5-Hydroxtryptamine Receptors in Systemic Hypertension: an arterial focus

5-hydroxytryptamine (5-HT, serotonin) was named for its isolation from blood serum (sero-) and ability to contract smooth muscle (-tonin). Thus, its relationship with the cardiovascular system began with its discovery. This review will focus on the effects of 5-HT and its receptors in the vasculature, with a focus on their involvement in high blood pressure (hypertension). Two seemingly contradictory bodies of evidence exist that make it difficult to assign any one function to 5-HT in vascular control of blood pressure. In vitro, 5-HT is an established vasoconstrictor, the effects of which are amplified in hypertension. By contrast, 5-HT (or its precursor 5-hydroxytryptophan) lowers blood pressure when given chronically in vivo. We will discuss ideas that might help us understand these differences, discuss relatively new pharmacology parameters (e.g. biased, inverse agonism) as they pertain to 5-HT receptors, and pose questions that are vital to answer so as to understand the role played by 5-HT in control of blood pressure, especially as it pertains to vascular function. Our goal is to understand if the actions of 5-HT in hypertension are physiologically and clinically relevant. The community understands 5-HT has complex cardiovascular effects, and clinical studies have proven equivocal in terms of the involvement of 5-HT. This article provides a balanced view of evidence/literature that illustrates involvement of 5-HT in hypertension as controversial. It contributes new pharmacological knowledge of 5-HT compounds, and poses timely questions as to how this field can move forward. The take home message is that the cardiovascular effects of 5-HT are markedly complex such that we have not yet answered the question of whether 5-HT is beneficial or detrimental to hypertension. Introduction Serotonin (5-hydroxytryptamine, 5-HT) is a hormone/neurotransmitter found in species as diverse as fungi, plants and animals. 5-HT exerts its biological effects primarily through activation of receptors in the cell membrane. In 1957, two different 5-HT receptors were discovered [D and M type; 1] and the field of 5-HT receptors has blossomed in the last half-century. The International Union of Pharmacology (IUPHAR) is the society recognized for receptor classification, and the last receptor classification for 5-HT was updated in October 2009 [2,3]. At the present, seven major types for 5-HT receptors exist (5-HT1–5-HT7) and subtypes of several members exist. This review will focus on the 5-HT receptor subtypes that may be involved in high blood pressure (hypertension) and pays particular attention to the effects of 5-HT in the arterial vasculature. We will present a long standing conundrum with respect to the involvement of 5-HT in blood pressure control, namely that in vitro 5-HT is an arterial contractant, while in vivo 5-HT lowers blood pressure. Hypertension, defined as a systolic blood pressure greater than 140 mmHg or a diastolic blood pressure greater than 90 mm Hg, afflicts more than 70 million adults in the United States (wwwamericanheart.or/presenter.jhtml?identifier=4621), and places individuals at a significantly higher risk for stroke, myocardial infarction, coronary arterial and kidney disease. One of the original founders of the American Heart Association Council for High Blood Pressure Research, Irving Page, was a discoverer of 5-HT [4–6]; around the same time, the Italian scientist Vittorio Erspamer also chemically identified 5-hydroxytryptamine [7]. Since this time, 5-HT has ridden a roller coaster in terms of its causality and/or involvement in hypertension. As will be expanded on below, 5-HT is a potent vasoconstrictor in isolated arteries, but when given in vivo, 5-HT acts to reduce blood pressure. We will briefly introduce 5-HT, present some new ideas in receptor pharmacology, discuss both sides of the argument (5-HT as pro- or anti-hypertensive), and end with ideas and thoughts for future research. Throughout this review, we will pay focused attention to the pharmacology of 5-HT receptors, especially as it pertains to the arterial vasculature, and direct the reader to other relevant reviews that deal with topics we will not discuss (e.g. central regulation, renal regulation, heart function).