What Change In Cardiac Output Is Expected After An Increase In Resistance?
Control of Blood Pressure—Normal and Abnormal
Michael J. Joyner MD , ... John H. Eisenach MD , in Neurobiology of Disease, 2007
II. Key Elements of Short-Term Blood Pressure Regulation in Humans
Mean arterial pressure (MAP) is the product of cardiac output (CO) and total peripheral resistance (TPR):
TPR is a calculated variable and only MAP and CO can be measured. Whereas measuring arterial pressure is straightforward and can be done cheaply and noninvasively (with a simple blood pressure cuff, by one person with minimal training), measuring cardiac output or even obtaining a reasonably accurate, noninvasive estimate takes significant equipment and technical skill. Implicit in the earlier equation is the idea that MAP might be regulated by changing either CO or TPR (also called vascular resistance) [1–3]. If there is an acute fall in blood pressure, physiological responses that tend to maintain or improve CO occur, and the blood vessels are constricted so that vascular resistance rises. If blood pressure is raised acutely, generally opposite directional changes occur. How does this happen?
There are sensory afferents located throughout the cardiovascular system that respond to mechanical events associated with the cardiac cycle. In general there are two main groups of mechanoreceptors that play an essential role in the beat-to-beat regulation of arterial pressure so that MAP does not swing wildly with postural changes and during activities of daily living.
The carotid sinus and aortic arch possess the so-called arterial baroreceptors (these areas also possess chemoreceptors) that are innervated by cranial nerves IX and X, respectively (Fig. 1). Mechanosensitive afferents in these areas respond to changes in arterial pressure (i.e., stretch) and evoke reflex changes in heart rate and vascular resistance when there are changes in blood pressure. The arterial baroreceptors are stimulated when blood pressure is higher, with some afferents appearing more sensitive to static distention and others to phasic deformation (pulse pressure). When stimulated, the baroreceptors send signals to the brainstem cardiovascular centers that inhibit sympathetic outflow and stimulate cardiac vagal traffic, leading to vasodilation and a slower heart rate. When arterial pressure falls, afferent traffic from the baroreceptors falls; sympathetic outflow is no longer inhibited and vagal outflow is no longer stimulated. Thus, both heart rate and sympathetic vasoconstrictor tone increase. Figure 2 is an individual record of the heart rate and muscle sympathetic nerve responses to changes in arterial pressure evoked by sequential boluses of vasodilating and constricting drugs in a volunteer subject.
Figure 1. Schematic of key blood pressure–regulating systems in humans. This figure shows the carotid and aortic mechanoreceptors that respond to mechanical deformation in the great vessels associated with changes in arterial pressure. Information from the carotid receptors travels via the carotid sinus nerve to the brainstem cardiovascular centers. Information from the aortic mechanoreceptors travels via the vagus nerve. Together these receptors sense events related to changes in arterial pressure and evoke changes in heart rate and sympathetic outflow that help regulate arterial blood pressure. Not shown in this figure are the so-called cardiopulmonary receptors that are part of an extensive vagal afferent system that innervates the cardiac chambers, great veins, and other areas in the thorax.
(Reprinted, with permission, from Shepherd, J. T., and Vanhoutte, P. M. (1979). "The Human Cardiovascular System: Facts and Concepts." Raven Press, New York.) Copyright © 1979 
Figure 2. This figure demonstrates the concepts outlined in the text and Figure 1. It is an individual record of muscle sympathetic nerve activity (MSNA), heart rate (ECG), and arterial pressure. As part of the modified Oxford technique, changes in blood pressure are evoked by systemic boluses of nitroprusside (100 μg), followed 1 min later by the vasoconstrictor phenylephrine (150 μg). This evokes a predictable fall in blood pressure, followed by a rise in blood pressure. When blood pressure falls, there is a reflex increase in muscle sympathetic nerve activity and a speeding of the heart rate. After the phenylephrine bolus, blood pressure rises and sympathetic traffic is inhibited and heart rate falls.
(Unpublished figure courtesy of Dr. Nisha Charkoudian.)The thoracic cavity, great veins, and cardiac chambers are also innervated by mechanosensitive (and chemosensitive) afferents [2, 3, 10, 11]. At least some of these afferents sense mechanical events related to cardiac filling, and in general, when active, these afferents are sympatho-inhibitory. This means that when central blood volume is high, sympathetic outflow is reduced. In general, the cardiopulmonary afferents do not play a prominent role in the regulation of heart rate, but information from them can act centrally and modify the heart rate responses to arterial baroreceptor loading and unloading. Cardiopulmonary afferents can also modulate release of fluid-regulating hormones from the hypothalamus. When central blood volume is high the afferents are stimulated, and this inhibits the activation of fluid-retaining-hormone release and other mechanisms that conserve body fluids.
