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Effect of chronic experimental diabetes on vascular smooth muscle function in rabbit carotid artery
Abstract:
To understand the effects of diabetes on vascular smooth muscle function and the underlying mechanism(s) involved, we examined the responses to alpha-adrenoceptor agents, serotonin (5-HT), K+, and prostaglandins in the carotid artery of male New Zealand white rabbits with chronic diabetes (16 weeks) induced chemically by alloxan (100 mg/kg, intravenously) treatment. Isolated ring segments of diabetic rabbit carotid artery exhibited an increased (20-60%) maximal response to norepinephrine (NE), methoxamine, phenylephrine, and K+ as compared with controls. Responses to 5-HT were not significantly increased. Nevertheless, there were no significant differences in ED50 values of the agonists in either of the groups. Putatively selective alpha 2-adrenoceptor agonists (clonidine and guanabenz), prostaglandin E1 (PGE1) and prostaglandin I2 (PGI2) did not elicit any response in control vessels. In the diabetic state, however, these drugs contracted the artery in a dose-dependent fashion. Isoproterenol (0.1-10 microM) relaxed arterial rings previously contracted with all the agonists except PGE1 and PGI2, which were potentiated by isoproterenol. Contractions to PGE1 or PGI2 alone or in the presence of isoproterenol were reduced or abolished by 10(-5) M phentolamine. Under these conditions, isoproterenol exhibited its typical relaxatory action. Nifedipine was more potent in inhibiting the K+ response in diabetic carotid artery than in the controls. These results suggest an increased reactivity of diabetic rabbit carotid artery to alpha 2-adrenoceptor agonists, K+, PGE1, and PGI2 which may, at least in part, be due to an increased sensitivity of calcium channels in diabetic vessels. Contractile responses to PGE1 and PGI2 could be attributed to their action on adrenergic neurotransmission, thereby facilitating the release of NE from presynaptic nerve terminals. Furthermore, isoproterenol at a high dose (1 microM or more) may directly stimulate alpha-adrenoceptors. Whether or not this effect of isoproterenol is only prostaglandin-dependent is not clear.
Insights
Diabetes increases carotid artery reactivity to certain agents, possibly due to heightened calcium channel sensitivity. This vascular dysfunction in diabetes may involve prostaglandin-mediated adrenergic neurotransmission.
Area of Science:
- Vascular physiology
- Endocrinology
- Pharmacology
Background:
- Diabetes mellitus is associated with vascular complications.
- Vascular smooth muscle dysfunction contributes to diabetic cardiovascular pathology.
Purpose of the Study:
- To investigate the impact of chronic diabetes on carotid artery smooth muscle function.
- To elucidate the mechanisms underlying altered vascular responses in diabetes.
Main Methods:
- Alloxan-induced diabetes in New Zealand white rabbits (16 weeks).
- Isolated carotid artery ring segment analysis.
- Assessment of responses to alpha-adrenoceptor agonists, serotonin (5-HT), potassium chloride (K+), and prostaglandins (PGE1, PGI2).
Main Results:
- Diabetic rabbit carotid arteries showed increased maximal responses to norepinephrine, methoxamine, phenylephrine, and K+.
- Alpha 2-adrenoceptor agonists, PGE1, and PGI2, which were ineffective in controls, induced contractions in diabetic vessels.
- Nifedipine more potently inhibited K+-induced contractions in diabetic arteries, suggesting increased calcium channel sensitivity.
Conclusions:
- Diabetic rabbit carotid artery exhibits enhanced reactivity to alpha 2-adrenoceptor agonists, K+, PGE1, and PGI2.
- Increased calcium channel sensitivity may contribute to heightened vascular responses in diabetes.
- Prostaglandin-induced contractions might involve adrenergic neurotransmission and norepinephrine release.