Regional Vascular Resistance Research Articles

Altered hormonal regulation and blood flow distribution with cardiovascular deconditioning after short-duration head down bed rest

This study tested the hypothesis that cardiovascular and hormonal responses to lower body negative pressure (LBNP) would be altered by 4-h head down bed rest (HDBR) in 11 healthy young men. In post-HDBR testing, three subjects failed to finish the protocol due to presyncopal symptoms, heart rate was increased during LBNP compared with pre-HDBR, mean arterial blood pressure was elevated at 0, -10, and -20 mmHg and reduced at -40 mmHg, central venous pressure (CVP) and cardiac stroke volume were reduced at all levels of LBNP. Plasma concentrations of renin, angiotensin II, and aldosterone were significantly lower after HDBR. Renin and angiotensin II increased in response to LBNP only post-HDBR. There was no effect of HDBR or LBNP on norepinephrine while epinephrine tended to increase at -40 mmHg post-HDBR (P = 0.07). Total blood volume was not significantly reduced. Splanchnic blood flow taken from ultrasound measurement of the portal vein was higher at each level of LBNP post-compared with pre-HDBR. The gain of the cardiopulmonary baroreflex relating changes in total peripheral resistance to CVP was increased after HDBR, but splanchnic vascular resistance was actually reduced. These results are consistent with our hypothesis and suggest that cardiovascular instability following only 4-h HDBR might be related to altered hormonal and/or neural control of regional vascular resistance. Impaired ability to distribute blood away from the splanchnic region was associated with reduced stroke volume, elevated heart rate, and the inability to protect mean arterial pressure.

Endothelin and Aged Blood Vessels

Age is one of the most important risk factors for cardiovascular disease. For example, a 30-year-old male smoker with untreated hypertension, diabetes, dyslipidemia, and a strong family history of premature coronary heart disease (CHD) would have a 10-year coronary heart disease event rate of only 16% (“intermediate risk”) by Framingham criteria; however, given exactly the same risk profile for a 60-year-old, the risk climbs to >50%. Aging, particularly sedentary aging, leads not only to the development of atherosclerosis but also to ventricular and arterial stiffening.1 This reduces functional capacity and contributes to chronic diseases of the elderly, such as systolic hypertension or heart failure with a preserved ejection fraction. In the search for the underlying mechanism for this effect of sedentary aging, one common feature that has been identified universally in older men is an increased baseline vascular tone,2 which has both hemodynamic and metabolic consequences.3 Although this age-related increase in vascular tone is mediated in part by a chronically elevated sympathetic α-adrenergic vasoconstriction,2 endothelial function also plays a critical role in vascular stability and the regulation of vasomotor function. The endothelium regulates vascular tone through the release of dilator and constrictor substances. Endothelin (ET)-1 is the most potent endothelium-derived constricting factor and influences peripheral vascular tone by interacting with ETA and ETB receptors on smooth muscle cells and the endothelium.4 Several animal studies have examined the profound effects of vascular aging on the ET-1 pathway and support a central role for ET-1 to explain the age-related increase in vascular tone.5–7 In the present issue of Hypertension , Van Guilder et al8 present new and important information regarding the role of aging and physical fitness on the vasomotor effects of ET-1. Using a cross-sectional design in a small but carefully studied …

General Anesthetics and Vascular Smooth Muscle

General anesthetics threaten cardiovascular stability by causing changes in cardiac function, vascular reactivity, and cardiovascular reflexes and significantly alter distribution of cardiac output to various organs. Their overall impact is often systemic hypotension, which is attributable to myocardial depression, peripheral vasodilation, and attenuated sympathetic nervous system activity. However, one could be more causative than the others, depending on anesthetic agents and cardiovascular factors inherent in patients (e.g., coexisting heart disease). It is generally believed that most general anesthetics attenuate sympathetic nervous system outflow from the central nervous system, thereby decreasing vascular resistance in peripheral circulations. Indeed, in previous in vivo studies, during administration of various general anesthetics, vascular resistance was decreased in most peripheral circulations; however, it was unaffected or increased in some peripheral circulations. General anesthetics may act directly on vascular smooth muscle and/or endothelial cells in various vascular beds, influencing total peripheral and/or regional vascular resistance, and hence organ blood flow. This article reviews previously reported direct (i.e., nonneural) vascular actions of general anesthetics and discusses their underlying mechanisms, their in vivo relevance, and the future of research for general anesthetic vascular pharmacology.

