Spontaneous and induced arterial disease in the dog: pathology and pathogenesis.

The spontaneous arterial diseases of the dog relevant to safety assessment studies of drugs are the extramural coronary arteritis of Hartman, intramural coronary arteriosclerosis (with amyloid deposition) occurring in older dogs with cardiac disability, intramural arteriosclerosis without amyloid deposition in the left ventricle of dogs with congenital subaortic stenosis or in the right ventricle in dogs with severe pulmonic stenosis, and necrotizing polyarteritis (nodosa). Experimentally induced lesions include right atrial necrosis and arteritis produced by minoxidil and theobromine, extramural coronary arteritis produced by positive inotropic/vasodilator drugs, intramural coronary arteriosclerosis associated with decreased peripheral resistance and tachycardia induced by hypotensive drugs (including antihypertensive and positive inotropic/vasodilator agents), and intramural arteriosclerosis associated with rapid ventricular pacing. The pathogenesis of none of these lesions is known. The left ventricular subendocardial and papillary muscle intramural coronary arterial lesions are associated with hyperdynamic activity and, in the case of drugs and subaortic stenosis, the possibility of lowered perfusion pressure and tachycardia. This has led to the supposition that these are ischemic lesions, but the evidence available either does not support or refutes that conclusion since subendocardial coronary flow and perfusion pressure are adequate with pacing tachycardia and in toxicity trials. Necrotizing polyarteritis appears to be an immune mediated disease that may appear in genetically prone beagles when they are placed under the stresses of experimental manipulation and/or a new environment. Since the right atrial minoxidil lesion can also be produced by theobromine in dogs and minoxidil can cause a left atrial lesion in swine, it is neither species nor drug specific. Its cause, however, escapes us. There appears to be little in common between the extramural coronary artery Hartman lesion and that caused by positive inotropic/vasodilator drugs. Left ventricular subendocardial and papillary muscle intramural coronary arterial lesions induced by ventricular pacing at 250 beats/min for 2 months are generally similar to those seen in toxicity trials with peripheral vasodilator drugs that induce tachycardia in electrocardiograms exceeding 200 beats/min, although in acute pacing experiments subendocardial perfusion is adequate at these heart rates. Coronary artery autoregulation may be compromised or so destabilized by the drugs that episodes of underperfusion can account for these lesions.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparison of arterial wall properties in young and old racing greyhounds.

Arteries were obtained from several sites in young (YGH) and old racing greyhounds (OGH). Segments were used for the determination of arterial wall mechanics under conditions of active (norepinephrine) and passive (Ca2+ free and 2 mM EGTA) smooth muscle. Contiguous segments were used for the chemical analysis of connective tissue, water and electrolyte content. The passive stiffness of arteries from OGH was consistently greater than that of the YGH. Collagen content and the collagen-elastin ratio were larger at all sites in the OGH. However, the connective tissue changes were not considered to be of sufficient magnitude to explain the changes in passive mechanics. Maximum values of active stress development were generally lower in arteries from the OGH as was their relative cell content. Active stress development normalized to smooth muscle cell cross-section was not uniformly changed in arteries from OGH. In spite of the lower active stress development in some arteries, the ability of smooth muscle to constrict lumen diameter was not different between OGH and YGH at transmural pressures in the physiological range. While a number of changes occur in arteries of purebred greyhounds with aging, they appear to occur in such a fashion that normal function is not grossly altered.

Baroreceptor reflex cardiovascular control in mongrel dogs and racing greyhounds.

The open-loop carotid sinus baroreflex control of arterial pressure-flow relations were compared in mongrel dogs and racing greyhounds (GH) anesthetized with alpha-chloralose. The carotid sinuses were bilaterally isolated and perfused under controlled pressure. Pulsatile pressure and flow were simultaneously measured in the ascending aorta, the celiac, superior mesenteric, left renal, and right iliac arteries. Open-loop set point values of mean arterial pressure were higher in GH before and after vagotomy. Reflex gains were similar before vagotomy but lower in GH after vagotomy. The overall range of control of arterial pressure was the same before vagotomy but smaller in GH after vagotomy. The variation of mean arterial pressure with mean carotid sinus pressure in GH was shifted toward higher pressure levels similar to resetting. The overall effects of vagotomy on carotid sinus baroreceptor reflex responses were smaller in GH. Operating point values of regional resistance were generally smaller in GH. Operating point sensitivities of regional resistance were the same except for the iliac bed, which was more sensitive in GH. These results document significant regional differences in the baroreceptor control of regional hemodynamics between mongrels and greyhounds that could contribute to altered responses especially to "hypertensive" perturbations.

