Vasodilatory Effect of Basic Fibroblast Growth Factor in Isolated Rat Cerebral Arterioles: Mechanisms Involving Nitric Oxide and Membrane Hyperpolarization.

Abstract

Basic fibroblast growth factor (bFGF), a potent mitogen, acutely dilates cerebral blood vessels and may be effective in reducing cerebral infarction. However, the vasodilatory mechanism, which may involve nitric oxide (NO), is not completely understood. This study investigated whether membrane hyperpolarization is also involved in this mechanism. Membrane potential (MP) of smooth muscle cells and vessel diameter of isolated intracerebral arterioles were simultaneously measured following extraluminal application of bFGF in rats. The involvement of NO and adenosine triphosphate-sensitive potassium (K ATP ) channels in bFGF-induced vasodilation and membrane hyperpolarization was evaluated using specific inhibitors, N G -monomethyl-L-arginine (L-NMMA, 10 -4 M) and glibenclamide (GB, 10 -5 M), respectively. The resting MP was recorded at a mean value of -31.9 ± 4.5 mV. bFGF (1 to 1000 ng/ml) produced significant vasodilation and hyperpolarization. Treatment with L-NMMA caused vasoconstriction and significantly attenuated bFGF-induced vasodilation without affecting membrane hyperpolarization. In the presence of GB, the membrane potential was significantly depolarized but the vessel diameter was only marginally reduced, so bFGF-induced membrane hyperpolarization was inhibited while arteriolar dilation was attenuated. These results suggest that bFGF-induced vasodilation is mediated by a mechanism involving both NO and membrane hyperpolarization, and that membrane hyperpolarization is caused by the activation of K ATP channels.

Potassium Channels and Neurovascular Coupling

“…99 It has also been reported that K ATP channel activation mediates parenchymal arteriolar membrane hyperpolarization in response to basic fibroblast growth factor. 100 Glibenclamide-sensitive K ATP currents measured in pial artery SMCs are activated by synthetic vasodilators such as pinacidil, as well as by endogenous vasodilators such as calcitonin gene-related peptide and VIP. 101,102 While there is evidence that supports the presence of K ATP channels in parenchymal arteriolar SMCs, the biophysical properties of K ATP channels in these vessels are not known, and the functional role of K ATP channels in regulating parenchymal arteriolar tone requires further characterization.…”

Fibroblast growth factor-2-induced cardioprotection against myocardial infarction occurs via the interplay between nitric oxide, protein kinase signaling, and ATP-sensitive potassium channels

“…Vascular studies have demonstrated that the vasoactive action of FGF2 is mediated in part by K ATP channels (Cuevas et al 1991;Boussairi and Sassard 1994;Tiefenbacher and Chilian 1997;Kajita et al 2001). Both cardiac sarcK ATP and mitoK ATP channels have been implicated in I-R injury and to be important effectors of cardioprotection, including ischemic preconditioning (Schultz et al 1997;Gross and Fryer 1999;Grover and Garlid 2000;O'Rourke 2000).…”

“…Certain biological actions, in particular vascular and angiogenic functions, of FGFs have been shown to occur through nitric oxide (NO) signaling (Huang et al 1997;Tiefenbacher and Chilian 1997;Cuevas et al 1999;Hampton et al 2000;Parenti et al 2001) or ATPsensitive potassium (K ATP ) channel activity (Cuevas et al 1991;Boussairi and Sassard 1994;Tiefenbacher and Chilian 1997;Kajita et al 2001). Hampton and colleagues determined that exogenously FGF2 applied prior to ischemia was able to protect the heart from postischemic dysfunction in hearts in an inducible nitric oxide synthase (iNOS)-dependent manner (Hampton et al 2000).…”

“…Vascular studies have implicated K ATP channel activation in the signal transduction and biological activity of FGF1 and FGF2 in angiogenesis and vasodilation (Cuevas et al 1991;Boussairi and Sassard 1994;Tiefenbacher and Chilian 1997;Kajita et al 2001). However, there is no evidence, to date, as to the involvement of K ATP channels (whether mitochondrial or sarcolemmal) in the cardioprotective effect mediated by FGF2.…”