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.     

Adrenomedullin release in the rat mesenteric resistance artery

Adrenomedullin (AM) is a potent vasodilator peptide whose major source is the vascular wall. In the present study, the mechanism of release of AM was investigated in the rat mesenteric resistance artery. The isolated mesenteric vascular bed was perfused with Krebs solution at a constant flow rate (5 ml/min) and AM in the perfusate was measured by a highly sensitive enzyme immunoassay (Immunoenzymometric assay; IEMA) method. In preparations without endothelium, spontaneous release of AM was detected in the perfusate (68.7+/-5.8 fmol/ml, n=45). Periarterial nerve stimulation (PNS, 4 and 8 Hz) caused 11.4+/-3.9% (4 Hz) and 9.1+/-3.5% (8 Hz) decreases in the spontaneous release of AM. Removal of Ca2+ from the medium did not affect the spontaneous AM release, but abolished the PNS-induced inhibition of spontaneous AM release. Perfusion of 10nM calcitonin gene-related peptide (CGRP) or 0.1 microM capsaicin (inducer of CGRP release) inhibited significantly the spontaneous AM release. PNS (8 Hz)-induced inhibition of spontaneous AM release was antagonized by CGRP(8-37) (CGRP receptor antagonist). These results suggest that AM is mainly released from vascular smooth muscle cells of the rat mesenteric artery and endogenous or exogenous CGRP inhibits AM release.     

Influence of serotonin on myocardial blood flow in the presence and absence of a coronary arterial stenosis: observations in domestic swine

This study tested the hypothesis that 5-HT may impair coronary flow regulation by inappropriately increasing arteriolar tone in the coronary circulation. Ten closed chest, domestic swine were studied both in the presence and in the absence of a severe artificial intraluminal coronary stenosis. A 5-French micromanometer catheter with fluid lumen was placed in the left anterior descending coronary artery and used to record pressure and infuse 5-HT (40 and 100 micrograms/min) into the coronary circulation. For the stenosis phase of the protocol the catheter was embedded in the artificial stenosis. Hemodynamics, regional myocardial blood flow (microsphere technique), coronary vascular resistance, lactate consumption, and oxygen metabolism were measured at control and at 5 min of each 5-HT dose. In the absence of coronary artery stenosis (i.e., full vasodilatory reserve), there was no change in regional myocardial blood flow or coronary vascular resistance during 5-HT infusion. In the presence of a severe coronary stenosis (i.e., limited vasodilator reserve) 5-HT produced a significant (P less than 0.05) decrease versus control in the distal left anterior descending: circumflex zone endocardial blood flow ratio (0.63 +/- 0.19, mean +/- 1 SD, to 0.55 +/- 0.15) and a significant (P less than 0.05) increase versus control in endocardial (50.6 +/- 16.6 to 61.2 +/- 19.8 mm Hg/ml/min/g) and transmural (49.9 +/- 9.5 to 57.2 +/- 12.8) coronary vascular resistance. Thus, 5-HT does not impair coronary flow regulation when full vasodilatory reserve is present. When coronary vasodilatory reserve is impaired by the presence of a severe proximal stenosis, 5-HT causes modest impairment of endocardial flow regulation.     

Increased vasodilator responsiveness to BRL 34915 in spontaneously hypertensive versus normotensive rats: contrast with nifedipine

The blood pressure-lowering potency and activity of BRL 34915, a new vasodilator and putative stimulator of potassium efflux from vascular smooth muscle, was investigated in conscious spontaneously hypertensive rats (SHR) and normotensive rats (NTR) after intravenous administration and compared with that of the calcium channel blocker, nifedipine. In SHR, BRL 34915 (3-100 micrograms/kg) or nifedipine (10-3000 micrograms/kg) produced similar reductions in mean arterial pressure of 58 +/- 3% and 55 +/- 3%, respectively. BRL 34915 (ED30% = 13.8 micrograms/kg) was 15.3 times more potent than nifedipine (ED30% = 207 micrograms/kg) in SHR. In contrast, only a 1.7-fold difference in potency was observed in NTR between BRL 34915 (ED30% = 123 micrograms/kg) and nifedipine (ED30% = 182 micrograms/kg). The potency ratio (ED30% NTR/ED30% SHR) for BRL 34915 was 8.83 whereas nifedipine had a ratio of 0.88, reflecting the greater responsiveness of the SHR to BRL 34915. Systemic hemodynamics were monitored in anesthetized SHR and NTR to determine the basis for the reductions in blood pressure. BRL 34915 (3-100 micrograms/kg iv) lowered mean arterial pressure in both groups solely by decreasing total peripheral vascular resistance, since no changes in cardiac output were observed. Relaxation responses were also obtained in phenylephrine-contracted isolated aortic strips from both strains of rat to ascertain whether differences in responsiveness existed at this level of the vasculature. No significant difference in the potency of BRL 34915 (3-10 microM) as a vasodilator was found in aortas from SHR or NTR. These results indicate that, unlike nifedipine, BRL 34915 is a more potent vasodepressor agent in SHR than in NTR and suggests that the potassium efflux stimulator may preferentially relax resistance vessels in the hypertensive rat.     

