The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology

β-Adrenoceptor blocking agents (β-blockers) that at low concentrations antagonize cardiostimulant effects of catecholamines, but at high concentrations also cause cardiostimulation, have been appearing since the late 1960s. These cardiostimulant β-blockers, coined non-conventional partial agonists, antagonize the effects of catecholamines through a high-affinity site (β1HAR), but cause cardiostimulation mainly through a low-affinity site (β1LAR) of the myocardial β1-adrenoceptor. The experimental non-conventional partial agonist (−)-CGP12177 increases cardiac L-type Ca2+ current density and Ca2+ transients, shortens action potential duration but augments action potential plateau, increases heart rate and force, as well as causes arrhythmic Ca2+ transients and arrhythmic cardiocyte contractions. Other β-blockers, which do not cause cardiostimulation, consistently have lower affinity for β1LAR than β1HAR. These sites were verified and the cardiac pharmacology of non-conventional partial agonists confirmed on recombinant β1-adrenoceptors and on β1-adrenoceptors overexpressed into the heart. A targeted mutation of Asp138 to Glu138 virtually abolished the pharmacology of β1HAR but left intact the pharmacology of β1LAR. Non-conventional partial agonists may be beneficial for the treatment of peripheral autonomic neuropathy but probably due to their arrhythmic propensities, may be harmful for the treatment of chronic heart failure.

Detection and prevention of distributed denial of services attacks by collaborative effort of software agents, first prototype implementation

Distributed Denial of Services DDoS, attacks has become one of the biggest threats for resources over Internet. Purpose of these attacks is to make servers deny from providing services to legitimate users. These attacks are also used for occupying media bandwidth. Currently intrusion detection systems can just detect the attacks but cannot prevent / track the location of intruders. Some schemes also prevent the attacks by simply discarding attack packets, which saves victim from attack, but still network bandwidth is wasted. In our opinion, DDoS requires a distributed solution to save wastage of resources. The paper, presents a system that helps us not only in detecting such attacks but also helps in tracing and blocking (to save the bandwidth as well) the multiple intruders using Intelligent Software Agents. The system gives dynamic response and can be integrated with the existing network defense systems without disturbing existing Internet model. We have implemented an agent based networking monitoring system in this regard.