Augmented vasoconstriction is a hallmark of hypertension and is mediated partly by hyperstimulation of G protein couple receptors (GPCRs) and downstream signaling components. Although GPCR blockade is a key component of current anti-hypertensive strategies, whether hypertension is better managed by directly targeting G proteins has not been thoroughly investigated. Here, we tested whether inhibiting G q/11 proteins in vivo and ex vivo using natural cyclic depsipeptide, FR900359 (FR) from the ornamental plant, Ardisia crenata, and YM-254890 (YM) from Chromobacterium sp. QS3666, or it's synthetic analog, WU-07047 (WU), was sufficient to reverse hypertension in mice. All three inhibitors blocked G protein-dependent vasoconstriction, but to our surprise YM and WU and not FR inhibited K +-induced Ca 2+ transients and vasoconstriction of intact vessels. However, each inhibitor blocked whole-cell L-type Ca 2+ channel current in vascular smooth muscle cells. Subcutaneous injection of FR or YM (0.3 mg/kg, s.c.) in normotensive and hypertensive mice elicited bradycardia and marked blood pressure decrease, which was more severe and long lasting after the injection of FR relative to YM (FR t1/2 ≅ 12 hr vs. YM t1/2 ≅ 4 hr). In deoxycorticosterone acetate (DOCA)-salt hypertension mice, chronic injection of FR (0.3 mg/kg, s.c., daily for seven days) reversed hypertension (vehicle SBP: 149 ± 5 vs. FR SBP: 117 ± 7 mmHg), without any effect on heart rate. Our results together support #
Background: According to the World Health Organization, cardiovascular disease is the number one cause of death globally, claiming millions of lives each year with an increasing prevalence. Myocardial infarction (MI) makes up a large sum of these deaths each year. While MI in itself is lethal, there are several complications that can increase the morbidity and mortality of an MI, such as left ventricular wall rupture and aneurysms. Case Presentation: We present a case of an elderly male with an extensive cardiac history who presented with a non-ST segment myocardial infarction (NSTEMI) managed with percutaneous coronary intervention. Hours after, he became hemodynamically unable and was found to have a pseudoaneurysm of the left ventricle. Despite aggressive efforts, his pseudoaneurysm ruptured and he ultimately succumbed to his condition. Conclusions: Left ventricular pseudoaneurysm is usually seen after myocardial infarctions with a rupture rate of up to 45% leading to a mortality rate of about 50%. While cardiac catheterization with left ventriculography is the gold standard for diagnosis, echocardiography can also be used as an alternative. Treatment is emergent cardiac surgery but still holds a high operative risk. Therefore, patients may be medically stabilized and managed prior to ultimate surgical intervention.
Chronic blockade of individual G protein coupled receptors (GPCRs) has proven to be inadequate strategy for managing hypertension partly because the subcellular heterotrimeric G proteins that propagate intracellular signaling can simultaneously couple to several other vasopressor receptors. Whether blood pressure can better be controlled by directly targeting G proteins has not been thoroughly investigated due to paucity of selective, cell-permeable inhibitors. Here, we tested whether chemical inhibition of Gq/11 proteins in vivo and ex vivo using recently discovered small-molecule inhibitor ligands, YM-254890 (YM), FR-900359 (FR) and WU-07047 (WU) is sufficient to reverse hypertension in mice. Using ex vivo vessel reactivity assay, we found that Gq/11 inhibitors markedly reduced vasoconstriction evoked with phenylephrine (PE), vasopressin, endothelin-1, and the thromboxane analog U-46619. Blockade of PE-induced contractility by the Gq/11 inhibitors showed the following rank-order potency: FR LogIC50 -0.008 ± 0 > YM LogIC50 -0.49 ± 0 > WU LogIC50 -64.95 ± 6.4. YM and WU but not FR inhibited PE-induced vasoconstriction through G protein-dependent and independent pathways by blocking L-type calcium channel-mediated Ca 2+ influx. Acute subcutaneous injection of FR and YM (0.3 mg/kg, s.c.) in normotensive and N ω -Nitro-L-arginine methyl ester (L-NAME) hypertension mice elicited marked hypotension, which was more severe (ΔSBP = -25 ± 2.7 vs. ΔSBP = -21 ± 2.2 mmHg) and long lasting (FR t1/2 ≅ 12 hr vs. YM t1/2 ≅ 4 hr) after the injection of FR relative to YM. In DOCA-salt hypertension mice, chronic injection of FR (0.3 mg/kg, s.c., daily for seven days) reversed hypertension (vehicle SBP: 149 ± 5 vs. FR SBP: 117 ± 7 mmHg) and sustained blood pressure reduction several days after terminating the injection regimen (DOCA SBP: 141 ± 2 vs. SBP 5 days post FR: 128 ± 5 mmHg). Our results together support the hypothesis that increased Gq/11 activity in blood pressure-regulating organs is involved in the pathogenesis of hypertension, and that direct systemic blockade of Gq/11 reverses hypertension. The findings provide clear evidence for targeting Gq/11 in the cardiovascular system as an effective therapy for treating hypertension.
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