Browsing Pathways

Angiotensin is a peptide hormone that causes vasoconstriction and a subsequent increase in blood pressure. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin also stimulates the release of aldosterone, another hormone, from the adrenal cortex. Aldosterone promotes sodium retention in the distal nephron, in the kidney, which also drives blood pressure up. (Wikipedia)

Angiotensin is a peptide hormone that is part of the renin-angiotensin system responsible for regulating fluid homeostasis and blood pressure. It is involved in various means to increase the body's blood pressure, hence why it is a target for many pharmceutical drugs that treat hypertension and cardiac conditions. Angiotensin II, the primary agent to inducing an increased blood pressure, is formed in the general circulation when it is cleaved from a string of precursor molecules. Angiotensinogen is converted into angiotensin I with the action of renin, an enzyme secreted from the kidneys. From there, angiotensin I is converted to the central agent, angiotensin II, with the aid of angiotensin-converting enzyme (ACE) so that it is available in the circulation to act on numerous areas in the body when an increase in blood pressure is needed. Angiotensin II can act directly on receptors on the smooth muscle cells of the tunica media layer in the blood vessel to induce vasoconstriction and a subsequent increase in blood pressure. However, it can also influence the blood pressure by aiding in an increase of the circulating blood volume. Angiotensin II can cause vasopressin to be released, which is a hormone involved in regulating water reabsorption. Vasopressin is created in the supraoptic nuclei and they travel down the neurosecretory neuron axon to be stored in the neuronal terminals within the posterior pituitary. Angiotensin II in the cerebral circulation triggers the release of vasopressin from the posterior pituitary gland. From there, vasopressin enters into the systemic blood circulation where it eventually binds to receptors on epithelial cells in the collecting ducts of the nephron. The binding of vasopressin causes vesicles of epithelial cells to fuse with the plasma membrane. These vesicles contain aquaporin II, which are proteins that act as water channels once they have bound to the plasma membrane. As a result, the permeability of the collecting duct changes to allow for water reabsorption back into the blood circulation. Angiotensin II also has an effect on the hypothalmus, where it helps trigger a thirst sensation. Correspondingly, there will be an increase in oral water uptake into the body, which would then also increase the circulating blood volume. Another way that angiotensin II helps increase the blood volume is by acting on the adrenal cortex to stimulate aldosterone release, which is responsible for increasing sodium reuptake in the distal convoluted tubules and the collecting duct. It is formed when angiotensin II binds to receptors on the zona glomerulosa cells in the adrenal cortex, which triggers a signaling cascade that eventually activates the steroidogenic acute regulatory (StAR) protein to allow for cholesterol uptake into the mitochondria. Cholesterol then undergoes a series of reactions during steroidogenesis, which is a process that ultimately leads to the synthesis of aldosterone from cholesterol. Aldosterone then goes to act on the distal convoluted tubule and the collecting duct to make them more permeable to sodium to allow for its reuptake. Water subsequently follows sodium back into the system, which would therefore increase the circulating blood volume. In addition, potassium and hydrogen are also being excreted into the urine simultaneously to maintain the electrolyte balance.

The monoamine oxidase is an enzyme that catalyzes the oxidative deamination of many amines like serotonin, norepinephrine, epinephrine, and dopamine. There are 2 isoforms of this protein: A and B. The first one is found in cells located in the periphery and breakdown serotonin, norepinephrine, epinephrine, dopamine, and tyramine. The second one, the B isoform, breakdowns phenylethylamine, norepinephrine, epinephrine, dopamine, and tyramine. This isoform is found in the extracellular tissues and mostly in the brain. An amine oxidase is an enzyme that catalyzes the oxidative cleavage of alkylamines into aldehydes and ammonia. Amine oxidases are divided into two subfamilies based on the cofactor they contain. Amine oxidases catalyze oxidative deamination reactions, producing ammonia and an aldehyde. These enzymes are critical to both homeostatic and xenobiotic metabolic pathways and are involved in the biotransformation of aminergic neurotransmitters (such as catecholamines, histamine, and serotonin) as well as toxins and carcinogens in foods and the environment. The monoamine oxidases (MAOs) are well studied and have been targets for drug therapy for more than 60 years. MAOs are flavin-containing mitochondrial enzymes distributed throughout the body. In humans, two isoenzymes of MAO have been identified, encoded by two genes located on the X chromosome: MAO-A and MAO-B. Each isoenzyme can be distinguished by certain substrate specificities and anatomic distribution (Table 4.9), although MAO-A has the distinction of being the sole catecholamine metabolic enzyme in sympathetic neurons. In neural and other selective tissues, MAOs catalyze the first step in the degradation of catecholamines into their aldehyde intermediaries, which is further processed by catechol-O-methyltransferase. The ubiquity of biogenic amines and their central role in neural and cardiovascular function make MAOs highly relevant to clinical anesthesia. The interactions between MAO inhibitors and drugs commonly used in anesthesia have been well described. Although genetic polymorphisms in MAO genes exist and are of great interest in the fields of neurology and psychiatry, to date none have been identified that specifically concern the handling of anesthetic agents.

