Neuropeptide Y modulates vasoconstriction in coronary microvessels in the beating canine heart

The purpose of this study was to determine whether neuropeptide Y has a direct vasoconstrictor effect at low doses, mimicking the physiological plasma concentration on the specific site(s) of coronary arterial microvessels in in situ beating canine left ventricles. Coronary microvessels were directly observed by means of an intravital microscope and video system equipped with a floating objective. Epi-illuminated fluorescence coronary microangiography was performed in open-chest anesthetized dogs (n = 14) to examine the changes in internal diameter of epimyocardial arterial microvessels. Flow velocity of fluorescently labeled microshperes in capillaries was also measured (n = 6). To eliminate secondary effects of neuropeptide Y on coronary microvessels via autonomic nervous modulation, experiments were conducted under pharmacological blockade of the regional autonomic nervous system by intracoronary injection of propranolol, 50 micrograms/kg; phentolamine, 100 micrograms/kg; and atropine, 5 micrograms/kg. Aortic pressure and heart rate were kept constant during the experiments. Intracoronary infusion of three different doses of neuropeptide Y (1, 10, and 100 pmol/kg/min) for 5 minutes significantly constricted small microvessels (less than 100 microns in diameter) (-5.2 +/- 1.4%, -8.5 +/- 1.5%, and -14.0 +/- 1.7%; p less than 0.05 versus before neuropeptide Y at each dose), medium microvessels (100-200 microns in diameter) (-5.5 +/- 1.6%, -10.6 +/- 1.8%, and -16.8 +/- 2.1%, p less than 0.05 versus before neuropeptide Y at each dose), and large microvessels (greater than 200 microns in diameter) (-3.6 +/- 0.6%, -5.8 +/- 0.8%, and -10.0 +/- 1.1%; p less than 0.05 versus before neuropeptide Y at each dose) in a dose-dependent manner. Capillary flow velocity was reduced by 17.2 +/- 3.1% by an intracoronary dose of 100 pmol/kg/min of neuropeptide Y (p less than 0.05). The present study indicates that low doses of neuropeptide Y exert a homogeneous direct vasoconstrictor effect on various sizes of coronary arterial microvessels and reduce capillary flow velocity. These results suggest that neuropeptide Y may play a physiological role in modulating coronary microvascular tone.     

The effect of alpha- and beta-adrenergic agonists and blockers on postprandial pancreatic polypeptide release in dogs

The influence of adrenergic agonists--phenylephrine (alpha), isoproterenol (beta), and salbutamol (beta 2)--and of adrenergic blockers--phentolamine (alpha), pranolol (beta), and practolol (beta 1)--on the postprandial pancreatic polypeptide (PP) release has been assessed in five Labrador retrievers. Infusions of phenylephrine, 0.12 mg kg-1h-1; isoproterenol, 3 micrograms kg-1h-1; salbutamol, 12 micrograms kg-1h-1, did not significantly affect PP release. Propranolol, 0.5 mg kg-1, and propranolol, 0.5 mg kg-1, + phentolamine, 1 mg kg-1, combined, given as intravenous boluses before the meal significantly reduce PP release (44% and 58% of controls, p less than 0.05), whereas phentolamine, 1 mg kg-1, and practolol, 1 mg kg-1, had no effect. Phenylephrine combined with phentolamine and isoproterenol combined with propranolol and practolol did not influence PP secretion. It is concluded that the postprandial PP release is stimulated by beta 2-adrenergic mechanisms.     

Effects of regional alpha- and beta-blockade on resting and hyperemic coronary blood flow in conscious, unstressed humans