Respiratory muscle blood flows during physiological and chemical hyperpnea in the rat.

Whether the diaphragm retains a vasodilator reserve at maximal exercise is controversial. To address this issue, we measured respiratory and hindlimb muscle blood flows and vascular conductances using radiolabeled microspheres in rats running at their maximal attainable treadmill speed (96 +/- 5 m/min; range 71-116 m/min) and at rest while breathing either room air or 10% O(2)-8% CO(2) (balance N(2)). All hindlimb and respiratory muscle blood flows measured increased during exercise (P < 0.001), whereas increases in blood flow while breathing 10% O(2)-8% CO(2) were restricted to the diaphragm only. During exercise, muscle blood flow increased up to 18-fold above rest values, with the greatest mass specific flows (in ml. min(-1). 100 g(-1)) found in the vastus intermedius (680 +/- 44), red vastus lateralis (536 +/- 18), red gastrocnemius (565 +/- 47), and red tibialis anterior (602 +/- 44). During exercise, blood flow was higher (P < 0.05) in the costal diaphragm (395 +/- 31 ml. min(-1). 100 g(-1)) than in the crural diaphragm (286 +/- 17 ml. min(-1). 100 g(-1)). During hypoxia+hypercapnia, blood flows in both the costal and crural diaphragms (550 +/- 70 and 423 +/- 53 ml. min(-1). 100 g(-1), respectively) were elevated (P < 0.05) above those found during maximal exercise. These data demonstrate that there is a substantial functional vasodilator reserve in the rat diaphragm at maximal exercise and that hypoxia + hypercapnia-induced hyperpnea is necessary to elevate diaphragm blood flow to a level commensurate with its high oxidative capacity.     

Hemodynamic effects of calcitonin gene-related peptide in conscious rats

The cardiovascular effects of calcitonin gene-related peptide (CGRP) were examined in conscious, unrestrained rats. Changes in mean arterial pressure, heart rate and cardiac output were continuously monitored before and after i.v. bolus injection of CGRP (0.1-5 micrograms/kg). Injection of the peptide caused dose-dependent reductions in mean arterial pressure (-24 +/- 4 mmHg), which were accompanied by marked tachycardia. Cardiac output was significantly increased after CGRP but little change was observed in stroke volume. CGRP also reduced total peripheral resistance (-46 +/- 6%). These data indicate that the hypotensive actions of CGRP are mediated through peripheral vasodilation rather than through reductions in cardiac output. Pretreatment with propranolol significantly reduced the tachycardia responses to CGRP from 81 +/- 11 beats/min to 36 +/- 4 beats/min, but did not abolish the increase in heart rate. These data suggest that CGRP produces a tachycardia through reflex increases in cardiac sympathetic tone and through possible direct positive chronotropic effects on the heart.     

Metabolic forearm vasodilation is enhanced following Bier block with phentolamine

