Vascular coupling

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

Serotonin agonists G-protein coupled 5-HT receptors 5-HT3 ion channels cAMP (5-HT-,) t cAMP (5-HT4 7) t PLC (5-HT2) l Release of excitatory neuropeptides l Neurogenic inflammation f vasoconstriction Myocardial infarction, stroke, peripheral vascular occlusion... 

Yang LV, Radu CG, Roy M et al (2007) Vascular abnormalities in mice deficient for the G Protein-coupled receptor GPR4 that functions as a pH sensor. Mol Cell Biol 27 1334-1347... 

Endothelin-1, one of the most potent physiologic vasoconstrictors, is an important contributor to HF pathophysiology.9 Endothelin-1 binds to two G-protein coupled receptors, endothelin-A (ET-A) and endothelin-B (ET-B). Endothelin-A receptors mediate vasoconstriction and are prevalent in vascular smooth muscle and cardiac cells. Endothelin-B receptors are expressed on the endothelium and in vascular smooth muscle, and receptor stimulation mediates vasodilation. Levels of ET-1 correlate with HF functional class and mortality. 

The potent antidiuretic hormone AVP orchestrates the regulation of free water absorption, body fluid osmolality, cell contraction, blood volume, and blood pressure through stimulation of three G-protein-coupled receptor subtypes Vi-vascular types a and b, V2-renal, and V3-pituitary. Increased AVP secretion is the trademark of several pathophysiological disorders, including heart failure, impaired renal function, liver cirrhosis, and SIADH. As a consequence, these patients experience excess water retention or inadequate free-water excretion, which results in the dilution of sodium concentrations, frequently manifesting as clinical hyponatremia (serum sodium concentration <135mmol/L). This electrolyte imbalance increases mortality rates by 60-fold. Selective antagonism of the AVP V2 receptor promotes water... 

What is the role of intracellular Ca2+ waves due to Ca2+ release from the SR In many cell types stimulation results in Ca2+ waves rather than a maintained increase of [Ca2+] . Summation of such waves in many cells can result in a maintained contraction. Indeed, recent work suggests that these waves are implicated in the genesis of vascular tone (Peng et al 2001). It is important for us to consider how widespread in smooth muscle excitation-contraction coupling are such waves. 

Bolton TB, Aaronson PI, MacKenzie I 1988 Voltage-dependent calcium channel in intestinal and vascular smooth muscle cells. Ann NY Acad Sci 522 32 -2 Bolton TB, Prestwich SA, Zholos AV, Gordienko DV 1999 Excitation-contraction coupling in gastrointestinal and other smooth muscles. Annu Rev Physiol 61 85—115 Bramich NJ, Hirst GDS 1999 Sympathetic neuroeffector transmission in the rat anococcygeus muscle. J Physiol 516 101—115... 

Histamine (B). Histamine is stored in basophils and tissue mast cells. It plays a role in inflammatory and allergic reactions (p. 72, 326) and produces bronchoconstriction, increased intestinal peristalsis, and dilation and increased permeability of small blood vessels. In the gastric mucosa, it is released from enterochromaffin-like cells and stimulates acid secretion by the parietal cells. In the CNS, it acts as a neuromodulator. Two receptor subtypes (G-pro-tein-coupled), H and H2. are of therapeutic importance both mediate vascular responses. Prejunctional H3 receptors exist in brain and the periphery. 

Thrombin, a serine protease, cleaves fibrinogen into fibrin to create a fibrous plug and also amplifies its own production through the activation of factor XI and cofactors V and Vlll. Thrombin also plays a crucial role in the activation of platelets through the cleavage of the protease-activated receptors on the platelet surface. Antagonists of G-protein-coupled protease-activated receptor PARi have been synthesised to study the role of thrombin PARi receptor in thrombosis and vascular injury. Thrombosis is the most common cause of death in the industrialised world and, whether through venous thromboembolism, myocardial infarction or stroke, ultimately involves the inappropriate activity of... 

Available evidence suggests that a single unifying mechanism does not exist but rather that various vasodilators may act at different places in the series of processes that couple excitation of vascular smooth muscle cells with contraction. For example, the vasodilators known as calcium channel antagonists block or limit the entry of calcium through voltage-dependent channels in the membrane of vascular smooth muscle cells. In this way, the calcium channel blockers limit the amount of free intracellular calcium available to interact with smooth muscle contractile proteins (see Chapter 14). 

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