Our purpose was to determine if there are basal adrenergic influences on the coronary circulation in humans. We studied 56 patients with denervated hearts after cardiac transplantation and 19 normally innervated patients with angiographically normal coronary arteries. Coronary blood flow velocity was measured during cardiac catheterization with a subselective 3F intracoronary Doppler catheter. Heart rate was controlled by atrial pacing. Epicardial coronary artery diameter was measured by automated analysis of digital coronary angiograms. Coronary flow reserve was assessed by intracoronary papaverine hydrochloride (12 mg) injections. Regional sympathetic blockade was produced by intracoronary injections of phentolamine (3 mg, alpha) and propranolol (2 mg, beta) or metoprolol (3 mg, beta 1). After alpha-blockade, mean arterial pressure fell significantly (p less than 0.05) in both the denervated transplant (-5.8 +/- 1.5%) (mean +/- SEM) and normally innervated patients (-12.6 +/- 3.2%). Reductions in coronary flow velocity also were observed in these groups (-8.2 +/- 2.3% and -9.2 +/- 5.8%, respectively). Calculated coronary vascular resistance was unchanged. Similar changes were seen when patients were pretreated with beta-blockade before alpha-blockade. Nonspecific beta-blockade did not affect mean arterial pressure but decreased coronary velocity (innervated, -11.6 +/- 3.9%; denervated, -9.3 +/- 2.4%) and increased coronary vascular resistance (innervated, 15.4 +/- 6.7%; denervated, 10.2 +/- 3.7%). Coronary vascular resistance did not rise in either group after selective beta 1-blockade with metoprolol. Coronary flow reserve did not change in either patient group after either alpha- or beta-blockade. Changes in epicardial coronary artery diameter were small and generally not significant. These data suggest that alpha-receptor-mediated vascular tone is negligible in both denervated transplant patients and normally innervated patients. Additionally, the increase in vascular resistance after nonselective beta-blockade is the result of direct beta 2 vascular effects. Our data further suggest that there is little adrenergically mediated epicardial artery tone (either humoral or neural) at rest and that maximal vasodilator responses are not limited by adrenergically mediated vasomotor tone.     

Simultaneous endocardial and epicardial monophasic action potential recordings during brief periods of coronary artery ligation in the dog: influence of adrenaline, beta blockade and alpha blockade

Local differences in the time course of recovery of excitability during the early phase of myocardial ischaemia are important in the genesis of arrhythmias. Catecholamines are known to encourage the formation of arrhythmias and adrenergic blockade is a recognised therapeutic regime. The purpose of this study was to compare the effect of short periods of coronary artery ligation on endocardial and epicardial repolarisation time, to assess any disparity between the two surfaces, and investigate the influence of catecholamines and adrenergic blockade. Simultaneous left ventricular endocardial and epicardial monophasic action potentials (MAPs) were recorded during short periods of left anterior descending coronary artery (LAD) ligation in 9 open chested dogs. Recordings were made during two 90 s periods of LAD ligation. Two further ligations were made during infusion of adrenaline (1 microgram.kg-1.min-1). Subsequently ligations were made after beta blockade with propranolol (0.25 mg.kg-1) and then in the presence of a combination of alpha blockade (phentolamine, 0.15 mg.kg-1) and beta blockade. MAP duration was measured at 90% repolarisation. LAD ligation produced a marked shortening of MAP duration epicardially with only minimal shortening endocardially, which resulted in a highly significant difference between the repolarisation times on the two surfaces. The disparity between surfaces tended to be augmented by adrenaline and was significantly minimised by either beta blockade alone or in combination with alpha blockade. Our results show rapid development of substantial regional differences in repolarisation time between endocardium and epicardium in response to "ischaemia".(ABSTRACT TRUNCATED AT 250 WORDS)     