The extent to which sympathetic nerve activity restrains metabolic vasodilation in skeletal muscle remains unclear. We determined forearm blood flow (FBF; ultrasound/Doppler) and vascular conductance (FVC) responses to 10 min of ischemia [reactive hyperemic blood flow (RHBF)] and 10 min of systemic hypoxia (inspired O(2) fraction = 0.1) before and after regional sympathetic blockade with the alpha-receptor antagonist phentolamine via Bier block in healthy humans. In a control group, we performed sham Bier block with saline. Consistent with alpha- receptor inhibition, post-phentolamine, basal FVC (FBF/mean arterial pressure) increased (pre vs. post: 0.42 +/- 0.05 vs. 1.03 +/- 0.21 units; P < 0.01; n = 12) but did not change in the saline controls (pre vs. post: 0.56 +/- 0.14 vs. 0.53 +/- 0.08 units; P = not significant; n = 5). Post-phentolamine, total RHBF (over 3 min) increased substantially (pre vs. post: 628 +/- 75 vs. 826 +/- 92 ml/min; P < 0.01) but did not change in the controls (pre vs. post: 618 +/- 66 vs. 661 +/- 35 ml/min; P = not significant). In all conditions, compared with peak RHBF, peak skin reactive hyperemia was markedly delayed. Furthermore, post-phentolamine (pre vs. post: 0.43 +/- 0.06 vs. 1.16 +/- 0.17 units; P < 0.01; n = 8) but not post-saline (pre vs. post: 0.93 +/- 0.16 vs. 0.87 +/- 0.19 ml/min; P = not significant; n = 5), the FVC response to hypoxia (arterial O(2) saturation = 77 +/- 1%) was markedly enhanced. These data suggest that sympathetic vasoconstrictor nerve activity markedly restrains skeletal muscle vasodilation induced by local (forearm ischemia) and systemic (hypoxia) vasodilator stimuli.     

Effects of long-term losartan and L-arginine treatment on haemodynamics, glomerular filtration, and SOD activity in spontaneously hypertensive rats

Recently, it has been reported that losartan, an angiotensin II receptor (ATR) antagonist, depresses the angiotensin II-induced production of superoxide radicals. Also, in spontaneously hypertensive rats (SHR) endothelial dysfunction is associated with decreased nitric oxide (NO) synthesis. In this study, we examined the effects of long-term ATR blockade and L-arginine supplementation on the haemodynamic parameters, glomerular filtration, and oxidative status in SHR. Adult male SHR were treated with losartan (10 mg/kg) and with the NO donor L-arginine (2 g/kg) for 4 weeks. The animals were divided into the following experimental groups: control (n = 7), L-arginine (n = 7), losartan (n = 7), and L-arginine + losartan (n = 7). Mean arterial pressure (MAP), regional blood flow, urea clearance, and activity of superoxide dismutase (SOD) were measured at the end of treatment. MAP was significantly reduced in the losartan group compared with the control group (133.3 +/- 7.3 vs. 161.5 +/- 14.5 mm Hg). Aortic blood flow was significantly higher and aortic vascular resistance was significantly lower in all treated groups than in the control. Urea clearance rose significantly in the L-arginine + losartan group compared with control (393.27 +/- 37.58 vs. 218.68 +/- 42.03 microL x min(-1) x 100 g(-1)) as did the activity of SOD (1668.97 +/- 244.57 vs. 1083.18 +/- 169.96 U/g Hb). Our results suggest that the antihypertensive effect of losartan and L-arginine in SHR is not primarily mediated by increased SOD activity. Also, combined treatment with ATR blockade and L-arginine supplementation has a beneficial effect on renal function that is, at least in part, mediated by increased SOD activity in SHR.     

Dynamic regulation of leg vasomotor tone in patients with chronic heart failure.

We examined the central hemodynamic (n = 5) and leg blood flow (n = 9) responses to one- and two-leg bicycle exercise in nine ambulatory patients with chronic heart failure due to left ventricular systolic dysfunction (ejection fraction 17 +/- 9%). During peak one- vs. two-leg exercise, leg blood flow (thermodilution) tended to be higher (1.99 +/- 0.91 vs. 1.67 +/- 0.91 l/min, P = 0.07), whereas femoral arteriovenous oxygen difference was lower (13.6 +/- 3.1 vs. 15.0 +/- 2.9 ml/dl, P less than 0.01). Comparison of data from exercise stages matched for single-leg work rate during one- vs. two-leg exercise demonstrated that cardiac output was similar while both oxygen consumption and central arteriovenous oxygen differences were lower, indicating relative improvement in the cardiac output response at a given single-leg work rate during one-leg exercise. This was accompanied by higher leg blood flow (1.56 +/- 0.76 vs. 1.83 +/- 0.72 l/min, P = 0.02) and a tendency for leg vascular resistance to be lower (92 +/- 54 vs. 80 +/- 48 Torr.l-1.min, P = 0.08) without any change in blood lactate. These data indicate that, in patients with chronic heart failure, leg vasomotor tone is dynamically regulated, independent of skeletal muscle metabolism, and is not determined solely by intrinsic abnormalities in skeletal muscle vasodilator capacity. Our results suggest that relative improvements in central cardiac function may lead to a reflex release of skeletal muscle vasoconstrictor tone in this disorder.     