For many years it was assumed that the cardiopulmonary afferents served as an early warning system so that small reductions in central blood volume subtly deactivated the cardiopulmonary afferents and evoked increases in sympathetic outflow before the arterial baroreceptors sensed a fall in arterial pressure (Fig. 3). However, this view has been challenged by studies in humans showing that small changes in central blood volume affect mechanical events that are likely sensed by the arterial receptors (for discussion, see [11]). This highlights the difficulty of studying blood pressure regulation in humans. First, for anatomical reasons, in humans it is difficult to isolate all but the carotid receptors for selective stimulation. Second, any reflex responses evoked by "selective" activation of one afferent pool evoke changes in systemic hemodynamic variables that are sensed by the other afferent pools, which then (in turn) evoke additional compensatory responses that make it difficult to interpret the overall behavior of the system.
Figure 3. Integrated blood pressure and hemodynamic responses to graded venous pooling evoked by lower body suction. Throughout the period of suction up to 40 mm Hg (roughly similar to standing up), there is little change in mean aortic (arterial) pressure. During lower levels of suction there is no change in pulse pressure, but as suction increases, pulse pressure falls. Heart rate typically does not increase dramatically until there is a fall in pulse pressure. This observation has been used to argue that arterial baroreceptors are the main afferent system regulating the orthostatic heart rate responses in humans. In contrast to changes in arterial pressure and heart rate, right atrial pressure falls immediately with mild levels of venous pooling, and this evokes marked vasoconstriction, as noted by the reduction in forearm blood flow. In the classical view, these data argue that changes in central venous pressure sensed by so-called cardiopulmonary receptors play an important role in regulating sympathetic outflow during orthostatic stress. It is of interest that there is little change in splanchnic blood flow until more severe levels of venous pooling and that there is also a graded increase in renin release.
(Reprinted, with permission, from [2,3,10].)In summary, arterial and perhaps cardiopulmonary receptors play a key role in the short-term regulation of arterial pressure in humans. Stimulation of these receptors by stretch associated with increased arterial pressure or central blood volume inhibits sympathetic outflow to blood vessels and stimulates vagal outflow to the heart. When blood pressure falls, there is less baroreceptor afferent activity and therefore more sympathetic outflow to vessels and withdrawal of vagal tone to the heart; responses that tend to maintain or increase arterial pressure.
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Cardiovascular System
Mark Kester PhD , ... Kent E. Vrana PhD , in Elsevier's Integrated Review Pharmacology (Second Edition), 2012
Mechanism of action
ACE inhibitors reduce total peripheral resistance by blocking the actions of ACE, the enzyme that converts angiotensin I to angiotensin II ( Fig. 8-5). Recall that angiotensin II is a potent vasoconstrictor and stimulates release of aldosterone from the adrenal cortex, which causes sodium and water retention. ACE inhibitors are balanced vasodilators, meaning that they cause vasodilation of both arteries and veins. Unlike other vasodilators, this class of drugs does not exert reflex actions on the sympathetic nervous system (tachycardia, increased cardiac output, fluid retention). Finally, as angiotensin II also possesses mitogenic activity in the myocardium, inhibition of angiotensin II may lead to diminished myocardial hypertrophy or remodeling, situations often seen in patients with hypertension or HF.
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Vasoactivity of Flavonols, Flavones and Catechins
Owen L. Woodman , in Beer in Health and Disease Prevention, 2009
Flavonols and Flavones in Hypertension
An increase in total peripheral resistance resulting from both structural and functional changes in the arterioles is a characteristic of hypertension, and endothelial dysfunction is an important contributor to the increase in arteriolar tone. This may involve impaired release of NO ( Yang and Kaye, 2006) and/or a decrease in NO bioavailability due to increased inactivation by superoxide anions (Paravicini and Touyz, 2006). As flavones and flavonols both enhance NO activity and exert antioxidant effects, they are logical candidates for investigation for the treatment or prevention of hypertension. The efficacy of the flavonol quercetin has been investigated in a variety of models of hypertension in rats (Table 85.1). Duarte and colleagues reported that quercetin reduces systolic blood pressure in spontaneously hypertensive rats (Duarte et al., 2001; Sanchez et al., 2006) as well as in rats where hypertension is induced by NOS inhibition (Duarte et al., 2002), DOCA salt (Galisteo et al., 2004) or impaired renal perfusion (Garcia-Saura et al., 2005). In each of these studies, together with that by another research group (Jalili et al., 2006), quercetin failed to alter arterial pressure in normotensive control animals. There is clear evidence that the antihypertensive actions of quercetin are associated with an improvement in endothelial function together with a reduction in oxidant stress. Quercetin treatment improves endothelium-dependent relaxation in aortae from hypertensive rats without affecting endothelium-independent relaxation (Duarte et al., 2001, 2002; Ajay et al., 2003, 2006; Galisteo et al., 2004; Garcia-Saura et al., 2005; Sanchez et al., 2006). In addition quercetin exerts a number of actions suggesting that antioxidant activity may contribute to the antihypertensive outcomes. Several studies report that quercetin lowers biomarkers of oxidant stress such as urinary isoprostane, plasma malondialdehyde, and plasma and liver thiobarbituric acid-reactive substances (Duarte et al., 2001; Galisteo et al., 2004; Garcia-Saura et al., 2005; Jalili et al., 2006). Sanchez et al. (2006) also demonstrated that the significantly greater superoxide generation by aortae from spontaneously hypertensive rats, in comparison to normotensive Wistar–Kyoto controls, was lowered by quercetin treatment, an effect that was accompanied by a decreased expression of the NADPH oxidase subunit p47phox. There is considerable evidence supporting a critical role for NADPH oxidase-derived ROS in hypertension (Paravicini and Touyz, 2006). This is the first evidence that quercetin might target an important mechanism in the pathogenesis of hypertension.