The monoamine oxidase is an enzyme that catalyzes the oxidative deamination of many amines like serotonin, norepinephrine, epinephrine, and dopamine. There are 2 isoforms of this protein: A and B. The first one is found in cells located in the periphery and breakdown serotonin, norepinephrine, epinephrine, dopamine, and tyramine. The second one, the B isoform, breakdowns phenylethylamine, norepinephrine, epinephrine, dopamine, and tyramine. This isoform is found in the extracellular tissues and mostly in the brain. The mechanism of action of the MAOIs is still not determined, it is thought that they act by increasing free serotonin and norepinephrine concentrations and/or by altering the concentrations of other amines in the CNS. mine oxidases are divided into two subfamilies based on the cofactor they contain. Amine oxidases catalyze oxidative deamination reactions, producing ammonia and an aldehyde. These enzymes are critical to both homeostatic and xenobiotic metabolic pathways and are involved in the biotransformation of aminergic neurotransmitters (such as catecholamines, histamine, and serotonin) as well as toxins and carcinogens in foods and the environment. The monoamine oxidases (MAOs) are well studied and have been targets for drug therapy for more than 60 years. MAOs are flavin-containing mitochondrial enzymes distributed throughout the body. In humans, two isoenzymes of MAO have been identified, encoded by two genes located on the X chromosome: MAO-A and MAO-B. Each isoenzyme can be distinguished by certain substrate specificities and anatomic distribution (Table 4.9), although MAO-A has the distinction of being the sole catecholamine metabolic enzyme in sympathetic neurons. In neural and other selective tissues, MAOs catalyze the first step in the degradation of catecholamines into their aldehyde intermediaries, which is further processed by catechol-O-methyltransferase. The ubiquity of biogenic amines and their central role in neural and cardiovascular function make MAOs highly relevant to clinical anesthesia. The interactions between MAO inhibitors and drugs commonly used in anesthesia have been well described. Although genetic polymorphisms in MAO genes exist and are of great interest in the fields of neurology and psychiatry, to date none have been identified that specifically concern the handling of anesthetic agents.

Aldosterone is a hormone produced in the zona glomerulosa of the adrenal cortex. It's function is to act on the distal convoluted tubule and the collecting duct of the nephron to make them more permeable to sodium to allow for its reuptake (in addition to allowing potassium wasting). As a result, water follows the sodium back into the body. The water retention contributes to an increased blood volume. Angiotensin II from the circulation binds to receptors on the zona glomerulosa cell membrane, activating the G protein and triggering a signaling cascade. The end result is the activation of the steroidogenic acute regulatory (StAR) protein that permits cholesterol uptake into the mitochondria. From there, cholesterol undergoes a series of reactions in both the mitochondrion and the smooth endoplasmic reticulum (steroidogenesis) where it finally becomes aldosterone.

Angiotensin-converting enzyme (EC 3.4.15.1), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstrictor angiotensin II. Therefore, ACE indirectly increases blood pressure by causing blood vessels to constrict. ACE inhibitors are widely used as pharmaceutical drugs for treatment of cardiovascular diseases. Other lesser known functions of ACE are degradation of bradykinin, substance P, and amyloid beta-protein. Angiotensin converting enzyme (ACE) is well known for its dual actions in converting inactive Ang I to active Ang II and degrade active bradykinin (BK), which play an important role in the control of blood pressure. Since the bottle neck step is the production of pressor Ang II, this was targeted pharmacologically in 1970s and successful ACE inhibitors such as captopril were produced to treat hypertension. ACE2 was identified as the receptor for SARS (severe acute respiratory syndrome) coronavirus, which caused the outbreak of an epidemic in 2002–2003. Two isozymes of ACE are present in mammals: somatic ACE and testis ACE. Somatic ACE possesses two catalytic domains (N- and C-domains) and a C-terminal transmembrane segment (stalk). Somatic and testis ACEs in humans contain 1,306 and 665 aa residues, respectively. Testis ACE only possesses one catalytic domain. Both catalytic domains are zinc-metallopeptidase with the active motif HEMGH where the two histidine residues coordinate the zinc ion. The stalk anchors the enzyme on the membrane and is susceptible to be cleaved by shedding enzymes, resulting in plasma ACE activity. Somatic ACE is expressed in various tissues including blood vessels, kidney, intestine, adrenal gland, liver, and uterus, and is especially abundant in highly vascular organs such as retina and lung. Testis ACE is expressed by postmeiotic male germ cells and high-level expression is found in round and elongated spermatids. ACE2 is expressed in lung, liver, intestine, brain, testis, heart, and kidney. Lung possesses the highest amount of ACE. Expression of ACE is affected by steroids and thyroid hormone, but the details of the regulation are not clear. ACE is under promoter regulation by hypoxia-inducing factor 1α (HIF-1α), which upregulates the ACE expression under hypoxic conditions, resulting in an increase in Ang II concentration. The well-known function of ACE is the conversion of Ang I to Ang II and degradation of BK, which all play an important role in controlling blood pressure. ACE also acts on other natural substrates including encephalin, neurotensin, and substance P. Besides being involved in blood pressure control, ACE possesses widespread functions including renal development, male fertility, hematopoiesis, erythropoiesis, myelopoiesis, and immune responses. ACE has been the target of hypertension control since the 1970s. ACE inhibitors are prescribed as the sole or combinational treatment of high blood pressure, for the dual effects of lowering Ang II and slowing down BK degradation. Angiotensin II binds to the type 1 angiotensin II receptor (AT1), which sets off a number of actions that result in vasoconstriction and therefore increased blood pressure. The B2 (bradykinin 2) receptor is constitutively expressed and participates in bradykinin's vasodilatory role, it is a G protein coupled receptor.