Expression of an angiotensin-(1-7)-producing fusion protein in rats induced marked changes in regional vascular resistance

We have described a transgenic rat line that expresses an angiotensin-(1-7)-producing fusion protein, the TGR(A1-7)3292. In these rats, testis acts as an angiotensin-(1-7) biological pump, increasing its plasma concentration 2.5-fold. In this study, we performed hemodynamic measurements in TGR(A1-7)3292 and age-matched Hannover Sprague-Dawley (SD) control rats, using fluorescent microspheres. Urethane-anesthetized transgenic rats had similar levels of baseline blood pressure (99 +/- 3 mmHg) as did SD rats (101 +/- 3 mmHg). However, pronounced differences were observed in other hemodynamic measurements. TGR(A1-7)3292 rats presented a significant increase in stroke volume (0.29 +/- 0.01 vs. 0.25 +/- 0.01 ml in SD), increased cardiac index (24.6 +/- 0.91 vs. 21.9 +/- 0.65 ml.min(-1).kg) and decreased total peripheral resistance (3.9 +/- 0.13 vs. 4.5 +/- 0.13 mmHg.ml(-1).min.100 g). The increase in stroke volume in transgenic rats may be partially explained by the small decrease in heart rate (326 +/- 7.0 vs. 359 +/- 6.0 beats/min in SD). Strikingly, TGR(A1-7)3292 rats presented a substantial decrease in the vascular resistance in lung, spleen, kidney, adrenals, brain, testis and brown fat tissue with no significant differences in the left ventricle, mesentery, skin, gastrocnemius muscle and white fat tissue. These results corroborate and extend previous results observed after acute angiotensin-(1-7) infusion, showing that chronic increase in circulating angiotensin-(1-7) produces sustained and important changes in regional and systemic hemodynamics. Moreover, our data suggest a physiological role for angiotensin-(1-7) in the tonic control of regional blood flow.

Effect of the Calcimimetic, Cinacalcet, on Regional Vascular Resistance and Blood Ionized Calcium in Uremic and Normal Rats

Cinacalcet (CIN) decreases serum PTH and Ca in ESRD patients with SHPT and also produces acute elevations in blood pressure (BP) in uremic rats. To test the hypothesis that CIN produces acute hypertension through vasoconstriction of multiple vascular beds, the regional hemodynamic effects of CIN were delineated in anesthetized rats and correlated to changes in BP and iCa2+. Male SD rats were subjected to 5/6 nephrectomy (NX) or no surgery (Normal); at 7–8 weeks uremia rats were instrumented to record BP, heart rate and regional blood flow (carotid, mesenteric, hindlimb). CIN (1, 3, 10 mg/kg; 30 min/dose) or VEH was infused over 90 min. Change from baseline in CIN vs. VEH was analyzed by repeated measures ANOVA, Dunnett’s (∗p<0.05). In NX, CIN decreased iCa2+ from 1.22±0.02 mmol/L at baseline to 1.10±0.02∗, 0.97±0.02∗ and 0.91±0.03∗ mmol/L and produced increases in BP (from 119±6 mmHg to 129±5, 142±4∗, and 145±3∗ mmHg at the end of each infusion). At 1 mg/kg carotid (CVR) and mesenteric (MVR) vascular resistance increased to 16±6%∗ above baseline (VEH=3±2%) and 18±6∗% above baseline (VEH= −1±2%), respectively. Hindlimb (HVR) vascular resistance trended upward to 13±8% above baseline (VEH = −2±2%). At 3 mg/kg increases in CVR (38±10%∗), MVR (40±8%∗) and HVR (39±14%∗) were exacerbated; at 10 mg/kg values remained at or near these levels. The effects of CIN on iCa2+, BP and VR in Normal rats were similar to NX. Thus, at doses producing reductions in iCa2+ CIN acutely increases BP in uremic and non-uremic rats, responses that occur in parallel to vasoconstriction in vascular beds fed by the carotid, mesenteric, and hindlimb arteries.

