Intracerebroventricular insulin-like growth factor-1 decreases feeding in diabetic rats.

Insulin-like growth factor-1 (IGF-1) is a hormone that is important in the regulation of growth processes and additionally has been demonstrated to modulate metabolic and autonomic responses. Some of its effects are mediated by the central nervous system (CNS), and there are IGF-1 receptors dispersed throughout the CNS. Both IGF-1 and insulin alter peripheral metabolic and autonomic nervous activity by a central mechanism, and the well-defined role of insulin in the regulation of feeding, especially in diabetes, led us to investigate the effect of chronic central administration of IGF-1 on metabolic and feeding parameters in normal and diabetic rats. Normal and diabetic rats with intracerebroventricular cannulas were given IGF-1, insulin (0.5 nmol/animal), or artificial cerebrospinal fluid via cannula twice daily for 4 d. Blood samples were collected on d 2 and 4, and the body weights and food intake were recorded daily. IGF-1 administered intracerebroventricularly did not alter plasma glucose, insulin, body weight, or food intake in normal rats. However, in diabetic animals, IGF-1 decreased food intake but did not alter blood glucose or plasma insulin. In correlated studies, intracerebroventricular insulin decreased food intake in both normal and diabetic animals. From these studies, we conclude that IGF-1 may act centrally to decrease food intake in the hyperphagic diabetic animals but not in normal animals. This suggests that diabetic animals have an increased sensitivity to CNS IGF-1.

The effect of diabetes and sex on nitric oxide-mediated cardiovascular dynamics.

Diabetes is associated with impaired cardiovascular responses that are especially prominent in females. Since nitric oxide (NO)-mediated effects on cardiovascular dynamics are altered in diabetes, we evaluated the effect of L-NAME, a nitric oxide synthase (NOS) antagonist, on mean arterial pressure (MAP), heart rate (HR), and selective vascular flows in both male and female normal and diabetic rats as an index of NO activity. Rats were made diabetic using streptozotocin and maintained for 5-6 weeks. Following anesthesia with urethane/alpha-chloralose, the femoral artery and vein were cannulated for recording and sampling, and flow probes were placed on the iliac, renal, and superior mesenteric arteries. A bolus infusion of L-NAME (10mg/ kg) resulted in a rapid +52% and +68% increase in MAP in normal female and male rats, respectively. However, diabetic females' and males' responses were significantly lower (44% and 45%, respectively) when compared with their normal counterparts. The decreased HR in response to the peak pressor effect of L-NAME was more prominent in normal females compared with normal males (-14% vs 2%). The results in diabetic females and males were equivalent (-6% vs -9%, respectively). L-NAME decreased the conductance (flow/MAP) an average of 65% in all three vascular beds in normal female rats. In diabetic females, the iliac and superior mesenteric responses to L-NAME were less, and the renal conductance was contrastingly increased 23%. The response to L-NAME was comparable (-62%) in the renal and superior mesenteric and less (-40%) in the iliacs of normal versus diabetic males. We concluded that diabetes is associated with a decreased pressor response to NOS inhibition. And the impaired constriction response of the renal vessels noted in female diabetic rats may provide a basis for the increased renal pathology observed in diabetic humans.

Autonomic and endothelial dysfunction in experimental diabetes.

The effect of streptozotocin induced diabetes on autonomic regulation of heart rate and endothelial function was examined in Sprague-Dawley rats. Weanling rats (3-4 weeks of age) of either sex were randomly assigned to a non-diabetic (male 5, female 6) or diabetic (male 4, female 5). Diabetes was induced with a single intraperitoneal (IP) injection of streptozotocin (STZ, 100 mg/kg). Nondiabetic rats received an IP injection of saline. Eight weeks after injection, rats were chronically instrumented with a left jugular venous catheter and a left carotid arterial catheter. After recovery (5 days) cardiac sympathetic tonus, parasympathetic tonus and intrinsic heart rate were determined. On an alternative day, the pressor response to nitric oxide synthase inhibition (NOS-X) was determined in areflexic rats. Cardiac sympathetic tonus (72 +/- 13 vs. 41 +/- 7), parasympathetic tonus (-51 +/- 10 vs. -22 +/- 7), and intrinsic heart rate (368 +/- 6 vs. 292 +/- 9), were reduced in diabetic rats. Furthermore, diabetic rats had a smaller pressor response (A33 +/- 7 vs. A66 +/- 5) to NOS-X. These results document impaired autonomic control of heart rate and endothelial dysfunction in 8-week streptozotocin induced diabetic rats.