Table 85.1. Studies that have investigated the antihypertensive actions of quercetin and flavone
| Treatment | Model of hypertension | Biomarkers significantly affected | Biomarkers not significantly affected | Reference |
|---|---|---|---|---|
| Quercetin (10 mg/kg/day, oral, 5 weeks) | Spontaneously hypertensive rat |
|
| Duarte et al. (2001) |
| Quercetin (5 or 10 mg/kg/day, oral, 6 weeks) | NOS inhibition (1 -NAME 75 mg/100 ml drinking water) |
|
| Duarte et al. (2002) |
| Quercetin (10 mg/kg/day, oral, 5 weeks) | Uninephrectomy and DOCA salt (12.5 mg/week sc, 5 weeks) |
| Galisteo et al. (2004) | |
| Quercetin (10 mg/kg/day, oral, 4 weeks) | Spontaneously hypertensive rat |
| Endothelium-independent relaxation (SNP) | Ajay and Mustafa (2005) |
| Flavone (10 mg/kg/day, oral, 4 weeks) | Spontaneously hypertensive rat |
| Ajay and Mustafa (2005) | |
| Quercetin (10 mg/kg/day, oral, 5 weeks) | Two-kidney, one clip Goldblatt rats |
|
| Garcia-Saura et al. (2005) |
| Quercetin (10 mg/kg/day, oral, 13 weeks) | Spontaneously hypertensive rat |
|
| Sanchez et al. (2006) |
| Quercetin (1.5 g/kg chow) | Abdominal aortic constriction in rats |
|
| Jalili et al. (2006) |
Notes: The flavonol quercetin has been demonstrated to reduce arterial pressure, and to exert a number of other beneficial cardiovascular outcomes, in a variety of rat models of hypertension. Flavone has also shown a similar decrease in SBP in spontaneously hypertensive rats.
- a
- SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate.
- b
- Left ventricle to body weight ratio.
- c
- Kidney to body weight ratio.
- d
- Malondialdehyde.
Despite these positive findings with quercetin, there is an absence of human intervention studies using flavonols to test their potential antihypertensive activity. Whilst two studies report that quercetin did not alter arterial pressure, in both cases the subjects had normal blood pressure and, given the observation that quercetin does not affect arterial pressure in normotensive rats, the outcome of those studies is predictable. The efficacy of quercetin as an antihypertensive in humans awaits an intervention trial using a suitable group of hypertensive subjects.
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Vascular Remodeling and Rarefaction in Hypertension
Matthew A. Boegehold , in Comprehensive Hypertension, 2007
PHYSIOLOGY AND PATHOPHYSIOLOGY
In many forms of hypertension, TPR is elevated in direct proportion to arterial pressure. Cardiac output tends to be normal, and there is often little or no change in its fractional distribution among different organs—indicating a fairly uniform increase in vascular resistance throughout the peripheral circulation. 31, 32 Under these conditions, tissue blood flows are preserved at or near normal values in hypertensive individuals. 32 The elevated arterial pressure is transmitted well into the microvasculature, but the increased resistance of small arteries and arterioles effectively dissipates this pressure increase such that pressure in the smallest arterioles is often normal in hypertensive individuals 2 (Figure 15-6). Therefore, in addition to preventing tissue overperfusion increased precapillary resistance in the hypertensive state can effectively shield most capillary networks from abnormally high hydrostatic pressures, which in turn would prevent excessive transcapillary water filtration and tissue edema. The exact contribution of structural versus functional changes to the overall increase in precapillary resistance can vary from organ to organ in hypertensive individuals, and (as implied previously) can change with the stage of hypertension.