Blood pressure and vascular reactivity in ACTH‐treated mice with ouabain‐resistant α2 Na‐K‐ATPase

We have shown that alterations in the ouabain-binding characteristics of the α1 and α2 subunits of the Na-K-ATPase (NKA) can influence cardiovascular function in vivo. Notably, we have reported that ACTH-induced hypertension is prevented in mice expressing a mutant, ouabain-resistant α2NKA isoform. To explore this ACTH-resistance, we evaluated regional vascular resistance in ouabain-resistant α2NKA (α2R) and ouabain-sensitive α2NKA mice (wild type: WT). Mice were treated for 5–6 days with ACTH, or sham treated, then prepared for blood pressure and flow measurements. In untreated mice, there were no differences in blood pressure, renal and mesenteric blood flow or vascular resistance under baseline conditions, and sensitivity to phenylephrine (PE) was comparable between the two groups. In ACTH-treated mice, resting blood pressure was lower in α2R than in WT, confirming that hypertension is prevented in these mutants. Following ACTH-treatment, renal and mesenteric blood flow decreased significantly in α2R, but not in WT mice. Calculations of vascular resistance confirmed that resting vascular resistance was paradoxically elevated in the hypertension-resistant α2R mice. PE-responsiveness was also enhanced in the ACTH-treated α2R mice compared to untreated, whereas PE-responsiveness was not altered by ACTH in WT. These data suggest that the anti-hypertensive phenotype of ouabain-resistant α2NKA mice occurs in spite of increased reactivity in these vascular beds.

Baroreflex responses to electrical stimulation of aortic depressor nerve in conscious SHR

Baroreflex responses to changes in arterial pressure are impaired in spontaneously hypertensive rats (SHR). Mean arterial pressure (MAP), heart rate (HR), and regional vascular resistances were measured before and during electrical stimulation (5-90 Hz) of the left aortic depressor nerve (ADN) in conscious SHR and normotensive control rats (NCR). The protocol was repeated after beta-adrenergic-receptor blockade with atenolol. SHR exhibited higher basal MAP (150 +/- 5 vs. 103 +/- 2 mmHg) and HR (393 +/- 9 vs. 360 +/- 5 beats/min). The frequency-dependent hypotensive response to ADN stimulation was preserved or enhanced in SHR. The greater absolute fall in MAP at higher frequencies (-68 +/- 5 vs. -38 +/- 3 mmHg at 90-Hz stimulation) in SHR was associated with a preferential decrease in hindquarter (-43 +/- 5%) vs. mesenteric (-27 +/- 3%) resistance. In contrast, ADN stimulation decreased hindquarter and mesenteric resistances equivalently in NCR (-33 +/- 7% and -30 +/- 7%). Reflex bradycardia was also preserved in SHR, although its mechanism differed. Atenolol attenuated the bradycardia in SHR (-88 +/- 14 vs. -129 +/- 18 beats/min at 90-Hz stimulation) but did not alter the bradycardia in NCR (-116 +/- 16 vs. -133 +/- 13 beats/min). The residual bradycardia under atenolol (parasympathetic component) was reduced in SHR. MAP and HR responses to ADN stimulation were also preserved or enhanced in SHR vs. NCR after deafferentation of carotid sinuses and contralateral right ADN. The results demonstrate distinct differences in central baroreflex control in conscious SHR vs. NCR. Inhibition of cardiac sympathetic tone maintains reflex bradycardia during ADN stimulation in SHR despite impaired parasympathetic activation, and depressor responses to ADN stimulation are equivalent or even greater in SHR due to augmented hindquarter vasodilation.

Adenosine receptors in the response to sepsis: what do receptor-specific knockouts tell us?

in this issue Dr. Lee and colleagues (8a) demonstrate that the A3 adenosine receptor subtype (A3R) protects against a septic challenge. In this regard, the A3R joins the A1R and A2AR in similar investigations. Although the focus of their investigation was the A3R, Dr. Lee and colleagues directly

Lesions of the commissural nucleus of the solitary tract abolish the pressor response produced by CVLM deactivation.

