Biomedical subjects

D B Jennings

Publications and source records attributed to D B Jennings.

At least 37 records · Page 2Linked to original sources

PubMed1993

Angiotensin II stimulates respiration in awake dogs and antagonizes baroreceptor inhibition.

The effects of intravenous infusions of physiologic doses of angiotensin II (AII) on expired ventilation (VE) and acid-base balance were determined in awake dogs. A control infusion of saline was followed by AII infusion, initially with mean arterial pressure (MAP) raised 15%, and then with MAP at control levels by concurrent infusion of sodium nitroprusside (SNP). To control for SNP, the protocol was repeated using arginine vasopressin (AVP). Ventilatory responses to CO2 (VRC) were measured at the end of these protocols and separately with MAP elevated during infusion of AII. With AVP, increased MAP inhibited VE, heart rate (HR) and metabolism. However, with MAP elevated during AII infusion, stimulation by AII opposed baroreceptor reflexes and these variables, as well as plasma AVP, did not change. When MAP was lowered to control during AII infusion all variables increased. With AII, PaCO2 followed VE changes, decreasing 3 Torr with MAP at control levels; however, [H+] remained constant due to a decrease in arterial strong ion difference. The stimulatory effects of AII were not due to SNP; SNP did not stimulate VE during AVP infusion. The slope of the VRC was unaltered by AII infusion or MAP; however, AVP reduced the VRC slope. Physiological increases in AII stimulate VE and other systems at normal MAP and maintain several regulatory systems at control levels during baroreceptor inhibition.

Acid-Base Equilibrium↗

PubMed1993

Renin-angiotensin system stimulates respiration during acute hypotension but not during hypercapnia.

We reported that intravenous infusion of angiotensin II (ANG II) stimulated ventilation (VE) in conscious dogs. Other studies in our laboratory have demonstrated that increases in respiration occurred in association with activation of the renin-angiotensin system during acute hypotension and during hypercapnia. Therefore, in conscious dogs (n = 5), we examined the effects of ANG II receptor blockade with intravenous saralasin (0.5 micrograms.kg-1.min-1) on respiratory responses during progressive nitroprusside-induced hypotension and during the ventilatory response to increased inspired fraction of CO2 (VRC). During hypotension (mean arterial pressure decreased approximately 20%) combined with ANG II receptor blockade, VE, heart rate, and arginine vasopressin increases were attenuated compared within unblocked studies. With ANG II receptor blockade during hypotension, alveolar ventilation and arterial PCO2 (PaCO2) were unchanged, which contrasted with a doubling of alveolar ventilation and a decrease of 4.8 +/- 1 Torr in PaCO2 in unblocked studies. During hypercapnia, the slope of the VRC was not affected by ANG II receptor blockade, but with 6.5% inspired CO2 fraction, VE and PaCO2 were lower than in unblocked studies. These results indicated that ANG II contributed to the respiratory response to a modest hypotension but did not affect respiratory sensitivity to CO2.

Acute Disease↗

PubMed1992

Biological effects of rat iso-atrial natriuretic peptide and brain natriuretic peptide are indistinguishable from each other.

Rat brain natriuretic peptide (rBNP) and iso-atrial natriuretic peptide (iso-rANP) were discovered independently by two research laboratories. They are considered to be members of the B-type natriuretic peptides. Except for the Gln/Leu substitution at position 44, the amino acid sequence of iso-rANP is identical with that of the C-terminal 45 amino acids of rat pro-BNP and with the 5-kDa cardiac peptide from rat atria. To determine whether this amino acid substitution can modify the known biological effects of rBNP and iso-rANP, the present investigation examined the cardiovascular and renal responses, vasorelaxant effect, receptor binding characteristics, and cyclic GMP production by the two peptides in relation to that of rat atrial natriuretic peptide (rANP). Results indicate that rBNP and iso-rANP are indistinguishable from each other in terms of these known biological activities of atrial natriuretic peptide. We therefore conclude that rBNP and iso-rANP are identical peptides and that the amino acid substitution at position 44 represents a polymorphic form of the rat B-type natriuretic peptide.