If structural remodeling of the resistance vasculature leads to reduced luminal diameters at any given level of vascular tone, the hemodynamic resistance of these vessels will clearly be increased. The extent to which this remodeling increases the overall vascular resistance of an organ or tissue will depend not only on the magnitude of the diameter reductions but on the fraction of total resistance that normally resides in the remodeled vessels. The fractional distribution of hemodynamic resistance within any vascular bed can be experimentally determined from localized pressure measurements, which provide information on the network's pressure profile (such as that shown in Figure 15-6) and thereby allowing the investigator to calculate the dissipation of pressure across each of the series-coupled segments (e.g., feed arteries, proximal arterioles, distal arterioles, capillaries, and so on). To date, this detailed information has only been obtained in animal models of hypertension, where it has revealed a considerable degree of variability in the hemodynamic importance of structural changes. For example, a structural reduction in arteriolar diameters has been estimated to account for most of the increased resistance to blood flow in the cremaster muscle of rats with two-kidney one-clip hypertension, 33 whereas similar changes contribute little to increased hindquarter vascular resistance in the SHR. 34
Rarefaction is more localized within the resistance network than is remodeling, occurring only among the smallest arterioles. 23 However, because these vessels are responsible for a considerable fraction of total network resistance in many vascular beds the impact of rarefaction on whole-organ resistance can also be substantial. Experimental and theoretical studies indicate that in some forms of hypertension the fraction of the total increase in network vascular resistance due to arteriolar rarefaction can approach that due to active increases in microvascular tone. 18, 35
Whether occurring through eutrophic or hypertrophic remodeling, a structural reduction in resistance vessel diameters can also provide a mechanical advantage for resistance vessels by reducing circumferential wall stress. In this event, less smooth muscle force generation would be required to maintain resting vascular diameter at any level of transmural pressure. 4, 36 Consequently, a remodeled arteriole can maintain its active diameter and participate in flow regulation at higher luminal pressures than can a normal arteriole 36, 37 —an adaptation that is clearly advantageous in the hypertensive state. This adaptation is evident in some vascular beds during autoregulation, which is defined here as the tendency of an organ to maintain constant blood flow despite changes in perfusion pressure. As shown in Figure 15-7, the range of pressures over which vascular resistance can be adjusted to preserve normal blood flow (i.e., an organ's "autoregulatory range") can be shifted upward in hypertensive individuals.
The mechanical advantage associated with resistance vessel remodeling can be reinforced if there is also an increased contribution of passive wall elements to total wall tension. This would further reduce the level of active force required to offset elevated luminal pressure. 4 However, that portion of total wall tension attributable to passive (as opposed to active) tension is largely determined by passive wall distensibility, and studies conducted in hypertensive animals indicate that this characteristic does not uniformly change with hypertension in all vascular beds. For example, passive arteriolar wall distensibility is decreased in the intestine of the SHR 4 but is increased in the cerebral cortex of the stroke-prone SHR—possibly due to a dispro portionate increase in more distensible wall elements (i.e., smooth muscle and elastin). 38 Furthermore, the passive distensibility of mesenteric, coronary, and cremaster muscle resistance vessels from SHR are not different from those of their normotensive counterparts. 21, 39, 40
In many tissues, local blood flow regulation is the result of a complex interplay among metabolic, myogenic, and endothelium-dependent mechanisms. In hypertension, each of these mechanisms can be altered by molecular and/or biochemical changes within the endothelium or smooth muscle of resistance vessels. 20, 41 However, structural changes may also be important in this regard. The magnitude of resistance vessel constriction in response to any stimulus is determined in part by the length/tension relationship of its vascular smooth muscle such that a maximal response will occur only when resting smooth muscle length is within some optimal range. If this resting length is changed by vessel wall remodeling, this could produce a nonspecific change in vascular responsiveness to constrictor stimuli. Furthermore, remodeling not only reduces a vessel's capacity for maximal dilation but can be accompanied by a reduced responsiveness to vasodilators at submaximal concentrations. 42 To the extent there are changes in responsiveness to vasoconstrictor and/or vasodilator stimuli, and to the extent rarefaction can limit the network's capacity for homogenous flow distribution, structural changes in the resistance vasculature could have profound effects on local blood flow regulation. Mathematical modeling suggests that the ability of a tissue to regulate its own oxygen delivery can become compromised in hypertensive individuals due to the heterogeneous distribution of blood flow that accompanies microvascular rarefaction, leaving the PO2 in some tissue regions highly sensitive to changes in tissue metabolism. 43