Heterogeneous microvascular coronary alpha-adrenergic vasoconstriction

We tested the hypothesis that humoral or neurogenic alpha-adrenergic activation in the coronary circulation would produce heterogeneous vascular reactions. To accomplish this, the epicardial coronary microcirculation was viewed through an intravital microscope using stroboscopic epi-illumination. Microvascular diameters were measured under control conditions during beta-adrenergic blockade (propranolol 1 mg/kg) and beta-adrenergic blockade with pacing; during coronary alpha-adrenergic activation in the presence of beta-adrenergic blockade with three doses of norepinephrine infusion (0.1, 0.5, and 1.0-2.0 micrograms/kg/min) or three frequencies of bilateral stellate nerve stimulation (2, 10, and 20 Hz); and during combined alpha- and beta-adrenergic blockade (phentolamine 2 mg/kg and propranolol 1 mg/kg). Diameters of both arterial and venous vessels were reduced during beta-adrenergic blockade but returned back to baseline with pacing. At the lowest level of norepinephrine infusion or frequency of bilateral stellate stimulation, microvessel constriction was not observed. At the higher doses of norepinephrine a -5.1 +/- 0.9% (1.0-2.0 micrograms/kg/min) and a -4.0 +/- 1.1% (0.5 micrograms/kg/min) decrease in diameter of arterial vessels greater than 100 microns in diameter were observed (p less than 0.05). At 10 Hz and 20 Hz of stellate stimulation, diameter decreased by -4.8 +/- 1.9% and -4.4 +/- 2.1%, respectively, in these relatively large vessels. Small coronary arterioles (less than 100 microns diameter) dilated significantly during the highest levels of nerve stimulation (9.2 +/- 2.5% increase in diameter) or infusion rate of norepinephrine (13.6 +/- 2.7% increase in diameter) (p less than 0.05). These constrictor and dilator responses were abolished following combined alpha- and beta-adrenergic blockade. Norepinephrine infusion resulted in a decrease in diameter of coronary veins and venules (7.2 +/- 1.3%) (p less than 0.05), whereas stellate stimulation did not significantly reduce venous and venular diameters. In summary, the coronary venous and venular vasculature responds to alpha-adrenergic activation from circulating norepinephrine but is not affected by stellate stimulation. In contrast, stellate stimulation and norepinephrine infusion elicit similar responses in the coronary arterial and arteriolar microvasculature. Constriction occurs in vessels greater than 100 microns in diameter, whereas dilation predominates in vessels less than 100 microns in diameter. Such heterogeneous arterial responses would undoubtedly result in a redistribution of coronary vascular resistance toward larger coronary arteries and arterioles.     

Regulation of coronary blood flow by counteraction of coronary vascular alpha and beta adrenergic activation during experimental pliable coronary stenosis

In order to evaluate the role of adrenergic receptor-mediated vasomotions of large epicardial coronary arteries in changing coronary blood flow (CBF), the effects of intracoronary norepinephrine (NE), 1.0 microgram/min, were examined in dogs with coronary stenosis which preserved stenosis vasomobility. In untreated dogs, NE caused no significant changes in CBF and stenosis resistance (SR). In dogs treated with propranolol, NE decreased CBF by 65 +/- 7.0% (mean +/- SE) and produced 12-fold intensification of SR followed by LV dP/dt reduction. Similar detrimental responses to NE were observed in dogs treated with atenolol. In dogs treated with phentolamine, NE increased CBF by 33 +/- 5.6% and decreased SR by 65 +/- 7.1%. When NE was administrated directly distal to the stenosis to exclude responses of the stenosed coronary segment, NE failed to affect CBF and SR. These results indicated that alpha receptor stimulation intensified stenosis severity, profoundly decreased CBF and evoked myocardial ischemia, whereas beta stimulation dilated coronary stenosis and increased CBF. The net effects of NE were due to balanced alpha and beta stimulation. Thus, disproportionate activation of alpha and beta (probably beta 1) adrenergic receptors in large coronary arteries with pliable stenosis could modulate their tone and plays an important role in the regulation of CBF.     

Effect of acidosis on contraction of microvascular smooth muscle by alpha 1- and alpha 2-adrenoceptors. Implications for neural and metabolic regulation

Our previous studies have identified that adrenergic regulation of large arterioles and venules in skeletal muscle uses both postjunctional alpha 1- and alpha 2-adrenoceptors, whereas terminal arterioles appear to be subserved primarily by alpha 2-receptors. Adrenergic constriction of terminal arterioles is known to be particularly susceptible to inhibition by increased tissue metabolic rate. The purpose of this study was to examine the influence of tissue acidosis on alpha 1- and alpha 2-adrenoceptor constriction of skeletal muscle microvessels to determine if this differential receptor distribution might have significance in neural-metabolic interactions. Intravital microscopy of rat cremaster skeletal muscle was used to obtain concentration-response curves (diameter changes) of large distributing arterioles (mean diameter, 100 microns), small precapillary arterioles (20 microns), and capacitance venules (150 microns) for addition to the tissue bath of alpha-adrenergic agonists during normal pH (7.4) and during tissue bath acidosis (pH 7.1) produced by increasing bath PCO2. The following alpha-agonists were used: phenylephrine (alpha 1), B-HT 933 (alpha 2), and norepinephrine (mixed alpha 1/alpha 2). Acidosis had no effect on baseline diameter of the three vessel types, indicating a lack of effect on "intrinsic tone." Acidosis also had no effect on large microvessel sensitivity to phenylephrine but markedly reduced responses to B-HT 933. Acidosis had no effect on large arteriolar and venular sensitivity to norepinephrine but markedly decreased (x300) small precapillary arteriolar sensitivity. These data suggest that 1) alpha 2- but not alpha 1-adrenoceptor-mediated constriction of microvessels may be selectively sensitive to modest reductions in tissue pH, and 2) the prevalence of alpha 2-receptors on terminal arterioles and the marked sensitivity of alpha 2 constriction to tissue acidosis may contribute to the particular susceptibility of neural constriction at this level of the microcirculation to metabolic inhibition.     