A medullary circuitry involving the nucleus of the solitary tract (NTS) and the ventrolateral medulla (caudal and rostral) is essential to control the sympathetic discharge directed to the cardiovascular system. In the present study we sought to investigate the effects on mean arterial pressure (MAP), heart rate (HR) and regional vascular resistances produced by combining electrolytic lesions of the commissural nucleus of the solitary tract (commNTS) and the deactivation of the caudal ventrolateral medulla (CVLM) with the GABAA agonist muscimol. Male Holtzman rats (n = 8/group) anesthetized with urethane (1.0 g/kg) + chloralose (60 mg/kg) iv were used. In sham rats, bilateral injections of muscimol (120 pmol) into the CVLM increased MAP (181 ± 6 mmHg, vs. control pre-injection: 104 ± 3 mmHg), HR (418 ± 16 bpm, vs. control pre-injection: 322 ± 12 bpm) and renal, mesenteric and hindquarter vascular resistances. However, in commNTS-lesioned rats, muscimol into the CVLM reduced MAP (67 ± 5 mmHg), HR (279 ± 8 bpm), renal, mesenteric and hindquarter vascular resistances below control baseline levels. The results suggest that important pressor mechanisms arise from the commNTS and CVLM to control vascular resistance and arterial pressure in the condition of the present study. Financial support: FAPESP, CNPq/PRONEX

Point: The muscle metaboreflex does restore blood flow to contracting muscles

Imposed reductions in oxygen delivery to active skeletal muscle during dynamic exercise in conscious dogs evoke a powerful pressor response, termed the muscle metaboreflex. During submaximal work rates, the major mechanism used by this reflex is to increase cardiac output (CO), which generates a

Organ‐specific ligation‐induced changes in harmonic components of the pulse spectrum and regional vasoconstrictor selectivity in Wistar rats

It has been shown previously that the amplitudes of the harmonic components of the pulse spectrum vary in specific patterns when the arteries leading to different organs are ligated, with the variations in the harmonics being linearly additive. Since ligation can be regarded as a vast increase in organ resistance, the present study examined the potential of using these ligation-induced variations in the pulse spectrum as reference parameters for an increase in vascular resistance and for regional vasoconstrictor selectivity. A vasoconstrictor, either arginine vasopressin (AVP) or angiotensin II (Ang II), was infused into anaesthetized Wistar rats via the femoral vein for 1 h. The distinct harmonic-specific drug effects on the pulse spectrum were simulated by combining renal artery and superior mesenteric artery ligations in different ratios, the ratio with the lowest mean square difference determining the regional drug selectivity. The ratios indicated that the effect of AVP on the pulse spectrum was attributable to the combined effect of ligating the renal and superior mesenteric arteries, while the effect of Ang II was attributable to ligation of the renal artery. The results are comparable with those of investigations of regional vascular resistance performed using traditional methods. Our findings indicate that the ligation-induced variations in the pulse spectrum can be used to determine regional increases in vascular resistance. This implies that blood pressure can be used as the sole parameter to determine which arterial bed has been affected by the vasoconstrictor, and how seriously.

Effects of BW245C, a prostaglandin dp receptor agonist, on systemic and regional haemodynamics in the anaesthetized rat

1. Prostaglandin D (DP) receptor agonists have been shown to induce hypotension in rat models, possibly via peripheral vasodilation. However, it is not known which tissues and organs are most responsive. 2. In the present study, BW245C, a DP receptor-selective agonist, was administered to Inactin (Sigma, St Louis, MO, USA)-anaesthetized rats. Animals received three serial i.v. infusions (17 min each) of either BW245C (escalating doses of 0.3, 3 and 30 microg/kg; n=6) or vehicle (6% ethanol in normal saline; n=6). Mean arterial pressure (MAP) and heart rate were monitored continuously and regional blood flow was determined by the radionuclide-labelled microsphere method at baseline and at the end of each infusion. 3. It was found that BW245C dose-dependently reduced MAP; blood flow increased in forelimb skeletal muscle and skin, resulting in decreases in the regional vascular resistance (RVR) of skeletal muscle to -6+/-13, -53+/-11 and -68+/-6% of baseline following 0.3, 3 and 30 microg/kg BW245C, respectively (P<0.05 vs vehicle treatment for the two higher doses), and skin to -29+/-8, -55+/-8 (P<0.05) and -30+/-16% of baseline, respectively. Relative to vehicle, blood flow and RVR for brain, heart, lung, liver, stomach and kidney were not significantly affected by BW245C. 4. These results demonstrate that the hypotension resulting from DP receptor activation in the rat is mediated primarily through vasodilation of arterioles of skeletal muscle independent of changes in blood flow to vital organs.

