6-Amino-3-Methyl-4-(2-nitrophenyl)-1,4-Dihydropyrano[2,3-c]Pyrazole-5-Carbonitrile Shows Antihypertensive and Vasorelaxant Action via Calcium Channel Blockade

Several 4H-pyran derivatives were designed and synthesized previously as vasorelaxant agents for potential antihypertensive drugs. In this context, the objective of the present investigation was to determine the functional mechanism of vasorelaxant action of 6-amino-3-methyl-4-(2-nitrophenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1) and its in vivo antihypertensive effect. Thus, compound 1 showed significant vasorelaxant action on isolated aorta rat rings pre-contracted with serotonin or noradrenaline, and the effect was not endothelium-dependent. Compound 1 induced a significant relaxant effect when aortic rings were contracted with KCl (80 mM), indicating that the main mechanism of action is related to L-type calcium channel blockade. Last was corroborated since compound 1 induced a significant concentration-dependent lowering of contraction provoked by cumulative CaCl2 adding. Moreover, compound 1 was capable to block the contraction induced by FPL 64176, a specific L-type calcium channel agonist, in a concentration-dependent manner. On the other hand, docking studies revealed that compound 1 interacts on two possible sites of the L-type calcium channel and it had better affinity energy (−7.80+/−0.00 kcal/mol on the best poses) than nifedipine (−6.86+/−0.14 kcal/mol). Finally, compound 1 (50 mg/kg) showed significant antihypertensive activity, lowering the systolic and diastolic blood pressure on spontaneously hypertensive rats (SHR) without modifying heart rate.

Rare case of coronary spastic angina during treatment of invasive group A streptococcal sepsis

The underlying mechanisms of coronary spastic angina (CSA) is not well understood. It is unclear if an infection can trigger coronary vasospasm; the co-occurrence of sepsis and CSA has rarely been reported. We describe the case of a 47-year-old man who suddenly developed a complete atrioventricular block and an episode of cardiac arrest while undergoing treatment for sepsis secondary to invasive group A streptococci. Emergency coronary angiography and provocation revealed spasm of the right coronary artery, which had led to the atrioventricular block. The spasm was relieved following administration of calcium-channel blockade, and no subsequent recurrence was documented. Due to several underlying mechanisms, sepsis may be a potential risk factor of coronary spasm and episodes of this condition have been missed or misdiagnosed. Physicians should be aware of CSA as a potential complication during treatment of sepsis.

Abstract 12885: Sleepless Nights and Squeamish Days: A Conundrum of Recurrent Myocardial Ischemia

A 63-year old Caucasian female with history of aortic valve replacement and CAD with prior drug-eluting stent placement (DES) to proximal LAD and LCX, presented as a hospital transfer with recurrent episodes of chest pain. Chest discomfort was described as severe chest pressure, radiating to bilateral upper extremities. Episodes were not associated with significant exertion and frequently occurred at night/early morning. Of note, the patient had undergone coronary angiography at the outside hospital, revealing no in-stent restenosis or new coronary lesions. Soon after the patient’s arrival in the CCU, she developed profound chest pressure, accompanied by hypotension, diaphoresis and nausea. Her 12-lead ECG revealed 2-mm ST-elevation in aVR, accompanied by ST-depression in inferior, anterior, and apical leads. Initial high-sensitivity (hs)-troponin T was 26 ng/L. She was given sublingual nitroglycerin and was started on a nitroglycerin and nicardipine infusion, with resolution of symptoms after ~30 minutes, followed by normalization of hs-troponin T. A transthoracic echocardiogram did not reveal focal left ventricular (LV) wall motion abnormalities, mild LV hypertrophy was present. Given the patients’ presentation with no in-stent restenosis or new lesions, frequent episodes of chest pain-not related to exertion with occurrence at nighttime and early morning, her presentation was deemed to be consistent with epicardial coronary vasospasm. Subsequently, the patients’ anti-anginal regimen was uptitrated to include extended-release nitrates, calcium-channel blockade, and I Na blockade. Unfortunately, she continued to have frequent episodes of profound angina, accompanied by hypotension, and significant ischemic ECG changes. This prompted us to pursue bilateral sympathectomy. Subsequently, the patient had resolution of prior symptoms. She was continued on an anti-vasospastic regimen, consisting of extended release nitrates and calcium-channel blockade. This case represents the challenging management of medication-resistant epicardial coronary artery vasospasm. As previously described, sympathectomy remains an effective therapeutic option for management in these difficult and life-threatening situations.

Paradigma baru penggunaan statin: efek kardioprotektif atau penyebab onset baru diabetes melitus?

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors atau yang biasa disebut sebagai statin, merupakan obat yang sudah digunakan sejak 30 tahun silam dan merupakan salah satu obat yang paling sering digunakan untuk terapi dislipidemia. Menurut hasil terbaru dari banyak studi observasional, randomized controlled trials (RCTs) dan meta-analyses telah mengonfirmasi adanya korelasi kejadian diabetes melitus (new-onset diabetes mellitus/NODM) setelah inisiasi penggunaan statin. Mekanisme spesifik terkait pengaruh statin terhadap kejadian diabetes melitus masih belum sepenuhnya dipahami, namun gangguan fungsi sel beta pankreas melalui calcium channel blockade, berkurangnya sensitivitas jaringan terhadap insulin akibat berkurangnya ekspresi GLUT 4, rendahnya kadar adiponektin dan mungkin mekanisme lainnya diduga menjadi faktor pencetus NODM. Sebagaimana yang kita tahu, statin digunakan dalam terapi dislipidemia serta pencegahan baik primer maupun sekunder terhadap kejadian penyakit kardiovaskular melalui efek pleiotropiknya. Namun, dengan adanya keterkaitan kejadian NODM maka makna protektif penggunaan statin menjadi berkurang. Pada artikel ini akan dibahas mengenai kemungkinan mekanisme statin terkait kejadian NODM dan makna penggunaanya sebagai pencegahan penyakit kardiovaskular.