An indispensable role for the brain renin-angiotensin system (RAS) has been documented in most experimental animal models of hypertension. To identify the specific efferent pathway activated by the brain RAS that mediates hypertension, we examined the hypothesis that elevated arginine vasopressin (AVP) release is necessary for hypertension in a double-transgenic model of brain-specific RAS hyperactivity (the "sRA" mouse model). sRA mice experience elevated brain RAS activity due to human angiotensinogen expression plus neuron-specific human renin expression. Total daily loss of the 4-kDa AVP prosegment (copeptin) into urine was grossly elevated (≥8-fold). Immunohistochemical staining for AVP was increased in the supraoptic nucleus of sRA mice (~2-fold), but no quantitative difference in the paraventricular nucleus was observed. Chronic subcutaneous infusion of a nonselective AVP receptor antagonist conivaptan (YM-087, Vaprisol, 22 ng/h) or the V(2)-selective antagonist tolvaptan (OPC-41061, 22 ng/h) resulted in normalization of the baseline (~15 mmHg) hypertension in sRA mice. Abdominal aortas and second-order mesenteric arteries displayed AVP-specific desensitization, with minor or no changes in responses to phenylephrine and endothelin-1. Mesenteric arteries exhibited substantial reductions in V(1A) receptor mRNA, but no significant changes in V(2) receptor expression in kidney were observed. Chronic tolvaptan infusion also normalized the (5 mmol/l) hyponatremia of sRA mice. Together, these data support a major role for vasopressin in the hypertension of mice with brain-specific hyperactivity of the RAS and suggest a primary role of V(2) receptors.

Chronic exogenous deoxycorticosterone acetate and high dietary sodium (DOCA‐salt model) results in hypertension and elevated resting metabolic rate (RMR), through activation of the brain renin‐angiotensin system. We hypothesized that endoplasmic reticulum (ER) stress within the brain mediates the cardiovascular and metabolic consequences of DOCA‐salt treatment. C57Bl/6J mice were instrumented with radiotelemetric blood pressure probes and infusion pumps to deliver the chemical chaperone Tauroursodeoxycholic Acid (TUDCA, 5.28 ug/day) or aCSF vehicle into the lateral cerebral ventricle (ICV) and treated concurrently for three weeks with DOCA‐salt. Mean arterial pressure (24 hour MAP: aCSF 114.0 ± 3.0, n=13 vs TUDCA 116.5 ± 7.4, n=15 mmHg) and heart rate (528 ± 10 vs 529 ± 6 BPM) did not differ before treatments. Following DOCA‐salt, MAP increased comparably (+14.4 ± 5.3 vs +12.7 ± 8.6 mmHg), but ICV TUDCA suppressed the bradycardic effect of DOCA‐salt (−81 ± 15 vs −44 ± 9 BPM, P<0.05), supporting a possible role for ER stress in baroreflex regulation. RMR at thermoneutrality was lower with ICV TUDCA than with aCSF after 3 weeks of DOCA‐salt (DOCA+aCSF 3.38 ± 0.07, n=9 vs DOCA+TUDCA 3.16 ± 0.06, n=11 mL O2/100g/min, P=0.03), but body mass did not diverge (+0.90 ± 0.42 vs +0.91 ± 0.23 g/3 wk). These data support potential roles for brain ER stress in both the cardiovascular and metabolic effects of DOCA‐salt treatment.

Hypertension in many animal models is sensitive to inhibition of the brain renin-angiotensin system (RAS). We examined mice with transgenic hyperactivity of the brain RAS (sRA mice) to determine whether this manipulation is sufficient to cause hypertension, and to identify the causative mechanism. sRA mice exhibit brain-specific increases in angiotensin (ANG) peptide production through neuron-specific expression of human renin (synapsin promoter) and expression of human angiotensinogen through its own promoter. We determined both through tail-cuff and radiotelemetric methods that sRA mice are hypertensive (SBP; control 112±2 vs sRA 127±5 mmHg, P=0.02). Despite normal plasma osmolality and moderate hyponatremia, sRA mice exhibit double the number of vasopressin-expressing neurons in the supraoptic nucleus (P=0.002), as detected by immunohistochemistry. Plasma levels of the vasopressin pro-segment, copeptin, were reduced in sRA mice (140±19 vs 68±21 pg/mL, P=0.02), which correlated with severe polyuria (1.8±0.3 vs 12.3±1.6 mL/day, P<0.001). Indeed, total daily copeptin loss in the urine was significantly increased almost twenty-fold in sRA mice (7.9±4.3 vs 154.4±62.4 pg/day, P=0.03), highlighting an increase in vasopressin secretion per unit time. The baseline hypertension of sRA mice was completely reversed by chronic infusion of the dual V 1A / V 2 receptor antagonist, conivaptan (22 ng/hr, 10 days, s.c.; 113±5 mmHg, P=0.02). Preliminary experiments demonstrate that infusion of the selective V 2 receptor antagonist, tolvaptan (22 ng/hr, 10 days, s.c.), has similar effects. Further, while abdominal aorta and mesenteric arteries demonstrate selective desensitization to vasopressin and down-regulation of the V 1A receptor (38% of control, P<0.05), renal V 2 receptor expression remained normal in sRA mice. Together, these data demonstrate major roles for vasopressin and its V 2 receptor in the hypertension caused by elevated brain RAS activity.