The loss of small arterioles, and by extension the capillaries that arise from them, also has important consequences for solute and water exchange between the vascular compartment and surrounding tissue. For example, rarefaction of only the most distal arterioles, which could have a relatively modest effect on total network resistance and blood flow, could dramatically reduce the efficiency of tissue oxygen delivery by increasing the heterogeneity of flow among those capillaries that remain perfused. 35 Separate from, but possibly potentiated by, this flow heterogeneity an overall reduction in the number of perfused capillaries and small arterioles will lead to decreased oxygen delivery due to (1) a reduction in the total capillary surface area available for exchange and (2) an increase in the mean diffusion distance between any respiring cell and the nearest perfused vessel (Figure 15-4). This reduction in oxygen delivery has been confirmed with direct measurements of tissue PO2 in tissues that exhibit arteriolar and capillary rarefaction in the hypertensive state. 43, 44
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Sport and the Brain: The Science of Preparing, Enduring and Winning, Part C
Nathan Wood , ... Lee Moore , in Progress in Brain Research, 2018
2.2.2 Cardiovascular reactivity
Heart rate, cardiac output, and total peripheral resistance were estimated using a non-invasive impedance cardiograph device (Physioflow Enduro, Manatec Biomedical, Paris, France). The validity of this device during rest and exercise has previously been established (see Charloux et al., 2000). The Physioflow measures impedance changes in response to a high-frequency (75 kHz) and low-amperage (1.8 mA) electrical current emitted via electrodes. Following preparation of the skin using disposable razors, abrasive electrode gel, and alcohol wipes (Sherwood et al., 1990), six spot electrodes (Physioflow PF-50, Manatec Biomedical, Paris, France) were positioned on the thorax of each participant: two on the supraclavicular fossa of the left lateral aspect of the neck, two near the xiphisternum at the mid-point of the thoracic region of the spine, one on the middle part of the sternum, and one on the rib closest to V6. After entering anthropometric details (i.e., height and mass), the Physioflow was calibrated over 30 heart cycles while each participant sat still and quietly in an upright position. Two resting systolic and diastolic blood pressure values were then taken (one before and another after the 30 heart cycles) using a digital blood pressure monitor (Omron M4 Digital BP meter, Cranlea & Co., Birmingham, UK). The mean blood pressure values were then entered into the Physioflow to complete the calibration procedure.
Heart rate, cardiac output, and total peripheral resistance were estimated continuously for 5 min during a resting period, and a further minute after the pressure manipulation instructions (see Section 2.3 for more details). To avoid the influence of movement artifacts, all participants remained seated, still, and quiet throughout both of these time periods, which were separated by approximately 60 s when the pressure manipulation instructions were delivered. Reactivity, or the difference between the final minute of rest and the minute after the pressure manipulation instructions, was examined for all three cardiovascular variables (as Moore et al., 2012). Heart rate reactivity is considered a cardiovascular marker of task engagement, with larger increases in heart rate reflecting greater engagement (a pre-requisite of challenge and threat states; Seery, 2011). Cardiac output and total peripheral resistance are acknowledged as cardiovascular indices that differentiate challenge and threat states, with a pattern consisting of higher cardiac output and lower total peripheral resistance reactivity more reflective of a challenge state (Seery, 2011). Heart rate and cardiac output were estimated directly by the Physioflow, while total peripheral resistance was calculated using the formula: [mean arterial pressure × 80/cardiac output] (Sherwood et al., 1990). Mean arterial pressure was calculated using the formula: [(2 × diastolic blood pressure) + systolic blood pressure/3] (Cywinski, 1980). Unfortunately, due to technical problems with the Physioflow, cardiovascular data could not be recorded for two participants.
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Symptoms and Signs of Postural Tachycardia Syndrome (POTS)
Julian Stewart , in Primer on the Autonomic Nervous System (Third Edition), 2012
High Flow POTS
Patients are characterized by normovolemia and reduced total peripheral resistance while supine due to reduced peripheral vasoconstriction in the lower extremities. There is increased supine cardiac output compared to healthy volunteers. Relative lower extremity vasodilation persists during orthostatic stress causing venous pooling in the legs. This is not caused by abnormality of leg venous capacitance properties but rather by decreased release of norepinephrine from post ganglionic sympathetic nerves evidenced by a decrease in radioactive norepinephrine spillover [9]. Blood flow and blood volume are redistributed to the lower extremities and enhanced microvascular filtration as well as dependent venous pooling account for the central hypovolemia and postural tachycardia. A peripheral neuropathy is also evidenced by reduced distal sweating and some patients may have a variant of autonomic autoimmune neuropathy. Thus high flow POTS corresponds closely to neuropathic POTS and evidence suggests a mechanism involving partial sympathetic denervation.
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Alcuronium
In Meyler's Side Effects of Drugs (Sixteenth Edition), 2016
Cardiovascular
Tachycardia, hypotension, and a fall in total peripheral resistance all occur to an extent similar to that seen with d-tubocurarine, according to most studies [3–6]. Others have reported that these effects are short-lived [7]. Doses of 0.2 mg/kg or more may be associated with the more extreme cardiovascular effects. Blockade of cardiac muscarinic receptors [8], histamine release, and, possibly, some ganglionic blockade (although it has a very low ganglion-blocking activity in animals) [8] may all play a role in the production of the cardiovascular effects of alcuronium.
