2 transamidase activity in insulin secretion using a coisogenic model that expresses a mutant form of TG2 (TG2R579A), which is constitutively active for transamidase activity. Intraperitoneal GTTs and ITTs revealed no significant differences between WT and TG2R579A/R579A mice. Given that neither deletion nor constitutive activation of TG2 transamidase activity altered basal responses, or responses to a glucose or insulin challenge, our data indicate that glucose homeostasis in mice is TG2 independent, and question a link between TG2 and diabetes.

The hypotensive actions of losartan suggest that although the RAS provides an important contribution to BP, it contributes little, if at all, to the hypertension-induced or the greater stress-induced pressor responses in Schlager mice. The effects of pentolinium suggest that the SNS is mainly responsible for hypertension in BPH/2J mice. However, the RAS inhibits sympathetic vasomotor tone during inactivity and prolongs sympathetic activation during periods of adverse stress, indicating an important sympatho-modulatory role.