Arterial baroreflex regulation of regional vascular conductance at rest and during exercise.

We tested the hypothesis that dynamic exercise resets the operating point and attenuates the spontaneous gain of the arterial baroreflex regulation of mesenteric and hindlimb vascular conductance in hypertensive rats. Eleven adult male spontaneously hypertensive rats were chronically instrumented with left carotid arterial catheters and Doppler ultrasonic flow probes around the superior mesenteric and left common iliac arteries. After the rats recovered, arterial baroreflex function was examined by recording reflex changes in conductance in response to spontaneous changes in mean arterial pressure before exercise and during steady-state treadmill running at 6 and 18 m/min. Dynamic exercise reduced the spontaneous baroreflex gain of mesenteric conductance (by 51 and 36%) and maximum mesenteric conductance (by 24 and 32%) at 6 and 18 m/min, respectively. In sharp contrast, dynamic exercise increased the spontaneous maximum iliac conductance (by 32 and 47%) without changing the spontaneous gain. Sinoaortic denervation eliminated the relationship between mean arterial pressure and conductance by reducing the mesenteric (92%) and iliac (68%) vascular conductance gain. These results demonstrate that dynamic exercise has differential effects on the regulation of mesenteric and iliac vascular conductance in hypertensive rats.

Vascular dilatatory responses to sodium nitroprusside (SNP) and alpha-adrenergic antagonism in female and male normal and diabetic rats.

Diabetes is associated with impaired vascular dilatatory responses that appear to be influenced by sex as well as diabetic state. Therefore, we hypothesized that vascular and sympathetic control function exhibit a greater deterioration following the induction of diabetes in female than in male rats. We conducted a comparative determination of the effect of sodium nitroprusside (SNP, a nitrous oxide donor) and that of an alpha1-adrenergic antagonist, prazosin, on selective vascular flows, mean arterial pressure (MAP), and heart rate (HR), in female and male normal and diabetic rats. Rats were made diabetic using streptozotocin (50 mg/kg, iv) and maintained for 5-6 weeks. Following anesthesia with urethane/alpha-chloralose, the femoral artery and vein were cannulated for recording and sampling. Flow probes were placed on the iliac, renal, and superior mesenteric arteries. SNP (1, 5, 10, and 20 microg/kg) infusions resulted in a dose-dependent decrease in MAP in normal and diabetic rats. The decrease in MAP in normal males was 37% less at the 20 microg/kg concentration of SNP when compared to normal females. The HR was not significantly changed in response to the hypotensive effect of SNP; however, reflex tachycardia was more prominent in diabetic males. The vascular conductance (flow/MAP) was increased by SNP in normal and diabetic rats in a dose-dependent fashion; however, the responsiveness was decreased in the iliac and superior mesenteric and increased in the renal arteries in diabetics when compared to normals. Diabetic males were 42% and 28% less responsive to SNP in the iliac and superior mesenteric arteries, respectively. On the other hand, diabetic females were 1.5-fold more responsive in the renal artery when compared to normals. Prazosin (4 mg/kg) decreased the MAP in normal and diabetic rats to a comparable degree. Prazosin increased the vascular conductance in all three vascular beds in normal and diabetic rats with the greater increase occurring in the iliac (118%) and superior mesenteric (110%) arteries. We concluded that diabetes is associated with an increased response to NO in the renal vessels and a decreased response in the iliac and superior mesenteric vessels in both females and males. alpha-Adrenergic tone was greatest in diabetic female and male rats. This study suggests that decreased vascular flow in diabetes is a result of a combination of decreased sensitivity to NO and increased adrenergic tone.