Ischemia and necrotizing enterocolitis: Where, when, and how

While it is accepted that ischemia contributes to the pathogenesis of necrotizing enterocolitis (NEC), three important questions regarding this role subsist. First, where within the intestinal circulation does the vascular pathophysiology occur? It is most likely that this event begins within the intramural microcirculation, particularly the small arteries that pierce the gut wall and the submucosal arteriolar plexus insofar as these represent the principal sites of resistance regulation in the gut. Mucosal damage might also disrupt the integrity or function of downstream villous arterioles leading to damage thereto; thereafter, noxious stimuli might ascend into the submucosal vessels via downstream venules and lymphatics. Second, when during the course of pathogenesis does ischemia occur? Ischemia is unlikely to the sole initiating factor of NEC; instead, it is more likely that ischemia is triggered by other events, such as inflammation at the mucosal surface. In this context, it is likely that ischemia plays a secondary, albeit critical role in disease extension. Third, how does the ischemia occur? Regulation of vascular resistance within newborn intestine is principally determined by a balance between the endothelial production of the vasoconstrictor peptide endothelin-1 (ET-1) and endothelial production of the vasodilator free radical nitric oxide (NO). Under normal conditions, the balance heavily favors NO-induced vasodilation, leading to a low resting resistance and high rate of flow. However, factors that disrupt endothelial cell function, eg, ischemia-reperfusion, sustained low-flow perfusion, or proinflammatory mediators, alter the ET-1:NO balance in favor of constriction. The unique ET-1-NO interaction thereafter might facilitate rapid extension of this constriction, generating a viscous cascade wherein ischemia rapidly extends into larger portions of the intestine.

Role of pressor mechanisms from the NTS and CVLM in control of arterial pressure

In the present study, we investigated the effects of inhibition of the caudal ventrolateral medulla (CVLM) with the GABA(A) agonist muscimol combined with the blockade of glutamatergic mechanism in the nucleus of the solitary tract (NTS) with kynurenic acid (kyn) on mean arterial pressure (MAP), heart rate (HR), and regional vascular resistances. In male Holtzman rats anesthetized intravenously with urethane/chloralose, bilateral injections of muscimol (120 pmol) into the CVLM or bilateral injections of kyn (2.7 nmol) into the NTS alone increased MAP to 186 +/- 11 and to 142 +/- 6 mmHg, respectively, vs. control: 105 +/- 4 mmHg; HR to 407 +/- 15 and to 412 +/- 18 beats per minute (bpm), respectively, vs. control: 352 +/- 12 bpm; and renal, mesenteric and hindquarter vascular resistances. However, in rats with the CVLM bilaterally blocked by muscimol, additional injections of kyn into the NTS reduced MAP to 88 +/- 5 mmHg and mesenteric and hindquarter vascular resistances below control baseline levels. Moreover, in rats with the glutamatergic mechanisms of the NTS blocked by bilateral injections of kyn, additional injections of muscimol into the CVLM also reduced MAP to 92 +/- 2 mmHg and mesenteric and hindquarter vascular resistances below control baseline levels. Simultaneous blockade of NTS and CVLM did not modify the increase in HR but also abolished the increase in renal vascular resistance produced by each treatment alone. The results suggest that important pressor mechanisms arise from the NTS and CVLM to control vascular resistance and arterial pressure under the conditions of the present study.

