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Small-molecule WNK inhibition regulates cardiovascular and renal function.
The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinaseExpand
Drug effects on the CVS in conscious rats: separating cardiac output into heart rate and stroke volume using PKPD modelling
Previously, a systems pharmacology model was developed characterizing drug effects on the interrelationship between mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistanceExpand
PKPD modelling of the interrelationship between mean arterial BP, cardiac output and total peripheral resistance in conscious rats
The homeostatic control of arterial BP is well understood with changes in BP resulting from changes in cardiac output (CO) and/or total peripheral resistance (TPR). A mechanism‐based and quantitativeExpand
Pharmacodynamic and Pharmacokinetic Characterization of the Aldosterone Synthase Inhibitor FAD286 in Two Rodent Models of Hyperaldosteronism: Comparison with the 11β-Hydroxylase Inhibitor Metyrapone
Aldosterone synthase (CYP11B2) inhibitors (ASIs) represent an attractive therapeutic approach for mitigating the untoward effects of aldosterone. We characterized the pharmacokinetic/pharmacodynamicExpand
Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors.
Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure.Expand
Design and synthesis of a potent and selective endothelin-converting enzyme inhibitor, CGS 35066.
CGS 26303 has previously been shown to inhibit human endothelin converting enzyme-1 (ECE-1) with an IC50 of 410 nM and to be efficacious in several animal disease models. However, it is a more potentExpand
Evaluation of the cardiovascular effects of arecoline in the anesthetized dog
Arecoline has been reported to improve memory deficits, but a relatively short half‐life and adverse cardiovascular effects have limited its use. The purpose of this study was to compare theExpand
Aldosterone synthase inhibition: cardiorenal protection in animal disease models and translation of hormonal effects to human subjects
BackgroundAldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone. In vitro studies with recombinantExpand
Age and muscle-type modulated role of intramyocellular lipids in the progression of insulin resistance in nondiabetic Zucker rats.
The effect of muscle fiber type and maturation on intramyocellular lipid (IMCL) content and its relationship to insulin resistance was investigated. Intramyocellular lipid content in slow-twitchExpand
Pharmacologic profile of CGS 24128, a potent, long-acting inhibitor of neutral endopeptidase 24.11.
We compared the pharmacologic profiles of thiorphan, a neutral endopeptidase (NEP) inhibitor which is cleared rapidly from the circulation, and CGS 24128, an inhibitor with a much longer half-lifeExpand