Effects of trigeminal neurotransmitters on piglet pial arterioles.

We investigated effects of calcitonin gene-related peptide (CGRP), substance P (SP), and neurokinin A (NKA) on pial arterioles in newborn pigs. Pial arteriolar diameter was determined using a closed cranial window and intravital microscopy. Initial diameters were approximately 100 microns. Calcitonin-gene related peptide dilated pial arterioles by 22 +/- 8% at 10(-9)M and by 34 +/- 6% at 10(-8)M (n = 8), and this response was not significantly altered by prior administration of indomethacin (5mg/kg, iv) (n = 6) or administration of NG-methyl-L-arginine (5mg/kg, iv, and 10(-3)M in CSF) (n = 10). Substance P dilated arterioles at 10(-10)M through 10(-5)M (maximal response = 23 +/- 3%) (n = 6), and this response was unaffected by indomethacin administration (n = 6). In contrast, NG-methyl-L-arginine blocked much of the pial arteriolar dilation to SP. Unlike the other two peptides, NKA did not change pial arteriolar diameter. Radioimmunoassay determinations indicated that cerebrospinal fluid levels of 6-keto-prostaglandin F1 and prostaglandin E2 did not change appreciably during application of CGRP or SP. We conclude that CGRP and SP but not NKA are dilator stimuli in the piglet pial circulation. Dilation by CGRP probably involves direct activation of receptors on vascular smooth muscle, while SP probably partially dilates pial arterioles via release of an endothelium-dependent relaxing factor.     

Mechanism for pressor response to nonexertional heating in the conscious rat

The purpose of this study was to determine the systemic hemodynamic mechanism(s) underlying the pressor response to nonexertional heat stress in the unrestrained conscious rat. After a 60-min control period [ambient temperature (Ta) 24 degrees C], male Sprague-Dawley rats (260-340 g) were exposed to a Ta of 42 degrees C until a colonic temperature (Tc) of 41 degrees C was attained. As Tc rose from control levels (38.1 +/- 0.1 degrees C) to 41 degrees C, mean arterial blood pressure (carotid artery catheter, n = 33) increased from 124 +/- 2 to 151 +/- 2 mmHg (P less than 0.05). During this period, heart rate increased (395 +/- 5 to 430 +/- 6 beats/min, P less than 0.05) and stroke volume remained unchanged. As a result, ascending aorta blood flow velocity (Doppler flow probe, n = 8), used as an index of cardiac output, did not change from control levels during heating, but there was a progressive Tc-dependent increase in systemic vascular resistance (+30% at end heating, P less than 0.05). This systemic vasoconstrictor response was associated with decreases in blood flow (-31 +/- 9 and -21 +/- 5%) and increases in vascular resistance (94 +/- 16 and 53 +/- 8%; all P less than 0.05) in the superior mesenteric and renal arteries (n = 8 each) and increases in plasma norepinephrine (303 +/- 37 to 1,237 +/- 262 pg/ml) and epinephrine (148 +/- 28 to 708 +/- 145 pg/ml) concentrations (n = 12, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcitonin gene-related peptide and adrenomedullin release in humans: effects of exercise and hypoxia

Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are potent vasorelaxant peptides. This study examined exercise-induced changes in CGRP and AM levels in 12 healthy sea level natives at sea level (SL) and subsequently after 24 h (HA1) and 5 days (HA5) in high altitude hypoxia (4559 m). Plasma values of CGRP, AM, calcitonin, noradrenaline, adrenaline, lactate and heart rate were measured at rest and during maximal exercise (W(max)). On each study day, the dopamine D(2)-receptor antagonist, domperidone (30 mg; n=6), or no medication (n=6) was given 1 h before exercise. W(max) at SL, HA1 and HA5 increased CGRP and AM along with heart rate, lactate and catecholamines, whereas, calcitonin remained unchanged. The maximal CGRP levels at W(max) were significantly decreased at HA1 (74.3+/-6.1 pmol/l; p=0.002) and HA5 (69.6+/-6.0 pmol/l; p<0.001) compared to maximal CGRP at SL (85.1+/-4.9 pmol/l). A similar pattern was observed for lactate and the relation between CGRP and lactate release showed a close linear correlation (r(2)=0.63, P<0.0001). Domperidone produced a marked increase in noradrenaline at W(max), but had no affect on CGRP or AM. In conclusion, CGRP release during hypoxic exercise does not respond to domperidone-induced changes in circulating levels of noradrenaline, rather the release may be directly related to the production of lactate.     

