Physiology
Cardiovascular
Most vasoconstrictors act to bring about this effect by which of the following mechanisms of action:
Answer:
The endothelium plays a vital role in regulation of vascular tone (as well as regulation of haemostasis, angiogenesis and inflammatory response). Most vasoconstrictors bind to G-protein coupled receptors which mediate elevation in intracellular [Ca2+], leading to vascular smooth muscle contraction. Important vasoconstrictors include endothelin-1, angiotensin II and noradrenaline. The increase in intracellular [Ca2+] is brought about by release of Ca2+ from the sarcoplasmic reticulum and by depolarisation and entry of Ca2+ via L-type voltage-gated Ca2+ channels. Most types of vascular smooth muscle do not generate action potentials, but instead depolarisation is graded, allowing graded entry of Ca2+.Vascular Tone Regulation
Physiology / Cardiovascular / Peripheral Vascular System
Last Updated: 21st April 2019
Basis of Vasoconstriction
Most vasoconstrictors bind to G-protein coupled receptors which mediate elevation in intracellular [Ca2+], leading to vascular smooth muscle contraction. Important vasoconstrictors include endothelin-1, angiotensin II and noradrenaline.
The increase in intracellular [Ca2+] is brought about by release of Ca2+ from the sarcoplasmic reticulum and by depolarisation and entry of Ca2+ via L-type voltage-gated Ca2+ channels. Most types of vascular smooth muscle do not generate action potentials, but instead depolarisation is graded, allowing graded entry of Ca2+.
Basis of Vasodilation
Vasodilation occurs by decreasing intracellular [Ca2+] through sequestration by the sarcoplasmic reticulum Ca2+ ATPase and by removal from the cell by a plasma membrane Ca2+ ATPase and Na+/Ca2+ exchange.
Most endogenous vasodilators cause relaxation by increasing cyclic guanosine monophosphate (cGMP) (e.g. nitric oxide) or cyclic adenosine monophosphate (cAMP) (e.g. prostacyclin, beta-adrenergic receptor agonists), which activate protein kinases causing substrate level phosphorylation. L-type Ca2+ channel blocker drugs are clinically effective vasodilators.
Endothelial Function
The endothelium plays a vital role in regulation of vascular tone (as well as regulation of haemostasis, angiogenesis and inflammatory response).
In response to substances in the blood, endothelial damage or changes in blood flow, it can synthesise several important substances; nitric oxide and prostacyclin are important vasodilators and endothelin-1 and thromboxane A2 are potent vasoconstrictors.
Nitric oxide (NO) production by the endothelium is increased by factors that elevate intracellular Ca2+, including local mediators such as bradykinin, histamine and serotonin, and some neurotransmitters (e.g. substance P). Increased flow (shear stress) also stimulates NO production and additionally activates prostacyclin synthesis. The basal production of NO continuously modulates vascular resistance. Nitric oxide also inhibits platelet activation and thrombosis.
Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide which is released from the endothelium in the presence of many other vasoconstrictors, including angiotensin II, antidiuretic hormone (ADH) and noradrenaline, and may be increased in disease and hypoxia.
The eicosanoids prostacyclin (PGI2) and thromboxane A2 (TXA2) are synthesised by the cyclooxygenase pathway from arachidonic acid, which is made from membrane phospholipids by phospholipase A2.
| Vasoconstricting Agents | Vasodilating Agents |
|---|---|
| Endothelin-1 | Nitric oxide |
| Thromboxane A2 | Prostacyclin |
| Angiotensin II | Beta-agonists |
| Noradrenaline (alpha 1-receptors) | Calcium-channel blockers |
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