Insulin and beta adrenergic effects during endotoxin shock: in vivo myocardial interactions

STUDY OBJECTIVE - Catecholamine concentrations are raised during endotoxin shock and may be responsible for myocardial insulin resistance in such a condition. The purpose of the investigation was to examine the effect of insulin on myocardial contractility and glucose uptake in the presence of beta adrenergic blockade during endotoxin shock. DESIGN - Endotoxin shock was obtained in dogs by giving S Typhimurium endotoxin intravenously (1 mg.kg-1) and the cardiac responses to insulin were determined under hyperinsulinaemic (4 U.min-1) euglycaemic clamp conditions during continuous beta adrenergic blockade (propranolol 150 micrograms.kg-1 + 5 micrograms.kg-1.min-1). SUBJECTS - 19 mongrel dogs of either sex, weight 20-25 kg, were studied under pentobarbitone anaesthesia. Seven dogs received endotoxin plus propranolol, and seven others received propranolol alone (control group). Five dogs received endotoxin but no propranolol or insulin. All other procedures were the same in each group. MEASUREMENTS and RESULTS - The exposed heart was prepared for coronary sinus blood sampling and measurements of circumflex artery blood flow (Q), instantaneous left ventricular pressure, and left ventricular wall thickness. Glucose uptake was calculated from product of Q and aortic-coronary sinus concentration difference. End systolic pressure-dimension relationship was used to assess contractility. Myocardial performance was assessed from left ventricular dP/dtmax. Basal shock measurements were made 60 min post endotoxin. beta Adrenergic blockade did not interfere with insulin stimulated glucose uptake in controls, but was unable to restore the uptake response during endotoxin shock. Contractility was increased during endotoxin shock and this effect was abolished by beta adrenergic blockade. In controls the only variable affected by beta adrenergic blockade was left ventricular dP/dtmax (decreased). Insulin increased contractility during beta adrenergic blockade in controls but not in shock. Myocardial performance was depressed during shock. In controls, insulin increased myocardial performance; in shock this response was attenuated. CONCLUSIONS - The findings confirm that the myocardium becomes less responsive to the glucose uptake stimulating and positive inotropic effects of insulin during endotoxin shock. The data show that beta adrenergic activity is responsible for the increased contractile state of the heart during acute endotoxin shock, but is not the cause of the observed insulin resistant state.     

Exercise-induced coronary arterial spasm: Angiographic demonstration,documentation of ischemia by myocardial scintigraphy and results of pharmacologic intervention

Exercise-induced coronary arterial spasm is an infrequently recognized phenomenon whose mechanism and management are not well established. In two patients with reproducible exercise-induced S-T segment elevation and angina pectoris thallium-201 scintigraphy showed areas of reversible anteroapical hypoperfusion, and gated radionuclide ventriculography revealed anteroapical hypokinesia with a decrease in left ventricular ejection fraction at peak exercise. During coronary arteriography, supine exercise provoked occlusive spasm of the left anterior descending coronary artery, which at rest had only minimal plaques'. Consequently, treadmill testing was performed with five different pharmacologically provoked interventions: direct vasodilatation (nitrates), alpha adrenergic blockade (phenoxybenzamine), beta adrenergic blockade (propranolol), calcium flux blockade (verapamil), and prostaglandin inhibition (indomethacin). Exercise-induced coronary arterial spasm, manifested as S-T segment elevation and angina, was prevented by nitrates, but was not eliminated by short-term oral administration of an alpha or beta blocking agent, a calcium antagonist or a prostaglandin inhibitor. Further, beta adrenergic blockade appeared to be detrimental. Thus, this study demonstrates (1) that coronary arterial spasm may be the underlying mechanism of at least some cases of exertional angina associated with transient perfusion deficits and left ventricular dysfunction, and (2) that it may be prevented by oral nitrates.     