Amino Acids↗

PubMed1992

Role of right heart receptors in the control of renin, vasopressin, and cortisol secretion in dogs.

We have reported that increased left heart pressure inhibits increases in plasma renin activity (PRA), arginine vasopressin (AVP), and cortisol during arterial hypotension. The goal of this study was to determine whether increases in right heart pressure also inhibited hormonal responses to hypotension. Seven dogs were chronically instrumented with inflatable cuffs around the ascending aorta (AA), the pulmonary artery (PA), and the thoracic inferior vena cava (IVC), as well as with catheters in both atria, the abdominal aorta, and vena cava. The IVC, the PA, and the AA cuffs were inflated on different days to cause step reductions in mean arterial pressure (MAP) of 5, 10, 20, and 30% below control MAP. Graded constriction of the AA caused large increases in left atrial pressure and plasma atrial natriuretic peptide (ANP), but had no effect on plasma AVP or cortisol and caused only a small increase in PRA at the maximal reduction of MAP. Constriction of the IVC reduced both atrial pressures and plasma ANP, but stimulated increases in PRA, AVP, and cortisol. Constriction of the PA increased right atrial pressure and plasma ANP and caused increases in plasma AVP and cortisol that were similar to responses during IVC constriction, but the PRA response was only half (P < 0.05). These results indicate that increasing pressure on the right side of the heart can attenuate the PRA response to hypotension, and suggest that the inhibition is mediated by the rise in plasma ANP.

Animals↗

PubMed1992

Ventilation is stimulated by small reductions in arterial pressure in the awake dog.

Changes in arterial pressure commonly accompany respiratory adaptations. The purpose of this study was to determine, in awake dogs (n = 6), the degree to which small acute decreases in arterial pressure affect ventilation and acid-base balance. Mean arterial pressure (MAP) was reduced by 6 +/- 2, 10 +/- 3, and 16 +/- 2% by intravenous infusion of sodium nitroprusside for sequential 20-min periods. In another experiment, the ventilatory response to hypercapnia was determined during MAP reduction of 16 +/- 3%. Step reductions in MAP were accompanied by increases in minute ventilation (maximum increase 152 +/- 75%) and step reductions in arterial PCO2 (PaCO2; maximum reduction -4.8 +/- 0.8 Torr). Although eupneic PaCO2 threshold was lowered during MAP reduction, ventilatory sensitivity to CO2 remained unchanged. Despite the lowered PaCO2, arterial [H+] remained constant (acid-base balance was maintained) as a result of a concurrent decrease in strong ion difference. Plasma renin activity increased during MAP reduction (93 +/- 39%) and may have contributed to the increase in minute ventilation, inasmuch as angiotensin II can stimulate respiration by a central mechanism. Evidence is provided that nitroprusside is unlikely to be a primary factor in these hypotensive responses. We conclude that relatively modest decreases in MAP have a consistent stimulatory effect on respiratory control. Therefore it is important to take into account effects of small changes in MAP when interpreting mechanisms for respiratory responses in awake animals.

Acid-Base Equilibrium↗

PubMed1991

Plasma clearance and tissue binding of rANP[99-126] and iso-rANP[1-45] in the rat.

Plasma clearance and tissue binding of atrial natriuretic peptide (ANP) and iso-ANP were compared in Inactin-anaesthetized rats. It was found that the plasma half-life of iso-ANP was comparable to ANP. Appearance of trichloroacetic acid-soluble radioactivity of iso-ANP in the plasma was considerably slower than that of ANP, suggesting that the metabolic process of these two peptides may be different. Although the binding distribution of these two peptides was similar, the total binding of iso-ANP to organs other than the kidney was much lower. The kidney, lung, heart and adrenal gland appeared to be major target organs for iso-ANP. Autoradiography showed that iso-ANP bound specifically to the renal glomerulus and proximal part of the proximal tubule. This latter binding site in the kidney was not apparent with ANP, suggesting that iso-ANP may exerts its physiological action at different sites in this organ.

