Protein kinase G regulates the basal tension and plays a major role in nitrovasodilator‐induced relaxation of porcine coronary veins

Abstract

Background and purpose: Coronary venous activity is modulated by endogenous and exogenous nitrovasodilators. The present study was to determine the role of protein kinase G (PKG) in the regulation of the basal tension and nitrovasodilatorinduced relaxation of coronary veins. Experimental approach: Effects of a PKG inhibitor on the basal tension and responses induced by nitroglycerin, DETA NONOate, and 8-Br-cGMP in isolated porcine coronary veins were determined. Cyclic cGMP was measured with radioimmunoassay. PKG activity was determined by measuring the incorporation of 32 P from g-32 P-ATP into the specific substrate BPDEtide. Key results: Rp-8-Br-PET-cGMPS, a specific PKG inhibitor, increased the basal tension of porcine coronary veins and decreased PKG activity. The increase in tension was 38% of that caused by nitro-L-arginine. Relaxation of the veins induced by nitroglycerin and DETA NONOate was accompanied with increases in cGMP content and PKG activity. These effects were largely eliminated by inhibiting soluble guanylyl cyclase with ODQ. The increase in PKG activity induced by the nitrovasodilators was abolished by Rp-8-Br-PET-cGMPS. The relaxation caused by these dilators and by 8-Br-cGMP at their EC 50 was attenuated by the PKG inhibitor by 51-66%. Conclusions and implications:These results suggest that PKG is critically involved in nitric oxide-mediated regulation of the basal tension in porcine coronary veins and that it plays a primary role in relaxation induced by nitrovasodilators. Since nitric oxide plays a key role in modulating coronary venous activity, augmentation of PKG may be a therapeutic target for improving coronary blood flow. IntroductionThe coronary venous system has long been considered a passive conduit from which coronary blood flows into the right atrium. There is accumulating evidence to show that coronary veins exhibit potent contractile response to vasoconstrictors such as noradrenaline, 5-HT, U46619, endothelin-1 and KCl (Chilian at al., 1989; Cocks et al., 1989a, b;Gulbenkian et al., 1994;Saetrum Opgaard et al., 1996;Saetrum Opgaard and Edvinsson, 1997;Zhang et al., 2004) and marked relaxant response to vasodilators such as sodium nitroprusside, isoprenaline, adenosine and vasoactive intestinal peptide (Gulbenkian et al., 1994;Banitt et al., 1995;Saetrum Opgaard et al., 1995;Saetrum Opgaard and Edvinsson, 1997). Canine coronary veins demonstrate 5-to 10-fold greater sensitivity to endothelin-1 than the coronary arteries (Cocks et al., 1989a, b Endothelium-derived nitric oxide (EDNO) plays a pivotal role in the regulation of the coronary circulation (Drexler, 1999). In porcine coronary veins, EDNO is released under basal conditions and in response to bradykinin (Zhang et al., 2004). Both in vitro and in vivo studies show that porcine coronary venules dilate in response to flow stimuli in an EDNO-dependent manner. Such a phenomenon may contribute to the adjustment of postcapillary resistance to maintain optimal myocardial perfusion and fluid filtration across the capillary wa...

Nitric Oxide–Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries

“…Both ECs and SMCs from PAs showed a strong expression of PKG (Figure 5B). Similar to L‐NNA, GC inhibitor ODQ (3 μmol/L)44 and PKG inhibitor Rp‐8‐Br‐PET‐CGMPS (PET; 30 μmol/L)45 increased the baseline sparklet activity by ≈2‐fold (Figure 5C), confirming that GC‐PKG signaling constitutively inhibits TRPV4 channels in PA endothelium. In the presence of GC or PKG inhibitor, L‐NNA was unable to further increase the activity of TRPV4 sparklets (Figure 5C, left ).…”

Endothelium-derived NO, but not cyclic GMP, is required for hypoxic augmentation in isolated porcine coronary arteries

“…This interpretation is strengthened by the results obtained with inhibitors of protein kinase G and protein kinase A (24) at concentrations believed to be effective in vascular smooth muscle (30,31). When soluble guanylyl cyclase is activated and produces cyclic GMP, the cyclic nucleotide predominately activates protein kinase G (34,42,43). Hence the lack of significant effect of these inhibitors on hypoxic augmentation implies that the response does not depend on cyclic GMP.…”

Effects of Papaverine on Twitches in Mouse Diaphragm

“…The concentrations of 8-br-cGMP used in our study were sufficient to inhibit contraction of smooth muscles in coronary vein [20] and mesenteric artery [21] . Nitric oxide is known to increase the cGMP content by stimulating guanylate cyclase, thus relaxing smoothmuscle contractions [22,23] .…”