Our laboratory uses a model of intrauterine growth restriction (IUGR) induced by placental insufficiency in the rat to examine the developmental origins of adult disease. In this model only male IUGR offspring remain hypertensive in adulthood, revealing sex-specific differences. The purpose of this study was to determine whether testosterone with participation of the renin-angiotensin system (RAS) contributes to hypertension in adult male IUGR offspring. At 16 wk of age a significant increase in testosterone (346 Ϯ 34 vs. 189 Ϯ 12 ng/dl, P Ͻ 0.05) was associated with a significant increase in mean arterial pressure (MAP) measured by telemetry in IUGR offspring (147 Ϯ 1 vs. 125 Ϯ 1 mmHg, P Ͻ 0.05, IUGR vs. control, respectively). Gonadectomy (CTX) at 10 wk of age significantly reduced MAP by 16 wk of age in IUGR offspring (124 Ϯ 2 mmHg, P Ͻ 0.05 vs. intact IUGR) but had no effect in control (125 Ϯ 2 mmHg). A significant decrease in MAP in intact IUGR (111 Ϯ 3 mmHg, P Ͻ 0.05 vs. untreated intact IUGR) and castrated IUGR (110 Ϯ 4 mmHg, P Ͻ 0.05 vs. untreated CTX IUGR) after treatment with enalapril for 2 wk suggests a role for RAS involvement. However, the decrease in blood pressure in response to enalapril was greater in intact IUGR (⌬36 Ϯ 1 mmHg, P Ͻ 0.05) compared with CTX IUGR (⌬15 Ϯ 2 mmHg), indicating an enhanced response to RAS blockade in the presence of testosterone. Thus these results suggest that testosterone plays a role in modulating hypertension in adult male IUGR offspring with participation of the RAS.

This study underscores the importance of the renal microcirculation in renovascular disease. Intra-renal administration of VEGF preserved renal MV architecture and function of the stenotic kidney, which in turn preserved renal haemodynamics and function and decreased renal fibrosis. These observations suggest that preventing renal MV loss may be a potential target for therapeutic approaches for patients with chronic renovascular disease.

Angiotensin-(1-7) [ANG-(1-7)] is a recently described heptapeptide product of the renin-angiotensin system. Because biosynthesis of ANG-(1-7) increases in animals treated with cardioprotective drugs and inactivation of the gene for angiotensin converting enzyme 2 [an enzyme involved in the biosynthesis of ANG-(1-7)] leads to the development of cardiac dysfunction, it has been suggested that ANG-(1-7) has cardioprotective properties. To directly test this possibility, we have generated transgenic rats that chronically overproduce ANG-(1-7) by using a novel fusion protein methodology. TGR(A1-7)3292 rats show testicular-specific expression of a cytomegalovirus promoter-driven transgene, resulting in a doubling of circulating ANG-(1-7) compared with nontransgenic control rats. Radiotelemetry hemodynamic measurements showed that transgenic rats presented a small but significant increase in daily and nocturnal heart rate and a slight but significant increase in daily and nocturnal cardiac contractility estimated by dP/d t measurements. Strikingly, TGR(A1-7)3292 rats were significantly more resistant than control animals to induction of cardiac hypertrophy by isoproterenol. In addition, transgenic rats showed a reduced duration of reperfusion arrhythmias and an improved postischemic function in isolated Langendorff heart preparations. These results support a cardioprotective role for circulating ANG-(1-7) and provide a novel tool for evaluating the functional role of ANG-(1-7).

Chronic pressure-mediated baroreflex activation suppresses renal sympathetic nerve activity. Recent observations indicate that chronic electrical activation of the carotid baroreflex produces sustained reductions in global sympathetic activity and arterial pressure. Thus, we investigated the effects of global and renal specific suppression of sympathetic activity in dogs with sympathetically-mediated, obesity-induced hypertension by comparing the cardiovascular, renal, and neurohormonal responses to chronic baroreflex activation and bilateral surgical renal denervation. After control measurements, the diet was supplemented with beef fat while sodium intake was held constant. After 4 weeks on the high-fat, when body weight had increased ~a 50%, fat intake was reduced to a level that maintained this body weight. This weight increase was associated with an increase in mean arterial pressure from 100±2 to 117±3 mm Hg and heart rate from 86±3 to 130±4 bpm. The hypertension was associated with a marked increase in cumulative sodium balance despite ~ a 35% increase in GFR. The importance of increased tubular reabsorption to sodium retention was further reflected by ~ a 35% decrease in fractional sodium excretion. Subsequently, both chronic baroreflex activation (7 days) and renal denervation decreased plasma renin activity and abolished the hypertension. However, baroreflex activation also suppressed systemic sympathetic activity and tachycardia and reduced glomerular hyperfiltration while increasing fractional sodium excretion. In contrast, GFR increased further after renal denervation. Thus, by improving autonomic control of cardiac function and diminishing glomerular hyperfiltration, suppression of global sympathetic activity by baroreflex activation may have beneficial effects in obesity beyond simply attenuating hypertension.