Animals↗

PubMed1990

Acute changes in osmolality and renin and respiratory control of arterial PCO2 and [H+].

To investigate whether osmoreceptor mechanisms or the renin-angiotensin system might be involved in respiratory regulation of H+ homeostasis, plasma osmolality was acutely lowered by approximately 10 mOsm in 7 awake mongrel dogs by a gastric water load (20 ml.kg-1 distilled, deionized water). Plasma renin activity (PRA) was measured as an indicator of angiotensin II levels. During these studies PaCO2 and [H+]a reflected the spontaneous level of ventilation (VE); higher levels of VE were correlated with lower PaCO2 and [H+]a, indicating a nonchemical drive to breathe. Stimulation of ventilation to lower PaCO2 following the water load was positively correlated with increase in PRA and decrease in plasma osmolality, but not with change in osmolality alone. An increased VE, a decreased ventilatory response curve (VRC) threshold for PaCO2, and a lower PaCO2 occurred with increase in PRA. Conversely, a lower or acutely decreased PRA, due to administration of arginine vasopressin, was correlated with a lower VE, an increase in the VRC threshold for PaCO2, and a higher PaCO2. Ventilatory control of PaCO2 during acute lowering of osmolality may be related to a central inter-action between osmolality and the renin-angiotensin system.

Angiotensin I↗

PubMed1990

The disulfide bonded ring of iso-rANP, unlike that of rANP, has potent cardiovascular activity.

Iso-atrial natriuretic peptide (iso-rANP), a 45 amino acid peptide with a disulfide bond between residues 23 and 39, is a newly discovered second atrial hormone with considerable homology with rat atrial natriuretic peptide (rANP). We have reported that iso-rANP(1-45) has effects similar to rANP in anesthetized rats in causing hypotension, a decrease in heart rate, and an increase in urine flow and electrolyte excretion. In the present experiments, we found that, unlike the ring peptide of rANP (rANP(105-121)), bolus injections of the ring peptide of iso-rANP (iso-rANP(23-39)) had considerable effects on the circulation but only small effects on the kidney, compared with iso-rANP(1-45). However, the effects of iso-rANP(23-39) in causing hypotension and decreasing heart rate were transient compared with those of iso-rANP(1-45). When we substituted a glycine for arginine into the ring portion of iso-rANP at position 36, so that there were only three amino acids different from the ring of rANP, biological activity of iso-rANP(23-39) was retained. In our bioassay system, all of the circulatory effects and most of the renal effects of rANP are mediated via vagal sensory afferents. We found that the effects of the ring peptide of iso-rANP on the circulation and the kidney were unchanged following vagotomy. The results indicate that iso-rANP(23-39) mediates at least some biological effects by membrane receptor mechanisms different from those of rANP and that the ring portion of iso-rANP probably contributes to nonvagally mediated responses of iso-rANP(1-45).

Amino Acid Sequence↗

PubMed1990

Infusion of iso-rANP(1-45) or (17-45) increases plasma immunoreactive ANP and lowers plasma renin activity and aldosterone.

We have reported that a second rat atrial natriuretic peptide, iso-rANP (1-45), as well as the putative ANP homologue, iso-rANP (17-45), elicited circulatory and renal responses in the rat similar to those found after administration of ANP. Iso-rANP also interacted with ANP to potentiate the observed biological activity in the rat. In the present studies in awake dogs, intravenous infusion of low doses (6.3-50 pmol.kg-1.min-1) of iso-rANP(1-45) and iso-rANP(17-45) increased plasma immunoreactive ANP and suppressed plasma renin activity (PRA) and aldosterone. Iso-rANP, like ring-deleted analogues of ANP, may have displaced ANP from ANP clearance receptors to increase plasma ANP concentration, since factors influencing myocardial ANP release were not changed. The effect of iso-rANP (1-45) and (17-45) in lowering PRA and plasma aldosterone may therefore have been indirect, via ANP stimulation of active guanylate cyclase-linked ANP receptors. However, an additional direct effect of iso-rANP on an active receptor cannot be excluded.