Functional distribution of alpha 1- and alpha 2-adrenergic receptors in the coronary microcirculation.

BACKGROUND. The goal of this study was to determine the functional distribution of alpha 1- and alpha 2-adrenergic receptors in the epicardial coronary microcirculation. This goal was accomplished by intracoronary administration of the selective alpha 1-adrenergic agonist phenylephrine and the selective alpha 2-adrenergic agonist BHT-933 during measurements of coronary microvascular diameters in the beating heart. METHODS AND RESULTS. Experimental measurements were made under conditions with intact vasomotor tone and during coronary hypoperfusion (i.e., under conditions with autoregulatory mechanisms intact and blunted, respectively). Administration of selective alpha 1- and alpha 2-adrenergic antagonists, prazosin and SKF 104078, respectively, confirmed that the agonists were preferentially activating the desired adrenergic receptor subtype because the vasoconstrictor effects of the agonists were completely blocked by the appropriate antagonist. With baseline coronary vasomotor tone intact, phenylephrine caused constriction (8 +/- 3% decrease in diameter, p less than 0.05) of small coronary arteries (vessels greater than 100 microns in diameter) but did not produce constriction of coronary arterioles (vessels less than 100 microns in diameter). During coronary hypoperfusion, phenylephrine caused constriction (p less than 0.05) of both small coronary arteries and arterioles, 6 +/- 2% and 11 +/- 3% decreases in diameter, respectively. BHT-933 did not cause significant changes in microvascular diameters under control conditions but substantially and selectively decreased arteriolar diameters during hypoperfusion (24 +/- 6% decrease in diameter, p less than 0.05). CONCLUSIONS. In the intact, autoregulating coronary circulation, coronary arterioles escape from the effects of adrenergic activation but coronary arteries do not; rather, they can exhibit alpha 1-adrenergic coronary vasoconstriction. During coronary hypoperfusion, when autoregulatory adjustments are blunted, coronary arterioles are sensitive to both alpha 1- and alpha 2-adrenergic agonists, demonstrating significant constrictor responses. Also, the magnitude of coronary alpha 2-adrenergic arteriolar constriction (24% decrease in diameter) is significantly greater than that of alpha 2-adrenergic constriction (11% decrease in diameter) (p less than 0.05). Thus, alpha 1- and alpha 2-adrenergic activation produce different constrictor effects in the coronary microcirculation under baseline conditions when autoregulatory adjustments are intact and during coronary hypoperfusion when autoregulation is blunted. The data suggest that alpha 2-adrenergic receptors are preferentially distributed in arterioles, whereas alpha 1-adrenergic receptors are located throughout the coronary microcirculation. Importantly, the data also suggest that intrinsic autoregulatory adjustments in tone (i.e., autoregulatory escape) can override either alpha 1- or alpha 2-adrenergic constriction in coronary arterioles.     

Coronary microvascular resistance in hypertensive cats.

Chronic systemic hypertension has been shown to alter the distribution of vascular resistance in many microvascular beds. The purposes of this study were to assess the effects of chronic systemic hypertension on the pressure distribution in the coronary microcirculation and to determine the microvascular site where coronary vascular resistance is increased. Cats were made hypertensive using a one-kidney, one-wrap model (Page model). A servonulling system was used to directly measure pressures in the epimyocardial microvessels of the beating left ventricle in normotensive and hypertensive cats. In chronically hypertensive cats, mean arterial pressure was 153 +/- 5 mm Hg compared with 98 +/- 3 mm Hg in normotensive cats (p less than 0.05). Left ventricular mass was increased approximately 34% in hypertensive cats (9.4 +/- 0.3 versus 7.0 +/- 0.3 g, p less than 0.05). Myocardial perfusion measured using radiolabeled microspheres was not different between hypertensive and normal cats. Coronary vascular resistance of the left ventricle was increased in hypertensive cats (0.90 +/- 0.08 versus 0.66 +/- 0.05 mm Hg x min x 100 g/ml, p less than 0.05). Microvascular pressures were measured in three groups of microvessels: small, less than 200 microns; medium, 200-300 microns; and large, greater than or equal to 300 microns. Mean microvascular pressures of large, medium, and small arterial microvessels in hypertensive cats were 144 +/- 8, 127 +/- 6, and 115 +/- 7 mm Hg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of norepinephrine on the coronary microcirculation.

