Medical Pharmacology Chapter 5:  Autonomic Pharmacology:  Adrenergic Drugs

 
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Epinephrine

Epinephrine Effects on Smooth Muscle

Vascular Tone
  • Vascular Tone59

    • Vascular tone defines a general contractile state of either a vessel or vascular region.

    • The term describes the "level of activation" and refers to a distribution of responses given that all vessels in a certain vascular region do not exhibit the identical vascular state.

    • The basal tone, for arterioles, is one of partial constriction even if all external influences are eliminated.

      • Therefore, arterioles are described as having some "basal tone."

      • Such tone may be due in part to smooth muscle cells exhibiting an inherent resistance to being stretched, given that they are typically pressurized, as constituents of pressurized arterioles.

        • Influences that modulate this basal tone include the following effects:

          • neural

          • hormonal

          • local

    • Local effects on arteriolar tone are based on relationships between tissue metabolic activity and blood supply.59

      • For instance, oxygen levels fall during circumstances in which cellular metabolism uses oxygen to a greater extent than supply from blood flow; furthermore, the opposite condition occurs upon excess oxygen delivery to tissue.

        • Reduced oxygen levels decrease arteriolar tone, promoting vasodilation while increased oxygen levels promote vasoconstriction. This relationship is one example of a feedback mechanism setting arteriolar tone.

      • Other substances that increase in concentration with skeletal muscle exercise include CO2, H+ and K+. Increases in these chemicals promote arteriolar dilation.

      • Some cells, under circumstances of increased metabolic activity or reduced oxygen, release adenosine, a potent vasodilator.

        • Adenosine
      • The arteriolar tone depends on summative actions of a variety of substances.

      • When vasodilator chemicals enter the interstitial space to an extent related to tissue metabolism, the same vasodilators are removed by blood flow.

        • The balance between elaboration of the substances and their removal by blood flow dictates whether or not or to what extent arteriolar dilation follows.

    • Endothelial cells which line vascular inner surfaces are important in defining vascular tone.59

      • One classical pharmacological finding was that acetylcholine application caused vasodilation of intact vessels but promoted vasoconstriction if those vessels had been previously stripped of endothelial cell lining.

        • Such experimental findings suggested that endothelial cells elaborated a local factor that reduced vascular tone. This factor was originally named "endothelial-derived-relaxing-factor" or EDRF, and was subsequently determined to be nitric oxide.

        • Nitric oxide (N-O) synthesis depends both on the amino acid precursor arginine and the enzyme nitric oxide synthase.

          • Nitric oxide synthase activity is regulated by intracellular [Ca2+].

          • Relaxation by nitric oxide depends on its increasing cyclic GMP (cGMP).

        • In addition to acetylcholine, bradykinin, substance P, and vasoactive intestinal peptide (VIP) all induce increased endothelial cell nitric oxide release due to receptor linkage with receptor-dependent Ca2+ channels.

          • Bradykinin
          •  

            Substance P

          •  

            Vasoactive Intestinal Peptide (VIP)

             

        • Mechanical induction of nitric oxide due to flow-related shear forces on endothelial cells is mediated by stretch-sensitive Ca2+ channels.

        • Under resting conditions, some basal nitric oxide is present, since inhibition of nitric oxide synthase results in enhanced vascular resistance.

        • Other vasoactive agents produced by endothelial cells include other vasodilators such as "endothelial-derived-hyperpolarizing-factor" (EHDF) and prostacyclin (PGI2) and the vasoconstrictor, endothelin.

    • The most important mechanism for reflex vascular control is neural activity of fibers innervating arterioles.59

      • Activity of autonomic sympathetic nerves is central in defining total peripheral resistance, an important determinant  of systemic arterial pressure.

        • As described earlier, the mechanism by which norepinephrine increases arteriolar tone requires activation of smooth muscle α1-adrenergic receptors.

        • The linkage, described as "pharmacomechanical", is based on G protein linkage of α-adrenergic receptors to phospholipase C and subsequent Ca2+ release from intracellular stores mediated by the second messenger IP3.

        • Electrophysiological studies demonstrate that sympathetic vasoconstrictor nerves fire continually, i.e., "tonic firing."

          • By this mechanism, a neurogenic effect, normal arteriolar tone is higher than basal tone.

            • Reduction of normal tonic vasoconstrictor sympathetic activity causes relative vasodilation and increases local blood flow.

            • Changes in sympathetic nerve activity constitute an important regulatory mechanism of blood flow.

            • Additionally, for a given level of sympathetic nerve activity, the amount of norepinephrine released can be changed by presynaptic effects.

              • Increased extracellular K+, adenosine, acetylcholine, some prostaglandins, and by norepinephrine-mediated feedback, reduce presynaptic norepinephrine release associated with a given level of sympathetic nerve activity.

              • Feedback inhibition of norepinephrine release by norepinephrine is effected by α2-adrenergic receptors localized presynaptically.

 

 

 

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