Regional hemodynamic responses to nicotine in conscious and anesthetized dogs: comparative effects of pentobarbital and chloralose

This study was conducted in 12 dogs to evaluate regional hemodynamic responses during intravenous infusion of nicotine (36 micrograms/kg/min) in the conscious state and compare them with those in the same dogs following either pentobarbital (n = 6) or chloralose anesthesia (n = 6). Values for regional blood flow were obtained with 15-microns radioactive microspheres and used to calculate regional vascular conductance. In the conscious state, nicotine increased aortic pressure (+70%) and caused hyperventilation that reduced arterial PCO2 (-44%). These systemic effects were associated with decreases in vascular conductance in the renal cortex (-48%), pancreas (-81%), duodenum (-58%), and cerebral cortex (-55%), whereas no significant change in vascular conductance was evident in spleen, liver, or myocardium. Pentobarbital anesthesia blunted the increases in aortic pressure and respiratory activity and the reductions in vascular conductance in the renal cortex, pancreas, duodenum, and cerebral cortex during nicotine infusion. In contrast, chloralose anesthesia accentuated the increase in aortic pressure and the decrease in vascular conductance in the renal cortex during nicotine infusion, while it converted no change in vascular conductance in the spleen into a decrease and no change in vascular conductance in the myocardium into an increase. Chloralose anesthesia blunted nicotine-induced hyperventilation. These findings demonstrate that general anesthetic agents may have markedly different effects on cardiovascular reflex pathways. They emphasize the importance of considering the particular characteristics of the anesthetic agent used in interpreting results from studies of cardiovascular pharmacology and physiology in anesthetized animals.     

Nongenomic vasodilator action of progesterone on primate coronary arteries.

In the present investigation, we test the hypothesis that progesterone can rapidly relax, via a nongenomic mechanism, persistent flow occluding, agonist-activated coronary artery (CA) vasospasm, and hyperreactive vascular muscle cell (VMC) Ca(2+) responses in ovariectomized rhesus monkeys. CA vasospasm, induced by injection of 100 microM serotonin and 1 microM U-46619 (5-HT+U; 1 ml/30 s), resulted in a decrease in CA diameter (phi) from 1.8 +/- 0.2 to 0.3 +/- 0.1 mm at the site of focal constriction. Injection of 100 ng progesterone into the CA significantly relieved the severe vasoconstriction (1.3 +/- 0.2 mm) and reestablished distal flow in 3 min; the preconstriction phi was completely restored in 8.2 +/- 2.6 min (n = 6). Similarly, cell impermeant albumin-conjugated progesterone, but not albumin-conjugated 17 beta-estradiol, decreased 5-HT+U stimulated VMC Ca(2+) responses (250 +/- 34% of basal 30 min after stimulation) back to the prestimulation level (113 +/- 17% of basal) in 25 min (half time = 7 min). The presence of a rapid vasodilator action of progesterone in the primate CA and isolated VMC suggests its benefits in hormone replacement therapy may also include nongenomic vascular relaxant actions.     

Altered muscle metaboreflex control of coronary blood flow and ventricular function in heart failure