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Cardiovascular Medications in Pregnancy
Thomas R. Easterling , in Clinical Pharmacology During Pregnancy, 2013
17.4 Pharmacodynamics of hemodynamically active drugs in pregnancy
Hemodynamically active drugs generally have primary effects on TPR, HR or SV. Changes in each of these parameters will affect CO. A reduction in vascular resistance can be induced through a number of pathways: direct action on vascular smooth muscle (e.g. hydralazine), inhibition of calcium channels (e.g. nifedipine), inhibition of central adrenergic output through central alpha stimulation (e.g. clonidine), or inhibition of the angiotensin system (e.g. angiotensin converting enzyme inhibitors). A reduction in CO can be achieved through either a reduction in heart rate or a reduction in stroke volume. The hemodynamic action of vasodilators can be represented as a vector in Figure 17.3 that runs perpendicular to the isometric lines of vascular resistance. A reduction in TPR results in a reduction in MAP and an increase in CO. In the upper left of the chart, changes in TPR result in relatively small changes in MAP and disproportionately large changes in CO. In the upper right portion of the chart, similar changes in TPR result in relatively small changes in CO and large changes in MAP and potentially hypotension. A reduction in CO will result in a vector of change parallel to isometric lines of resistance and an associated fall in MAP. On the upper left portion of the chart, lines of TPR are steep resulting in substantial changes in MAP with small changes in CO. In the upper right portion of the chart, large changes in CO are needed to lower MAP. Adding vectors, head to tail, can be used to predict the potential effects of combined drug therapy.
Figure 17.3. Cardiac output vs. mean arterial pressure with total peripheral resistance represented by diagonal isometric lines. Vectors of change associated with treatment with atenolol, furosemide, hydralazine, clonidine and captopril are represented.
The pharmacodynamic effects of several individual drugs in pregnancy are plotted in Figure 17.4. Hydralazine [14] and captopril [15] demonstrate clear vasodilatory effects as described above. The direction of the hemodynamic vector of change of individual patients in these studies was fairly consistent as represented by the mean vector. The magnitude of effect varied. The pharmacodynamic effect of nifedipine has been reported in severely hypertensive patients. As would be expected, a reduction in MAP was associated with a fall in TPR and a rise in CO [16]. The data are not reported in a manner to permit plotting a vector. Nifedipine has been reported to significantly induce cerebral vasodilation that would be expected to increase cerebral perfusion pressure which is associated with adverse outcome in women with preeclampsia [17].
Figuer 17.4. Cardiac output vs. mean arterial pressure with total peripheral resistance represented by diagonal isometric lines. Vectors representing a reduction in TPR generally run perpendicular to liners of resistance. Vectors representing a reduction in CO generally run parallel with some tendency towards increasing resistance.
The vector for atenolol, a β-blocker, runs roughly parallel to lines of resistance but with a tendency towards increasing TPR [14]. The primary effect of a reduction in CO achieved by a reduction in heart rate is blunted by a rise in stroke volume. The effect on MAP is countered to some degree by a rise in TPR. As with hydralazine and captopril, the direction of individual vectors was fairly consistent while the magnitude of the vectors varied among patients. Pharmacodynamic data in pregnancy is not available for metoprolol or propranolol, other commonly used β-blockers. One could infer similar actions from class effects from these drugs.
The vector for furosemide, a diuretic, also runs generally parallel to lines of resistance and with a tendency towards increasing resistance [18]. The primary impact on reducing CO is achieved through a reduction in SV with some associated blunting of effect from a rise in HR. The pharmacodynamic effects of other diuretics have not been reported. Inference from class effect may again be considered.
The pharmacodynamic effects of clonidine, a central alpha agonist, and labetalol, a combined α- and β-blocker, are more complex [19]. Clonidine has been studied and the reported vector of change is displayed in Figure 17.4. The vector is vertical, intermediate between that expected from a vasodilator and a β-blocker. Unlike other drugs reported, a large variability of effect was observed across patients; some exhibited changes consistent with vasodilator action; others with changes consistent with beta blockade. Given its mechanism of action, the final effect may be dependent on the character of individual patient's central adrenergic tone. As will be discussed below, the differences in hemodynamic effect may be relevant to the fetus. Labetalol is a combined α- and β-blocker. It is a chiral drug with two diastereomeric pairs of racemates. Two are pharmacologically inactive; (RR)-labetalol is a nonselective beta antagonist; (SR)-labetalol is an alpha adrenergic antagonist and operates as a vasodilator [20]. The intravenous use of the drug has a 7:1 ratio of beta:alpha effect compared to a 3:1 effect as an oral agent [21] due to differential clearance of isomers. While intravenous use usually results in a reduction in HR, oral use frequently does not.
The hemodynamic effects of some drugs in pregnancy are well described. Some generalizations of effect by class of drug are reasonable. An understanding of the individual effects of single drugs in the paradigm of vectors described above can assist the clinician in achieving a desired effect, particularly in the context when more than a single drug is required. In most clinical settings, pharmacodynamic response cannot be assessed with bedside measurements of hemodynamics. However, pharmacodynamic response to β-blockers can be assessed by change in heart rate, and response to diuretic can be assessed by change in serum beta naturetic peptide.
