Thursday, November 30, 2023
This activity is intended for cardiologists, urologists, internists, and primary care physicians.
The goal of this activity is to educate cardiologists, urologists, internists, and primary care physicians about the use of alpha blockade in two very common diseases in the older male: hypertension and benign prostatic hypertrophy.
Upon completion of this activity, participants should be able to:
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the sponsorship of the University of Minnesota. The University of Minnesota is accredited by the Accreditation Council on Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
The University of Minnesota designates this educational activity for a maximum of 1 hour in Category 1 credit towards the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.
For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]
There are no fees for participating in or receiving credit for this
online educational activity. For information on applicability and
acceptance of continuing education credit for this activity, please
consult your professional licensing board.
This activity is designed to be completed within the time
designated on the title page; physicians should claim only those
credits that reflect the time actually spent in the activity. To
successfully earn credit, participants must complete the activity
online during the valid credit period that is noted on the title page.
Follow these steps to earn CME/CE credit:
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To maintain effective perfusion of the body's organs, the cardiovascular system must meticulously regulate arterial pressure. It does this by continuously altering cardiac output and/or systemic vascular resistance. For the purposes of this review, we will disregard the usual emphasis on cardiac output and concentrate instead on the physiologic control of vascular resistance, especially as it is regulated by alpha-adrenergic innervation.
Preservation of adequate perfusion pressure requires maintenance of appropriate resistance to blood flow by the arterial vasculature. In the systemic vasculature, the major factor controlling vascular resistance is smooth muscle tone, which helps regulate the most important determinant of resistance to flow, the cross-sectional area of a vessel.
There are 2 major neurohormonal systems that regulate cardiovascular function, including smooth muscle tone: the autonomic nervous system (ANS) and the renin-angiotensin system (RAAS). The peripheral ANS has 3 main components:
In addition to the blood vessels, the urinary bladder, penis, and prostate also have smooth muscle cells that are innervated by SNS and PNS neurons to help regulate micturition, erection, and ejaculation.
In this review, we are concerned with 2 components of SNS function: vasomotor neurons, which regulate vascular resistance, and lumbosacral neurons, which modulate lower urinary tract outlet resistance. We will review recent advances in the molecular basis of SNS neurotransmission and their implications for clinical medicine.
The circulatory system. The inner layer of the blood vessel wall comprises the endothelium, which is now known to be more than an inert anatomic barrier through which blood flows as though through a tube. Instead, the endothelium is an important physiologic organ that is also innervated, like smooth muscle, by the SNS.
Almost all vasomotor nerves are adrenergic. Two types of adrenergic receptors (adrenoceptors), alpha and beta, are found in the vasculature. Figure 1 [click here to view] depicts the current classification of all the known human adrenoceptor subtypes. As seen in Figure 2, [click here to view] these are distributed in 2 anatomic areas. In the heart, beta1-adrenoceptors predominate and stimulate the rate and force of cardiac contractions. The alpha-adrenoceptors predominate in the innervation of the vascular smooth muscle and also in the lower urinary tract (Figure 3). [click here to view] In both cases, the sympathetic nervous system's adrenergic neurotransmitter, norepinephrine, produces its physiologic effects by binding to these adrenoceptors.
The alpha- and beta-adrenoceptors are further subdivided into 9 subtypes (alpha1A, alpha1B, alpha1D, alpha2A, alpha2B, alpha2C, beta1, beta2, and beta3). Two other candidates (alpha1L and beta4) may simply be conformational states of alpha1A- and beta1-adrenoceptors, respectively. The classification of alpha-adrenoceptors does not include an alpha1C-receptor, because the original alpha1C-receptor was later determined not to be unique and it was reclassified as an alpha1A-receptor.
Although the precise roles for each of these adrenoceptor subtypes in the regulation of blood pressure are not completely defined, it is known that these adrenoceptors actively participate in the regulation of the vascular tone, either directly or indirectly (through the release of nitric oxide). A number of sympathetic abnormalities, most notably an increased adrenergic nervous system activity, have been identified as potential causes of high blood pressure. Studies have demonstrated an increase in both cardiac beta-adrenergic and vascular alpha-adrenergic drive in both borderline and mild hypertension.
