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(Circulation. 1999;99:558-563.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Coronary Arteriolar Dilation to Acidosis

Role of ATP-Sensitive Potassium Channels and Pertussis Toxin–Sensitive G Proteins

Hiroshi Ishizaka, MD, PhD; Siva R. Gudi, PhD; John A. Frangos, PhD; Lih Kuo, PhD

From the Department of Medical Physiology, Microcirculation Research Institute, Texas A&M University Health Science Center, College Station (H.I., L.K.), and the Department of Bioengineering, University of California at San Diego, La Jolla (S.R.G., J.A.F.). Dr Ishizaka is currently affiliated with the 2nd Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki, Japan.

Correspondence to Lih Kuo, PhD, Department of Medical Physiology, Microcirculation Research Institute, Texas A&M University Health Science Center, College Station, TX 77843-1114. E-mail lkuo{at}tamu.edu

Background—We previously demonstrated that coronary arteriolar dilation in response to acidosis is mediated by the opening of ATP-sensitive potassium (K_ATP) channels. However, the signal transduction involved in the K_ATP-channel activation during acidosis has not been elucidated. A recent study in cardiac myocytes implied that pertussis toxin (PTX)–sensitive G proteins may be involved in the signal transduction for K_ATP-channel activation. However, it remains unclear whether this transduction process also occurs in the vascular tissue and, in particular, whether it exerts functional dilation in response to acidosis.

Methods and Results—To examine the signaling pathway for acidosis-induced dilation, porcine coronary arterioles were isolated, cannulated, and pressurized for in vitro study. The GTPase activity in reconstituted G proteins was examined at different levels of pH. Extravascular acidosis (pH 7.3 to 7.0) produced a graded dilation of coronary arterioles. This dilation was not affected by removal of endothelium but was significantly attenuated after inhibition of K_ATP channels and G proteins by glibenclamide and PTX, respectively. Glibenclamide and PTX attenuated the acidosis-induced arteriolar dilation to the same extent, and combined administration of both inhibitors did not further inhibit the vasodilation. These results indicated that both inhibitors act on the same vasodilatory pathway. Furthermore, vasodilation of coronary arterioles to the K_ATP-channel opener pinacidil and to the endothelium-independent vasodilator sodium nitroprusside was not affected by PTX. Because PTX inhibited acidosis-induced vasodilation without inhibiting K_ATP-channel function, it is suggested that PTX inhibits the vasodilatory pathway upstream from K_ATP channels. GTPase activity in reconstituted G proteins was significantly enhanced by a reduction in pH, indicating that G proteins were directly activated by acidosis.

Conclusions—On the basis of these findings, we conclude that acidosis-induced coronary arteriolar dilation is mediated by the opening of smooth muscle K_ATP channels through the activation of PTX-sensitive G proteins.

Key Words: vasodilation • arteries • potassium • proteins

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