The role of the sympathetic nervous system in the regulation of large coronary artery tone has been well defined. Studies of adrenergic regulation of coronary-resistance vessels have largely been limited to indirect inferences based on flow measurement obtained in vivo. The purpose of the present study was to determine the effects of norepinephrine (NE) on the coronary microcirculation using direct in vitro approaches. Porcine coronary microvessels (80-200 microns in diameter) were pressurized in isolated organ chambers. Diameters were measured using a Halpern microvessel imaging apparatus. After preconstriction with leukotriene D4, NE caused complete relaxation. Relaxations to NE were inhibited by propranolol. Relaxations to NE were also inhibited by LY83583 (which depletes cGMP) and hemoglobin (which binds endothelium-derived relaxing factor, EDRF). NE caused minimal or no constriction in both preconstricted and nonpreconstricted microvessels even in the presence of hemoglobin and propranolol. In conclusion, NE predominantly dilates porcine coronary microvessels, both by beta-adrenoceptor activation and by stimulating release of EDRF. There is minimal alpha-adrenoceptor-mediated constriction of coronary microvessels.     

Adrenergic modulation of interdigestive pancreatic secretion in humans.

Whether the adrenergic pathways participate in the control of interdigestive pancreatic function in humans is uncertain. To determine if changes in alpha- or beta-adrenergic tone modulate interdigestive pancreatic enzyme output, 16 healthy subjects were intubated with an orojejunal tube to collect and quantify pancreatic trypsin secretion and record motility. After observation of a complete interdigestive cycle (control period), eight groups of two subjects each received 2-hour intravenous infusions of the alpha- and beta-agonist epinephrine (50 ng.kg-1.min-1), the alpha-antagonist phentolamine (5 mg/2 min followed by 500 micrograms/min), the beta-antagonist propranolol (5 mg/2 min followed by 80 micrograms/min), or saline as control, alone or in combination. Drugs were assigned in a random mode according to a 2(3) factorial design. Analysis of variance showed that epinephrine decreased trypsin output by 43% (P less than 0.05). By contrast, trypsin output was increased fourfold in the presence of phentolamine (P less than 0.01), whereas propranolol had no effect. These data suggest that an inhibitory alpha-adrenergic tone modulates human interdigestive pancreatic enzyme secretion whereas beta inputs are less important.     

Haemodynamic effects of intracoronary neuropeptide Y in dogs: resistance to alpha adrenergic blockade.

STUDY OBJECTIVE--Neuropeptide Y is a peptide isolated from brain and neural tissue around human coronary arteries. It has been shown to produce coronary vasoconstriction and myocardial ischaemia. The purposes of this study were (a) to determine whether the vasoconstriction induced by neuropeptide Y was mediated by alpha adrenergic receptors in vivo, and (b) to determine the time course of the effect and whether it was reproducible with a second administration. DESIGN--Neuropeptide Y (200 micrograms over 2 min) was given by intracoronary injection on two occasions 1 h apart to group I dogs (control). In group II the second dose was preceded by treatment with the alpha blocker phenoxybenzamine (4-10 mg.kg-1). The time course and magnitude of the effect was studied in the two groups to determine the effects of alpha blockade and of repeated neuropeptide Y dosage. EXPERIMENTAL MATERIAL--14 mongrel dogs (n = 7 per group) were anaesthetised with chloralose for a left thoracotomy to measure coronary blood flow, aortic pressure, left ventricular pressure, and heart rate. MEASUREMENTS AND MAIN RESULTS--Reproducible prolonged increases in coronary vascular resistance occurred after the first [33(SD 18)%] and second [34(17)%] doses of neuropeptide Y. At this infusion rate mean aortic pressure increased with each dose by 21% and coronary blood flow decreased by 7%. In group II dogs, phenoxybenzamine given intravenously 20 min after the first dose of neuropeptide Y reduced mean aortic pressure by 15-20 mm Hg. In this group neuropeptide Y also caused reproducible increases in coronary vascular resistance before (36%) and after (46%) alpha blockade. CONCLUSIONS--Neuropeptide Y constricts coronary arteries in vivo by mechanisms that do not require intact alpha adrenergic receptors, and the coronary vasoconstriction was prolonged and reproducible.     

