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Alterations in rat coronary vasoreactivity and vascular protein kinase C isoforms in Type 1 diabetes

¹Department of Kinesiology and ²The Noll Physiological Research Center, Pennsylvania State University, University Park, Pennsylvania 16802

Submitted 2 May 2003 ; accepted in final form 2 July 2003

Vascular complications associated with diabetes mellitus (DM) have been linked to activation of PKC-dependent signaling pathways in both human and animal models of DM. To determine whether aberrant PKC signaling mechanisms specifically impact the coronary circulation, we assessed isolated coronary artery (CA) responses after the induction of Type 1 DM. Male Sprague-Dawley rats were subjected to partial pancreatectomy (DM; n = 23) and compared with age-matched controls (CTL; n = 19). Vasoreactivity was assessed in single CAs (250 µm internal diameter) after abluminal administration of the G_q-dependent vasoconstrictors endothelin (ET)-1 (10^–10–10^–9 M) and U-44619 (10^–9–10^–5 M) or the voltage-gated Ca²⁺ channel agonist BAY K 8644 (10^–9–10^–5 M) with and without the PKC inhibitor bisindolylmaleimide (Bis; 10^–6 M). Dilator responses to ACh (10^–9–10^–5 M) were also assessed. ET-1 resulted in significantly greater constriction in the DM versus CTL group (50 ± 4% vs. 33 ± 5%, P < 0.0001), whereas responses to U-44619 and BAY K 8644 were similar between groups. Importantly, inhibition of ET-1 and U-44619 constriction by Bis occurred in the DM but not CTL group (P < 0.05). Western blotting on isolated CAs revealed greater levels of PKC-, PKC-_I, and PKC-_II by 22%, 15.3%, and 17.6%, respectively, in the DM versus CTL group (P < 0.05), whereas PKC- and PKC- protein levels were unchanged. DM was also associated with attenuated CA dilation after ACh treatment (P < 0.0566) and reductions in endothelial nitric oxide synthase protein levels versus CTL (P < 0.03). These data suggest that Ca²⁺-dependent PKC signaling pathways, particularly for ET-1, play a greater role in modulating CA vasoconstrictor responses in DM versus CTL. These data further suggest that aberrant CA constrictor and dilator responses are likely to contribute to the coronary vascular pathology associated with DM.

vascular smooth muscle; endothelium; endothial nitric oxide synthase; endothelin; partial pancreatectomy

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