Therapeutic administration of hCG in pregnant women with preeclamptic risk

Recent studies revealed functional extragonadal gonadotropin receptors in the human body: fallopian tube, myometrium, endometrium, cervix, uterine and spiralate arteries, breast, umbilical cord, etc. The human hCG/LH receptor mRNA and protein were found in endothelial and vascular smooth muscle layers of uterine arteries, more abundant in the spiral arteries, therefore in the part of uterine circulation important in regulation of vascular resistance. In vivo hCG administration decreased blood flow resistance in human uterus and in vitro hGG increased vasodilating eicosanoids levels in vascular walls. Nevertheless, beginning with the 16th week of gestation, there is a spectacular growth of the human fetal brain, forcing placenta to a second trophoblastic wave of invasion which targets spiralate myometrial arteries. This process calls for angiogenetic factors such as VEGF and PlGF. Recently, it was documented that hCG provides angiogenetic stimulus. These data initiated the study presented here. The question raised was whether hCG treatment can improve clinical outcome in pregnant women over their 20th week of gestation with preeclamptic risk.

Tumor selective antivascular effects of the novel antimitotic compound ABT-751: an in vivo rat regional hemodynamic study.

Selective induction of vascular damage within a growing tumor is a potentially important approach in the search for potent anticancer therapeutics. Tubulin-binding (antimitotic) agents destabilize cellular microtubules, suppress tumor growth, and exert antivascular effects with varying degrees of tumor selectivity in preclinical models. The tumor-selective, antivascular effects of ABT-751, a novel, orally active antimitotic agent, currently in phase II clinical development, were characterized in vivo in the present study. We developed an in vivo rat model designed to quantify acute changes in regional vascular resistance (VR) in both tumor and non-tumor vascular beds simultaneously. Tissue-isolated tumors (1 g) with blood flow supplied by a single epigastric artery were grown in rats. Subsequently, tumor blood flow was measured under anesthesia in solid tumors and also in mesenteric, renal, and normal epigastric arteries. Phenylephrine-induced (1 micromol/kg) increases in VR were not different between tumor and non-tumor epigastric arteries, suggesting that tumor vessels possess relatively normal vasoconstrictive function. ABT-751 (3, 10, and 30 mg/kg; i.v.) produced modest transient increases in mean arterial pressure with no effect on heart rate. Tumor VR increased to 75+/-36, 732+/-172, and 727+/-125% above baseline, respectively (P<0.05 for the 10 and 30 mg/kg doses), whereas VR in normal epigastric arteries was not significantly affected. Administration of ABT-751 produced transient modest ( P<0.05) increases in mesenteric VR and no effect on renal VR. These results demonstrate that ABT-751 produces marked reductions in tumor blood flow in the intact rat at doses that exert negligible effects on normal vascular function.

Nitric Oxide Inhibits ATP Release from Erythrocytes

Erythrocytes have been reported to release ATP from intracellular stores into the surrounding environment in response to decreased oxygen tension and mechanical deformation. This erythrocyte-derived ATP can then act on purinergic receptors present on vascular endothelial cells, resulting in the synthesis and bidirectional release of nitric oxide (NO). NO released abluminally produces relaxation of vascular smooth muscle, thereby increasing vascular caliber, leading to a decrease in deformation-induced ATP release from erythrocytes. In contrast, NO released into the vascular lumen could interact directly with formed elements in the blood, including the erythrocyte. Here, we investigate the hypothesis that NO functions in a negative-feedback manner to inhibit ATP release from the erythrocyte. The NO donor N-(2-aminoethyl)- N-(2-hydroxy-2-nitrosohydrazino)-1,2-ethylenediamine (spermine NONOate) decreased total pulmonary resistance in a dose-dependent manner when administered to isolated perfused rabbit lungs. ATP release from rabbit erythrocytes in response to decreased oxygen tension or mechanical deformation was inhibited by preincubation with spermine NONOate (100 nM, 20 min). Importantly, incubating rabbit erythrocytes with spermine (100 nM, 20 min), the polyamine remaining after the liberation of NO from spermine NONOate, did not affect decreased oxygen tension-induced ATP release. Mechanical deformation-induced ATP release was also inhibited when erythrocytes were preincubated with spermine NONOate. However, NO-depleted spermine NONOate had no effect on mechanical deformation-induced ATP release from rabbit erythrocytes. These data provide support for the hypothesis that NO inhibits ATP release from erythrocytes, thereby identifying an additional role of NO in the regulation of vascular resistance.