Stimulation of human pancreatic polypeptide secretion by hypoglycemia is independent of adrenergic mechanisms

Human pancreatic polypeptide (HPP) increases after insulin-induced hypoglycemia. To determine whether adrenergic mechanisms contribute to this increase in normal man, six subjects were studied on two occasions: once after insulin alone and once after insulin plus simultaneous alpha (phentolamine)- and beta (propranolol)-adrenergic blockade. Despite comparable hypoglycemia (51 +/- 4 vs. 49 +/- 4 mg/dl), the increase in HPP did not differ in the presence or absence of adrenergic blockade (721 +/- 215 vs. 736 +/- 193 pg/ml, respectively). These findings suggest that HPP secretion during hypoglycemia is not dependent on adrenergic mechanisms.     

The role of alpha 1- and alpha 2-adrenergic receptors in mediation of coronary vasoconstriction in hypoperfused ischemic myocardium during exercise

This study was carried out to test the hypothesis that adrenergic coronary vasoconstriction limits blood flow to hypoperfused regions of myocardium during exercise. The vasoconstrictor influence of alpha-adrenergic receptor subtypes was assessed by use of selective adrenergic blocking agents. Dogs chronically instrumented with a circumflex coronary artery hydraulic occluder and an intra-arterial catheter underwent treadmill exercise in the presence of a coronary stenosis that decreased distal perfusion pressure to 40 mm Hg. Myocardial blood flow was measured with radioactive microspheres (15 microns) before and during selective alpha 1- or alpha 2-adrenergic receptor blockade produced by intracoronary infusion of prazosin (1 microgram/kg/min x 10 min) or idazoxan (1 microgram/kg/min x 10 min), respectively. Coronary perfusion pressure was held equal before and during receptor blockade with the hydraulic occluder. Compared with control exercise, subendocardial blood flow increased during alpha 1-receptor blockade with prazosin from 0.60 +/- 0.14 to 1.12 +/- 0.17 ml/min/g (p less than 0.05), and mean transmural flow increased from 1.07 +/- 0.19 to 1.60 +/- 0.22 ml/min/g (p less than 0.05). In contrast, subendocardial and mean transmural blood flow were not different from control during selective alpha 2-adrenergic receptor blockade with idazoxan (0.48 +/- 0.10 vs. 0.67 +/- 0.14 ml/min/g, p = 0.33, and 0.82 +/- 0.15 vs. 1.02 +/- 0.20 ml/min/g, p = 0.45, respectively). These data indicate that even in the presence of a coronary stenosis that causes substantial myocardial underperfusion during exercise, residual coronary vasoconstrictor tone is present in ischemic myocardium, and this vasoconstriction is mediated predominantly by the alpha 1-adrenergic receptor.     

Direct effects of hydralazine on cardiac contractile function, haemodynamics, and myocardial energetics in isolated myocardium

The direct cardiac effects of hydralazine were studied in isolated working rat heart, isolated cat right ventricular papillary muscle, and isolated rabbit right atrium. The haemodynamics, myocardial energetics, and contractility of isolated hearts were measured at hydralazine concentrations of 0.01, 0.1, 0.5, 1.0, 10 and 100 mumol.litre-1. Coronary flow was significantly increased (greater than or equal to 21%, p less than 0.01) in paced (325 beats.min-1) rat hearts at greater than or equal to 0.5 mumol.litre-1 hydralazine and in spontaneously beating hearts (greater than or equal to 37%; p less than 0.05) at greater than or equal to 1.0 mumol.litre-1 hydralazine. The increases in coronary flow occurred without significant increases in heart rate, contractility (dP/dtmax), or coronary perfusion pressure. Myocardial oxygen consumption was not significantly changed at any hydralazine concentration in spontaneously beating hearts and was unaltered in paced hearts except for a small significant increase (9.8%) at 10 mumol.litre-1. A negative inotropic effect was apparent at 100 mumol.litre-1 hydralazine as indicated by a significant reduction of dP/dtmax (paced and non-paced hearts), peak aortic flow rate (non-paced), and maximum left ventricular pressure (paced). In isolated cat papillary muscles and rabbit right atria, cumulative hydralazine log dose-response curves (0.1-1000 mumol.litre-1) were obtained. A positive inotropic effect that could be abolished by beta adrenergic blockade was produced in papillary muscles only at concentrations greater than or equal to 100 mumol.litre-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diameter change and pressure-red blood cell velocity relations in coronary microvessels during long diastoles in the canine left ventricle