The bladder. The exact role of the adrenergic nervous system in the regulation of micturition remains uncertain. Early findings suggested that 2 types of spinal alpha1-adrenoceptor mechanisms are involved in reflex bladder activity. There are facilitatory alpha1-adrenoceptors in bulbospinal pathways from the brainstem to the lumbosacral spinal cord, and these contribute to neural control of the lower urinary tract. In the urinary outflow tract, alpha1-adrenoceptors are located in smooth muscle cells of the neck of the urinary bladder, capsule of the prostate, and fibromuscular stroma of the prostate. Alpha1-adrenoceptor stimulation in the bladder outflow tract increases resistance to urine flow. Alpha1-adrenoceptors have 2 further effects:
For control of the micturition reflex, selective alpha1-adrenoceptor antagonists may be used, and it is thought that these have dual sites of action, in the central nervous system and in the smooth muscle of the lower urinary tract (Figure 3).
Figure 1. Two types (alpha and beta) of adrenoceptors are found in the vasculature, which have 9 receptor subtypes.
Two types of adrenoceptors (alpha and beta) are found in the vasculature. Figure 1 depicts the current classification of human adrenoceptors. Within these 2 types of alpha and beta adrenoceptors, there are now 9 identified subtypes (alpha1A, alpha1B, alpha1D, alpha2A, alpha2B, alpha2C, beta1, beta2, and beta3) and 2 other candidates (alpha1L and beta4), which may be conformational states of alpha1A- and beta1-adrenoceptors, respectively. The classification of alpha-adrenoceptors does not include an alpha1C-receptor; the previously described alpha1C-receptor was not unique and it was reclassified as an alpha1A receptor. Remarkably, the vascular endothelium is now known to be more than a passive anatomical barrier, which contacts the blood. Instead, the endothelium is an important organ possessing at least five different adrenoceptor subtypes (alpha2A, alpha2C, beta1, beta2, and beta3), which either directly or through the release of nitric oxide actively participate in the regulation of the vascular tone. The precise roles for each of these multiple subtypes of adrenoceptors in the regulation of blood pressure are not completely defined.
Figure 2. Alpha1-adrenoceptors stimulate smooth muscle contractions in the blood vessels and the urinary outflow tract. Beta1-adrenoceptors are located in the heart.
In general, it is the alpha1-subtype, located postsynaptically in smooth muscle, that, when stimulated, produces vasoconstriction of the blood vessel. Sympathetic overactivity in hypertension results in an excess stimulation of postsynaptic alpha1 adrenoceptors. In the urinary outflow tract, alpha1-adrenoceptors are located in smooth muscle cells of the neck of the urinary bladder, capsule of the prostate, and fibromuscular stroma of the prostate. Alpha1-adrenoceptor stimulation in the bladder outflow tract increases resistance to urine flow. In the heart, beta1 adrenoceptors predominate and stimulate the rate and force of cardiac contractions.
Figure 3. Alpha1-adrenoceptors in the central sympathetic nervous system contribute to neural regulation of the lower urinary tract.
The exact role of sympathetic pathways in the central nervous system for the regulation of micturition remains uncertain. There are facilitatory alpha1-adrenoceptors in bulbospinal pathways from the brainstem to the lumbosacral spinal cord, which contribute to neural control of the lower urinary tract. Early findings suggest 2 types of spinal alpha1-adrenoceptor mechanisms are involved in reflex bladder activity. First, the frequency of reflexes to urinate is inhibited by afferent alpha1-adrenoceptors in the spinal cord. Second, the descending limb of the micturition reflex pathway may be facilitated by alpha1-adrenoceptors. Selective alpha1-adrenoceptor antagonists may have dual sites in the central nervous system and the smooth muscle of lower urinary tract.