Aldosterone↗

PubMed1989

Isolation and characterization of iso-rANP, a new natriuretic peptide from rat atria.

Using a specific radioimmunoassay we have isolated and sequenced a new 45-amino acid peptide from rat atria which exhibits similar physiological and pharmacological properties to rat atrial natriuretic peptide (rANP). We have termed the new peptide iso-rANP, because of its functional and structural similarities to rANP. Amino acid sequence differences show that iso-rANP is genetically distinct from rANP. Iso-rANP has a single disulfide bond between residues 23-39 and this portion of the peptide shows substantial homology to rANP and to porcine brain natriuretic peptide (BNP). Little homology is evident at the N- and C-termini of iso-rANP and ANP. Iso-rANP is equipotent with rANP in eliciting diuresis, natriuresis and hypotension in the bioassay rat.

Amino Acid Sequence↗

PubMed1989

Cardiovascular and renal effects of iso-rANP, a second natriuretic peptide from rat atria.

Administration of a newly discovered second atrial peptide, iso-atrial natriuretic peptide (or iso-rANP(1-45) for the rat), caused hypotension, decreased heart rate, diuresis, and increased renal excretion of Na+, K+, and Cl- in the anesthetized rat. Bolus injections of chemically synthetic iso-rANP(1-45) had circulatory and diuretic activity equal to or greater than rANP(99-126) but, at low doses, a lesser effect on renal electrolyte excretion. The synthetic peptide fragment, iso-rANP(17-45), analogous in structure to rANP(99-126), had attenuated activity on the circulation, and at low doses, attenuated activity on the kidney. At higher doses, where renal responses to rANP(99-126) were less (downside of a biphasic response), both iso-rANP(1-45) and (17-45) had greater effects on water and electrolyte excretion than rANP(99-126). Injections of iso-rANP(1-45) and (17-45) increased hematocrit, whereas rANP(99-126) did not; furthermore, unlike rANP(99-126), iso-rANP did not affect arterial plasma Na+ concentration. The heart produces at least two genetically different atrial natriuretic peptides which affect the circulation and salt and water balance.

Amino Acid Sequence↗

PubMed1988

Osmolality, NaCl dietary intake, and regulation of ventilation by CO2.

The ventilatory response to CO2 (VR) was examined in six awake dogs during the 2nd week of sequential dietary periods of low NaCl (less than 5 meq NaCl/day), high NaCl (approximately 120 meq NaCl/day), and then repeated low NaCl. Water intake was maintained constant at 77 ml.kg-1.day-1. PCO2 of arterial blood (PaCO2) and the PaCO2 threshold of the VR increased between the high-NaCl and the second low-NaCl period; the PaCO2 threshold did not change between the first low-NaCl and the high-NaCl period. In contrast, arterial [H+] ([H+]a) threshold of the VR increased between the first low-NaCl period and the high-NaCl period, but did not change further in the second low-NaCl period. Variations in [H+]a threshold of the VR between dogs on high- and low-NaCl diets were correlated with plasma osmolality, and this accounted for a positive linear relation between [H+]a and plasma osmolality. During the high-NaCl period, the arterial strong ion difference [[SID]a = ([Na+] + [K+]) - ([lactate-] + [Cl-])] decreased, forcing [H+]a to increase. However, during high-NaCl diet, PaCO2 decreased relative to plasma osmolality, counterbalancing the decrease in [SID]a and maintaining the relation between [H+]a and plasma osmolality. The compensatory mechanism for the decrease in PaCO2 during high NaCl was a shift in the relation between PaCO2 threshold of the VR and plasma osmolality to a lower PaCO2 threshold. Chemoreceptor, osmoreceptor, and/or humoral mechanisms are potentially involved in these respiratory adaptations to alterations in electrolyte and water balance.

Animals↗

PubMed1988

H+ homeostasis, osmolality, and body temperature during controlled NaCl and H2O intake.