Evaluation of a direct blood pressure measurement technique for canine toxicity studies.

Repeated direct puncture of the central ear (intermediate auricular) artery to obtain mean arterial blood pressure in control and hypertensive dogs was evaluated. Unilateral nephrectomy and partial constriction of the contralateral renal artery were performed on four dogs to create hypertension. Ear artery blood pressure measurements and electrocardiograms were recorded twice pretest and after surgery at Weeks 1, 2, 4, 6, 8, 9, 10, and 11 on control (n = 6) and hypertensive (n = 4) dogs. Mean ear arterial blood pressures from the hypertensive dogs were significantly increased from Weeks 2 to 11. Indwelling omocervical artery catheters were implanted in both control and hypertensive dogs at Week 8. Mean omocervical artery blood pressures from hypertensive dogs were significantly increased at Weeks 8 through 11. Mean omocervical artery pressures were only significantly increased over mean ear artery pressures at Week 8 for control dogs and at Week 10 for hypertensive dogs. Nonspecific electrocardiographic changes in the ST-T segment and U waves occurred with greater frequency in hypertensive dogs than in control dogs. Hypertensive dogs developed subendothelial proliferation in the renal artery and aorta, and a proliferative vasculopathy in the heart and lungs. This ear artery technique was used successfully in two canine toxicity studies of different ICI pharmaceutical compounds. The ear artery method for measuring mean arterial blood pressure is suitable for canine toxicity studies and is a reasonably accurate measurement of systemic pressure.

Coherence of cardiac output with rate changes.

In awake or lightly anesthetized dogs increases in heart rate (HR) induced by atrial pacing affect cardiac output (CO) and stroke volume (SV) in a predictable way that is represented by a SV-HR relationship (dSV/dHR). Under our experimental conditions where normal regulation of atrial rate was bypassed, atrial rate was the independent variable and CO and SV were dependent variables. As HR is increased, CO and SV are modified by reflex and other circulatory regulators. The dSV/dHR relation characterized the circulatory response to increasing HR. A single dSV/dHR curve consistently predicted responses under a number of different conditions (standing, recumbent, awake, various anesthetics, beta-adrenergic stimulation, or depression) and thus appeared as an expression of cardiac function. Alterations of the circulation by stellate ganglion or vagal stimulation, volume loading, aortic compression, and ventricular pacing were not represented by the same dSV/dHR function. The dSV/dHR function (including its linear version as reported by others for anesthetized dogs) showed that, when SVs were larger at low rates, maximum CO occurred at a higher HR. Recognition of this arithmetic-based feature resolves apparent contradictory findings reported in the literature.

Evolution of the electrocardiogram in young dogs during the first 12 weeks of life.

In 36 normal pups the evolution of the ECG during the first 12 weeks was studied. Sixteen pups were randomly selected, healthy pups; 20 were normal littermates from dog families with congenital heart disease. The direction of P, QRS, and T vectors was determined, and the modal QRS axis (vector) was constructed from lead I and AVF in the frontal, from lead I and V10 in the transverse, and from lead AVF and V10 in the sagittal plane. Except for the T wave directly after birth, no marked difference in the ECG evolution between the two groups was found. After birth the modal QRS vector was almost exclusively directed to the right. The modal QRS vectors in the first, second, and third weeks were significantly different from each other. By the twelfth week all vectors were directed to the left and the majority was oriented leftward and caudally. In the serial ECG tracings the change from right ventricular to left ventricular dominance was seen to be progressive. The R/S ratio in the left chest leads increased from less than 1.0 at week 1 to a multiple of 1.0 after the sixth week. The changes occurring in scaler ECG's were mirrored in VCG's recorded in selected pups.

Evolution of the electrocardiogram in young dogs with congenital heart disease leading to right ventricular hypertrophy.