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Ion Channels and Calcium Signaling in the Microcirculation
William F. Jackson , in Current Topics in Membranes, 2020
1 Introduction
Arterioles in the peripheral microcirculation substantially contribute to total peripheral resistance and blood pressure ( Pries & Secomb, 2011; Renkin, 1984; Zweifach & Lipowsky, 1984); control blood flow to and within organs and tissues; and modulate the pressure in capillaries and venules contributing to tissue fluid filtration/reabsorption. These arteriolar functions are effected by vascular smooth muscle cells (VSMCs) (Davis, Hill, & Kuo, 2011; Renkin, 1984) that wrap in a single circumferential layer around the endothelial cell "tube" that forms the basic structure of arterioles (Rhodin, 2014; Simionescu & Simionescu, 1984). For the purpose of this chapter, arterioles are defined as arterial vessels with a single layer of VSMCs and that are embedded within the parenchyma which they perfuse. Feed arteries (or resistance arteries), the last branch of the arterial system before arterioles, are external to the parenchyma and generally have more than one layer of VSMCs overlying the endothelium. Changes in the contractile activity of the VSMCs (contraction or relaxation) produce coordinated constriction or dilation of the arteriolar lumen resulting in changes in the hydraulic resistance to fluid flow and changes in the pressure drop along the length of these vessels (Zweifach & Lipowsky, 1984). A hall-mark feature of arterioles is pressure-induced myogenic tone, the steady-state contractile activity of vascular smooth muscle cells in the arteriolar wall that sets the baseline degree of contraction of the VSMCs at a given blood pressure (Davis et al., 2011; Davis & Hill, 1999; Hill, Zou, Potocnik, Meininger, & Davis, 2001; Johnson, 1980). Arterioles can either constrict or dilate in response to physiological or pathophysiological stimuli from this baseline level of tone (Davis et al., 2011; Renkin, 1984).
Vascular smooth muscle cells express a diverse array of ion channels that contribute to myogenic tone and its regulation (Tykocki, Boerman, & Jackson, 2017). This includes more than five classes of K+ channels (Tykocki et al., 2017), one or more classes of voltage-gated Ca2+ channels (Tykocki et al., 2017), several types of Cl− channels (Bannister et al., 2012; Dam, Boedtkjer, Aalkjaer, & Matchkov, 2014; Dam, Boedtkjer, Nyvad, Aalkjaer, & Matchkov, 2014; Heinze et al., 2014; Hubner, Schroeder, & Ehmke, 2015; Leblanc et al., 2015; Matchkov, Boedtkjer, & Aalkjaer, 2015) and a variety of transient-receptor-potential (TRP) channels (Tykocki et al., 2017) expressed in the plasma membrane and two or more Ca2+ permeable channels in the endoplasmic reticulum (Tykocki et al., 2017) that can be involved in the generation and modulation of myogenic tone. The purpose of this chapter is to review the functional expression of a number of these channels in VSMCs that appear to importantly contribute to the regulation of myogenic tone in arterioles in the peripheral microcirculation. The reader is directed to a recent extensive review of ion channel expression and function in arterioles and resistance arteries for a more general treatment of this topic (Tykocki et al., 2017). Ion channel expression and function in endothelial cells will not be discussed and the reader is directed to recent reviews for information and references on that topic (Jackson, 2016b; Thakore & Earley, 2019).