Arterial PCO2, arterial [H+] ([H+]a), electrolytes, and osmolality, as well as rectal temperature (Tre), were monitored in six awake dogs over sequential 12- or 13-day periods in which their NaCl intake was first less than 5 meq/day, then approximately 120 meq/day, and finally less than 5 meq/day. Water intake was maintained constant at 77 ml.kg-1.day-1 throughout. During low-NaCl periods, decreases in body and plasma water, indicated by weight loss did not prevent lower arterial [Na+] ([Na+]a), arterial [Cl-] ([Cl-]a), and osmolality relative to the high-NaCl period. During high dietary NaCl, the arterial strong ion difference [[SID]a = ([Na+]a + [K+]a) - (arterial [lactate-] + [Cl-]a)] was lower. From physicochemistry, this lowered [SID]a results in a higher [H+]a. However, independent of NaCl intake, [H+]a was positively correlated with plasma osmolality; moreover, [H+]a, relative to plasma osmolality, was higher at lower Tre than at higher Tre. We speculate that this spectrum of plasma osmolality and body temperature may contribute to the creation of an appropriate protein pK to match plasma [H+]a. We also found that the difference between plasma [protein] (measured by the biuret test) and [ATOT]a (an estimation of plasma protein as total weak acid from physicochemistry) was related to plasma osmolality, [SID]a, and [Na+]a. These latter relations may reflect the effect of plasma water concentration (osmolality) and strong ions on the pK of plasma proteins.

Animals↗

PubMed1988

Carotid bifurcation sympathectomy and deafferentation: respiration during hypercapnia.

The respiratory effects of hypercapnia were studied in six awake cats 1) after bilateral sympathectomy of the carotid bifurcations and 2) after bilateral section of the carotid sinus nerves. When cats breathed either 2 or 4% CO2 in air, neither denervation affected the absolute level of ventilation, the percent change in ventilation, or the range of breath-to-breath variability in ventilation (V). However, in all six cats tidal volume (VT) increased for some levels of breath V after sympathectomy of the carotid bifurcations during inhalation of 4% CO2 in air. Moreover, after the subsequent carotid deafferentation, increased VT during fractional concentration of inspired CO2 (FICO2) of 4% persisted in four of six cats. Thus increased VT after sympathectomy could not be attributed to increased carotid chemoreceptor afferent activity but may have been due to reduced baroreceptor activity. On the other hand, sympathectomy-induced differences in breath timing, present during inhalation of 2% CO2, were reversed to intact values after sinus nerve section. In contrast to 2% CO2, changes in respiratory timing in intact cats associated with 4% CO2 were not altered significantly by sympathectomy or deafferentation of the carotid bifurcations. The latter indicates that above a critical FICO2 central mechanisms, unrelated to the carotid bifurcation, dominated respiratory timing in the hypercapnic awake cats.

Animals↗

PubMed1987

Effects of hypercapnia on variability of normal respiratory behavior in awake cats.

Resting quiet awake cats breathing air in a steady state have a range of respiratory behavior, and this encompasses nonpurring and purring (D. B. Jennings and P. C. Szlyk, Can. J. Physiol. Pharmacol. 63: 148-154, 1985). On a given study day, individual cats usually breathed in a limited part of their potential respiratory range. Respiratory pattern, such as average breath frequency (f) and average tidal volume (VT) utilized for a given level of ventilation (V), could be predicted when cats breathed air; as well, inspiratory (TI) and expiratory (TE) times were specific for a given breath f. Inhalation of 2% and 4% CO2 in air caused an average increase in ventilation of 16 and 100%, respectively but breath-to-breath variability of V, f, and VT persisted at each fractional concentration of inspired CO2 (FICO2). The range of different V utilized breath to breath when breathing 2% CO2 overlapped with V during air control studies. Substantial overlap with control V also occurred in three of six cats when breathing 4% CO2. The most consistent effect of progressive hypercapnia was to increase VT and decrease f at a given level of V; increase in V during hypercapnia was accounted for by an increase in mean inspiratory flow (VT/TI). Hypercapnia also caused the fraction of breathing cycle devoted to inspiration (TI/TT) to increase at low f but not at high f.