In 18 pups obtained from a breeding colony established for investigation of hereditary heart disease, ECG's were recorded shortly after birth. The ECG's, as well as clinical examinations, were repeated weekly in pups surviving the first week of life. The QRS modal axis was constructed in the frontal, transverse and sagittal planes. Cardiac catheterization was performed on all pups reaching the age of 8 to 12 weeks. VCG's were taken on selected pups. All dogs were necropsied terminally. In pups with severe pulmonic stenosis a pathological right ventricular hypertrophy was recognized immediately after birth. No evolution to a left ventricular dominance occurred in the serial tracings. Pups with milder grades of right ventricular outflow obstruction showed a normal evolution pattern or some minor deviations from the normal QRS complex evolution. In pups with patent ductus arteriosus (PDA) and left-to-right shunt, there was no difference from the normal ECG evolution within the first 12 weeks of life, except for some increase in amplitude. Two cases of PDA and right-to-left shunt were not different from the "physiologic right ventricular hypertrophy" at birth, but developed a severe right ventricular hypertrophy pattern within the first 12 weeks of life without any clinical signs of a left-to-right shunting within the period.

Arterial baroreceptor reflexes in young and old racing greyhounds.

The characteristics of the carotid sinus baroreceptor (CSB) reflex control of arterial pressure-flow relations were studied in young (18 mo) and old (10.5 yr) racing greyhounds anesthetized with chloralose. Pressure and flow were simultaneously measured in the ascending aorta, the celiac, superior mesenteric, renal, and iliac arteries under steady-state conditions of pulsatile perfusion of the isolated carotid sinuses before and after bilateral cervical vagotomy. Operating-point (OP) values of mean pressure were not significantly different between the young or old greyhounds, but OP values of cardiac output were lower and of peripheral resistance were higher in the older animals. OP values of regional resistances were higher in the older animals, but only those of the celiac and mesenteric beds were significantly different. Values of OP sensitivity of central hemodynamic variables were not decreased in the older animals. OP values of renal and iliac resistance sensitivity tended to be lower in the older animals. The overall range of control of the various hemodynamic variables by the CSB was lower in the older group only in the case of iliac resistance. The characteristics of the CSB were not uniformly depressed in the older animals but were relatively well maintained compared with those of the younger group.

Red cell cholesterol enrichment and spur cell anemia in dogs fed a cholesterol-enriched atherogenic diet.

A diet supplemented with cholesterol and coconut oil is atherogenic in dogs. The purpose of the present study was to examine the effects of this diet on red cells in pure-bred beagles and greyhounds. Within 3 days after the initiation of this diet red cell cholesterol/phospholipid increased and membrane fluidity decreased, with maximum changes attained by 12 weeks. Serum lipoprotein cholesterol/phospholipid also increased, and serum from cholesterol-fed dogs transferred cholesterol to normal red cells. Significant abnormalities of liver function developed in all cholesterol-fed dogs. Hematocrit declined beginning at 6 weeks, with a parallel increase in osmotic fragility. Reticulocytes were elevated in beagles but normal in greyhounds. Red cell morphology resembled acanthocytes or spur cells. All red cell parameters returned to normal within 4 weeks after stopping the diet. These studies demonstrate that a cholestrol-enriched, atherogenic diet causes profound and reversible changes in the lipid composition, membrane fluidity, and morphology of red cells in dogs.

Alterations in carotid sinus reflex control of arterial hemodynamics associated with experimental hyperlipemia in the racing greyhound.

We administered a high cholesterol diet to racing greyhounds and studied its effects on the characteristics of carotid sinus reflex control of arterial pressure-flow relations. Dogs were anesthetized with halothane, and pressure and flow were simultaneously measured in the ascending aorta and the celiac, mesenteric, renal, and iliac arteries. The carotid sinuses were isolated bilaterally and perfused with a physiological salt solution under controlled conditions. The variation of regional pressure-flow relations and regional vascular resistance was assessed as a function of mean carotid sinus pressure (MCSP) with the vagi bilaterally sectioned to eliminate aortic arch afferents. Some differences were found in set point (i.e., MCSP = mean arterial pressure) values of hemodynamic variables; cardiac output and renal and iliac flows were significantly lower. Control and set point values of mean arterial pressure were not significantly different between the two groups. The variation of every hemodynamic variable with the exception of heart rate with carotid sinus pressure was attenuated markedly in the diet-treated dogs. Substantial lesions were found involving the entire carotid sinus region of every diet-fed animal. These results suggest that pathological alterations in the carotid sinus region are at least in part responsible for a reduction in the sensitivity of carotid sinus baroreflexes associated with atherosclerosis.