Historical Perspectives

Historical Perspectives

Transmitter characteristics of cutaneous, renal and skeletal muscle small arteries in the rat.

We studied transmitter characteristics of proximal and distal arteries supplying skin (saphenous artery and its medial tarsal branch), kidneys (terminal branches of renal artery and interlobar arteries) and skeletal muscle (proximal and distal sections of external sural artery). Artery segments were mounted in an isometric myograph and intramural nerves were activated by electrical field stimulation. Adrenergic and purinergic components of the neurogenic response were blocked using phenoxybenzamine and alpha,beta-methylene adenosine triphosphate (mATP), respectively. Arteries from skin or kidney developed rapid and prominent neurogenic contractile responses, with half-maximal amplitude reached within 5-15 s; responses in proximal vessels were greater than in distal vessels. Arteries from skeletal muscle responded to sympathetic stimulation with a moderate contraction developing over 1 min or more, the response of distal segments was greater than that of proximal segments. In skeletal muscle vessels the sympathetically evoked contraction was completely blocked by phenoxybenzamine, whereas in skin and renal vessels it was the combined effect of noradrenaline and adenosine triphosphate (ATP). Given alone, mATP did not change the magnitude of the response to nerve stimulation, but increased its latency and also potentiated the response to exogenous noradrenaline. In all vascular beds, distal vessels were more sensitive to noradrenaline and mATP. It thus appears that the noradrenaline/ATP ratio of the sympathetic vasoconstrictor response differs between vascular beds in a way that is consistent with known differences in the selective regulation of regional vascular resistance by the sympathetic nervous system.

Pregnancy and steroid hormones enhance the systemic and regional hemodynamic effects of calcitonin gene-related peptide in rats.

Calcitonin gene-related peptide (CGRP) is a potent vasodilator neuropeptide known to be involved in the regulation of vascular resistance. Several lines of evidence suggest that CGRP plays a role in the vascular adaptations that occur during normal pregnancy; however, the effects of exogenous CGRP on systemic and regional hemodynamics during pregnancy remain unknown. Therefore, the purpose of this study was to determine the hemodynamic effects of systemically administered CGRP in adult pregnant (Day 19) and ovariectomized (ovx) rats using the radioactive microsphere technique. In addition, we also used ovariectomized rats treated for 3 days with estradiol (E2), progesterone (P4), E2 + P4 in sesame oil, or oil only to assess if these hormones regulate the CGRP-induced hemodynamic changes. On the day of study, catheters were inserted into the left cardiac ventricle (through the right carotid artery), right jugular vein, and caudal tail artery. Hemodynamic studies using radioactive microspheres were then performed in conscious rats 3 h after recovery from anesthesia. Blood pressure and heart rate were continuously monitored, and left ventricular pressure was determined immediately prior to each microsphere injection. Microspheres labeled with either (141)Ce or (85)Sr were injected prior to and 2 min following the i.v. bolus injection of CGRP (270 pmol/kg body weight [BW]). Mean arterial pressure (MAP) and total vascular resistance in pregnant rats was lower than in ovx rats, and this was further decreased with an i.v. bolus injection of 270 pmol CGRP/kg BW. Cardiac output was elevated with further increases upon CGRP administration in pregnant but not in ovx rats. The CGRP-induced changes in MAP, total vascular resistance, and cardiac output in E2 + P4 -treated rats were similar to that observed in Day 19 pregnant rats, indicating that CGRP effects on these parameters during pregnancy may be modulated by steroid hormones. Both pregnancy and E2 + P4 treatment in ovx rats caused significant decreases in CGRP-induced resistance in mesenteric, coronary, and renal vasculature. Thus, the vasodilatory sensitivity to CGRP during pregnancy may be mediated through decreased total vascular resistance, particularly to coronary, mesenteric, and renal vascular beds. Thus, CGRP-induced vasodilatory effects may play a role in mediating vascular adaptations that occur during pregnancy and that steroid hormones may modulate these CGRP effects.