Animals↗

PubMed1987

Respiration in awake cats: sympathectomy and deafferentation of carotid bifurcations.

Respiratory effects of sympathectomy of the carotid bifurcations and, in a subsequent experiment, bilateral carotid sinus nerve section were examined in six awake resting cats. In each intact and denervated state, sequential breaths were analyzed at 10-min intervals up to 80 min. Individual breath frequency (f), tidal volume (VT), and ventilation (V = f X VT) were determined. In individual cats, sympathectomy or deafferentation could cause significant increases or decreases in ventilation or no change. Thus the range of spontaneous variability in breath V as well as minute ventilation (VE), averaged for the group, were not consistently altered in the same direction by either sympathectomy or deafferentation of the carotid bifurcations. Interestingly, in most cats after both sympathectomy (5 of 6) and deafferentation (4 of 6), VT increased and f decreased relative to V. Despite this, after sinus nerve section in two cats arterial PO2 decreased and arterial PCO2 tended to increase relative to VE, suggesting possible effects of deafferentation on ventilation-perfusion balance. Sympathectomy also affected timing such that inspiratory time began to exceed 0.5 of the breath duration at a lower breath f; this effect of sympathectomy was reversed to intact values by subsequent sinus deafferentation. Thus, in eupneic awake cats, sympathetics normally suppress reflex modulation of central timing from carotid chemoreceptors and/or baroreceptors.

Afferent Pathways↗

PubMed1985

Ventilation and respiratory pattern and timing in resting awake cats.

The purpose of this study was to characterize the variability and patterns of spontaneous respiratory behaviour in awake cats. Respiration was measured in six cats over 80 or 90 min by the plethysmographic technique. In three cats, arterial blood gases were measured. Breath frequency (f) and tidal volume (VT) varied considerably breath-to-breath, although on average, these measurements as well as average ventilation remained relatively constant. The incidence of breath ventilation (VT X 60/TTOT) and VT were distributed unimodally but the incidence of breath f had a bimodal distribution. In the low f range, average f was 22.5 breaths/min, and in the high f range, average f was 41.6 breaths/min. The latter range appeared to be associated with purring. Inspiratory duration (TI) was less than expiratory duration (TE) at low f but exceeded TE at high f. For a given breath ventilation there was a predictable f and VT. At shorter TI (higher f) mean inspiratory flow, an index of central respiratory drive, increased but VT decreased. This study indicates that "normal" control respiratory behaviour in awake cats is better described by the range and pattern of breathing than by average values.

Acid-Base Equilibrium↗

PubMed1985

Ventilation and acid-base balance in awake dogs exposed to heat and CO2.

Some awake quiet dogs pant at cool ambient temperature (Ta) and some do not pant even when acutely exposed to heat. The purpose of the study was to determine whether this puzzling variability in respiratory behavior diminished during prolonged heat. The contributions of thermal and CO2 drives to respiratory adaptations were also examined. Five awake dogs acclimated to 20 degrees C were studied before and 2 and 48 h following exposure to 30-31 degrees C. Rectal temperature did not change; the important thermal stimulus, even at 48 h, appeared to be the increase in peripheral temperature. Variability between nonpanting and panting persisted over 48 h. On the average, ventilation (VE) doubled during heat, largely due to increased dead space ventilation. Nonpanting dogs at cool Ta decreased the threshold of the ventilatory response to CO2. A panting dog at cool Ta changed its slope of the ventilatory response from negative to positive. During hypercapnia in acute heat, ventilatory pattern changed so that frequency increased and tidal volume decreased for a given VE. By 48 h of heat, the ventilatory response to CO2 returned to control in only two dogs, but the ventilatory pattern during hypercapnia returned to control in four dogs. Since thermal stimuli remained unchanged at 48 h, adaptations of respiratory control may have been related to progressive adjustments of strong ions and acid-base balance.

Acid-Base Equilibrium↗