The objective of this study was to determine whether coronary vascular resistance remains constant during long diastoles and whether critical closure of arterial microvessels occurs at zero-flow pressure. For this purpose, we directly measured internal diameters and red blood cell velocities in arterial and venous coronary microvessels during long diastoles under maximal vasodilation. The epicardial coronary microcirculation was viewed in anesthetized, open-chest mongrel dogs through an intravital microscope equipped with a newly developed floating objective. Coronary microvascular diameters and red blood cell velocities were measured with high-speed cinematography. During maximal vasodilation (150 micrograms/kg body wt i.v. dilazep), long diastoles were induced by vagal nerve stimulation. Internal diameters of all small arteries and arterioles (n = 12) gradually declined with decreasing aortic pressure during long diastoles, and the reduction of the diameter was greatest when aortic pressure was less than 35 mm Hg. The mean internal diameter (88.8 +/- 52.2 microns) at minimal aortic pressure (19.2 +/- 6.4 mm Hg) was significantly less than that at an aortic pressure of 100 mm Hg (116.2 +/- 68.5 microns, p less than 0.01). The internal diameters of small veins and venules remained nearly constant during long diastoles. When red blood cell progression in coronary microvessels stopped at the nadir of aortic pressure, all arterial coronary microvessels remained open; that is, there was no evidence of "critical closure."(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of adrenergic blockade on glucose-induced thermogenesis

The effect of alpha, beta, or combined sympathetic blockade on the increase in energy expenditure and concentrations of norepinephrine, glucose, and insulin following oral intake of 100 g of glucose was studied in lean subjects. Alpha blockade with intravenous (IV) phentolamine (n = 5) infusion increased oxygen consumption after glucose ingestion but no more than it increased the oxygen consumption when no glucose was given. Beta blockade with IV propranolol (n = 13) and combined alpha and beta blockade (n = 6) did not affect basal metabolic rate or the increase in metabolic rate after glucose ingestion. Phentolamine or combined propranolol plus phentolamine administration markedly increased plasma norepinephrine concentrations. Basal glucose and insulin concentrations were not affected by any of the infused drugs. Glucose-stimulated insulin concentrations were unchanged by propranolol and combined blockade, whereas there was a trend (P = 0.07) toward an increased response to glucose during phentolamine administration. These data do not support a role for the sympathetic nervous system in the increase in metabolic rate following glucose ingestion. The increase in metabolic rate during phentolamine administration can be attributed to beta adrenergic stimulation.     

Effects of converting enzyme inhibition and alpha receptor blockade on the angiotensin pressor response in the American alligator.

This study examines the effects of two converting enzyme inhibitors (captopril and enalaprilat) and two alpha-adrenergic receptor antagonists (phentolamine and phenoxybenzamine) on the pressor response produced by exogenous angiotensin I ([Asp1, Val5, Ser9] ANG I, fowl) and [Val5] angiotensin II (ANG II) in the American alligator (Alligator mississippiensis). Bolus administration of ANG I at 0.1, 0.5, and 1.0 micrograms/kg; ANG II at 0.05, 0.1, and 0.5 micrograms/kg; or norepinephrine (NE) at 2 micrograms/kg elicited dose-dependent increases in arterial blood pressure. Captopril (0.5 mg/kg/hr) and enalaprilat (300 micrograms/kg/hr) significantly reduced the response to ANG I, but not ANG II or NE. Both phenoxybenzamine (0.25 mg/kg/min) and phentolamine (1 mg/kg/hr) effectively blocked the NE pressor response (84 and 88%, respectively) and attenuated (42-80%) the pressor effects of ANG I and ANG II. These results support previous work suggesting the alligator may possess a renin-angiotensin system with characteristics similar to those found in mammals and other vertebrates. In addition, the pressor response to exogenously administered ANG I and ANG II was attenuated by alpha adrenergic receptor blockade and thus may be due, in part, to secondary catecholamine release.