alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1b) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.
Vasodilation following the infusion of acetylcholine is due to the release of endothelium-derived relaxing factor (EDRF). However, the role of EDRF in neurogenic coronary vasodilation, when acetylcholine is released outside the vessel at the adventitial-medial junction, has not been established. The action of EDRF in parasympathetic coronary vasodilation was tested in the present study using a specific inhibitor of EDRF synthesis, nitro-L-arginine methyl ester (L-NAME). Experiments were conducted on closed-chest, alpha-chloralose-anesthetized dogs with the heart paced at a constant rate. Phentolamine and propranolol were administered to block alpha- and beta-adrenergic receptors, and ibuprofen was given to inhibit prostaglandin synthesis. Intracoronary infusion of L-NAME decreased the coronary vasodilation in response to intracoronary acetylcholine or vagal stimulation. The coronary response to the endothelium-independent vasodilator nitroglycerin was unaffected by L-NAME. These data demonstrate that L-NAME specifically inhibits coronary vasodilation caused by acetylcholine and vagal stimulation, indicating that parasympathetic coronary vasodilation is dependent on EDRF.
Dihydropyrimidinones such as compound 12 exhibited high binding affinity and subtype selectivity for the cloned human alpha(1a) receptor. Systematic modifications of 12 led to identification of highly potent and subtype-selective compounds such as (+)-30 and (+)-103, with high binding affinity (K(i) = 0.2 nM) for alpha(1a) receptor and greater than 1500-fold selectivity over alpha(1b) and alpha(1d) adrenoceptors. The compounds were found to be functional antagonists in human, rat, and dog prostate tissues. Compound (+)-103 exhibited excellent selectively to inhibit intraurethral pressure (IUP) as compared to lowering diastolic blood pressure (DBP) in mongrel dogs (K(b)(DBP)/K(b)(IUP) = 40) suggesting uroselectivity for alpha(1a)-selective compounds.
Research efforts in the R 1 adrenergic receptor antagonist area have led to the discovery of some marketed antihypertensive drugs. 1 These agents apparently function by relaxing vascular smooth muscle which contains high concentrations of R 1 receptors. Researchers also found that R 1 receptors are abundant in the human prostate, bladder neck, and urethra, 2 and demonstrated that the use of nonselective R 1 receptor antagonists could provide symptomatic relief from the dynamic component of urinary flow problems resulting from increased adrenergic tone in males with hyperplastic prostates. 3 Subsequent to these findings, pharmacological and binding studies indicated there are three subclasses of R 1 receptors. The existence of these receptor subtypes, the R 1a , R 1b , and R 1d , has been confirmed through the use of molecular biological cloning techniques. 4 The study of a variety of tissue preparations led to the discovery of a heterogeneous distribution of the three R 1 receptors within animal and human tissues. Later,
A two-part experiment was designed to test the hypothesis that myocardial oxygen and carbon dioxide tensions, as measured by coronary venous oxygen and carbon dioxide tensions, determine coronary blood flow during increases in myocardial oxygen consumption. The left main coronary artery was pump-perfused at constant pressure in closed-chest, anesthetized dogs. Oxygenators in the perfusion circuit permitted control of coronary arterial gas tensions. The steady-state relation between coronary venous oxygen and carbon dioxide tensions and coronary flow at a constant myocardial oxygen consumption was determined by locally altering coronary arterial oxygen and carbon dioxide tensions. Values of coronary venous oxygen and carbon dioxide tensions and coronary flow were also obtained at normal coronary arterial gas tensions during pacing-induced increases in myocardial oxygen consumption. The data yielded a hyperbolic relation among coronary venous oxygen and carbon dioxide tension and coronary flow during constant myocardial metabolism, suggesting a synergistic interaction between myocardial oxygen and carbon dioxide tensions in determining coronary flow. This relation was then used to predict the coronary flow change during pacing-induced increases in myocardial metabolism. Approximately 40% of the flow response during pacing-induced increases in myocardial oxygen consumption was predicted. In conclusion, coronary venous oxygen and carbon dioxide tensions synergistically interact to produce steady-state changes in coronary flow at a constant myocardial oxygen consumption. Changes in myocardial oxygen and carbon dioxide tensions can account for about 40% of the change in coronary flow during moderate changes in myocardial oxygen consumption.
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