We investigated the effect of muscle metaboreflex activation on left circumflex coronary blood flow (CBF), coronary vascular conductance (CVC), and regional left ventricular performance in conscious, chronically instrumented dogs during treadmill exercise before and after the induction of heart failure (HF). In control experiments, muscle metaboreflex activation during mild exercise elicited significant reflex increases in mean arterial pressure, heart rate, and cardiac output. CBF increased significantly, whereas no significant change in CVC occurred. There was no significant change in the minimal rate of myocardial shortening (-dl/dt(min)) with muscle metaboreflex activation during mild exercise (15.5 +/- 1.3 to 16.8 +/- 2.4 mm/s, P > 0.05); however, the maximal rate of myocardial relaxation (+dl/dt(max)) increased (from 26.3 +/- 4.0 to 33.7 +/- 5.7 mm/s, P < 0.05). Similar hemodynamic responses were observed with metaboreflex activation during moderate exercise, except there were significant changes in both -dl/dt(min) and dl/dt(max). In contrast, during mild exercise with metaboreflex activation during HF, no significant increase in cardiac output occurred, despite a significant increase in heart rate, inasmuch as a significant decrease in stroke volume occurred as well. The increases in mean arterial pressure and CBF were attenuated, and a significant reduction in CVC was observed (0.74 +/- 0.14 vs. 0.62 +/- 0.12 ml x min(-1) x mmHg(-1); P < 0.05). Similar results were observed during moderate exercise in HF. Muscle metaboreflex activation did not elicit significant changes in either -dl/dt(min) or +dl/dt(max) during mild exercise in HF. We conclude that during HF the elevated muscle metaboreflex-induced increases in sympathetic tone to the heart functionally vasoconstrict the coronary vasculature, which may limit increases in myocardial performance.     

Adrenergic airway vascular smooth muscle responsiveness in healthy and asthmatic subjects.

The purpose of the present study was to determine the responsiveness of airway vascular smooth muscle (AVSM) as assessed by airway mucosal blood flow (Qaw) to inhaled methoxamine (alpha(1)-agonist; 0.6-2.3 mg) and albuterol (beta(2)-agonist; 0.2-1.2 mg) in healthy [n = 11; forced expiratory volume in 1 s, 92 +/- 4 (SE) % of predicted] and asthmatic (n = 11, mean forced expiratory volume in 1 s, 81 +/- 5%) adults. Mean baseline values for Qaw were 43.8 +/- 0.7 and 54.3 +/- 0.8 microl. min(-1). ml(-1) of anatomic dead space in healthy and asthmatic subjects, respectively (P < 0.05). After methoxamine inhalation, the maximal mean change in Qaw was -13.5 +/- 1.0 microl. min(-1). ml(-1) in asthmatic and -7.1 +/- 2.1 microl. min(-1). ml(-1) in healthy subjects (P < 0.05). After albuterol, the mean maximal change in Qaw was 3.0 +/- 0.8 microl. min(-1). ml(-1) in asthmatic and 14.0 +/- 1.1 microl. min(-1). ml(-1) in healthy subjects (P < 0.05). These results demonstrate that the contractile response of AVSM to alpha(1)-adrenoceptor activation is enhanced and the dilator response of AVSM to beta(2)-adrenoceptor activation is blunted in asthmatic subjects.     

Exposure to stress differential vascular adaptive response in spontaneously hypertensive and Wistar rats: Role of nitric oxide, and prehypertensive and hypertensive states

Stress-induced vascular adaptive response in SHR was investigated, focusing on the endothelium. Noradrenaline responses were studied in intact and denuded aortas from 6-week-old (prehypertensive) and 14-week-old (hypertensive) SHR and age-matched Wistar rats submitted or not to acute stress (20-min swimming and 1-h immobilization 25 min apart), preceded or not by chronic stress (2 sessions 2 days apart of 1-h day immobilization for 5-consecutive days). Stress did not alter the reactivity of denuded aorta. Moreover, no alteration in the EC50 values was observed after stress exposure. In intact aortas, acute stress-induced hyporeactivity to noradrenaline similar between strains at both age. Chronic stress potentiated this adaptive response in 6- and 14-week-old Wistar but not in 6-week-old SHR, and did not alter the reactivity of 14-week-old SHR. Maximum response (g) in intact aortas [6-week-old: Wistar 3.25+/-0.12, Wistar/acute 1.95+/-0.12*, Wistar/chronic 1.36+/-0.21*(+), SHR 1.75+/-0.11, SHR/acute 0.88+/-0.08*, SHR/chronic 0.85+/-0.05*; 14-week-old: Wistar 3.83+/-0.13, Wistar/acute 2.72+/-0.13*, Wistar/chronic 1.91+/-0.19*(+), SHR 4.03+/-0.17, SHR/acute 2.26+/-0.12*, SHR/chronic 4.10+/-0.23; inside the same strain: *P < 0.05 relate to non-stressed rat, +P < 0.05 related to acute stressed rat; n = 6-18]. Independent of age and strain, L-NAME and endothelium removal abolished the stress-induced aorta hyporeactivity. CONCLUSION: The vascular adaptive response to stress is impaired in SHR, independently of the hypertensive state. Moreover, this vascular adaptive response is characterized by endothelial nitric oxide-system hyperactivity in both strains.     

