Safety is an integral part of developing new medicines. Potential drugs can be withdrawn from development at any stage of the process if there are concerns over safety. In recent years, computer models that recreate physiology have been increasingly adopted in various aspects of drug development, including safety, to predict the effects of new drugs. The accuracy of this predictive model is however, dependent on the ability for animal data (which the model is usually based on) to be 'translated' to human data. As no animal is identical to humans, the difference between species needs to be understood for the model to be accurate.~Unwanted effects on the cardiovascular system is one of the most common causes of safety related discontinuation of a drug. The present study focuses on generating high quality human cardiovascular data that is comparable with existing animal data. This will be achieved through the collection of detailed pharmacokinetic and pharmacodynamic data following administration of drugs that are known to affect the cardiovascular system through a range of mechanisms. This will be first performed in healthy participants before extending it to those with pre-existing (or risk-factors for) cardiovascular disease. The aim is to understand the differences between species and the study populations and using the collected data to help inform how a translational model is to be built.~Study Design: Single centre, single (participant) blind, within subject, drug administration study~Drugs used in study:~Salbutamol - a beta-2-adrenergic agonist~Nicardipine - a dihydropyridine calcium channel antagonist~Dobutamine - a beta-1-adrenergic agonist~Phenylephrine - a selective alpha-1-adrenergic agonist~Verapamil - a phenylalkylamine calcium channel antagonist~Phentolamine - a non-selective alpha adrenergic antagonist~Study Population:~The study will take place in three parts (A, B and C), with each part representing population groups that are of interest.~Part A (16 participants): Healthy individuals with no identifiable cardiovascular risk factors will be recruited for this part of the study. The aim of this part is to enable the collection of physiological data after drug administration in a 'normal' cardiovascular system.~Part B (8 participants): Part B will involve the recruitment of participants who may possess an altered/challenged cardiovascular system. Participants recruited will possess one of the following factors: known diagnosis of diabetes, known diagnosis of hypertension, obesity (BMI>30), age >65. The data collected will provide information on how potential changes to baseline cardiovascular physiology may affect the effect of the drug.~Part C (8 participants): In order to understand the impact of medicines on cardiovascular physiology in the absence of the autonomic nervous system regulation, we will recruit participants with dysfunction of the autonomic system to Part C of the study.~Maximum duration of participation for each participant:~1x screening (1 hour duration), 4x study visits (8 hour duration each) with minimum 72 hours gap in between visits. Maximum duration is 4 months to complete all visits.
Unwanted effects on the cardiovascular system is one of the most common causes of safety related discontinuation of a drug. This study aims to develop an in silico model of the human cardiovascular system that can be used to predict unwanted cardiovascular effects of drugs. This will be achieved through a drug administration study that will generate comprehensive pharmacokinetic and pharmacodynamic data following the administration of the following drugs, all known to have effects on the cardiovascular system. Half the participants will receive: Placebo, Salbutamol, Nicardipine, Dobutamine and the other half will receive Placebo, Phenylephrine, Verapamil, Phentolamine.