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Cardiovascular Pharmacology
Carlos M. Ferrario , ... Jasmina Varagic , in Advances in Pharmacology, 2010
V The Ang-(1–7)/ACE2/Mas-R Axis in the Regulation of Pregnancy
Normal pregnancy is a physiological condition characterized by decreased total peripheral resistance, decreased or normal blood pressure ( August et al., 1990), and an increased renin angiotensin system activity (Nasjletti & Masson, 1972; Oelkers, 1996). Within the first few weeks of pregnancy, a rise in plasma Ang II levels is accompanied by increases in angiotensinogen, plasma renin activity (PRA), urinary and plasma aldosterone, and downregulation of AT1 receptors (Baker et al., 1990). Pregnant women possess decreased vascular responsiveness to Ang II (Gilbert et al., 2008; Rosenfeld, 2001; Shah, 2005) which is associated with downregulation of the AT1 receptor (Baker et al., 1990, 1992). New data suggest that increased estrogen and Ang-(1–7) levels compensate for the increased renin angiotensin system in pregnancy (Li et al., 1997). When nulliparous third trimester normal pregnant patients were compared to nonpregnant subjects, plasma Ang-(1–7) levels were significantly elevated in normal pregnant women as compared to nonpregnant women (Merrill et al., 2002). According to Merrill et al. (2002), plasma Ang-(1–7) and Ang II levels were 34 and 50% higher, respectively, in normal pregnant women as compared to nonpregnant subjects. Nogueira et al. (2007) confirmed the increase in plasma Ang I and Ang-(1–7) levels in a small sample of women with pregnancy and further reported a blunting of the Ang-(1–7) increase in pregnant women with gestational diabetes. Involvement of Ang-(1–7) in the evolution of normal pregnancy has been demonstrated by Valdes et al. (2001), who described a progressive increase in Ang-(1–7) urinary excretion throughout the gestational period to levels that were 10-fold higher than those reported during the menstrual cycle. In agreement with these observations, 24 h urinary excretion of Ang I, Ang II, and Ang-(1–7) was increased by 93, 44, and 60%, respectively, as compared to virgin animals in the diestrus phase of the estrus cycle of pregnant rats (Neves et al., 2003). The increase in urinary Ang-(1–7) levels may reflect local synthesis of the heptapeptide as kidney Ang-(1–7) and ACE2 immunostaining were enhanced in the inner cortex/outer medulla proximal and distal tubules throughout pregnancy in Sprague Dawley rats (Joyner et al., 2007). These results suggested that Ang-(1–7) through its associated enzyme ACE2 may function in blood pressure and/or hydro mineral balance during pregnancy. Additional studies involving blockade of Ang-(1–7) concluded that the diuresis seen during late gestation in normal pregnancy can be mechanistically regulated by Ang-(1–7) through increased water intake, decreased plasma arginine vasopressin (AVP), and downregulation of kidney aquaporin 1 (Joyner et al., 2008). Recent studies have shown wide distribution and generally colocalization of Ang-(1–7) and ACE2 throughout the human and rat uteroplacental unit during gestation (Joyner et al., 2008; Valdes et al., 2006). In the pregnant human uterus, Ang-(1–7) and ACE2 were found in the invading trophoblasts and in trophoblasts cells lining the uterine spiral arteries (Anton et al., 2009). While the uterine concentration of Ang I and Ang-(1–7) and ACE2 mRNA did not change with pregnancy, the concentration of Ang II was lower in the human uterus during pregnancy as compared to nonpregnant subjects (Anton et al., 2009). The relative gene expression of AT1 receptor, AT2 receptor, and mas-R was decreased in the uterus during normal pregnancy as compared to the uterus of nonpregnant subjects (Anton et al., 2009).
Temporal–spatial studies in the rat uterus during early and late gestation suggest that Ang-(1–7) and ACE2 may play an important role in implantation (Neves et al., 2008). During early pregnancy, Ang-(1–7) and ACE2 immunostaining was present in the implantation and interimplantation sites (decidua, luminal, and glandular epithelium, embryo, and ectoplacental cone) (Neves et al., 2003), whereas during late gestation, Ang-(1–7) and ACE2 were found on epithelial cells of the yolk sac and amnion.
The main sites of human placental Ang-(1–7) expression were in the syncytiotrophoblasts, cytotrophoblasts, blood vessel endothelium, and vascular smooth muscle of the primary and secondary villi (Valdes et al., 2006). Ang-(1–7) was also expressed in the maternal stroma in extravillous cytotrophoblasts, intravascular cytotrophoblasts, and decidual cells. ACE2 was expressed mainly in the syncytiotrophoblasts, cytotrophoblasts, villous blood vessel endothelium, and vascular smooth muscle cells of the primary villi while in the maternal stroma, ACE2 was expressed in the invading and intravascular trophoblast and the decidual cells (Valdes et al., 2006). The coincident location of Ang-(1–7) and ACE2 suggests an autocrine function of Ang-(1–7). Additionally, Ang-(1–7) may integrate with other vasodilators including nitric oxide, bradykinin, and prostaglandins to produce an autocrine/paracrine role in endometrial receptivity; trophoblast invasion; regulation of fetal, placental, and uterine perfusion; and the prevention of platelet aggregation in the intervillous space. Ang-(1–7) in the placenta may regulate vascular growth since Ang-(1–7) was shown to have antiangiogenic effects on human umbilical vein endothelial cells through a unique AT1–7 receptor that was sensitive to losartan (Anton et al., 2007).
The regulatory role of the Ang-(1–7)/ACE2/mas-R axis in blood pressure regulation in the pregnant state is further strengthened by reports of reduced plasma Ang-(1–7) levels in preeclamptic women (Velloso et al., 2007) and nulliparous preeclamptic third trimester patients matched for parity, race, and gestational age as compared to third trimester normal pregnant patients (Merrill et al., 2002). Additionally, Merrill et al. (2002) observed that there was a negative correlation between plasma Ang-(1–7) and both systolic and diastolic blood pressures, suggesting a potential contribution of reduced Ang-(1–7) on elevated blood pressure in preeclampsia.
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What Change In Cardiac Output Is Expected After An Increase In Resistance?
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