Arterial wall properties and dietary atherosclerosis in the racing greyhound.

The effects of experimental (dietary) atherosclerosis on arteries from racing greyhounds were studied. Measurements of pressure and external diameter were made on islated carotid and iliac arteries under active (norepinephrine, 5 microgram/ml) and passive (zero Ca2+ and 2 mM EGTA) smooth muscle conditions. Iliac arteries from diet-fed animals demonstrated substantial intimal lesions, but the carotid arteries were usually grossly involved. Arteries from atherosclerotic animals were stiffer during passive conditions, with the iliac arteries having the greater changes. In iliac arteries from treated animals, collagen and elastin contents were decreased, and the collagen-to-elastin ratio was increased; in carotid arteries from treated animals, elastin content was increased and the collagen-to-elastin ratio was decreased. The maximum range of control of arterial wall mechanics by smooth muscle was diminished in treated iliacs but unchanged in carotids. Both force development and constriction responses associated with smooth muscle activation were diminished in treated iliacs but unchanged in treated carotids. Mechanical properties of series elastic elements in treated iliacs were stiffer, but treated carotids were unchanged.

Malignant hyperthermia in a Greyhound.

A rapid rise in rectal temperature (to 45 C) in a young male Greyhound was attributed to the use of halothane and succinylcholine. Circulatory failure and death occurred within approximately 90 minutes of the onset of the hyperthermia.

Hemodynamic responses to stellate ganglion stimulation in mongrels and greyhounds.

A comparison of the effects of left stellate ganglion stimulation (SGS) on central and aortic hemodynamics has been made in chloralose-anesthetized mongrel (M), and greyhound (GH) dogs. Measurements of aortic pressure and flow, and left ventricular pressure were made during stimulation of the decentralized left SG at different frequencies from 0 to 20 Hz. The increases in aortic pressure and flow with SGS were larger in the GH, especially for low frequencies of stimulation. Stroke volume was increased with SGS in the GH at all stimulation rates, whereas in the M it was unchanged. A greater decrease in left ventricular end-diastolic pressure with SGS was found in the GH. These results suggest that differences exist in both the intrinsic and extrinsic control of cardiac output in the greyhound dog compared to the mongrel. These differences may be in part responsible for the elevated arterial blood pressure in the greyhound compared to the mongrel.

Comparison of arterial hemodynamics in the mongrel dog and the racing greyhound.

This study was undertaken to define certain differences in cardiovascular function between mongrel (M) and greyhound (GH) dogs. In unanesthetized, trained, chronically instrumented animals mean arterial pressure was significantly higher in the GH (118 vs. 98 mmHg). This was associated with a significantly higher cardiac index in the GH (4.3 vs 3.1 liters/min per m2) and a lower calculated peripheral resistance. Central venous renin activity was significantly lower in the GH when unanesthetized (1.51 vs. 2.88 ng/ml per h). Values of vascular impedance at several selected arterial sites were lower in the GH compared to the M, suggesting differences in arterial wall mechanical properties. The hydraulic power delivered to the aorta by the left ventricle in the GH was twice that of the M (1,166 vs. 564 mol wt). Oscillatory power represented a greater fraction of total aortic power in the GH (15.7 vs. 10.8%). Differences were also observed in the hemodynamic response to acute pentobarbital anesthesia. Thus the young adult GH is hemodynamically different from its mongrel counterpart. These differences bear some resemblance to hemodynamic changes seen in various types of experimental hypertension in animals and to those observed in the early phase of essential hypertension in man.

Altered arterial connective tissue in racing greyhound dogs.

Vascular collagen and elastin contents and the ratio of collagen/elastin (C/E) were studied in racing greyhound dogs, a breed which exhibits increased cardiac output. As compared to mongrel dogs, vascular C/E was lower, suggesting a greater distensibility of vessels as an adaptive response to hemodynamic stress.