Reversible impairment of forearm vasodilation after forearm casting

To examine whether the resumption of normal physical activity after forearm immobilization would reverse impaired vasodilation, the minimal vascular resistance was examined in six subjects who had forearm casts placed for broken forearm bones. Each subject was examined twice, once within 48 h after forearm cast removal and again approximately 29 days later. The formerly casted forearm and the opposite forearm (noncasted) were examined. Minimal vascular resistance decreased in the casted forearm from 3.0 +/- 0.4 to 2.6 +/- 0.5 mmHg.ml-1.min.100 ml (P less than 0.014). There was no change in the noncasted forearm: 2.5 +/- 0.3 vs. 2.5 +/- 0.3 mmHg.ml-1.min.100 ml. This study shows that maximal vasodilation improves with the resumption of normal physical activity and therefore demonstrates that immobilization is associated with a reduced forearm vasodilator capacity.     

Calcitonin gene-related peptide vasodilation of human pulmonary vessels

Human calcitonin gene-related peptide (CGRP) is localized to sensory neurons in pulmonary vessels and is a potent vasodilator. We have characterized the effects of CGRP in human pulmonary vessels and localized the receptors for this peptide by autoradiography. Fresh human lung tissue was obtained from eight patients undergoing surgery and small (200-400 microns ID) pulmonary arteries and veins were dissected free of surrounding connective and pulmonary tissue. Pairs of vessels were studied and in one of each pair the endothelium was left intact and from the other of each pair the endothelium was removed by gentle abrasion. For functional studies arteries (n = 9) and veins (n = 9) were suspended in an organ bath, precontracted with 1 microM prostaglandin F2 alpha. CGRP (10 pM to 10 microM) was added in a cumulative manner. CGRP caused a dose-dependent relaxation of endothelium intact human pulmonary arteries and veins with log EC50 values of -8.01 +/- 0.35 and -8.70 +/- 0.40, respectively (not significant). Removal of the endothelium did not diminish the vasodilator potency of CGRP in either vessel. For autoradiographic studies, cryostat sections of the small human pulmonary vessels with or without endothelium were used. 125I-CGRP densely labeled CGRP receptors on vascular smooth muscle and endothelial removal did not have any effect on grain density. We concluded that CGRP is a potent vasodilator of human pulmonary arteries and veins that is not dependent on an intact endothelium. These functional studies correlate with the distribution of CGRP receptors as localized by autoradiography.     

Potent vasoactive properties of endothelin 1 in human skin.

The effect of the endothelial cell-derived peptide endothelin 1 was investigated in human skin. Intradermal injection of endothelin 1 (1-100 pmol) caused a dose-dependent area of pallor that was associated with a significant reduction in basal skin blood flow, measured by laser-Doppler blood flowmeter (with 1 pmol endothelin, P = 0.012, analysis of variance). The coadministration of endothelin 1 (1-100 pmol) with the neuropeptide vasodilator calcitonin gene-related peptide (CGRP) inhibited the vasodilator response to CGRP (10 pmol) by up to 82.7 +/- 9.2% (with 100 pmol endothelin, P less than 0.001). The response of the prostanoid vasodilator prostaglandin E2 (10 pmol) was inhibited by endothelin in a similar manner. In addition to the vasoconstrictor effects, endothelin 1 produced a dose-dependent flare that surrounded the area of pallor, and this was associated with a significant increase in blood flow (P less than 0.05) within the flare area. The H1 antagonist terfenadine (120 mg po) significantly reduced the flare area associated with endothelin 1: flare 5 min after intradermal endothelin (10 pmol, placebo treated), 668 +/- 405 mm2; terfenadine treated, 201 +/- 257 mm2 (P less than 0.05). The flare was also significantly attenuated when endothelin (10 pmol) was injected into local anesthetic-treated skin. Thus intradermal injection of endothelin in humans causes long-lasting vasoconstriction at the site of injection and a surrounding flare. Results suggest that the flare component is partially histamine dependent and the result of an axon reflex. This study demonstrates the potent activity of endothelin in human skin. It is possible that endothelin could be relevant to the local response of skin to injury.