Microvascular Reactivity to Norepinephrine at Different Arteriolar Levels and Durations of Streptozocin-Induced Diabetes

1 Neuropathy is a frequently diagnosed complication of diabetes mellitus. Effective pharmacotherapy is not available. 2 The spontaneously diabetic BB/Wor rats develop secondary complications like neuropathy as do human diabetic patients. 3 BB/Wor rats treated with insulin via a subcutaneous implant show a significant impairment of sensory and motor nerve conduction velocity 6 weeks after the onset of diabetes mellitus. 4 Intraperitoneal treatment of diabetic BB/Wor rats with the Ca2+ antagonist, nimodipine (20 mg kg-'), from week 6 onwards every 48 h for a period of 6 weeks resulted in a significant increase of sensory and motor nerve conduction velocity. 5 Twelve weeks after the onset of diabetes mellitus BB/Wor rats show a 40% impairment of sciatic nerve blood flow as compared to the non-diabetic age-matched controls. Treatment with nimodipine (20 mg kg-') from week 6 onwards significantly increased the sciatic nerve blood flow as compared to placebo-treated diabetic BB/Wor rats. 6 The adrenergic responsiveness of the vasa nervorum of the sciatic nerve to tyramine and phenylephrine was investigated as a parameter for autonomic neuropathy. 7 The fact that nimodipine treatment restored the reduced response to tyramine independently of the reduced postsynaptic phenylephrine responsiveness indicates that nimodipine improves adrenergic responsiveness mainly at the presynaptic level.

Section: Discussionmentioning

confidence: 74%

Beneficial effect of the Ca²⁺ antagonist, nimodipine, on existing diabetic neuropathy in the BB/Wor rat

Kappelle¹,

Biessels²,

Bravenboer³

et al. 1994

“…These include alterations to both the purinergic (Belai et al, 1991) and peptidergic (Belai et al, 1987;D'Amato & Curro, 1990) components of rat gastrointestinal tissue, and impaired NANC neurotransmission in human corporal smooth muscle from impotent diabetic men (Saenz de Tejada et al, 1989). Furthermore, previous studies have demonstrated that the development of diabetes-induced changes may depend on the duration of the diabetic state (MacLeod & McNeill, 1985;Belai et al, 1988;Morff, 1990;Nowak et al, 1990). For example, in the myenteric plexus of STZ-diabetic rats, biochemical results showed a trend at 8 weeks for an increase in noradrenaline content, followed by a decrease in both tissue content and nerve fibre density at 16 and 24 weeks after diabetes induction (Belai et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Effect of diabetes and elevated glucose on nitric oxide‐mediated neurotransmission in rat anococcygeus muscle

Way

Reid

1995

Nitric oxide (NO)‐mediated neurotransmission is impaired in anococcygeus muscle from 8‐week streptozotocin‐induced diabetic rats. This study investigated the effects of insulin treatment, and the duration of diabetes on this impairment. In addition, the effect of in vitro exposure to elevated glucose has been investigated on NO‐mediated relaxations, in muscles from untreated rats. Relaxant responses to field stimulation (0.5‐5 Hz, 10 s train), sodium nitroprusside (SNP; 5 and 10 nM) and NO (1 and 3 μM) were significantly impaired in anococcygeus muscles from 8‐week diabetic rats, compared to responses from control rats. Insulin treatment (5 u Lente day−1, s.c.) of diabetic rats prevented the development of this impairment. Consistent with findings in 8‐week diabetic rats, relaxations induced by field stimulation, SNP and NO were attenuated in tissues from 2‐week and 4‐week diabetic rats compared to corresponding control responses, whereas relaxations to papaverine (3 and 10 μM) were not reduced. In contrast, diabetes of 3‐days duration did not affect relaxations to field stimulation, SNP or NO. Incubation of anococcygeus muscles from untreated rats in medium containing elevated glucose (44.1 mM) for 6 h, significantly impaired relaxations to field stimulation compared to responses obtained after normal glucose (11.1 mM) incubation. Relaxations to SNP and to NO were not affected by 6h exposure to elevated glucose. Similarly, incubation in hyperosmolar solutions containing mannose or sucrose for 6 h, impaired relaxations to field stimulation, but not to SNP or NO. The results indicate that the diabetes‐induced impairment of NO‐mediated neurotransmission in the rat anococcygeus muscle develops between 3 days and 2 weeks after the induction of diabetes with streptozotocin. Prevention of the impairment by insulin treatment suggests that it is specific for the diabetic state. In addition, the impairment may be related to hyperglycaemia and the consequent rise in osmolarity, since in vitro exposure to high glucose as well as to other hyperosmolar media impaired NO‐mediated relaxations to field stimulation.

“…Since the arterioles are the major site of vascular resistance, small changes in arteriolar sensitivity could have a significant effect on blood pressure, and the regulation of tissue blood flow (Morff, 1990).…”

Section: Discussionmentioning

confidence: 99%

The effect of insulin treatment and of islet transplantation on the resistance artery function in the STZ‐induced diabetic rat

Heygate

Davies

Holmes

et al. 1996

1 This study was designed to investigate the influence of insulin treatment and islet transplantation on the smooth muscle contractility and endothelium-dependent and independent relaxation of resistance arteries in the chemically induced streptozotocin (STZ) diabetic rat after 6-8 weeks, and 12-14 weeks of diabetes, compared to non-diabetic age-matched controls. 2 The morphology, and contractile responses to high potassium physiological salt solution (KPSS), KPSS containing 10-M noradrenaline (NAK), and concentration-response curves to noradrenaline (NA) of mesenteric resistance arteries were recorded, along with the endothelium-dependent relaxation responses to acetylcholine (ACh) and bradykinin (BK), and endothelium-independent relaxation to sodium nitroprusside (SNP). Concentration-response curves were then repeated in the presence of a nitric oxide synthase inhibitor, NG-nitro-L-arginine (L-NOARG). 3 Insulin-treated diabetic rats in the 12 week study demonstrated enhanced vascular contractility to KPSS, NAK and NA, compared to age-matched non-diabetic controls. 4 Incubation with L-NOARG resulted in both a significant increase in maximum contractile response, and sensitivity (pD2) to NA in the untreated diabetic group (6 weeks). A significant shift in sensitivity was also seen in the insulin-treated diabetic group. In the 12 week study, incubation with L-NOARG resulted in an increased maximum contractile response and sensitivity to NA in the insulin-treated diabetics. An increase in sensitivity was also observed in the untreated diabetic group. 5 Endothelium-dependent relaxation to ACh was significantly augmented in the untreated diabetics (6-weeks), compared to the control group. In the 12-week study, relaxation to both ACh and BK was not significantly different in any of the experimental groups when compared to the sham-operated nondiabetic controls. 6 Incubation with L-NOARG resulted in a significant attenuation of the maximum relaxation response to ACh and BK in all of the experimental groups, in the 6-and the 12-week study. 7 There was no significant difference in the maximum relaxation response or sensitivity to sodium nitroprusside between the diabetic groups and their age-matched controls in either the 6-week or the 12-week study. 8 The results of this study suggest an enhanced release of nitric oxide in the early stages of diabetes, which is more evident in the untreated diabetic rats than the insulin treated, and appears to normalize as the duration of diabetes progresses. This study also shows that the alteration in vascular reactivity of the resistance arteries can be restored to within normal limits by the transplantation of islets of Langerhans, and that islet transplantation is an effective strategy in the correction of the metabolic abnormalities associated with insulin-dependent diabetes.