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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Vasoconstrictor mechanisms in the cerebral circulation are unaffected by insulin resistance

¹Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157; and ²Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary 1082

Submitted 28 April 2004 ; accepted in final form 17 August 2004

Insulin-resistance (IR) impairs agonist-induced relaxation in cerebral arteries, but little is known about its effect on constrictor mechanisms. We examined the vascular responses of the basilar artery (BA) and its side branches in anesthetized Zucker lean (ZL) and IR Zucker obese (ZO) rats using a cranial window technique. Endothelin-1 (ET-1) constricted the BAs in both the ZL and ZO rats, but there was no significant difference between the two groups (ZL: 36 ± 8%; ZO: 33 ± 3% at 10^–8 M). Inhibition of the ET_A receptors by BQ-123 slightly increased the diameters of the BAs, with no difference shown between the ZL (6 ± 1%) and ZO (5 ± 3%) rats. Expressions of the ET_A receptors and ET-1 mRNA examined by immunoblot analysis and RT-PCR, respectively, were also similar in the ZL and ZO groups. Phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C (PKC), and the thromboxane A₂ (TxA₂) mimetic U-46619 constricted the BAs, but similarly to ET-1, there was no significant difference between the ZL and ZO groups (10^–6 M PDBu: ZL: 33 ± 2%; ZO: 32 ± 4%; and 10^–7 M U-46619: ZL: 23 ± 1%; ZO: 19 ± 2%). Inhibition of Rho-kinase with Y-27632 induced dilation of the BAs, and these responses were also comparable in the ZL and ZO rats (ZL: 39 ± 4%; ZO: 38 ± 2% at 10^–5 M). In contrast, nitric oxide-dependent relaxation to bradykinin was significantly reduced in the ZO rats (10^–6 M: 10 ± 3%) compared with ZLs (29 ± 7%, P < 0.01). These findings indicate that vasoconstrictor responses of the BA mediated by ET-1, TxA₂, PKC, and Rho-kinase are not affected by IR.

diabetes; protein kinase C; rho kinase; endothelin; thromboxane

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