Do Optimal Antihypertensive Drug Regimens Allow Blood Pressure Normalization in All Patients With Resistant Hypertension?

Do Optimal Antihypertensive Drug Regimens Allow Blood Pressure Normalization in All Patients With Resistant Hypertension?

Hypertension. 2013 Aug 5;
Waeber B, Feihl F

HubMed – drug

Potassium Channel Openers Increase Aortic Elastic Fiber Formation and Reverse the Genetically Determined Elastin Deficit in the BN Rat.

Hypertension. 2013 Aug 5;
Slove S, Lannoy M, Behmoaras J, Pezet M, Sloboda N, Lacolley P, Escoubet B, Buján J, Jacob MP

Hypertension is a cardiovascular disorder that appears in more than half of the patients with Williams-Beuren syndrome, hemizygous for the elastin gene among 26 to 28 other genes. It was shown that the antihypertensive drug minoxidil, an ATP-dependent potassium channel opener, enhances elastic fiber formation; however, no wide clinical application was developed because of its adverse side effects. The Brown Norway rat was used here as an arterial elastin-deficient model. We tested 3 different potassium channel openers, minoxidil, diazoxide, and pinacidil, and 1 potassium channel blocker, glibenclamide, on cultured smooth muscle cells from Brown Norway rat aorta. All tested potassium channel openers increased mRNAs encoding proteins and enzymes involved in elastic fiber formation, whereas glibenclamide had the opposite effect. The higher steady-state level of tropoelastin mRNA in minoxidil-treated cells was attributable to an increase in both transcription and mRNA stability. Treatment of Brown Norway rats for 10 weeks with minoxidil or diazoxide increased elastic fiber content and decreased cell number in the aortic media, without changing collagen content. The minoxidil-induced cardiac hypertrophy was reduced when animals simultaneously received irbesartan, an angiotensin II-receptor antagonist. This side effect of minoxidil was not observed in diazoxide-treated animals. In conclusion, diazoxide, causing less undesirable side effects than minoxidil, or coadministration of minoxidil and irbesartan, increases elastic fiber content, decreases cell number in the aorta and, thus, could be suitable for treating vascular pathologies characterized by diminished arterial elastin content and simultaneous hypertension. HubMed – drug

Determination of the In Vivo Selectivity of a New ?-Opioid Receptor Antagonist PET Tracer 11C-LY2795050 in the Rhesus Monkey.

J Nucl Med. 2013 Aug 5;
Kim SJ, Zheng MQ, Nabulsi N, Labaree D, Ropchan J, Najafzadeh S, Carson RE, Huang Y, Morris ED

(11)C-LY2795050 is a novel ?-selective antagonist PET tracer. The in vitro binding affinities (Ki) of LY2795050 at the ?-opioid (KOR) and ?-opioid (MOR) receptors are 0.72 and 25.8 nM, respectively. Thus, the in vitro KOR/MOR binding selectivity is about 36:1. Our goal in this study was to determine the in vivo selectivity of this new KOR antagonist tracer in the monkey.To estimate the ED50 value (dose of a compound [or drug] that gives 50% occupancy of the target receptor) of LY2795050 at the MOR and KOR sites, 2 series of blocking experiments were performed in 3 rhesus monkeys using (11)C-LY2795050 and (11)C-carfentanil with coinjections of various doses of unlabeled LY2795050. Kinetic modeling was applied to calculate regional binding potential (BPND), and 1- and 2-site binding curves were fitted to these data to measure (11)C-LY2795050 binding selectivity.The LY2795050 ED50 at MOR was 119 ?g/kg based on a 1-site model for (11)C-carfentanil. The 1-site binding model was also deemed sufficient to describe the specific binding of (11)C-LY2795050 at KOR. The ED50 at KOR estimated from the 1-site model was 15.6 ?g/kg. Thus, the ED50 ratio for MOR:KOR was 7.6.The in vivo selectivity of (11)C-LY2795050 for KOR over MOR is 7.6. (11)C-LY2795050 has 4.7-fold-lower selectivity at KOR over MOR in vivo as compared with in vitro. Nevertheless, on the basis of our finding in vivo, 88% of the PET-observed specific binding of (11)C-LY2795050 under baseline conditions will be due to binding of the tracer at the KOR site in a region with similar prevalence of KOR and MOR. (11)C-LY2795050 is sufficiently selective for KOR over MOR in vivo to be considered an appropriate probe for studying the KOR with PET. HubMed – drug